Dr. Andrew's Opinions

Tranquillizer use rife amongst OTP subjects world-wide, most legally prescribed.

2012-01-16T02:00:00.000+11:00

Prolonged use of benzodiazepines is associated with childhood trauma in opioid-maintained patients. Vogel M, Dürsteler-MacFarland KM, Walter M, Strasser J, Fehr S, Prieto L, Wiesbeck GA. Drug & Alcohol Dependence 2011 119:93-98

Dear Colleagues,

While these authors have emphasised an association between childhood trauma and benzodiazepine (BZD) use, their study tells us much more about opioid dependent patients in treatment in Switzerland and beyond. Their bibliography is also exemplary and it clearly demonstrates that the current approach, zero tolerance in the main, is simply not working. As the authors state: “if abstinence from BZD is conveyed as primary treatment aim, as has generally been the norm in the past, this finding illustrates the limits of current therapeutic management and therapeutic options”.

We are told that ‘point’ and ‘lifetime’ BZD use reportedly occurs in 18-55% and 35-94% of OTP patients from numerous reports including from Australia. The current surveys were taken in two large opioid maintenance programs in Basel, Switzerland. These provided a variety of medications, including prescribed heroin, both oral and injected, methadone, morphine, buprenorphine and codeine.

Of 315 patients approached, 193 (61%) responded to a survey including childhood trauma (a validated instrument ‘CTQ’ was used), drug use and other clinical and demographic characteristics. Reports of drug use were confirmed with urinalysis showing a high degree of concordance. Psychiatric diagnoses were obtained from the detailed medical files which were updated regularly.

The rate of reported benzodiazepine use in the current sample was 61%, 47% being ‘prolonged’ (>2 months duration) while lifetime use was 85%. Thus almost half of the cohort had prolonged use at some time in the previous five years.

There was at least one childhood trauma sub-score of moderate to severe level in 67% of the subjects who completed the survey. As well as BZD use, the degree of trauma was significantly related to methadone dose (or equivalent for other opioids).

After multivariate analysis the authors found that there was an association between prolonged benzodiazepine use and (1) excessive childhood trauma, (2) hepatitis C, (3) psychiatric family history and (4) methadone dose in milligrams. The odds ratios were 1.5, 4.0, 2.3 and 1.01

Rather than using the loaded (British) term ‘misuse’, these authors wisely stick to ‘use’. They also categorise sedative use into (1) ‘hedonistic’ or ‘recreational’ use, (2) self-medication to counteract or amplify the effects of primary drugs of abuse (eg. to ‘come down’ from stimulants), (3) prescription use for anxiety, insomnia, PTSD, panic disorders, etc, and (4) ‘off-label’ prescription as benzodiazepine ‘maintenance’. The great majority of patients obtained their BZD from legal prescription (84% of those with ‘prolonged use’).

The authors point out that none of these associations can prove causality. This will always be difficult to determine when so many overlapping issues occur in OTP patients such as childhood abuse, PTSD and self medication. However, the authors seem persuaded that ‘zero tolerance’ is no longer tenable as a policy, just as it did not work for opioids (or alcohol in a different era). They support the measured prescription of benzodiazepines in research trials as advanced by Liebrenz in Addiction.

In our own practice we provide diazepam under close supervision and in limited quantities to those who are unwilling or unable to cease the use of benzodiazepines, and who agree to alcohol abstinence, in the context of OTP.

Summary written by Andrew Byrne ..

Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874

2011-10-06T02:38:00.003+11:00

First publication on Suboxone film gives little clinical information.

2011-10-01T02:22:00.006+10:00

Clinical Pharmacology and Therapeutics ‘Perspectives’, Letter to the Editor.

Advance online publication 28 September 2011. [see response by Strain et al.]

Commercial Factors Override Science in Combination Addiction Drug Trial

A Byrne [1]

To the Editor:

Strain et al. have performed a detailed and thorough treatment induction trial of a novel sublingual buprenorphine “film” or “wafer” in their article “Induction of
Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films.”1 However, the appropriate test for any new medication is a randomized, blinded comparison using accepted protocols against existing effective interventions, with outcome measures such as retention, drug-use parameters, and toxicology.

Instead, these authors compare a newly introduced formulation of an old drug (buprenorphine/naloxone film) with a nonapproved and unvalidated medication (buprenorphine film). In going to great lengths to show complex documentation on the differences in withdrawal characteristics between the two treatments (by means of
multifarious, complex graphs), the authors appear to believe that it is important to determine whether such differences exist, even though neither of the treatments involves any known “quantity” and that these differences are of little relevance to clinical practice.

It is a false premise that the apparent absence of differences between two treatments indicates their equivalence. Strain et al. do not make such a claim, but others may misinterpret such results in this way, just as has happened with Suboxone (combination with naloxone) and Subutex (pure), which, remarkably, have still not been subjected to equivalence testing except in a small pilot study.2. Strain et al. do not make it clear what they were trying to demonstrate in their paper, which is one of the first reports of buprenorphine in a more soluble sublingual film/wafer preparation.

I am not aware of evidence that withdrawal symptoms during induction are linked to retention, an outcome that is known to be strongly associated with benefits to drug-dependent patients. In my experience, some recipients of successful buprenorphine and methadone treatment have experienced unpleasant withdrawal symptoms during
the induction period. Furthermore, Strain and colleagues’ study involved the use of multiple induction doses of buprenorphine over many hours, an induction regimen that is not used in clinical practice to the best of my knowledge. It would probably also be costly and difficult to implement in actual practice.

It is of concern that the authors raise the issue of drug packaging because this was not tested in their protocols. Indeed, their subjects were administered doses as in most addiction research and were apparently not given doses to take home as occurs in the field. In the abstract and twice again in the text, the reader is told about new individual packaging that is alleged to be safer than that for the existing product, which is marketed by the same manufacturer (which also supported the research). Rather than the blister packs used elsewhere, in the United States buprenorphine tablets are apparently dispensed loose in packs of 30. While the film or wafer preparation reportedly comes in an individual unit-dose format with child-resistant packaging, this could just as easily be used for existing preparations if the latter are considered by the company to be unsafe due to incidents with accidental childhood poisonings. 3

Hence, it is a liberty to introduce such discussions into the report of a study that ostensibly examined the physiological effects of introducing two buprenorphine products to dependent patients and in which most medication was given under supervision. It is also claimed that serial numbers will allow tracking for drugs that may be diverted onto the black market. This would depend on chain-of-custody supply as well a new layer of detailed record keeping, the cost of which is unknown—nor is it known whether this type of measure can be effective. Such research is awaited, and speculation by these authors is unhelpful in my view, especially in a study funded by the manufacturer.

Conflict of interest.
The author operates a private addiction clinic in which buprenorphine and methadone are used in opioid maintenance treatments. He does not consider this to constitute an actual or potential conflict with respect to the study discussed but includes the information for completeness and transparency.

© 2011 ASCPT
1. Strain, E.C., Harrison, J.A. & Bigelow, G.E. Induction of opioid-dependent individuals onto buprenorphine and buprenorphine/naloxone soluble-films. Clin. Pharmacol. Ther. 89, 443–449 (2011).
2. Bell, J., Byron, G., Gibson, A. & Morris, A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone) in treatment of opioid dependence. Drug Alcohol Rev. 23, 311–317 (2004).
3. Boyer, E.W., McCance-Katz, E.F. & Marcus, S. Methadone and buprenorphine toxicity in children. Am. J. Addict. 19, 89–95 (2010).

1Private practice, Redfern, Australia.
Correspondence: A Byrne (ajbyrne@ozemail.com.au)

Advance online publication 28 September 2011.

doi: 10.1038/clpt.2011.166

See also this blog: Click here

The response letter does not address most of the above nor does it do credit to its renowned authors due to its patronising invective. Copy on request.

Launch of Suboxone Film - Sydney Olympic Site - August 2011

2011-09-13T20:06:00.005+10:00

Product launch by Reckitt Benckiser - Suboxone Film 2mg and 8mg for opioid maintenance. Sydney Olympic site - Novotel 7pm Tuesday 23rd Aug 2011

Dramatis personae: Dr Mark Hardy (Chair); Mr Ruari Macdonald (Reckitt Benckiser); Prof Nicholas Lintzeris (Langton Centre); Mr Peter Muhleisen (Hunter NE area pharmacist); Ms Simone Cass (Consumer Representative).

Headings: Is combination buprenorphine best practice? Why is the film being marketed now? Is it bio-equivalent? No childhood poisonings in Oz. Prison diversion under postage stamps, etc. Pharmacists: unsung heroes of dependency treatments. Is dosing ‘films’ really faster? Were consumers consulted adequately?

## This was a rather unedifying event, proving, sadly, how much our field of medicine is now influenced by the pharmaceutical industry. It seemed as though not one person in the large assembly questioned the wisdom of swapping from one unproven mixed drug to another on the appointed day. And the recent appearance of a half-price ‘generic’ buprenorphine (at least in America) was not raised.

I personally do not prescribe combination buprenorphine at all so this launch was largely hypothetical in my case. I spoke to Dr Alex Wodak earlier in the day and was reassured to learn that he and his colleagues at St Vincent’s Hospital currently prefer to prescribe buprenorphine without naloxone and for the same reasons: a lack of good research evidence on equivalence, safety and effectiveness. My advice to doctors and pharmacists is to demand this evidence before prescribing any new drug. Products approved by the TGA and promoted by State health authorities are not automatically ‘best practice’ in the field.

The dinner guests were told that the new Suboxone SL ‘film’ was approved from September on condition that the tablets were withdrawn within two years because they are not bio-equivalent, the film being more highly soluble. It would be helpful to know what proven advantage the PBS committee found in this product that justifies the switch from the existing sublingual tablet. This is particularly the case since the ‘film’ formulation has been used as a vehicle to smuggle buprenorphine into prisons in the US on writing paper, under postage stamps and envelopes. It is important to justify any known disadvantages of a new formulation with the potential benefits, especially when a new drug effectively locks out generic competition. A more highly soluble product which dissolves more rapidly may also have a greater potential for intravenous use. An internet search can quickly confirm some of these harmful concerns, most notably injecting.

Even if one were to accept that naloxone reduces some diversion, the pure product is certainly the preferred medication during pregnancy … and probably also in women who may become pregnant … and also for inductions of new patients onto the drug. The pure medication was used in the controlled research which supported buprenorphine treatment for addiction. It was also the pure product which is used in France where widespread buprenorphine treatment started in 1995. There are no serious moves, I understand, to use the combination drug in France, although it is a registered therapeutic product in the EU generally. One wonders what the French know that we do not (or does ‘market saturation’ solve many of the problems found elsewhere?). I cannot understand why, with its purported advantages, the company is not marketing a film version of the pure drug, even if just for pregnant patients. Such a form was supplied by the company to Strain et al. for their induction trial. The promise of unique identifiers on each sachet of the film as a means to detect and prevent diversion seems to have lapsed so ‘pill-counts’ and diversion tracing cannot be done. Yet another disappointment.

The evidence supporting reduced diversion with the combination tablets/films is scant anyway and lacks scientific rigour in my view. Reports of the widespread injection use of the combination drug are legion and go back 20 years (‘The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand’. See below.). If there is a disincentive to inject the combination drug, it is modest in degree and it can be little greater than that of buprenorphine alone in current users of heroin, morphine or methadone due to its well known ability to induce the extremely unpleasant ‘precipitated withdrawal reaction’. On the other hand, there is little or no aversive effect in those currently taking buprenorphine nor in those without a current tolerance, so these groups can inject either preparation with impunity. The latter may include some patients in detoxification facilities or prisons as well as opiate naïve individuals. Furthermore, the evidence that is available indicates that the deterrent effects in persons who are actively using opioids may be associated with less safe injection practices (‘Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market’. See below.).

Despite these disadvantages, I remain a great supporter of buprenorphine as a dependency treatment option. I first prescribed it (exceptionally) over 20 years ago ‘off-label’ to dependent patients. The original combination product buprenorphine and naloxone was approved for maintenance prescription about 6 years ago in Australia. We were strongly encouraged to prescribe it by each State and Territory Health Department. There were also guidelines for unsupervised use in certain circumstances, based, we were told, on a single overseas study. However, close reading shows it mostly used supervised dosing and is of limited relevance to Australia (Fudala et al. 2003). Apart from better results than with placebo (only in America or Russia could placebo be used in this context) this study showed a trend for better abstinence outcomes in those taking 16mg of pure buprenorphine compared with those taking the combination product (sixteen percent more clear urine tests in those on pure buprenorphine). The trial was not sufficiently ‘powered’ to make this difference statistically significant. Paradoxically, if pure buprenorphine had shown significant superiority, buprenorphine might have had a very different story in America.

In the scramble to develop new guidelines for unsupervised use in 2006 (and contrary to its own long standing practice) the Royal Australasian College of Physicians accepted a six figure sum from the manufacturer/distributor to help ‘educate’ the profession. And this was using a combination drug which their chief dependency education officer Dr James Bell stated at the time was “therapeutically identical” to the pure product. It was a shame such funds were not made available when the original product appeared on the market five years earlier when the original drug was introduced.

We were told that in Australia the major complaint about Suboxone tablets was that they took too long to be absorbed. Hence the company had developed the new film preparation as a response to this. By contrast, Americans were told last year that the main reason for the company introducing the new ‘film’ preparation was the issue of childhood poisonings from Suboxone tablets (see Strain et al 2011, almost 1000 such reports annually by 2008 in America). I was surprised to learn that despite these worrying statistics, buprenorphine is still sold by American pharmacies as loose tablets in regular pill bottles (albeit with child-resistant caps). Even paracetamol/acetaminophen is sold in blister packs in Australia and elsewhere to avoid this problem.

At the drug launch dinner the childhood poisonings were mentioned numerous times yet there have apparently been no cases in Australia to date. Of itself, this would seem to be a lesson in public health safety. It would seem wrong-headed to address the dangers of existing tablets by introducing a new patented product rather than by promptly changing the loose packaging to blister packs.

There was a warning from Professor Lintzeris that although he believed that most diversion of buprenorphine was of limited clinical significance, the treatment (Subutex) had been banned in Singapore and Finland after reported diversion and misuse. He emphasised also that the use of unsupervised buprenorphine treatment could be at risk if patients were seen to divert medication. Such treatment was introduced into France and America, and in a limited manner here in Australia, with almost no research base (see above). The study which is quoted in the literature, Fudala et al., did not examine supervision in any rigorous way. Regarding diversion, the panel members seemed unaware of the New Zealand experience the early 1990s with Temgesic NX (buprenorphine 0.2mg plus naloxone 0.17 mg). This was another major lesson in public health policy which was published in D&A Dependence (Robinson et al, 1993). In succession over a short period of time the pure drug and then combination buprenorphine were each withdrawn from the New Zealand market due to the wholesale abuse (the company states it was for ‘purely commercial reasons’).

In question time Professor Kate Conigrave of Sydney University asked if the company proposed to make Suboxone in a 0.4mg size for patients who are detoxing or for finer dose titration. Product manager Ruari McDonald answered in the negative. He stated further that few if any other countries had 0.4mg Subutex and that Australian doctors were “lucky” that it was available. To this Professor Lintzeris volunteered that he hardly ever finds the need for doses smaller than 2mg. He told his fellow professorial colleague that at Langton Centre they did not use 0.4mg tablets much at all (meaning that they did use it, at least occasionally, I presume). He said that one should not draw a false parallel between small reductions on methadone as this was just not necessary with buprenorphine – yet he did not explain this assertion or give any supporting references. Furthermore, he contended that such a low-dose preparation would not have enough naloxone to deter injecting … although it was unclear how much naloxone he was referring to, 0.1, 0.17 or 0.34mg or other. Robinson reported that Temgesic NX, with over three times the proportion of naloxone than Suboxone, was nevertheless the most commonly injected drug by more than half of those applying for methadone treatment in Wellington in 1991. This was one of the first reports of widespread injecting of a prescribed analgesic (see Quigley 1984; Strang 1985 for incident cases).

The Reckitt Benckiser company earned my highest admiration ten years ago when, against the odds, it managed to have Subutex approved in Australia despite the unfortunate New Zealand experience. Happily for the manufacturer’s shareholders since 2000 they have managed to “evergreen” the exclusive market for the product on two further occasions. First this was done by using the naloxone combination and more recently with the ‘film’. In this way the company has turned a relatively cheap drug into a high profit line. I note that the Wikipedia entry reveals numerous commercial feats as well as some disturbing findings against the company along the way. I was interested to note that associates of this company have contributed to publications and conference events relating to supposed cardiac complications of methadone. Some of these omitted appropriate conflict statements (details on request). Large studies in France and Norway have now shown the reported cardiac complications of methadone to be vanishingly rare while at the same time highlighting the aging and complex nature of the medical problems faced by our patient population.

It is worrying that neither the manufacturer nor anyone else has performed controlled studies on the equivalence of Subutex and Suboxone. It is hard to understand why this was not required by the TGA before approval of the combination product. Evidence for the safety and effectiveness of combination buprenorphine cannot necessarily be extrapolated from the pure product. The need for more than 50% higher doses in an open-label study changing to the combination product by Bell and colleagues has never been corroborated (nor refuted).

A front page New York Times article recently reported the smuggling of Suboxone films into American jails (link below). When I asked about this none of the panel members admitted to knowing about it, despite its obvious relevance to the evening’s proceedings. Professor Lintzeris said that he recalled reading something about ‘crushed up tablets’ (not films at all, apparently) being made into paint in children's pictorial offerings to ‘daddy in jail’. According to the report, since the introduction of Suboxone film, prisoners’ mail in America is now vetted, delayed and in many cases, shredded. Envelopes and stamps are removed, and reportedly due to the widespread reported practice of smuggling buprenorphine films into jails. One prison governor was quoted saying the situation was a ‘crisis’. Lintzeris then changed the subject to advocating buprenorphine treatment in prison. This was a good point but only limited practical relevance to the serious problems described in the report. Professor Lintzeris then also told us that we needed to make a distinction between ‘true’ diversion where the drug was used by another party and the situation where the drug was used by the intended recipient which was ‘not really diversion’. These matters remain for debate. The film’s introduction into the US a year ago should be considered a research trial of sorts, and one which is already showing worrying outcomes from my reading (see also Pennsylvania Attorney General report below).

I wondered if I was the only one in the room to be questioning the use of Suboxone films in future. Two large Sydney clinics I contacted at the time did not generally dispense the combination drug at all. I will continue to prescribe pure buprenorphine in my practice and when necessary, in order to hasten dissolution and/or reduce diversion we will continue to ‘scrunch’ the tablets. It has not been explained why the company is not marketing a film version of the pure product, something the company has tested, see Strain et al below.

On the night nobody mentioned the need for pharmacists to keep yet more drug books (at least for the next two years). To my mind the community pharmacists remain the unsung heroes of dependency treatment in Australia. These caring professionals still mostly charge the same as they did in the 1980s for a service which is now more complex and in some ways hazardous. Instead of just one drug book (for methadone), they will now need up to nine such books!

We were all handed a glossy brochure on the new buprenorphine combination “film” stating: “Clinically Interchangeable with the Suboxone Tablet”. The text included a graph of a single dose comparison with a 6 day run-off axis. The first day (the only one that matters to those taking daily doses) blood levels were substantially higher in the film subjects (eg. 3.0 versus 2.25 ng/ml for peak). This single-dose study finding may be augmented in daily maintenance dosing, showing quite clearly that the film and tablet forms are not interchangeable at all with a very substantial 33% higher blood level for film when compared to the tablet (presumably not crushed). The prominent title statement would seem to be directly countered by the graph provided on the same page, showing (or, better expressed, almost concealing) a substantially higher area under the curve (AUC) in the first 16 hours. Knowledge of the raised blood levels may make a prudent doctor consider a lower dose for those changing to the film product, despite advice to keep the dose constant and only reduce it where necessary. The variability in response was stressed by all speakers at the launch. I invite Reckitt Benckiser to submit a comment to my blog explaining this and will gladly post the response as a service to readers.

This same glossy hand-out states that “Suboxone Film dissolves faster than Suboxone Tablet”. It was disappointing that the company provided evidence for slightly faster dissolution times but omitted to state just how much longer it takes for the staff to open the tough little packets to reveal and then administer the flimsy films. I tried with the placebo and took 35 seconds to open one while the experienced nurse who ran one of the trials told me that she had got it down to about 15 seconds. And the pack does not always open as designed, sometimes needing scissors and therefore taking even longer. Most patients will need more than one pack and someone taking 22mg, for example, would need 5 (2x8mg and 3x2mg). One example quoted was that 2mg dissolved one minute faster (6 versus 7 minutes), yet to open the packs needed before administration could mean little is gained in staff and patient time. Advice that one does not need to observe the patient for so long due to adherence of the film is not based on evidence and remains to be demonstrated to be safe and effective, just like the preparation itself (at least in comparison to pure buprenorphine). Crushing tablets may be just as useful when time is limited or when dealing with challenging circumstances such as in the prison system.

In an early presentation we were told of the comprehensive post marketing survey published recently by Briony Larance et al. in D&A Dependence (n=440). It was perhaps the most important slide of the night although its significance was not emphasised by the speaker at the time. It demonstrated the enormous misuse of buprenorphine as published when compared to methadone. They showed that no less than one in eight supposedly “supervised” doses of buprenorphine (12%) were taken out of the dispensary compared with 1% for methadone(!). They also showed that buprenorphine patients consistently showed about double the rate of injecting drugs when compared with those on methadone. While there was less injecting of the combination drug, this finding is confounded because at the time it may have been used more widely unsupervised for those who were already more stable patients and therefore may be less likely to inject anyway. Clearly a proportion of these buprenorphine patients would be doing better on methadone … but this was neither the time nor the place.

Ms Cass spoke eloquently from a consumer perspective about communications, involvement with health professionals and ‘vulnerability’. While she and others had made out that consumer representation was a novel endeavour and it was not usual in other fields, my understanding is that it is now much more widespread than it was. Such moves are still inadequate and consumer involvement can always be improved. However, such input made an early start in Australia before many other countries and now there are respected voices from individuals, State and Federal organisations of several persuasions, which is as it should be. One of the earliest and most prominent is Family Drug Support which enjoys widespread respect in the Australian community (there is nothing remotely comparable in the United States according to my sources). NUAA and AVIL representatives were also at this meeting.

Despite the usual modern practice, there were no conflict statements given by the speakers which would seem to be a fault.

Comments by Andrew Byrne ..

Conflict statement: Reckitt Benckiser paid for my dinner but I paid my own train fare to Homebush Bay from Kings Cross. Reckitt Benckiser has sponsored refreshments and data projector for our post-graduate Concord study group.

References:
Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6

Larance B, Degenhardt L, Lintzeris N, Bell J, Winstock A, Dietze P, Mattick R, Ali R, Horyniak D. Post-marketing surveillance of buprenorphine-naloxone in Australia: Diversion, injection and adherence with supervised dosing. Drug and Alcohol Dependence 2011 In press.

Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Fudala PJ, Bridge TP, Herbert S, et al. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318

Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Am J Drug Alcohol Abuse 2009 Feb 12;1:1-5

Quigley AJ, Bredemeyer DE, Seow SS. A case of buprenorphine abuse. Medical Journal of Australia 1984 140:425-426

Strang J. Abuse of buprenorphine. Lancet. 1985 Sep 28;2(8457):725

Goodnough A. When Children’s Scribbles Hide a Prison Drug. New York Times 27 May 2011 page A1. http://www.nytimes.com/2011/05/27/us/27smuggle.html

Click here Full Pennsylvania report.

HARRISBURG Acting Attorney General Bill Ryan noted that Suboxone, a Schedule III prescription narcotic used to treat heroin addiction, was commonly produced in pill form, but now is being manufactured in thin film like strips very similar to the popular breath freshening strips. … charges [were announced] against eleven suspects, including five inmates, who allegedly smuggled prescription narcotics into the Carbon County Correctional Facility via the inmates’ incoming mail. The investigation, known as ‘Operation Postage Stamp’ began in January 2011 after the Warden at the Carbon County Correctional Facility intercepted three letters containing a Suboxone underneath the letters’ stamps.

http://en.wikipedia.org/wiki/Bart_Becht

http://en.wikipedia.org/wiki/Reckitt_Benckiser

Is levo-methadone the answer to so-called cardiac complications?

2011-06-17T01:53:00.014+10:00

McCance-Katz EF. (R)-methadone versus racemic methadone: what is best for patient care? Addiction 2011 106:687-688

Dear Readers,

I need to disagree with my respected colleague Dr Elinore McCance-Katz in her editorial in Addiction proposing the active isomeric formulation of methadone as a viable solution to the supposed problem with cardiac arrhythmias. She states, without any supporting reference: “Methadone confers some risk for cardiac adverse events and sudden death.” The research I have read shows that methadone actually reduces the risk of sudden death. It is also likely that methadone protects against serious cardiac events (Krantz 2001).

Addiction published Justo’s reassuring literature review of QT prolongation and torsade de pointes in methadone prescribed subjects yet now the world’s oldest dependency journal has joined the cardiac cargo cult with this piece. There are no new references for cardiac side effects, nor are we told about the recent reassuring literature from France and Norway showing the vanishing rarity of this arrhythmia in methadone patients (and a lack of reported mortality). Krantz et al 2009 is the Editorial’s main supporting reference yet this piece was so problematic that it was withdrawn and republished with an altered list of contributors, new conflict statement and changed title (see my review Click here).

Dr McCance-Katz cites this latter paper as the CSAT (Centre for Substance Abuse Treatment) consensus guideline which it was not. The terms ‘CSAT’, ‘consensus’ and ‘guideline’ were all expunged from the title in the formally re-published version (and for good reason, it would appear). CSAT’s official advice came later and was quite different from the recommendations in the Annals publication of March 2009. Krantz quotes Ballesteros, Shah, Sorg, Gagajewski as ‘a growing number’ of reports of ‘unexplained methadone-associated deaths’: yet there were none in Ballesteros; one from Sorg; none in Gagajewski; reducing, not increasing NM death rates in Shah. In practice, unexplained deaths in MMT subjects are very rare. Sudden death in the general (‘healthy’) community is reported at about 7 per 10,000 person/years (Ray 2001). It is problematic that this editorial quotes Krantz 2009 as supporting the link between methadone maintenance treatment and torsade de pointes when the evidence cited by Krantz is on shaky epidemiological grounds (Chugh's conclusions are not sustainable; Fanoe’s findings are fanciful (10-30% of OTP subjects allegedly develop unexplained syncope in a year).

Furthermore, Wedam’s RCT findings are quoted by Dr McCance-Katz and Krantz et al, despite their being consistent with the view that there is almost no risk of torsade de pointes, even in those with substantially prolonged QT intervals (>500ms). Wedam showed very high rates of QT prolongation in young patients new to treatment, yet this is the very group which rarely if ever develops torsade de pointes (vide ~100 case reports over 30 years on request).

To support the argument about the probable safety of (R)-methadone the editorial cites two studies which relate to QT intervals but not to arrhythmias. The author seems to have missed the point that QT prolongation is commonplace in methadone patients, having been reported in over 30% of patients in 1973 (Lipski). Yet such electrical observations do not appear to translate into torsade de pointes unless other factors supervene (electrolytes, other drugs, heart disease, alcohol, HIV, old age, etc). Furthermore, many or even most of the actual case reports have had normal QT intervals away from the arrhythmia episode. Justo reported a known intercurrent cause in 85% of cases. Hence these findings show the futility of ECG as a strategy to prevent torsade de pointes … and they emphasise the value of a good history and physical examination.

When thousands of patients (in Germany) are currently taking the isomeric form of methadone it would appear superfluous to examine theoretical or indirect electrical studies. Out of over 100 case reports in the literature, one single German anecdotal report describes torsade de pointes causing recurrent syncope in a patient taking racemic methadone 120mg, doxepin 100mg and a beta blocker. The patient did well when the beta blocker and doxepin were withdrawn and (R)-methadone (40mg) was substituted (Rademacher 2005). A preliminary communication on these issues from a German colleague was very reassuring, pointing out that some patients preferred the active form for its lower rate of adverse effects (constipation, sweating, sexual disturbance, etc). Swiss toxicologist Dr Chin Eap and colleagues showed that the change from racaemic to (R)-methadone led to only very modest decreases in QT interval (7.8ms two weeks after changing, p=0.06, n=39).

The French and Norwegian studies would appear to satisfy the call by Krantz and others for large national studies due to the relative low prevalence of the syndrome (sic). Norway (Anchersen, 2009) had four unexplained sudden deaths in a six year period. None was a suspected torsade case but these were the only ‘possible’ torsade deaths. Despite 15,000 patients taking methadone maintenance in France only three single torsade cases were reported to the French ‘pharmacovigilence’ department over eleven years along with seven unexplained deaths (Perrin-Terrin 2010). These figures are likely to be under-reported even though there was a nationwide awareness campaign including a ‘Dear Doctor’ letter to prescribers in France. None of the deaths was due to suspected arrhythmia yet even if they had all been due to torsade de pointes the prevalence would still be very low (0.06 per 100 patient years in the case of Norway) and may be comparable with matched subjects who are not taking methadone.

When torsade de pointes is recognised it is almost universally non-fatal. In fact, Salle and colleagues, who Krantz cites in claiming that the torsade mortality is ‘less than 20%’ in fact showed that following their initial group that over eight more years their institution had a torsade mortality of zero. Phibbs’ cardiology primer states: ‘.. torsade can be controlled 100% of the time’ which is consistent with the older French experience.

So where does this leave the baffled clinician? ‘Addiction’ has long had a bias emphasising problems with maintenance treatments in favour of demonstrating their benefits when used in appropriate circumstances (refs on request). ‘Addiction’ once published an item [Curran 1999] purporting to show that increased doses of methadone caused increased cravings (!). Letters from humble Australian and distinguished British authors on the subject were rejected so that its bizarre finding stands uncorrected to this day.

On one point Dr McCance-Katz and I agree: levo-methadone (the active isomer, (R)-methadone) is worth examining regarding its possible benefits in addiction treatments.

Comments by Andrew Byrne ..

References:

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395 [Byrne critique:Click here]

Rademacher S, Dietz R, Haverkamp W. QT prolongation and syncope with methadone, doxepin, and a beta-blocker. Ann Pharmacother 2005 39:1762-3

Ansermot N, Albayrak O, Schlapfer J, *Eap C, et al. Substitution of (R,S)-methadone by (R)-methadone: impact on QTc interval. Arch Intern Med. 2010;170(6):529-536

Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6

Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT:
Antipsychotics and the risk of sudden death. Arch Gen Psychia-
try 2001 58;12:1161-7

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8

Salle P, Rey JL, Bernasconi P, et al. Torsades de pointe. Apropos of 60 cases. Ann Cardiol Angeiol (Paris). Jun 1985;34(6):381-8

Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier

Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. N Engl J Med 2010; 363:2320-2331

Curran HV, Bolton J, Wanigaratne S, Smyth C. Additional methadone increases craving for heroin: a double blind, placebo controlled study of chronic opiate users receiving methadone substitution treatment. Addiction (1999) 94;5:665-674 Byrne’s commentary: Click here

Buprenorphine wafer/film inductions confusing.

2011-06-15T06:03:00.004+10:00

Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Strain EC, Harrison JA, Bigelow GE. Clinical Pharmacology and Therapeutics 2011 89: 443-449

Dear Colleagues,

I was intrigued when searching for research on the mooted new ‘wafer-film’ form of buprenorphine to find that Dr Strain and his experienced research colleagues have performed a detailed and thorough drug induction trial which nevertheless seems to be of little or no utility to the clinical field. The appropriate test for any new medication is a randomised, blinded comparison with an established intervention using standard outcome measures. In the field of dependency these include retention, drug use parameters, side effects, sero-conversions, mortality, etc.

In this study the authors compare a newly introduced formulation of an old drug (buprenorphine/naloxone ‘film’) with a non-approved and possibly non-validated medication (buprenorphine film). By going to complex lengths to document withdrawal differences (see multifarious bewildering graphs), the authors appear to believe it is important to determine if there is any such difference, despite neither being a known ‘quantity’ to start with.

It is a false premise that finding no difference between two treatments proves their equivalence. Such a conclusion may be a statistical ruse rather than a rubric, as pointed out by Walter Ling many years ago. Strain and colleagues do not make such a claim, yet it is possible that others may misinterpret the work in this way, just as has happened with Suboxone (combination with naloxone) and Subutex (pure) which remarkably have still yet to be subjected to even simple equivalence testing. The reader is still left with the question of what exactly Strain and colleagues were trying to demonstrate in this paper.

[This question was answered in a recent lecture by Dr Strain at a function organised by the manufacturer in Sydney, Australia: see my summary on the subject in which it is state that the manufacturer was fighting to have the FDA recommendation to do inductions only with pure buprenorphine, now a cheap generic drug in some countries.]

While it would be beneficial to avoid or minimise withdrawal symptoms during induction, it is not clear whether this is linked to retention rates. In our experience some of the most successful buprenorphine and methadone recipients had unpleasant periods of withdrawal during the induction period.

Another weakness of their study is that their treatment induction bares little resemblance to normal clinical practice, further limiting relevance to the real world. They gave multiple doses of buprenorphine over many hours, something which is not used routinely either in clinics or community practice to my best knowledge. Furthermore, it would probably be costly and difficult to implement in the field.

It is not at all clear why these authors include the issue of drug packaging. In the abstract and twice again in the text the reader is informed about new individual packaging which is alleged to be safer than the existing product. Yet both are marketed by the same company which also supported this research. Rather than blister packs which are used in most of the world, in America buprenorphine is apparently dispensed as loose tablets (and now wafers). The new wafer formulation reportedly comes as individual unit-dose format with child resistant packaging. This aspect was not tested in any way in the paper and it would appear that the researchers are taking liberties by introducing this matter into a paper which ostensibly examines the physiological effects of introducing two buprenorphine products to dependent patients and in which most medication was given under supervision such that the packaging format was irrelevant to the outcomes. This is quite unlike the manner in which buprenorphine is commonly used in America and France … but not in most other countries which use supervision (evidence based) treatments. The irony is that most of the evidence was from studies performed in the United States where it was apparently overlooked in the Act of Congress which gave a waiver allowing doctors to prescribe it from their offices as a drug to be dispensed like any other drug from the pharmacy.

It is further claimed that serial numbers will allow tracking for buprenorphine films which may be diverted onto the black market. This would depend on chain-of-custody supply as well a new layer of detailed record keeping the cost of which is unknown, nor is it known if this type of measure can be effective. In short, this is a peccadillo and should be tested properly rather than being speculated upon here.

The first lines of the abstract read more like an advertisement than a serious scientific study: “[buprenorphine film product] provides unit-dose, child-resistant packaging amenable to tracking and accountability, offers more rapid dissolution, and has a potentially preferred taste vs. tablets.” Note that inventive drug users have already found ways of exploiting the increased solubility of buprenorphine wafers as described in a front page New York Times article entitled “When Children’s Scribbles Hide a Prison Drug”

German hep C study reports excellent results.

2011-05-17T10:27:00.004+10:00

High rates of sustained virological response in hepatitis C virus-infected injection drug users receiving directly observed therapy with peginterferon alpha-2a (40KD) (PEGASYS) and once-daily ribavirin. Waizmann M, Ackermann G. Journal of Substance Abuse Treatment 2010 38:338-345

Dear Colleagues,

This report is more good news for those considering anti-viral treatment for hepatitis C from an opioid pharmacotherapy setting. The authors did a retrospective analysis of 49 opioid maintenance patients having anti-viral treatment for HCV infection over 3 year period. There were regular reviews of liver function tests, full blood counts and viral loads.

Out of 49 patients 48 obtained a sustained viral response (SVR). Side effects were modest and none required cessation or alteration of treatment schedules. Uniquely they gave treatment under supervision in the clinic on a daily basis with ribavirin given as single daily dose of 800mg (1200mg for genotypes 1/4) rather than the more usual twice daily regimen, given for 26 weeks (48 weeks for genotype 1/4). Furthermore, all patients were given antidepressant citalopram (Cipramil) 20mg daily starting 2 weeks before commencement of anti-viral drugs as a prophylactic regardless of whether they had clinical depression or not at the outset.

Study patients’ mean age was 30 years, 50% male; genotypes 1 (41%), 2 (4%), 3 (53%), 4 (2%). Subjects had to have been ‘stable’ for at least 3 of 6 months in opiate treatment. They were taking buprenorphine 0.6mg - 7.4mg or levo-methadone 10 - 50mg (equivalent to 20 - 100mg of the regular racemic methadone). They had been taking opiates for an average of 6 years and had HCV for an estimated 3.5 years. This makes it an earlier intervention than for most other series where opiate use/HCV were of substantially longer duration.

Their clinic in Leipzig typically treated a population of 125 patients on a daily basis including weekends. Doctors and counsellors were available on-site every day and a hotline was available to patients.

While the results seem extremely favourable, the authors cite another study with compliance rate of 100% and SVR rate of 94% from 17 HCV genotype 3-infected MMT patients treated with IF plus RBV, the former under observation and using psychosocial supports (Krook et al. Norway 2007).

These enviable results are also consistent with numerous studies showing improved results from directly observed treatment (DOT) in HIV anti-viral infection (see Sharkey 2011). There are also favourable reports in the treatment of tuberculosis, urinary tract infections, malaria and other conditions where adherence is crucial to success. Antabuse and naltrexone have also shown to be more effective with supervised dosing schedules, along with traditional methadone treatment.

We should all be encouraging our patients with HCV to consider assessment and treatment where appropriate. If these outcomes can be corroborated we should also probably consider the benefits of additional supervision of medication for better adherence as well as possibly once daily antivirals and antidepressants.

Comments by Andrew Byrne ..

Krook AL, Stokka D, Heger B, Nygaard E. Hepatitis C treatment of opioid dependants receiving maintenance treatment: Results of a Norwegian pilot study. 2007 European Addiction Research 13:216-221

Sharkey KM, Kurth ME, Anderson BJ, Corso RP, Millman RP, Stein MD. Directly observed antiretroviral therapy improves adherence and viral load in drug users attending methadone maintenance clinics: A randomized controlled trial. Drug Alc Depend 2011 114;2-3:245-248

Eric Strain talks about the buprenorphine film.

2011-04-10T06:59:00.001+10:00

“Clinical Advances in the management of opiate dependence”

Friday 11th March & Saturday 12th March, 2011. Intercontinental Hotel, Sydney.

“Suboxone Sublingual Film - the US Experience”

Organised by the Reckitt Benckiser company.

While this conference had been billed initially as an update in opioid pharmacotherapies, there were rumours around that it was actually a product launch. Indeed, the first power-point slide stated: "Suboxone Sublingual Film - the US Experience". Professor Eric Strain’s presentation kicked off the first of two papers on the Friday afternoon after a delightful luncheon in the Café Opera provided by the company. I first heard about a mooted wafer version of buprenorphine numerous years ago and was surprised to find that it is now being approved in Australia.

Drug research guru Eric Strain from Johns Hopkins in Baltimore spoke to an audience of about 80 doctors from around Australia and overseas who were welcomed by meeting chair Dr Sue Ballantyne from Brisbane. Unlike most such national and international meetings, I understand that the entire event, travel, meals, transfers and accommodation were all funded by the manufacturer. Indeed, one had the feeling that this was closer to advertising a new product than a balanced educational session.

Dr Strain said that in response to reports of childhood poisonings, slow dissolution, diversion, (*see stop-press below) and other problems with Suboxone sub-lingual tablets, the film version was developed. There were three main pieces of evidence supporting the ‘film’ (or wafer) … initially there were trials in volunteers of the film with pharmacological data measuring absorption - these were part of the registration process but have not been published. We were shown graphs of detailed blood levels, where the films were substantially better absorbed than the buprenorphine tablets with which they were compared. From the graphs we were shown, the levels in the hours after administration appeared to be consistently 20 - 28% higher in subjects given the films versus tablets. Then we were told of some strangely contradictory clinical research work showing that patients who were transferred to the ‘film’ version noted less effect from the film formulation, despite the higher levels in the parallel studies on non-addict volunteers. This was just one of numerous worrying inconsistencies in the field revealed on the day.

We were told that the combination version with naloxone has been approved in the US for about six months and I recall Dr Strain saying that it has now taken a large market share (50% or more in some areas, if I heard correctly).

The speaker then described his own trial in some detail, including the rationale for performing it, something which is not made clear in the article itself. It examined withdrawal symptom indices during the initiation period in two groups taking (1) pure buprenorphine films and the (2) combination film. Performed in volunteers, it showed no difference, although of course this does not prove that they are equivalent. Dr Strain explained that the need for the trial was the [allegedly unfair and inappropriate] FDA requirement under the long-standing US treatment guidelines that patients should be stabilised on pure buprenorphine and only transferred to the combination product later if appropriate (and never in pregnant or potentially pregnant women). He told the audience that few American doctors actually followed this rule and that the Reckitt company was actively fighting to have the provision removed by the FDA. To my mind the use of pure buprenorphine in new patients is just logical, just as with insulin, warfarin, cortisone or lithium. There may be other commercial implications but these should be secondary to good therapeutics. His study in essence showed what he wanted: that there was no significant difference in induction withdrawals between pure and combination product, something one could have predicted.

[Comment by AB: I can see why the company might be pressing for this sort of research to be done, yet it would seem to be a low priority clinically when there are so many unknowns in the field. It seems odd that an august institution like Johns Hopkins Medical Center would follow commercial considerations to this extent. As just one example, to date there has still been no simple ‘head to head’ comparison of the combination product against pure buprenorphine despite strong but unsubstantiated contentions from some quarters that they are the same. One non-blinded trial showed that stable patients sought 50% higher doses when transferred to the combination product (Bell et al.). The work that Dr Strain discussed at this very conference indicates that absorption is also affected by other constituents. Nor has there been any research to my knowledge on the important matter of patient matching, except by ‘trial and error’ which is hardly scientific.

Equally, there has been no persuasive community evidence produced to suggest that the combination product is any less likely to be abused or diverted than the pure product. Its parallel (pure) product for analgesia was widely abused in New Zealand according to Robinson’s report in D&A Dependence in 1991 (ref below). After nation-wide replacement of pure buprenorphine with the combination version (but with three times as much naloxone per mg) the subjects attending an addiction clinic who used/abused buprenorphine had dropped from 81% to 64%. This is a modest reduction indeed, especially considering the claims by some that naloxone inclusion reduces injecting substantially. At the same time Robinson reported that pharmaceutical morphine use increased from 68% to 86% (and morphine is a much more dangerous drug when used without supervision). Buprenorphine was subsequently withdrawn altogether in New Zealand and not reintroduced for almost 20 years. End of ‘editorial’!]

Dr Strain told the audience that the new formulation came in individual packs which were peeled open to reveal their contents which was a square or rectangle of gel-film which was then inserted by the patient under their tongue. It was hard to remove manually as it quickly merged with the buccal mucosa. Dr Strain went into some detail about why pink/orange was chosen to match the Suboxone tablets (he was surprised to learn from a delegate sitting nearby that in Australia Suboxone is not orange but white). The company may not know that in Australia the drug is often supervised (the only places I know where this does NOT occur by regulation are France and the US). Thus pink/orange may be the most difficult to detect in a patient’s mouth. Also, rather than a peel-pack, an applicator or inserter might be more practical, especially the custodial setting where large numbers of patients need to be given doses in a short space of time. A bright and contrasting colour would seem more sensible … so more effective consultation before introduction might have served the manufacturer and consumers better. This may also explain the fact that the company does not market a formulation smaller than 2mg. Many patients on Subutex are taking reducing (or sometimes increasing) increments of 0.4mg. In my experience most patients who successfully withdraw from the drug nearly always do so from such doses which are well under 2mg daily. It is a mystery to me why the company do not make smaller sized buprenorphine SL tablets available more widely. A sceptical reader might think that the company is more interested in patients remaining on treatment indefinitely!

Apart from reports of diversion (which Dr Strain said “where there’s a will there’s a way” or words to that effect), another part of the development rationale included worrying reports of children and even babies involved in Suboxone toxicity incidents in American emergency rooms. While Dr Strain initially raised this issue, when he was asked for details by an audience member at the end he said that he did not know any more about such events. I note that he writes in his recently published article (page 1) “unintentional exposure to B tablets in children under the age of 6 years has increased from 53 reported exposures in 2004 to 907 in 2008; from 2000 to 2008 there were 1,786 child-hood exposures to B”. This would seem to have answered the delegate’s enquiry to a tee.

Strain claimed that the use of the new “films” would be likely to reduce such occurrences … and one can only hope that he is right. Apparently Suboxone is sold as loose tablets in a bottle in America whereas elsewhere it is supplied in sealed blister packs. Further, the colour and flavour of Suboxone in America could make them much more interesting to young children than Subutex without the orange colouring and citrus flavouring. The pure formulation is indeed disgusting and children who tasted it would be most likely to quickly spit it out. Some Australian observers may think that we are being sold an American solution to an American problem.

We were told that there were about 300,000 taking buprenorphine in America on any one day. The total taking methadone maintenance in America was probably about 200,000 - and by law these were all restricted to registered clinics giving ‘comprehensive treatment’ under close supervision.

In answer to another question Dr Strain said that officially the next step in someone who was doing well on 2mg reductions was to go to second daily. Although second daily dosing can work well for maintenance patients, since reducing-dose patients are usually in withdrawals by the end of 24 hours the prospect of second daily dosing is just inappropriate when there is an option of reduction to 1.6mg. Unofficially, however, he said that the logical thing to do was to cut the tablet or patch in half. He said that Reckitts had said that they could not guarantee that the drug was evenly distributed amongst the dry tablet or the patch … yet Dr Strain said that this was not really tenable when the company seemed happy that the rectangle, cut from a large sheet of spray-dried film, was the same strength as the same sized rectangle next to it. This is another inconsistency of the presentation where the obvious answer was to use 0.4mg tablets which are commonly available in Australia at least.

Dr Strain’s conflict statement was given and I presume is the same as in his recent publication: “Dr Strain is a consultant to and paid member of the Scientific Advisory Board of Reckitt Benckiser Pharmaceuticals. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.”

Refs: Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6

Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318

* Stop press report sent from NDRI: “Eleven charged in "Operation Postage Stamp;" Drugs smuggled into Carbon County Prison under stamps”. http://www.attorneygeneral.gov/press.aspx?id=6035

Comments by Andrew Byrne .. Part II John Mendelson on prescription drug abuse summary.

“Prescription Opiate Dependence” - John Mendelson

2011-04-09T23:19:00.003+10:00

“Clinical Advances in the management of opiate dependence” (Part II)

Fri 11th March & Sat 12th March, 2011. Intercontinental Hotel, Sydney. Organised by the Reckitt Benckiser company.

[“Suboxone Sublingual Film - the US Experience” Eric Strain Part I]

“Prescription Opiate Dependence”

In the second plenary Professor John Mendelson from San Francisco spoke in detail about the epidemic of abuse of prescribed opioids in the USA. He pointed out the extent of this abuse, depending upon the definition, whereby a huge proportion of the population was involved in America. Most had originally obtained the drug from the family medicine cabinet. Vicodin was the most popular with 200 million prescriptions being issued in the past year. Methadone tablets for pain had increased 10 fold in just seven years. Oxycontin, we were reminded, was so abused now that it almost had the bad name of Heroin (which was also originally a trade name of the Bayer company). When the company recently reformulated their oxycodone product to be more long acting (it had previously been long acting in name only, he said) its popularity dropped proportionately. But we were reminded that the users who no longer chose Oxycontin may well have gone back to street heroin with its major complications of injecting, infections and overdose.

On no less than three occasions Mendelson mentioned the unpleasant and unpalatable possibility that Suboxone could end up being the next maligned drug like Xanax, Rohypnol, Normison capsules, LAAM, ‘Heroin’ and Oxycontin. Each of these has either been banned or else seriously restricted due to concerns, both real and constructed. On the positive side he pointed out that to date reports of misuse of buprenorphine was miniscule when compared with the other opiates (morphine, codeine, hydrocodone, oxycodone, methadone, etc). But like Dr Strain he implied that it was impossible to avoid diversion altogether.

Dr Mendelson stressed that a large proportion of respondents to a large survey had obtained the medication legally from medical sources and many of these were from one single doctor who was treating the patient (and sometimes supplying more than one end-user due to on-selling).

We were reminded that at least with prescribed drugs the patients ‘knew what they were getting’ and the risks were lower. He then did an infomercial for Big Pharma, saying how bad it was the drug companies made so much money out of all this when farmers in Afghanistan or Burma were being put out of business along with all those value-added industries all the way to the (American) consumers. While this was apparently not meant to be ‘tongue-in-cheek’, it did little to address the obvious problem of the chronic shortage of treatment facilities for those who need them most in both the US and Australia. It is not hard to estimate how many drug addicts could be treated for the earnings of the head of Reckitt Benckiser (reported to be thirty six million pounds in 2009 - see Wikipedia). This may place Professor Mendelson’s facetious comments into better perspective. I spoke to him collegially afterwards, pointing out that in our Medically Supervised Injecting Centre, the overdose rate for those injecting pharmaceuticals was a fraction of those using street drugs, nearing zero. Some Americans have trouble coming to terms with harm reduction measures like this (see my comments on subjects at risk below). On this subject, Dr Mendelson mentioned that he was in favour of the use of variable amounts of antagonists to deter and distract injectors as they would not know exactly what they were getting. This is rather contrary to our approach in Australia where the official policy is one of harm reduction.

Like a good lecturer, Mendelson went back to the origins by pointing out that there is nothing new in the world … drunkenness is mentioned in the first chapter of the Bible (Noah goes on a bender after landing the ark on Mount Ararat in Turkey - I am not making this up, you know!). Poppy seeds were found in graves in Mesopotamia where agricultural civilization had begun about seven millennia ago. The name for opium in Latin was Thebacium after Thebes where King Tut was buried and where the poppy was cultivated and its products used and revered. We were reminded that this was also the origin of the name for the alkaloid thebaine from which buprenorphine was originally derived by John Lewis in the 1960s in Bristol, working for Reckitt and Coleman in the quest for an opioid analgesic which did not cause constipation.

We then returned to Michelangelo’s impression of the drunkenness of Noah from the ceiling of the Sistine Chapel. We were then shown two views of a Renaissance architectural corner-piece showing Noah’s pot belly supposedly with veins representing the caput medusae of advanced liver failure. At this point I think he was using some licence with his audience – yet it was a nice cultural/historical foray in an action-packed presentation.

Dr Mendelson dealt with various means of overcoming the diversion problems including addition of antagonists, physical alterations to the product, etc but conceded that where there’s a will there’s a way regarding drug abuse (** see ‘operation postage stamp’ below).

He mentioned the early work of Mary Jeanne Kreek, when she was still a gastroenterologist, giving large doses of naloxone to patients orally to prevent constipation. One new formulation is claiming to do the same, yet another of the ‘me-too’ combination drugs with opiates. Of course mixing opiates with peanut butter will make them less interesting to addicts and one wonders what all this supposedly scientific approach is all about unless it is to do with patents and finance which mere doctors like me would know little about. I was reminded by Dr Robert Graham that when asked about this subject at the Suboxone tablet launch in 2006 the subject of ‘evergreening’ was carefully deflected and only confirmed in direct questioning after the session regarding some ‘exclusive marketing agreement’.

Professor Mendelson has a singular speaking style which leaves little room for oxygen. With a tilt at Cambridge syncopation, his rapid fire delivery is almost alarming as he shoots slide after slide in his compendium of topics to deal with. To start, he performed a spontaneous comedy session as the Apple computer serially froze, flat-lined and rebooted his power point presentation. He showed no hint of nerves despite the uncertainty of the moment.

We heard him initially in answer to the final question to Professor Strain’s talk, pointing out, amongst other things, that the only groups “at risk” for Suboxone injecting were (1) naïve users, (2) those who were in withdrawals and (3) those who were regular buprenorphine recipients. But he did not explain what he meant by “at risk”. I turned to my neighbours and said that they were only “at risk” of having a good time! (He agreed with this when I brought it up in the break).

He had insisted to a concerned questioner whose patients had asked for higher doses that the amount of naloxone absorbed was clinically insignificant and while it may look like there are substantial amounts for 4 to 8 hours after dosing on the graphs shown by Professor Strain, these were measured in picograms per 100ml and could not have had any clinical effect. Others may disagree. Comparative trial have still not been published.

We heard an anecdote about the taste of opiates, all of which are very bitter (hence a “taste” of heroin). However, we were informed that naloxone was the worst which Dr Mendelson once proved by passing it out at a high level meeting including Dr Alan Leishner who was so disgusted that he never gave out another research grant to the San Francisco team (!).

At this point the speaker introduced the famous pie chart of the costs of drug and alcohol abuse. But he pointed out that it had a difference as it was calculated from NEW hospital presentations compared with appendicitis (for instance) which may just occur and cause no more financial burdens beyond the immediate treatment period. On the other hand, most hospitals have about the same number of (new) drug related presentations as appendicitis … but because of the “frequent flyer” nature of dependency patients, the costs to society are vastly greater and were measured to nearly 400 billion dollars in the US alone. He rather seemed to simplify the input of prohibition, forgetting that without it the medical consequences would be very different and almost certainly a fraction of what they are currently. With just a modicum of harm reduction, HIV might be a rarity in his country as it is in Australia, New Zealand and Hong Kong where addicts share needles about as often and the rest of us share tooth brushes (yuck!).

Dr Mendelson went to some trouble to detail the measures which could be taken to reduce the misuse of drugs. He pointed out that ‘fear and fright’ campaigns like the DARE program in America did not work. He said that the effect of education campaigns was unknown. [He failed to mention the work of McBride from Perth and the companion trial in Ireland showed significant benefits in drug/alcohol use from high school education modules.] He would appear to be naturally moved towards pharmaceutical approaches to reduce abuse yet he pointed out many of the failures of this in the past and that it is a constant battle. On the other hand he may have been referring to public media education (and ‘scare’) campaigns which are very hard to prove an effect one way or another, even though they may sound perfectly logical. What is ‘education’ to one may be advertising, indoctrination or lobbying to others.

Pain and addiction treatments, he contended, could be considered one continuum with a grey area in the middle which may be larger than some of us had previously thought. In such a model, features of dependency would invoke additional supervision while stability and progress would permit more liberties with treatment. He did not mention the originators of this approach, Gourlay and Heit (at least that is my understanding) nor their use of the principles of “universal precautions” as adapted for our field. In concluding and looking to the future, he then mentioned something rather worrying to my mind. With digital and phone technology and high sensitivity urine testing some interventions would be possible which could not have been dreamed about before. I hate to think what he was referring to but he did not allow time for any more questions and insisted that we all repair for the dinner arranged at Luna Park’s Crystal Palace dining room. [I repaired elsewhere for a whisky, end-of-week devotions and a sing-along.]

As if a post-script, he said that the Purdue Company (who make Oxycontin I believe) should be sent a huge thank-you card from the Reckitt company. This seemed to be yet more ‘in house’ commercial references which may have gone over the heads of some in the audience.

** “Eleven charged in "Operation Postage Stamp
;" Drugs smuggled into Carbon County Prison under stamps”.

Reckitt’s seminar’s third talk was on Saturday morning: “Hepatitis C and Opiate Dependence” by Prof Paul Haber of Royal Prince Alfred Hospital, Sydney.

Paul Haber spoke about hepatitis C in the opioid pharmacotherapy setting. I arrived late and so cannot comment on the bulk of his presentation. Near to 10am Prof Haber was still discussing the need for regular assessments, treatment and follow-up for such patients. Despite being short of time, he craved the indulgence of the audience to say a few words about acute hepatitis C for which treatment could be very successful, preventing the onset of chronic hepatitis in a high proportion of cases. He also spoke about the seeming quandary regarding the costs of treatments into the future versus doing so at current prices, earlier in the course of the disease.

In question time I brought up the matter of Waizmann’s remarkable outcomes using some variations on the standard anti-viral regimen (ref #). By using double dose ribavirin once daily, supervised dosing and added citalopram ‘cover’ for all patients they reported nearly 100% sustained viral response in what sounds to be an average to difficult treatment group all taking maintenance therapies. The 49 subjects had a mix of genotypes and all but one of them achieved a sustained viral response.

Comments by Andrew Byrne ..

# Waizmann M, Ackermann G. High rates of sustained virological response in hepatitis C virus-infected injection drug users receiving directly observed therapy with peginterferon alpha-2a (40KD) (PEGASYS) and once-daily ribavirin. Journal of Substance Abuse Treatment 2010 38:338-345

Fourth talk Reckitt’s seminar was on “Polysubstance dependence” by Dr Mark Montebello of the Langton Centre in Sydney.

Following Dr Haber we heard psychiatrist Mark Montebello who looks like a tenor but sounds like a bass-baritone. He spoke about his publicity photo for the conference, not having one to hand, and the need to take unusual poses to prevent those self-conscious looks.

Dr Montebello’s erudite speech was on the difficult subject of polysubstance abuse in which he included amphetamine type stimulants, inhalants, cocaine, benzodiazepines and cannabis. For some reason he called the latter ‘marijuana’ (perhaps for the benefit of the American visitors). We were told of the complex nature of categorising these patients, not to mention dealing with the problem clinically.

In question time several doctors announced that they had used various benzodiazepines in reduction and maintenance in opiate patients. Dr Montebello said that he favoured the use of clobazam which could be detected in the urine specifically from most other ‘street’ and prescribed sedatives. One well meaning doctor insisted that alprazolam (Xanax) was his drug of choice for such prescriptions while this raised many eyebrows in others.

Dr Strain said that he had forgotten when he had last prescribed alprazolam (Xanax) for a private psychiatry patient. Nevertheless, he had recently started prescribing ‘longer acting benzodiazepines, especially oxazepam’, to certain pharmacotherapy patients with anxiety symptoms, finding useful outcomes and little abuse.

I raised the issue of benzodiazepine maintenance for a select group who had tried every alternative, utilising more supervision for new and unstable subjects with more liberties for long-term stable folk. Our practice had used the “say no to drugs” philosophy for a decade with little to show for it as about 50% of our patients, like other reports, continued to use benzodiazepines on urine testing. Having started to prescribe diazepam under supervision, we noted anecdotally a high degree of stability with patients largely avoiding alcohol, cocaine, amphetamine and heroin/opiates. We use diazepam doses between 5 and 25mg daily under supervision along with the usual opioid pharmacotherapy, either (pure) buprenorphine or methadone. My final comment was that the use of diazepam in this way had about as much evidence as methadone did in 1990, before the seminal controlled studies of Dr Strain’s group at Johns Hopkins.

I was interested to find that the audience lacked the usual academic, research and ‘admin’ people from our field but mostly clinicians like myself. I met three doctors from Melbourne, several from Queensland and one from WA. There were apparently over 80 attending from all over Australia plus some doctors from Malaysia, Indonesia, Taiwan and South Africa. The Reckitt company budget must be substantial indeed.

Comments by Dr Andrew Byrne ..

'MOTHER' study was really looking at babies, not mothers.

2011-04-08T00:18:00.003+10:00

“Treatment for Pregnant Opioid Abuse Dependent Women”
Karol Kaltenbach, PhD
Clinical Associate Professor, Thomas Jefferson University, Jefferson Medical College

“Live at St Lukes”. Psychiatry Grand Rounds Wednesday 23rd March 2011.

This presentation was a well constructed description of the MOTHER study in a context somewhat removed from the science in my view.

Dr Kaltenbach began by saying that "Families I speak to are all real worried about babies withdrawing from drugs when they are born to mothers on methadone". She said that this was the main purpose of their study: to examine paediatric outcomes from pregnancies randomised to methadone or buprenorphine. We were reminded how little formal research has been done on opiate addicted mothers and their offspring even though tens of thousands of cases have been treated in the case of methadone which is considered the ‘gold standard’. While technically neither drug is approved in pregnancy, methadone treatment is considered a priority option for opioid dependent pregnant women in most health systems (and waiting lists are often dispensed with). Further, and reassuringly, to date several hundred babies have been reported born to mothers on buprenorphine. So the best ‘research’ has actually been field experience with this matter as well as scores of observational reports from Finnegan, Kandell and others. There have been no consistent problems reported from either group apart from the occurrence of neonatal abstinence syndrome (NAS). It is my belief that such concerns over NAS can be addressed by reassurance that existing treatments are satisfactory but may delay baby’s discharge by a few days in some cases.

To her credit Dr Kaltenbach stressed at the outset that from their findings and others’, NAS is no more or less likely with either drug, about half the babies exhibiting symptoms in both groups. We were then given an overview of the trial, initial 1074 screened candidates from seven sites (US, Canada, Austria) , 175 randomised to methadone (89) or buprenorphine (86) on double blind, double dummy bases and with 58 buprenorphine and 73 methadone subjects completing the study. We were briefly shown data supporting no substantive differences between the groups in the usual relevant demographic details including drug use (those dependent on sedatives or alcohol had been excluded at initial assessment). Then we saw numerous tables of primary outcomes and secondary outcomes of the study (all fetal results, including mostly non-significant differences - eg. NAS score, birth weight, head circumference, gestational age, etc). It was emphasised by the speaker that three fetal characteristics were significantly better in the buprenorphine group. These were (1) total amount of morphine used (2) infant’s hospital stay and (3) duration of NAS (I noted that these are all derivatives of the same thing, viz: the severity of NAS as perceived by the treating doctors). My feeling is that it is an overstatement to say that these are three (separate) beneficial findings.

To my mind this trial, for the first time, proved that methadone is the drug of choice for opioid dependency in pregnancy … it also showed that the 58 mothers who finally had a baby on buprenorphine (almost 1000 original applicants didn't) had babies with slightly less protracted and/or severe withdrawal syndromes. And this is no surprise since buprenorphine is the weaker agonist drug and thus mothers with more severe dependencies may be more likely to have dropped out. While the authors provided some comparative evidence against this, on the other hand it would appear to be supported by their finding that ten times as many of the buprenorphine drop-outs stated that they were 'dissatisfied with the medication' (20 versus 2 in the methadone drop-outs).

Dr Kaltenbach did emphasise the health care budget and the issue of hospital stays for treatment of NAS. More important than concerns over NAS in my experience is that most expectant parents want to know: 'will our baby grow up healthy?' NAS can be managed relatively simply and its occurrence is not known to be associated with any negative long term outcomes (Finnegan, personal communication). Most important are the proven negative outcomes known for pregnancies of opioid dependent women who are denied adequate treatment. The costs of such complications to the health system, insurance companies, managed care organisations and society generally are substantial and would be vastly more than even the most comprehensive opioid dependency treatment program.

Despite the modest benefits to the offspring and disastrous consequences to the retention rates, we were told that the researchers believed that their data supported a conclusion that buprenorphine is now a ‘first line option’ in pregnancy. Their institution’s press office went further, stating that that buprenorphine is ‘superior to methadone’ in pregnancy, something which I believe is patently untrue and highly misleading.

If indeed this trial were intended to fairly determine outcomes of the respective drugs then the analysis should have included the patients who ‘failed to comply with the protocols’ and were discharged from treatment. In my clinical experience involuntary 'discharges' are exceedingly rare and in most cases would be involuntary ‘transfers’ so treatment would not be curtailed under any circumstances against the wishes of the patient.

My impression from this presentation was that one of the main goals of this study was to support buprenorphine treatment in the community in America where methadone is often not available. Indeed the very title MOTHER would seem to indicate that fetal outcomes were secondary rather than primary. This is intriguing since buprenorphine is already being used widely in pregnancy with excellent results in those women who can tolerate it. In fact the main conclusion from this study is that both drugs are needed for such women since neither has sufficiently high retention rates. As Dr Kaltenbach implied early in her talk, such research during pregnancy has serious ethical limitations (and my feeling is that without a safety net this trial was in the same category).

A doctor in England tried to do a trial of this nature in non-pregnant patients and over a two year period in their busy treatment clinic she reported that she could not recruit one single patient to randomise (Pinto). It is of concern that in the ‘MOTHER’ study that subjects stood to earn up to $5800 in incentives for compliance and so this may explain why they were able to recruit the women, many of whom had been in stable methadone treatment at the time of joining the study (although this detail was not given in the paper or presentation but in a parallel publication by the group). Thus approximately half such stable patients had their prescribed medication altered during the trial. Such an incentive for a pregnant woman in stable treatment seems to me to be unfair and unbalanced. That such women consented to altered treatment is little justification or consolation for the excess number who dropped out of treatment in my view. Dr Kaltenbach implied that the incentives were used as a ‘normal’ part of high quality treatment, ensuring that there would be no criticism that the women were denied state-of-the-art medical attention. I have never heard of incentives of this degree being used or recommended as “contingency” management (the ‘rewards’ for ‘good behaviour’ are usually modest compared to these sums and sometimes the equivalent of bubble gum or lottery tickets). It appears inescapable, however, that this trial could not have gone ahead without some such strong incentives.

Another detail was that daily attendance, including weekends is an onerous task, especially during pregnancy and is hardly consistent with high quality treatment claimed by the researchers. Yet this is just one more deficiency in a very troublesome trial protocol.

At her talk Dr Kaltenbach seemed uncertain of the Canadian site situation (which ended up providing no subjects at all for the trial, rather like Dr Pinto in England). Initially she said that the patients had the opportunity to get pharmacy pick-ups and daily attendance was no longer acceptable to them. Later in response to my comments she said that there were problems getting the Subutex, Suboxone and placebos to the hospital in Canada.

Dr Kaltenbach stated that the researchers originally wanted to recruit 350 candidates but since the numbers were only about half that they changed their alpha significance level to 0.03 … something I confess I find bizarre and unconvincing. In my view a difference in outcomes is either significant or it isn’t using traditional p values for group comparisons. Even just looking at the raw figures on drop-outs I believe most concerned parties would be able to decide which group they would liked their family member or patient to be in.

Dr Kaltenbach described the excess drop-outs in the buprenorphine group as ‘pretty dramatic’. Yet there is a claim in the paper that this difference is not significantly different! We then had some speculation about the reasons behind the poor buprenorphine results, including inadequate induction doses or inadequate withdrawals before starting (and I wonder if it is ethical to induce withdrawals in pregnant women at all). The reader should note that this trial used pure buprenorphine (Subutex) which is the agent used in nearly all the quality research while the combination drug (Suboxone) has still not been subjected to much if any comparative research to my reading.

While Dr Kaltenbach said that there was no reason to do so, it seemed traditional nowadays to put up a disclosure notice. She said that there were no declarations of interest as she did no consultancies for drug companies.

Comments by Andrew Byrne ..

Letter from New York ...

2011-04-06T22:32:00.001+10:00

Dear Colleagues,

I have had the privilege of spending time in Manhattan meeting up with colleagues, mostly of like minds, on issues of mutual interest.

At the same time, Americans are often also interested in the drug situation in Australia including related viral diseases, public health and the various studies being reported. Of course I was most interested in innovations here in America, including the buprenorphine film/wafer which has been mooted by the manufacturer for quite some years to overcome some of the problems with their SL tablets. See http://www.attorneygeneral.gov/press.aspx?id=6035 It is about ten dollars cheaper than the tablets according to a pharmacist I interviewed here which may account for its popularity currently. It also has some disadvantages it would appear.

Other highlights: ‘MOTHER’ study presentation: http://methadone-research.blogspot.com/2011/04/mother-study-was-really-looking-babies.html This issue became a front page New York Times item last Sunday (links on request).

I visited the Drug Policy Alliance where there is a team of dedicated workers intent on improving harm reduction services in the United States and beyond. They are always keen to hear of progress in Australia, needle programs, injecting facilities, etcetera. Several of their workers have been to the Beirut Harm Reduction Conference earlier this month where they met up with numerous Australians.

Across the road in West 36th Street I met up with Lynn Paltrow at the National Advocates for Pregnant Women. We heard of tragic cases of ignorance in certain states where women on methadone were charged with ‘supplying a drug to a minor’ and being separated from their children as a result. While we all appreciate the great advances undertaken in the United States but it is also clear that there is a Neanderthal side to their approach to drugs and drug use (see warnings on every bottle of alcohol sold in the US but note there is no alcohol percentage noted, even on Fosters!). Their system just seems rigid and less flexible than in other places like Australia.

Grand Rounds at Bellevue Hospital had an interesting presentation on the use of peer mentors for alcohol and drug affected patients. Dr Kathlene Tracy had done two studies, one in the Veterans Administration and one at NYU, looking at attendances for appointments before and after engagement of a mentor (who had been carefully chosen and vetted as being at least 6 months ‘clean’. This ‘buddy’ engagement improved compliance substantially at very modest cost and deserves closer examination, especially for severely disrupted patients with no homes, telephones or other means of support. The staff members at Bellevue were most obliging and invited me to lunch where we had on-going discussions led by Dr Marc Galanter who is their senior D&A specialist.

I give Journal Club at Rockefeller University (Kreek Labs) on Tuesday before returning home for Easter and my father’s birthday on Lord Howe Island (he is 84!).

There is a meeting with the newly formed users’ group here which is lobbying for better access to treatment for hepatitis C. At present the only ‘mandated’ intervention is an antibody test at entry to methadone treatment. For buprenorphine even that can be overlooked.
Best wishes from Manhattan.

Andrew Byrne ..

A FEW RECENT JOURNAL ITEMS WHICH MAY INTEREST YOU.

2011-03-11T01:06:00.004+11:00

Adding quetiapine (Seroquel) to naltrexone makes no difference to alcohol abstinence rates 61-72% at 4 months (Guardia et al in Barcelona).

No effect demonstrated in a good quality RCT of acamprosate for cocaine dependence (Kampman, O'Brien et al, Philadelphia).

Simojoki, Linzteris and Finland patients: “.. crushing of Subutex tablets does not significantly alter serum .. levels or the drug’s clinical effect ..”. They say crushing has no effect on dissolution time, contrary to our own experience (some chemists, cooks or clients may also disagree).

Cunningham et al compare buprenorphine induction at home with standard daily clinic initiation, finding some advantages in the home strategy … and few problems. This may be just what we need to reduce early treatment drop-outs for this otherwise excellent drug.

Extensive interviews with over 1000 pharmacotherapy patients show bimodal distribution for many aspects of dependency, indicating two categories of patients which are clinically distinct, justifying the DSM categories or levels of opioid dependence.

Strain et al compare cravings at induction of pure buprenorphine films (non-registered) versus buprenorphine/naloxone soluble-films (sometimes called wafers). It is disappointing that only the latter is being marketed because it is contraindicated in pregnancy yet women with young children are a target for measures against diversion and misuse which are claimed benefits of this formulation.

Pharmacist McNamara and colleagues select patients prescribed methadone for pain treatment and then report a (spurious) association with QT prolongation! Their paper has some interesting information but is no scientific treatise. One ‘high risk’ patient is on 5mg daily! One out of 7 patients died - not of torsade de pointes - but of ‘toxic shock’. Like most such papers, there are no cases of torsade. Nearly all (male) patients had QTc > 430ms BEFORE taking methadone(!). This is similar to Reddy’s paper from the Anderson Cancer Center.

The Iguana column in Addiction has rarely been a high point of scientific publication but this month makes no sense at all, at least to this antipodean reader. p685 [Full citations below]

Dear Colleagues,

These items are sent for your interest. I have not read them all fully but it is nice to see that our research colleagues are still working on basic efficacy trials using various combinations and comparisons. Some of these ‘stand up’ (like the superiority of methadone in pregnancy) while others reverse initial encouragement, such as the use of acamprosate for cocaine cravings. Both positive and negative findings are important to clinicians. The possibility of giving one or two initial doses of buprenorphine to candidates to take away and consume WHEN THEY ARE IN WITHDRAWAL may be a safe and beneficial innovation (Cunningham; Lee).

The first three items are high quality scientific comparisons (RCTs) while the last two items are here despite their poverty of content and rigour.

I hope they are of interest to readers.

Andrew Byrne ..

References:

Guardia J, Roncero C, Galan, J, Gonzalvo B, Burguete T, Casas M. A double-blind, placebo-controlled, randomized pilot study comparing quetiapine with placebo, associated to naltrexone, in the treatment of alcohol-dependent patients. Addictive Behaviors 2011 36;3:265-269

Kampman KM, Dackis C, Pettinati HM, Lynch KG, Sparkman T, O'Brien CP. A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. Addictive Behaviors 2011 36;3:217-221

Simojoki K, Lillsunde P, Linzteris N, Alho H. Bioavailability of buprenorphine from crushed and whole buprenorphine (Subutex) tablets. Euro Addiction Res 2010 16;2:85-90

Cunningham CO, Giovanniello A, Li X, Kunins HV, Roose RJ, Sohler NL. A comparison of buprenorphine induction strategies: Patient-centered home-based inductions versus standard-of-care office-based inductions. Journal of Substance Abuse Treatment 2011

Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home buprenorphine/naloxone induction in primary care. Journal of General Internal Medicine 2009 24:226-232

Shand FL, Slade T, Degenhardt L, Baillie A, Nelson EC. Opioid dependence latent structure: two classes with differing severity? Addiction 2011 106:590-598 http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03217.x/abstract

Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 26th Jan 2011 published on line ahead of print.

McNamara JK, Shinkazh N, Rim F, Zunga R, Cristian A. Methadone-Associated Prolongation of the QTc Interval at Doses Used for Chronic Pain. P&T February 2011 36;2:78-82 [references and conclusion on p107] http://www.nxtbook.com/nxtbooks/medimedia/pt_201102/#/28

News and Notes. Addiction 2011 p685

Possibly the last case report of torsade in a methadone patient. Now, how to treat it?

2011-02-22T17:17:00.005+11:00

Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection. John J, Amley X, Bombino G, Gitelis C, Topi B, Hollander G, Ghosh J. Cardiol Res Pract. 2010; 2010: 524764

Dear Colleagues,

This case history is instructive although it is not novel. To call this torsade "due to methadone" in the title is highly misleading and contrary to the paper’s data.

The daily methadone dose was low at 40mg (and ‘recently increased’); the patient was aged 50 and was also prescribed three antiviral agents and two antibiotics for HIV. These factors made the patient easily identifiable as a high risk case for numerous medical complications including torsade de pointes tachycardia. Importantly, one of the HIV drugs used has been reported elsewhere to cause torsade (atazanavir, as reported by Dabiesingh; Ly and others). Hence older age, atazanavir and HIV are thus all known to be specific risk factors for developing QT problems. There is also some evidence that HCV may be an independent risk factor for QT prolongation (Norden). From the literature I have searched it seems that most HIV subjects with torsade de pointes are not taking methadone.

Unfortunately, details of this patient’s dependency management are scanty and it seems that there was limited if any addiction specialty input. Note that the patient survived and even 23 days after the methadone was ceased still had QT prolongation and was considered to be in need of a pacemaker (ICD). The reader is not informed, but methadone may have been substituted by another drug, such as morphine. Either way, it would seem to indicate that the methadone was NOT the cause of the electrical perturbations in this patient, despite the alarmist title.

The authors concede that a dose level of 40mg (increased two months before the episode following two years of no illicit drug use) is very unlikely to be a significant causative factor for QT prolongation. The methadone may even have delayed the onset of torsade, for example, by keeping the patient from other cardio-toxic drugs including alcohol, cocaine and amphetamine. It is paradoxical that this very patient was administered another QT prolonging drug, the anti-arrhythmic amiodarone during resuscitation. This drug is similar to methadone in that it can reportedly cause QT prolongation but rarely induces torsade.

These authors cite Adelaide author Athanasos but do so rather selectively. While he does indeed describe U-waves, of uncertain clinical significance, his study found no cardiologic consequences of low to medium doses of methadone, the latter findings appear to be ignored in the current paper. It is intriguing that these authors would repeat Krantz and colleagues’ controversial and unproven advice (Ann Int Med) about performing annual ECGs on methadone patients (see responses in Annals, 4 against, none in favour). This very case report is yet another example in which such serial ECGs were performed and yet torsade occurred regardless. It seems that in America performing a test is sometimes seen as a defence regardless of its utility or otherwise.

That this patient is alive at 50 after having such serious complications of IV drug use as HCV, HIV and hepatoma is indeed a credit to the methadone and medical care received at this institution bearing the name of one of the most innovative doctors of all time, Maimonides (see his treatises on haemorrhoids, digestion, chicken soup and cohabitation).

Reports of torsade in methadone patients are not usually published any more, probably because the details are similar to over 100 other such reports - it would be like describing a 'routine' case of appendicitis. Furthermore, there have apparently been no fatalities from confirmed torsade to date to my best knowledge, at least in the past 15 years (an American text states that it should have a mortality of zero). According to the Journal's web site these authors would have paid over US$500 to have this vignette made public.

If nothing more, the report should be a wake-up call to all who treat middle aged opioid dependent patients and remind us to take greatest care when anti-virals, anti-fungals, antibiotics, etc are being prescribed, especially by others who may not be familiar with the dependency side of their patient’s treatment. The size of the methadone dose appears to be of little relevance (Krantz’s original series had 6 of 9 subjects taking between 65mg and 125mg, mean 96mg daily; Pearson reports one case at 29mg daily).

Comments by Andrew Byrne ..

Link to article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021856/

Correction for Jones article summary: I stated in an early draft that there was no fetal loss but in fact there were two such events, both in the methadone group. This was promptly corrected on the web site and I apologise for the mistake. Dr Jones has also pointed out that the trend for greater attrition in the buprenorphine group did not reach statistical significance. To my mind the authors have still not justified their comment that buprenorphine is now a ‘first line option’. Just because they showed no difference in retention/attrition, this does not prove that the two treatments are equivalent therapeutically. I believe that both drugs are extremely useful in opioid dependency and that methadone remains the gold standard (O’Connor 2010 JAMA) although it does not suit everyone or every situation.

Like randomised trials, patient choosing methadone also have much better retention.

2011-02-15T16:15:00.000+11:00

The SUMMIT Trial: A field comparison of buprenorphine versus methadone maintenance treatment. Pinto H, Maskrey V, Swift L, Rumball D, Wagle A, Holland R. Journal of Substance Abuse Treatment, 2010 39;4:340-352

Dear Reader,

This naturalistic description and follow up study from a drug service in England shows comparative retention rates in opiate maintenance patients with exhaustive comparisons between the two groups. The current study followed a previous abortive attempt at randomisation of the groups which failed to attract any subjects, so determined were they all on their preferred medication.

These authors enrolled 361 eligible applicants for opioid maintenance of whom 227 (63%) chose methadone with the rest opting for (pure) buprenorphine (37%).

Despite the methadone patients having ‘more severe substance abuse and psychiatric and physical problems’ their retention rate was substantially higher than the buprenorphine patients (70% vs. 43% at 6 months).

Only seven of 134 patients swapped from buprenorphine to methadone early in the trial (apparently none swapped the other way around). Of the remaining buprenorphine drop-outs 10 were planned detox episodes; 40 failed to attend; 13 were detained by police; 10 were involuntary discharges. Relating to buprenorphine retention the authors report that the only significant difference on multivariate analysis in the many features/opinions solicited from the subjects was a ‘belief as to whether buprenorphine blocked the effect of heroin’. While this belief is not soundly based, it might be a helpful street myth, keeping some patients away from dangerous drugs. However, it could also give some users a false sense of security in a high risk overdose situation.

The trial patients were prescribed a mean maximum daily dose for buprenorphine of 12mg (r 4-20mg); and for methadone of 73mg (r 10-170mg). There were two deaths in the methadone group, one in the induction period and another while on a stable dose of methadone caused by overdose of multiple depressants.

As in most such longitudinal studies the proportion of subjects successfully reducing their dose to zero was low - around 7% for buprenorphine and under 1% for those choosing methadone during a six month period. This is consistent with other research showing about 4% of opioid dependent people become abstinent each year (and this is regardless of the type of treatment - see Thorley’s seminal work from the UK).

Crucial to the results of this trial was the finding that 10% of the total said that they would not have attended if methadone were the only drug available. The derived figure of buprenorphine patients who stated that they would not have attended for methadone in the absence of an alternative was 28%. This is a novel finding to my knowledge but fits with clinical experience in other areas that greater choice yields greater patient acceptance, better enrolments, compliance (adherence) and retention. Apparently English health authorities are required to justify the expense of each medication and so this provides strong evidence in that regard which was one of the aims of the authors (see their previous paper).

Since these authors used pure buprenorphine SL tablets readers should be cautious about extrapolating these findings to buprenorphine-naloxone (Suboxone) … it may or may not be the case that buprenorphine-naloxone would have achieved similar results to pure buprenorphine on which most of the fundamental research has been performed to date (RCT, safety, etc). Another reason to favour pure buprenorphine is that it is available in 0.4mg tablets (in Australia). In our own practice we have at least a quarter of our patients taking increments requiring 0.4mg tablets.

While there must be end-points to any research trial, it would be instructive to know how many of the drop-outs had re-registered in treatment (if any). While the group was not able to examine this issue, other research would indicate largely negative results including a high mortality. Dr Bell investigated this from official enrolment statistics in New South Wales some years ago [Bell J, Burrell T, Indig D, Gilmour S. Cycling in and out of treatment; participation in methadone treatment in NSW, 1990–2002. Drug and Alcohol Dependence 2006 81; 1: 55-61]. Such research, as well as clinical experience with buprenorphine shows that there is indeed a ‘revolving door’ or ‘frequent flyer’ syndrome with this treatment, at least in comparison to methadone.

Because there was no randomisation to the intervention, this study does not give us scientific information about the different drugs. However, it does inform us for the first time I believe that the most seriously dependent patients are more likely to choose methadone and that they have a better retention rate in so doing. Less seriously dependent patients are more likely to choose buprenorphine and are more likely to drop out of treatment (and some successfully withdraw from treatment). So unsurprisingly, outcomes are a function of both the patient group and the treatment chosen. While this information is not a major benefit in individual clinical decision making, this study at the very least provides an excellent “barometer” by which we might measure our own practices regarding the proportion taking each drug and the dose ranges used.

Comments by Andrew Byrne ..

Say no to "just say no"! Give in, with therapeutic strings.

2010-12-21T19:04:00.001+11:00

Article printed in "OF SUBSTANCE".

"View from the coal face" … in Redfern, inner Sydney.

Commentary on Addiction editorial on benzodiazepine maintenance.

After many years of wrestling with the problem of benzodiazepine use in opioid dependency patients it was reassuring to read the prominent paper by Liebrenz and colleagues. Their hypothesis is an approach using what appear to be harm reduction principles, parallel to methadone maintenance. Our original practice policy was to ‘just say no’ but despite our entreaties, about one third of our patients continued to use benzodiazepines on urine testing. A number did succeed at abstinence, only to relapse with significant harms occurring due to disinhibited behaviour, often involving amnesia for the events.

Some patients were able to function almost normally while taking illicit benzodiazepines. Others became disorganised regarding their finances, housing and interpersonal relationships, some even coming to the attention of the police or emergency departments.

Although there appeared to be a number of patters of tranquillizer use, from binge and recreational use to quasi-therapeutic, we treated all such patients the same way initially, using diazepam 5mg tablets supervised at the clinic. Those currently abusing alcohol were excluded. Each patient needed to return at least once, about 3 hours after a witnessed dose for a brief examination to confirm their tolerance and exclude intoxication. All patients also had to agree to random urine testing and regular medical consultations to assess progress.

Our impression has been that when given access to diazepam under close supervision, stability returned to most such patients. A recent audit of our referral dependency practice showed that of 167 pharmacotherapy patients, (80% methadone, 20% buprenorphine) 30% were being prescribed benzodiazepines, mostly under supervision at the practice. The mean dose was 14mg daily (range 2mg - 25mg). One third were gainfully employed.

Thus we can confirm that some of the protocols alluded to in the forward thinking item in Addiction are feasible and are ripe for research. Enquiries showed that many of our colleagues had one or two pharmacotherapy patients taking long-term benzodiazepines and nearly all had organised supervised dosing at least once.

Benzodiazepine use has been the ‘elephant in the room’ in addiction treatment. While many centres still use an abstinence approach, many patients continue to use these drugs. Since benzodiazepines, along with alcohol, constitute a major source of drug-related harm it may be timely to reassess our approach. Severe restrictions on supply alone have historically never solved drug problems. Such restrictions also necessarily reduce access to those who need the drugs therapeutically. As with many other areas of public health, we believe that it is possible to translate the principles of ‘harm reduction’ to benzodiazepine use by utilizing the protocols of ‘universal precautions’ espoused by Dr Gourlay in Canada.

The use of benzodiazepine maintenance is probably at the same stage of ‘evidence’ as methadone treatment was in about 1980. It appears to be acceptable to the patient population; it appears to be safe in practice, yet definitive research is awaited to prove its effects … and to identify optimal dosing, supports and necessary supervision. Likewise oral morphine, injectable methadone and heroin assisted treatments are being trialled in several countries currently. Thus in our own patient group we found that supervised, low dose diazepam was worth offering to those who were unable or unwilling to give up benzodiazepines.

References:

Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874

Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med (2005) 6;2:107-112

Darke S, Ross J, Mills K, Teesson M, Williamson A, Harvard A. Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. D&A Review 2010 29:3:250-255

Byrne A. Benzodiazepines: the end of a dream. Aust Fam Physician 1994 23;8:1584-1585

See article summary by Libby Topp http://www.ofsubstance.org.au/images/archive/pdf/ofsubstance_2010_3.pdf

More drop-outs with buprenorphine in pregnancy.

2010-12-17T00:24:00.005+11:00

Reduced retention makes buprenorphine a poor second to methadone in pregnancy.

Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. NEJM 2010; 363:2320-2331

Dear Colleagues,

These authors assessed 1074 pregnant women from clinics in Austria, Canada and the USA for this comparison of methadone and buprenorphine regarding neonatal abstinence syndrome (NAS). There were 250 who declined to participate and another 650 did not fit inclusion criteria (alcohol, benzo use, medical conditions, for example) leaving 175 in the randomised comparison groups, blinded by a morphine wash-out period in hospital and use of ‘double dummy’ placebo. Pure buprenorphine (Subutex) was used to avoid prenatal exposure to naloxone (Suboxone is contraindicated in pregnancy). Over $1000 was available to subjects contingent on clear urine toxicology during the trial.

There were two peri-natal deaths reported from those who remained in the study, one from each group. There were two miscarriages (both in the MMT group). “The percentage of neonates requiring NAS treatment did not differ significantly between groups (P = 0.26), nor did the groups differ significantly with respect to the peak NAS score (P = 0.04) or head circumference (P = 0.04).” However, two other primary outcomes were significantly better in the buprenorphine group: (1) quantities of morphine used for neonatal abstinence syndrome (NAS) and (2): ‘total hospital stay’. The prognostic significance of these outcomes is unknown to my best knowledge.

The numbers of enrolled subjects were not large enough to show anything but very major outcome effects as being statistically significant. Previous experience has consistently shown only modest differences between methadone and buprenorphine regarding neonatal outcomes. Hence this trial was under-powered on the numbers to find minor differences to statistical significance.

Aside from the unsurprising neonatal outcomes, there were some dramatic and remarkable maternal findings which are mentioned but not brought to the prominence they deserve in my view. These differences are so great that they may even invalidate the neonatal findings (for example if those with high tolerance or rapid metabolism were more likely to drop out).

To my mind the two most important findings of the study are as follows:

The methadone group (n=89) had 16 drop-outs (18%) while the buprenorphine group (n=86) had 28 drop-outs (33%) [p=0.02]. Even more dramatic, of the 16 methadone drop-outs, 2 were due to ‘dissatisfaction with the medication’ while the corresponding number for the buprenorphine candidates was 20, a massive difference. These findings are discussed in the text but should probably also be enshrined in the title of the article. There is no point in having favourable neonatal outcomes if a third of the mothers have left treatment before term.

Even with its failings, I believe that this study provides the most persuasive evidence to date showing the safety and effectiveness of methadone in pregnancy. Indeed, it clearly demonstrates that, in the absence of contraindications, methadone should be the first line drug for opiate dependence in pregnancy (as in the non-pregnant). Yet despite their finding that almost twice as many women dropped out in the buprenorphine group, these authors state, somewhat clumsily: “Although there were no significant differences in overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy.”

Rather than an option, “first line” status implies an obligation in my book. Since buprenorphine is the only alternative medication licensed for opioid dependence then it is obviously an ‘option’, if a somewhat less effective one. This RCT confirms that during pregnancy, consistent with the existing body of research evidence, (pure) buprenorphine should be the second line drug and only used when methadone is found to be clinically inappropriate. I believe that it is unethical to prescribe Suboxone (buprenorphine/naloxone).

Comments by Andrew Byrne ..

http://methadone-research.blogspot.com/

French study shows torsade rare to vanishing.

2010-12-15T20:26:00.003+11:00

Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6;

Dear Colleagues,

These French authors have done our field a great service by replicating Anchersen’s national study from Norway which was so reassuring concerning the use of methadone in addiction treatment.

This study examined QT intervals in a small sample of methadone patients and then compared the results with national reports on adverse events involving methadone and/or cardiac issues including sudden death. These authors found a mean QT interval of 414 ± 29ms with no readings over 500ms, the level at which the risk of arrhythmia is believed to become significant. We are told that analysis of the 42 cases showed that longer QT intervals were associated with recent increases in methadone dose, tobacco smoking, the use of other medications and pre-existing cardiac disease. These findings are consistent with most other work published on this matter, with the notable exception of Wedam. The authors quote QT ‘dispersion’ which is the difference between the shortest and longest QT interval among the twelve leads readings on the standard cardiograph. Despite some initial promise, the significance of ‘dispersion’ has been questioned more recently and its relevance to methadone treatment is uncertain. Even normal values are not agreed upon by cardiologists.

The 550 reports to the official French ‘pharmcovigilence’ centre regarding methadone are of great interest and relevance to the current debate over supposed cardiac effects of methadone. In the ten years to 2007 only 5 reports (0.9%) involved QT problems, three of these with torsade de pointes including one death, a 19 year old who died after unsuccessful resuscitation. This case is not tabulated as having torsade but if he did, as implied in the text, he would represent the first confirmed death from torsade de pointes in the literature to my knowledge.

Over the ten years there were also 7 sudden deaths (1.3%) which the authors tabulate in detail. For some reason they postulate that some or all might be ascribed to arrhythmia. They state: “it is conceivable that serious toxicity might be mediated in part through cardiac effects rather than solely via respiratory depression.” Almost anything is ‘conceivable’ yet the real quesion is whether it is likely or even ‘credible’. In fact the data presented make it highly unlikely that torsade is involved to any significant degree, if at all. Were torsade the cause of just half of these deaths, and considering a reported mortality well under 10% (some say zero) then one would expect hundreds of non-fatal cases of torsade across France - yet only two were ever reported in the whole country over a ten year period. The expected under-reporting in such a voluntary scheme would apply to some extent to both mortality and torsade, even though the latter has become almost ‘notorious’ and was originally described in France and with a French name.

Further, these authors state of several deceased cases: ‘no overdose of methadone’. This is largely based on drug levels found at post-mortem. However, these are now known to be most unreliable alone in determining cause of death. Indeed, serious toxicity and death from narcotism have frequently been found with post-mortem blood methadone in the ‘therapeutic’ range while some patients in normal treatment have levels in or near the toxic range. Also, there are major changes in the levels of measurable methadone following death.

It seemed extraordinary that five of the deceased patients were being treated for psychosis so I wrote to the authors. I have now learned that certain antipsychotics are used commonly in France as alternatives to benzodiazepines, hence not all of these patients were schizophrenic. Each of these 5 patients who were prescribed anti-psychotics died in the first 5 days of methadone maintenance treatment for addiction and two were taking doses which were in excess of current guidelines. Nearly all were receiving four or more prescribed medications apart from the methadone. HIV drugs were involved in two cases. Hence these well-documented deaths also make it clear that polypharmacy is a major factor and the patients would have been self-evident as extremely high risk candidates for treatment.

This study makes it hard to understand the findings of Krantz who found more cases in his own small district than in the whole of France in a decade. Suffice it to say that the findings are even more reassuring than the national figures from Norway published by Anchersen and colleagues.

Comments by Andrew Byrne ..

Related article (includes one of the same authors): Molokhia M, Pathak A, Lapeyre-Mestre M, et al. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br. J. Clin. Pharmacol. 2008 66:386–395

In this exhaustive paper using a rational methodology an estimate is made of the incidence of drug induced long QT syndrome (LQTS) at 11 per million per year. The literature shows that over 50% are due to class III antiarrhythmics (presumably in those with existing cardiac rhythm disturbances), closely followed by anti-infective drugs and antihistamines (with presumably some antipsychotics). The drug methadone is not even mentioned in the entire paper so we presume that in 2008 it was not even on the radar for these experienced and thorough researchers. This casts yet further doubt of the contention of Dr Mori Krantz that cardiac problems constitute a public health priority in methadone treatment in America.

QT changes in babies aged one day uncertain relevance.

2010-12-14T20:31:00.001+11:00

Parikh R, Hussain T, Holder G, Bhoyar A, Ewer AK. Maternal methadone therapy increases QTc interval in newborn infants. Arch Dis Child Fetal Neonatal Ed 2010 doi:10.1136/adc.2009.181701

Dear Colleagues,

These authors set out to measure the QT interval in newborns for the first week of life from both ‘uncomplicated’ methadone mothers and ‘healthy’ or drug-free controls. The finding was that there was a small but significant increase on days 1 and 2 (~30ms) which was absent by days 4 and 7. On the first day of life there were 4 of 26 methadone exposed babies with QTc of greater than 500 yet these were all outliers, the 5th longest interval being less than 460ms. By day two only one was near 500ms while later readings were all below these levels. There were no cases of torsade de pointes nor any other rhythm disturbance.

As with other reports, the ability of experts to read QT intervals was limited. The inter-observer and intra-observer variations were given as minus 14 to plus 21ms. Hence it appears that a 30-40 ms difference in QT interval is a rather imprecise figure, since these 95% confidence limits are so wide.

A single case study by these authors in 2007 indicated movement of methadone across the placenta and changes in QT in the newborn, something which is hardly surprising but of unknown clinical significance.

I was not sure whether or not I should bring this to the attention of a wider readership, so slanted is the emphasis of the research and so lacking is it in practical clinical relevance. Ever since the commencement of the campaign to talk up the relevance of QT changes in methadone patients, new and supposedly ever more worrying facets of the problem have been ‘exposed’ - most recently questing whether testosterone levels are the cause! Or that racemic methadone was the problem and levo-methadone the solution (see refs below).

The premise here again seems to be that there are unexplained sudden deaths in methadone patients and their offspring and that a proportion of these may be due to torsade de pointes arrhythmia. Yet such a death has never been reported to my best knowledge. While some still-births or SIDS cases may possibly be due to torsades, the proportion must be extremely low owing to the paucity of reports of non-fatal cases (I could only find one confirmed case from the 1970s and it is reported that torsade mortality is very low or even zero).

Regarding adult cases, despite an aging population with a high rate of other serious illnesses and drug taking, reports of torsade de pointes arrhythmia in methadone patients continue to be sparse indeed. Furthermore, nearly all can be linked to significant risk factors other than (or as well as) the methadone. It is still possible that methadone actually lowers the rate of torsade de pointes - but only large prospective studies could prove that point … and such work would be impractical and expensive (and very probably unethical, considering the proven benefits of methadone treatment both for pregnancy and other outcomes).

Mori Krantz wrote that cardiac safety (in adults) was now a ‘national priority’. The references he used to support his thesis of increasing unexplained deaths in methadone patients (Balesteros; Sorg; Gagajewski; Shah) describe precisely the opposite on my own careful reading (none in Ballesteros; one from Sorg; none in Gagajewski; reducing, not increasing death rates in Shah’s report from New Mexico).

The main issue with the present item is balancing the small risks of methadone in pregnant women with the enormous risks of street heroin to the mother and baby. While a good alternative, buprenorphine is still less effective and technically not approved in pregnancy.

So in this case, as for adult opioid treatment, research energies have been devoted to a problem which is largely theoretical. Equally, we have seen new ‘guidelines’ and recommendations promulgated by health authorities, Colleges, hospitals, etc, each addressing an almost non-existent ‘problem’. One can only speculate at the reasons behind such moves concerning an established, effective drug. The same thing is happening for propoxyphene (Darvon, Digesic, Doloxene) which has just been withdrawn in America based on limited evidence of potential harm. This is against the actual evidence of 50 years of safe and effective use across the world as a second or third line opiate analgesic. According to some authors denigrating old drugs is a time-honoured tactic of drug companies to promote profits derived from more modern, patented and often very expensive drugs. I hasten to state that there is no evidence of this occurring with the current case.

The final line of this abstract says it all: “Bradycardia, tachycardia or an irregular heart rate in an infant born to a mother on methadone treatment should prompt investigation with a 12-lead ECG.” I would be concerned about any baby with an atypical pulse, NOT JUST the babies of mothers taking methadone.

Comments by Andrew Byrne ..

References:

Daniell HW. Does Methadone Prolong QTc Intervals by Depleting Testosterone Levels? Arch Int Med 2010 170;15:1407-8

Ansermot N, Albayrak O, Schlapfer J, et al. Substitution of (R,S)-methadone by (R)-methadone: impact on QTc interval. Arch Intern Med. 2010;170(6):529-536

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr Andrew Byrne MB BS (Syd) FAChAM (RACP)
Dependency Medicine,
75 Redfern Street, Redfern,
New South Wales, 2016, Australia
Email - ajbyrne@ozemail.com.au
Tel (61 - 2) 9319 5524 Fax 9318 0631 NO MOBILE
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

I am a deeply religious non-believer - this is a somewhat new kind of religion.
Albert Einstein d.1954. Me too! Andrew Byrne b.1954.

Three articles addressing problems with buprenorphine treatment.

2010-10-22T22:02:00.000+11:00

Dear Colleagues,

Three interesting articles (citations below) have come out recently each addressing a limitation of buprenorphine in clinical practice. Last week’s JAMA has a description of a trial using a depot form of buprenorphine in America. There is also a supporting editorial from Patrick O’Connor from Yale University who points out the restrictions of current opioid treatments and the need for alternatives.

Unsurprisingly, the implant patients had more opiate-free urine tests (40%) than placebo patients (25%) and better retention (60% versus 30%). Just over 50% of the recipients reported significant local reactions at the implant sites, both active and placebo groups but none had to be removed early. One developed frank cellulitis. The blood levels of buprenorphine were found to be in the low range yet it is pointed out that retention rate is about double that of trials of sublingual buprenorphine.

I find it hard to understand how the disadvantages of a fixed dose and surgical insertion of implants could outweigh the high patient acceptability and modest cost of custom dosing of sublingual buprenorphine.

Rather than comparing the buprenorphine 80mg implants with evidence based methadone maintenance treatment (O’Connor calls it the ‘gold standard’ in his editorial) these veteran researchers used placebo implants and ‘rescue’ sub-lingual buprenorphine as a control group. Nor was there any third group for comparison with existing treatments. In my experience this is what is commonly seen in drug company funded trials aimed at marketing approval rather than scientific investigations to determine clinically important questions (see below). O’Connor states that criticism of the use of a placebo group is moderated to some degree by the need for a definitive assessment of a new delivery method and the fact that the placebo group was smaller than the active cohort (55 versus 108) with supplemental sub-lingual buprenorphine available under certain circumstances. While this design may improve the statistical power of the findings, it lowers the credibility of the researchers involved in my view, like the HIV cases in Africa who were denied treatment ‘in the interests of science’. It must be said, sadly, that it is consistent with the much quoted statistic that up to 6 out of 7 American drug addicts are denied appropriate treatment.

The reader is informed that the study was funded by a pharmaceutical company whose personnel collected and monitored data and were involved in the design of the study, management, analysis, and interpretation of the data and preparation, review, and approval of the manuscript. One is left wondering just what the named authors did by comparison with the anonymous ones. The researchers’ financial disclosure statement runs to 33 lines of small print. This may be a record in my own reading.

Another report comes from Malaysia where the combination buprenorphine/naloxone tablet replaced the pure product which was being widely abused, including injecting. While there was a reduction in some harmful behaviour, the focus group reports make fascinating reading. They would appear to confirm James Bell’s finding that the combination product is significantly weaker than the pure product it replaced (a 50% increase was required on average). Malaysian patients here reported the need for double the dose for the same degree of effect when the antagonist was added, despite claims that its absorption is clinically insignificant.

The present researchers, who had previously investigated HIV transmission in Kuala Lumpur, state: “ … the results of the second wave survey suggest a continuing widespread [intravenous use buprenorphine/naloxone], at least in Kuala Lumpur.” “The introduction of BNX and withdrawal of BUP may have helped to reduce, but did not eliminate the problems with diversion and abuse.” Some addicts reported that the combination pill was not as desirable.

These findings accord with Robinson’s report from New Zealand 20 years ago when injecting of buprenorphine combination was so prevalent that it was withdrawn from the market completely. They also quote Bruce et al who concluded in 2009 that introduction of combination buprenorphine to Malaysia ‘did not reduce BNX injection or associated risk behaviors’. His group also found that the change to combination buprenorphine was associated with increased quantities injected in about half of the patients interviewed. Their informants also reported that injecting smaller quantities of the combination product or using additives of benzodiazepines or heroin could avoid withdrawal reactions. Paradoxically, the change to a combination drug had made buprenorphine generally less attractive, more expensive and less available to addicts than street heroin in many cases. It is surprising that such a study has not been performed in Australia where both forms of the drug are available and widely used.

The third report is from a group in New York which found high rates of precipitated withdrawal in commencements onto buprenorphine treatment (17%). Such reactions were more common with lower initial doses, recent methadone use and concurrent benzodiazepine use. To her great credit, Dr Whitley reported in 2007 on the co-locating of buprenorphine and methadone treatments. While she called this ‘novel’, for the rest of the world it is just normal. The American legislative requirement to isolate methadone prescribed patients is indeed bizarre and counter-productive.

One problem with the high rate of precipitated withdrawals may have been due to the use of combination product containing the antagonist naloxone. This is contrary to the original American treatment guidelines which advised stabilising patients on pure buprenorphine before transferring to the combination product.

Equivalence studies have still not been performed despite such research being relatively simple and cheap. Furthermore, despite 0.4mg pure product being marketed in Australia for ten years, there is still no low-dose combination product available (eg. 0.4mg or 0.2mg increments for those taking less than, say, 4mg daily). 40 years of experience with methadone have shown that carefully graduated dose reductions are often necessary to achieve abstinence.

It was the low potency preparations, both pure and combination, which became subject to wholesale abuse 20 years ago in New Zealand (Robinson, D&A Dependence 1993 13;1:86). I understand that in America the smallest tablet available is a non-bisectable 2mg pill, making reductions towards abstinence extremely challenging for patient and clinician alike. It would be like the lowest dose of methadone available being around 20mg daily in my estimation. Some ultimately successful abstinence patients have taken very low doses for a long period before eventually ceasing their pharmacotherapy.

Our own practice experience with buprenorphine inductions has been similar to what one might expect from the literature. We have had a very low rate of precipitated withdrawal reactions (<5%) but a failure rate for inductions of approximately 20-40%, mostly due to the drug not abolishing withdrawals. This is about double our failure rate with methadone. Our impression is that there are also excess early dropouts in those successfully inducted onto buprenorphine, as also reported by others.

Personal disclosure: I first prescribed buprenorphine (off-label) in 1986 and have been an enthusiastic supporter of its use for dependency ever since. While methadone is the ‘gold standard’ it does not suit everyone with opioid dependency. For many years our dispensary has had about 20% of our opioid pharmacotherapy patients taking (pure) buprenorphine. I personally do not prescribe the combination product due to the lack of safety and equivalence data as well as a lack of the 0.4mg preparation allowing low-dose titration. Our Concord Dependency Seminar group receives sponsorship for refreshments by Reckitt Benckiser who have also generously donated a data projector.

Comments by Andrew Byrne ..

Full citations:

Ling W, Casadonte P, Bigelow G, Kampman KM, Patkar A, Bailey GL, Rosenthal RN, Beebe KL. Buprenorphine Implants for Treatment of Opioid Dependence A Randomized Controlled Trial. JAMA 2010 304;14:1576-1583

Vicknasingam B, Mazlan M, Schottenfeld RS, Chawarski MC. Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia. Drug and Alcohol Dependence 2010 111;1/2:44-
http://www.ncbi.nlm.nih.gov/pubmed/20478668

Whitley SD, Sohler NL, Kunins HV, Giovanniello A, Li X, Sacajiu G, Cunningham CO. Factors associated with complicated buprenorphine inductions. J Subst Abuse Treat. 2010 39;1:51-57

Recent series of torsade cases - no deaths and no pacemakers needed.

2010-07-07T02:35:00.005+10:00

Ventricular arrhythmias in patients treated with methadone for opioid dependence. Hanon S, Seewald RM, Yang F, Schweitzer P, Rosman J. J Interventional Cardiac Electrophysiology 2010 28:19-22

After a single case report in 2008, it is to the credit of this group to have now added 11 more consecutive cases of ventricular arrhythmias in methadone patients treated at the Beth Israel Medical Center in New York over a two year period. This represents all known hospitalised referrals from the largest clinic system in America numbering over 6000 patients in 18 locations. It comprises some of the earliest such clinics with some patients who commenced treatment in the mid-1960s.

Two of the twelve reported patients already had pacemakers (actually implantable cardioverter defibrillators - ICD's) in place and their presentation was due to (successful but excessive) activation of the device. They were admitted to hospital for observation due to ‘storm’, meaning more than two malignant arrhythmias in a 24 hour period.

Three of the remaining 10 did not have torsade but other ventricular arrhythmias not known to be associated with QT prolongation. Thus seven torsade cases were diagnosed from a ‘mature’ clinic population of 6000 patients over a two year period. Eight of ten tachycardia cases had precipitating factors (apart from age and methadone) including potassium and/or magnesium disturbances (4 cases), pneumonia (2 cases) and prescription medication likely to prolong QT interval (4 cases). The mean age of those with no other risk factors was 56 years. No urine toxicology results are detailed, nor are alcohol/drug histories given for these worrying cases. A co-author informed me that none of these patients was HIV positive.

The article states: ‘An increasing number of cases of methadone-associated Torsades de Pointes (TdP) have been reported over the last several years [3–11]’. Of these references, however, only three actually report a case of TdP (Krantz 2002; Pearson 2005; Esses 2008). None of the other references report tosade cases (Wedam, Ehret, Byrne, Justo, Fanoe, Chugh). They are either commentaries, reviews or reports of QT prolongation without torsade de pointes. There have indeed been a small number of recent individual reports of TdP, nearly all with precipitating factors in high risk patients (Iskander, Lamont, Luthi, Prosser, Puri, Pimentel, Routier and Wong, one case each).

Although we are only given limited clinical details of these cases, this new report of 12 cases is pivotal. It is the first large hospital series reported since the subject came to prominence with Krantz’s remarkable and unique retrospective series of 17 cases in 2002. Despite initial fears, such a series has never been replicated elsewhere in the 8 years since. Unfortunately Krantz has never reported any clinical follow-up from his seminal 17 cases of torsade from 2002.

While a prevalence rate of torsade de pointes arrhythmia in methadone prescribed patients has not been published, this series from New York is probably our best indication to date. Torsade appears to be absent in young people and is extremely rare in the long-term methadone maintenance patient group. It is disappointing that despite anecdotal reports from many other great metropolitan hospitals in America, few if any have reported their torsade experience formally in this way.

Because of the rarity of this syndrome it has been difficult to determine the best way to approach therapy. We can best learn by combining experiences through such case reports. This present series allows us to add to the other ~100 reports in the literature, about 60 of which are detailed reports.

The New York findings are consistent with other reports, including:

* a mortality of zero
* no new patient in this current series required a pacemaker/ICD (two were admitted for activation of pre-existing ICD’s)
* one third were either asymptomatic (n=2) or minimally symptomatic (n=2, ‘pre-syncope’)
* transition to buprenorphine was only possible in a minority (25%)
* dose reductions were possible in almost half, most being associated with resolution of the arrhythmia
* age range 43-61, mean 54 years
* 75% of subjects were male

While optimal treatment of torsade remains to be determined some factors seem to be agreed. Giving potassium and magnesium infusions seems effective as an early measure, following cardioversion where indicated. Some cardiologists use isoprenaline or other inotropic/chronotropic agents to prevent the bradycardia which is often a prelude to the torsade tachycardia. Pacing with implantable cardiac defibrillator (ICD) was used in 25 of 62 cases reported in the literature.

Reducing methadone doses or transfer to buprenorphine may be feasible in certain cases. Long acting morphine may be useful in some subjects, initially as an in-patient measure. However, this may not be practicable long-term due to cost and/or regulatory restrictions outside of specialist pain management settings.

Doing regular cardiographs for the past 20 years, as recommended by some, would have been unlikely to assist these subjects.

Comments by Andrew Byrne .. http://methadone-research.blogspot.com/

REFERENCES:
Iskandar SB, Abi-Saleh BS, Mechleb BK, Fahrig SA.Methadone and torsade de pointes: case report and review of the literature. Tenn Med. 2007 100;2:35-7

Rademacher S, Dietz R, Haverkamp W. QT prolongation and syncope with methadone, doxepin, and a beta-blocker. Ann Pharmacother 2005; 39: 1762û3

Lamont P, Hunt SC. A twist on torsade: a prolonged QT interval on methadone. J Gen Intern Med. 2006 Nov;21(11):C9-C12

Prosser JM, Mills A, Rhim ES, Perrone J. Torsade de pointes caused by polypharmacy and substance abuse in a patient with human immunodeficiency virus. Int J Emerg Med 2008 1;3:217-20

Puri R, Roberts-Thomson KC, Young GD. HIV and Long QT syndromeùCause or coincidence? International Journal of Cardiology 2009 133;1:e9-e10

Wong SC, Roberts JR. Case files of the Drexel University Medical Toxicology Fellowship: Methadone-induced QTc prolongation. J Med Toxicol, 2007; 3: 190û194

Luthi B, Huttner A, Speck RF, Mueller NJ. Methadone-induced torsade de pointes after stopping lopinavir-ritonavir. Eur J Clin Microbiol Infect Dis, 2007; 26: 367û369

Pimentel L, Mayo D. Chronic methadone therapy complicated by torsades de pointes: a case report. J Emerg Med. 2008 34:287-90

Routhier DD, Katz KD, Brooks DE. QTc prolongation and torsades de pointes associated with methadone therapy. J Emerg Med. 2007 32;3:275-8

Byrne A, Hallinan R, Newman RG. Does electrocardiography improve methadone safety? Am J Health Syst Pharm 2010 67: 968-969 http://byrnehallinanpubs.blogspot.com/2010/06/blog-post.html

Should we be giving supervised Valium reductions or even maintenance? 2 recent papers.

2010-06-29T21:00:00.000+10:00

Agonist substitution - a treatment alternative for high-dose benzodiazepine-dependent patients? Liebrenz M, Boesch L, Stohler R, Caflisch C. Addiction. 2010 Apr 27 Early View

Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. Darke S, Ross J, Mills K, Teesson M, Williamson A, Harvard A. D&A Review 2010 29:3:250-255

Dear Colleagues,

Two prominent recent articles have highlighted an often neglected problem area for drug users in treatment. Benzodiazepine use/abuse has long been the ‘elephant in the room’ in addiction treatment. It is surprising to me that a ‘Just-say-no’ approach is often espoused for this particular problem where ‘harm reduction’ is the principle underlying public health and medical treatment in recent years. Yet we know that benzos, along with alcohol, constitute a major source of harm in the drug using population.

Darke and colleagues report that tranquillizer use parallels both physical and mental deterioration. This 3 year, prospective longitudinal study finds that initial use of benzodiazepines did not, however, predict poor progress in the medium to long term. Their study group included patients entering pharmacotherapy, detoxification and rehabilitation services as well as a non-treatment group recruited from community harm reduction services (needle services).

It is possible that much of this harm may be preventable given an appropriate approach. Benzodiazepines also feature prominently as an association in mortality reports by Darke and others.

In an editorial in Addiction, some Swiss workers propose ‘agonist substitution’ as a hypothesis which needs formal testing. They point out the differences with methadone maintenance as well as some similarities. They further detail possible problems, especially with shorter acting or injectable preparations. However, they also emphasise the known dangers of ignoring this issue when, despite current interventions, a high proportion of users remain unable or unwilling to withdraw from these drugs. From reports over many years we know that there is a wide regional variation in use with relatively low levels in some American cities (<10% dependent) up to very high levels reported in Israel (>50% in some clinic populations).

Over the years I have interviewed many clinicians about the question of prescribing benzodiazepines to dependent patients. My findings have been that the great majority of experienced clinic doctors have authorised supervised dispensing of long acting benzodiazepines, usually diazepam, in short or medium term use for at least some patients. Most, however, have been reluctant to do so long-term or for large numbers of patients in the absence of clear guidelines on the subject.

This lack of an accepted protocol is partly due to a lack of research evidence. Yet benzodiazepines, like opiates, are still prescribed widely in the general population for insomnia, anxiety and panic disorders, even if their use is not first line. Hence we should ensure that we strike the right balance between discouraging their use and making them available in a manner which is safe. Only a very small proportion of those who are prescribed benzodiazepines develop dependency problems, precisely as also occurs with opioids for pain. Overall sedative prescribing has dropped significantly over the years but some preparations have seen surges in recent years such as alprazolam. Flunitrazepam has been subject to certain restrictions in Australia and was never been approved/marketed in the United States.

There is no dispute about the use of diazepam in alcohol withdrawal, status epilepticus and panic disorders (see various expert guidelines). While its effectiveness for insomnia and anxiety is limited by tolerance, most GPs still use benzodiazepine prescription in some cases. Hence there is a case for benzodiazepine availability in dependency clinics, even if just to avoid prescription of large quantities unsupervised from other doctors. Whether this should be available low-term or high-dose is still controversial. Yet such a practice could be seen potentially as a “harm minimization”, knowing that quite the opposite can easily occur with community prescribing of unsupervised or “on demand” prescriptions.

Thus smaller quantities and increased supervision may be consistent with improvements to measurable indices of stability in dual addicted patients. The safest would be one tablet per day with all tablets being supervised … yet this may not be acceptable to some patients and may not be practicable in the clinic/pharmacy setting. It is certainly a time consuming enterprise and could not possibly be offered to large numbers of patients without specific funding. And such funding is unlikely to be provided without more formal research to demonstrate safety and effectiveness of such an approach.

Comments by Andrew Byrne ..

Pain and addiction conference New York City March 2010

2010-05-07T22:07:00.005+10:00

Pain and addiction conference, Beth Israel Medical Center. Friday 19th and Sat 20th March 2010. Selected items summarized by Andrew Byrne.

“Emerging Practices in Pain and Chemical Dependency - 2010 Update on Opioid Therapy”

Times have changed since I attended a progenitor of this pain conference in New York in 1996. The present conference was held at the Times Square Marquis Marriott Hotel, starting promptly at 7.30am. The conference room was crowded with perhaps 300 attending. I sat in the front row, near convenor Dr Russell Portenoy, pain expert from Beth Israel Medical Center. Also present at the front were Ricardo Cruciani, expert on cardiac effects in methadone pain patients; Joyce Lowinson, editor of the big text on dependency; Herman Joseph; Mary Jeanne Kreek; Charles Inturrisi and Howard Heit. The latter is a close research colleague of Canadian pain and dependency expert Doug Gourlay. Other contributors over the two day conference were Lisa Marsch, Randy Seewald, Martin Cheatle and Edwin Salsitz.

Each speaker gave a list of potential conflicts of interest including sponsorship from drug companies. One quipped that in the past this declaration was considered a badge of honour. Nowadays however, we were told it was more a matter of shame! It is interesting to consider the different situations of speakers with one single declared conflict of interest over those with many. “Render unto Caesar …”.

Russell Portenoy gave an over-arching review of the state of play in the fields of pain management, dependency, practice guidelines and the political and research angles. He pointed out that unlike addiction treatment, pain management practice guidelines could not be based on evidence as the evidence in most areas was still rudimentary.

Howard Heit gave the second key-note dissertation entitled ‘Understanding risk in terms of chemical dependency: abuse, addiction and diversion during pain treatment’. In it he quoted his recent article with Dr Doug Gourlay (‘Universal Precautions Revisited’ 2009) with its ‘ten point rules’ for assessing risk of dependency. He called them his Ten Commandments. These carefully codify what should normally be done in good practice: history and physical; differential diagnosis; patient education and consent (oral/written); treatment trial; clinical review … and finally: careful documentation of each step. These are part of the clinical interaction which can help reveal features of substance use instability as well as the benefits or otherwise of current pain treatment.

Dr Heit also covered pseudo-addiction in the pain patient (usually diagnosed in retrospect). He reminded us that all medical interventions need an ‘exit strategy’, outlining a way of contracting with the patient what might occur if all else failed in the therapeutic relationship. He spoke about a “golden moment” in the patient’s ‘growth’ when they realised they are through playing games and are addicted. This acceptance of addiction and associated lack of control can be very moving. A Sydney colleague once described this, saying the patient always had a tear in the eye as it was related. We were reminded about the continuum between chronic pain and addiction and the need to treat according to individual need, utilising all the means at our disposal after non-opioid measures have failed … including dose supervision, urine testing, drug diary, counselling, adjuvant prescribing (eg. antidepressants, anxiolytics) etc.

Dr Ricardo Cruciani gave a talk about choice of opioid and matching patient to appropriate treatment. He placed opioid prescribing into its proper clinical context along with other physical, surgical, psychological, life-style and alternative pharmacological approaches. He advised that in the absence of clear evidence opioid treatment is still considered effective and ‘conventional’ in many clinical settings. We were reminded of the risks of all such prescribing: abuse, addiction, diversion and overdose. Dr Cruciani broached the rising incidence of deaths involving methadone which was explained by Herman Joseph in question time as being related to the recent expansion of its use in pain patients. The long half life of methadone has particular benefits in pain management but also requires that physicians be wary of dose escalations which can be toxic.

Dr Cruciani also gave one of the three morning break-out sessions entitled “Methadone Cardiac Toxicity”. I was disappointed that he used such a ‘loaded’ title when methadone has still not been scientifically proven to have any clinical cardiac toxicity and may indeed be cardio-protective. Methadone is associated with electrical changes to the QT interval which are nearly always asymptomatic. Dr Cruciani gave a roll-out of the literature with more about the ‘unknowns’ that the ‘knowns’. He argued that more research needed to be done, but did not seem to take into account the 2009 publication from Norway which has seriously questioned the worrying deductions of Chugh and Fanoe. Using indirect methods, these both concluded that torsade may be very common, yet Anchersen’s comprehensive national study did not find one single confirmed arrhythmia case out of 90 deceased methadone patients in a 7 year period in Norway (and only 4 unexplained deaths). Dr Cruciani correctly emphasised how little we know about torsade de pointes tachycardia and the (supposed) toxicity of methadone. This is probably due to the paucity of cases seen in regular dependency or pain practice. I continue to meet doctors who have worked full-time in this area for decades without seeing a single case of syncope due to torsade de pointes. Two experienced colleagues responded separately from Melbourne this month - one had just seen his first case, an older female alcoholic patient, the other had seen none in 20 years.

Rather than having cardiac toxicity, it is quite possible that methadone treatment (at least for addiction) promotes cardiac health as pointed out eloquently by Mori Krantz in his paper with Stewart Leavitt from 2001. These authors proposed a likely lower risk of endocarditis, dyslipidaemia interventions, blood pressure treatment and smoking cessation programs which are all likely to be more effective in those taking methadone than in those using street drugs. There is also some indication of lower rates of myocardial infarction in MMT subjects (Gross; Marmor). Dr Lisa Borg’s work has shown that higher doses of methadone can reduce cocaine use while the work of Forest Tennant has implied that in some cases, alcohol use may diminish in those prescribed methadone. Both of these could be expected to cause less cardiac irritability and lowered chance of torsade, quite contrary to the prevailing scare campaign.

It is to his credit that Dr Cruciani has consistently said that there is still no evidence to alter existing practice. However, he leaves the door open to further research which might do so … and that caution needs to be exercised regarding the risk of torsade tachycardia. It was just a shame that he did not separate the two clear clinical groups: the young, ‘uncomplicated’ opioid users or pain subjects who have virtually no risk of this complication … as contrasted with an older, more complex group in which torsade risk is a reality, albeit very low. Reddy’s study from Texas has shown prospectively that methadone is safe in cancer patients even though QT intervals are often raised even before patients were prescribed the methadone. All clinicians who prescribe methadone will have to learn to deal with this problem as our patients get older and other life-saving drugs are co-prescribed (most notably anti-virals and anti-fungals). However, at present few will encounter more than one or two in a clinical lifetime so collaboration is essential to elucidate the best ways to deal with torsade de pointes cases.

I asked Dr Cruciani a loaded question regarding the use of methadone in over a million patients under close supervision and whether the almost complete absence of confirmed torsade deaths and paucity of non-fatal torsade reports were not more reassuring than the prospective evidence he and his ‘expert panel’ were calling for. Dr Cruciani seemed annoyed at the question and alluded to my suggestion of ignoring the cardiac risk until it was proven. I had stated that doctors who were ignorant of the issue probably give their patients better quality treatment than those who worry over it, thereby restricting doses or using a less effective drug in cases where there is a choice.

Dr Cruciani said that he would not advise anyone to ignore this issue. The evidence is now overwhelming that the issue of possible cardiac toxicity of methadone has been fanned along by ignorance, a long-standing prejudice against methadone, and also by strong commercial considerations. The idea that “we” cannot afford to ignore possible cardiac toxicity of methadone ‘until it is proven’ says more about the litigious and commercial setting of medical treatment in the USA rather than about a sober balancing of clinical risk and benefit of this medication. My view is to treat all patients individually. The risk of torsade - and many other rare but serious events - can be stratified by using simple clinical details. Screening ECG was recommended by only one of thirteen citations given by Dr Cruciani (Krantz 2009 did; Krantz 2007 did not). A compulsory ECG in the present state of knowledge (or ignorance) is more likely to harm the patient than help them in my view. The largest literature review by Justo found that 85-100% of torsade cases had predisposing factors such as hypokalemia, structural heart disease, older age, QT prolonging drugs, drugs slowing methadone metabolism, female sex, older age, HIV status, alcohol use/withdrawal, stimulant use, inter alia.

The audience then heard two interesting talks on subjects a little more peripheral to doctors and patients in the fields of addiction and pain management. Firstly Mary Jeanne Kreek spoke about genetic aspects of addiction and the work her lab has been doing for over twenty years. While she gave an excellent summary of the natural history of addiction, I venture to say that, while fascinating academically and promising for the future, few if any of their recent scientific papers on the genetics question have been of direct benefit to patients or public health. Dr. Kreek also provided some interesting insights about the early days at Rockefeller University working with Drs Dole and Nyswander. Dr Kreek omitted to mention that it was in fact Dr Robert Halliday in Vancouver who first used methadone for opioid addiction between 1959 and 1964. There were, however, major conceptual differences (Newman, 2009).

Dr Charles Inturissi then spoke about ‘hyperalgesia’ in those taking opioids short and long term. Once again, apart from the obvious situations of withdrawal and break-through pain, the relevance of such albeit interesting findings of ‘priming’, conditioning and increased pain sensitivity in some at certain periods seemed some distance from the clinical setting. If patients are still in significant discomfort they deserve consideration of a higher dose of additional medication/modality for relief of those symptoms. Much of clinical medicine involves relatively simple ‘trial and error’ strategies while the complex diagnostics/therapeutics are more the exception than the rule in my experience.

A lunch time talk by FDA official Mark Caverly quipped about the space shuttle having a supply of opioids which had passed their expiry date and needed to be destroyed. This normally requires a visit from an FDA official but an exception was made and the expired drugs were put into a fatal orbit and was witnessed by Hubble telescope to burn up on re-entry to the atmosphere (laughter from lunchtime audience). It is a interesting that nobody even considered that perhaps American law would not extend to outer space! On a more serious note, we were told that the FDA did not visit doctor’s offices very often - and when they did they did so “to help”. There are American doctors in jail for what in many other countries would have been considered relatively minor infringements of technical regulations on prescribing. As Dr Caverly also pointed out (and as it is in Australia too), the standard of health care is regulated by the States and FDA and national legislation only has overarching responsibilities under the Controlled Substance Act of 1970 (‘TGA’ in Australia).

In the first session after lunch (of salad, poached chicken, followed by blanc-mange) Dr Steven Passik spoke about numerous new medications which are either in development or recently released which contain constituents which are aimed at less abuse. In each case he referred to certain benefits, most of which consisted of quite modest trends, that there were fewer subjects likely to misuse particular medications, the prototype being combination buprenorphine utilising naloxone (originally used and discredited and withdrawn in the early 1990s in New Zealand).

Dr Passik mentioned a combination of morphine with naltrexone (Embeda, approved by FDA in 2009). This hardly sounded possible until he revealed that the antagonist was contained in a vitreous bead in the center of the pill which would normally not be absorbed but would pass intact through the gut. The theory is that if drug mis-users crushed the pill indiscriminately they could get a rude shock if injecting anything containing naltrexone which is a long acting opioid antagonist. In certain circumstances it could also be quite dangerous, inducing persistent vomiting and dehydration (this was not discussed).

Another combination in the final stages of approval was hydromorphone in a viscous gel which it was believed would discourage injecting. Another method was to use the ‘push-pull’ osmotic controlled delivery system which also delayed absorption according to the membrane put around a tablet which may also have some short acting component for pain control. Oxycodone provided in waxy micro-particles is another as yet investigational product under trial at present (“Deter-Ex”). Yet another is the ‘Oros’ technology which has an internal membrane for slow delivery of drugs such as methylphenidate (already approved) and hydromorphone (under investigation).

Niacin (vitamin B3) can also be added to other drugs to induce an unpleasant flushing (‘niacin reaction’) if taken at certain high dose levels. This raises the issue that adding just about anything to an opioid will make is less attractive to drug users, just like adding anything to neat alcohol will do likewise for an undiscerning alcoholic.

Dr Passik was at pains to point out that for every combination and anti-abuse device developed, there were those intent on thwarting the attempts. He detailed various ways including differential dissolution in water or alcohol, chemically manipulating them or simply crushing tablets intended to be swallowed whole.

Dr Passik did not touch on the issue that these medications are invariably far more expensive than morphine, methadone, aspirin, acetaminophen or most of the NSAIDs (eg. ibuprofen). This is related to the new opportunities for drug companies to re-patent old drugs and secure higher prices for what are essentially cheap drugs with modest development costs compared to brand new drugs.

As with the possible abuse mentioned for these newer drug combinations, buprenorphine/naloxone is also abused, most commonly perhaps by existing buprenorphine patients who can inject the drug with impunity as happened in New Zealand in 1991 (see Robinson’s landmark paper in D&A Dependence - 1993 33;1:81-6). Due to its stronger affinity with the opioid receptor the naloxone apparently has little or no antagonist effect.

In question time Dr Passik was asked (by me) if there were any other areas of medicine in which a second drug of no immediate benefit to the patient was added to known effective medications in this way. He said that he was not, but that compulsory treatment for tuberculosis might have some parallels. He did not cite the old use of naloxone with methadone invented in the 1970s and reported at one of the very first methadone conferences. This was quickly dropped as a ‘useless precaution’ (see Barber of Seville, Rossini 1813).

Yet another of these ethicals was reportedly released for use in America in March 2010: a waxy new Oxycontin formulation.

In parallel to the research on diversion potential, there is not much carefully controlled comparative research to show equivalence of efficacy of these new formulations, nor was this required by the FDA in all cases, such as Suboxone. The only small pilot study (n=17) showed that changing to the mixed product required a 50% increase in dose for the average patient when compared to the pure product, Subutex. This has never been replicated in other studies to my knowledge. Dr Russell Portenoy had detailed to the audience the importance of differentiating the concepts of efficacy and effectiveness. “Efficacy” is the ability of the drug when administered to obtain the desired effects whereas “effectiveness” goes further and determines if the benefits outweigh the costs and side effects in the field.

Saturday’s opening plenary was by Dr Martin Cheatle from Philadelphia who spoke with clarity about the prevalence of chronic non-cancer pain and the consequences of inadequate treatment. These included delayed healing, depression, stress, suicide and addiction. Up to 50 million Americans may suffer from this at some time and as many as 40% reporting inadequate pain relief from treatment received. The conflicting pressures in primary care were broached, initially the essential nature of opioid prescription for serious pain, yet the reported increase in non-medical use of opioid drugs increasing four-fold from 1990 to 2002, up to 2.5 million citizens being involved.

The second day saw yet another talk about opioid regulations (State regulations by Dr Aaron Gibson of the Carbone Cancer Center in Madison, Wisconsin. He tried to reassure the audience that visits by regulators to doctor’s offices hardly ever happen and they are not in the business of putting doctors in jail. More than any other country, I understand that America convicts doctors for matters relating to psycho-active drug prescribing. Many of us have colleagues who have experienced it, and often in circumstances which, while always regrettable, are not always the ‘hanging’ offences they are made out to be by the authorities who seem to need to make an example of such souls.

At another session entitled “Office-Based Buprenorphine Therapy for Opioid Addiction: Lessons for Pain Management” Randy M. Seewald of BIMC gave an enlightened description of her lower Manhattan dependency practice. Having originally worked in the hospital and methadone clinic system, she found private office practice to be liberating as well as challenging. One main difference was that in her new ‘middle class’ subjects drug diversion was a minor concern rather than the constant bug-bear it can be in the clinic population. Although unable to prescribe methadone in parallel with buprenorphine, and despite having ties with the buprenorphine manufacturer, she was frank enough to say that if one could have only one drug, her choice would be for methadone.

Dr Seewald told us of the high retention rates in her practice … but this corresponded with low rates of successful withdrawal from buprenorphine – she only related one or two cases. In question time I raised the matter of smaller dose increments than 2mg in the virtually unbisectable Suboxone tablets. Dr Seewald had used the 2mg Subutex which can be broken in two but 0.4 or 0.2mg sublingual preparations are apparently not available in America (perhaps the company wants patients to remain on their drug for life!). There was a discussion about the legal but off-label prescribing of Suboxone for pain management which paradoxically in America requires no special licence as it does for addiction patients, even at the same dose levels.

There were other sessions on Veterans’ issues (crucial with the huge numbers now returning injured from the Middle East wars); CBT; Pain Guidelines; Nursing issues; Quality of life, amongst others. By this stage of proceedings, however, I found I was developing a type of medical Stendhal syndrome. This called for an authentic Italian meal and large glass of pinot grigio to restore my sanity - which was kindly provided at the invitation of my generous American hosts.

Comments by Andrew Byrne .. http://methadone-research.blogspot.com/

References:

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml#anchor1222388

Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. Journal of Pain and Symptom Management 2004 28;4:301-303 http://www.redfernclinic.com/c/2009/11/methadone-safe-in-cancer-patients-with.php4

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338 http://www3.interscience.wiley.com/journal/118730811/abstract

Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395 http://www.annals.org/cgi/content/full/0000605-200903170-00103v1

Marmor M, Penn A, Widmer K, Levin R, Maslansky R. Coronary artery disease and opioid use. Am J Cardiol. 2004;93:1295-1297

Gross ER, Hsu AK, Gross GJ. Acute Methadone Treatment Reduces Myocardial Infarct Size via the mu-Opioid Receptor in Rats During Reperfusion. Anesthesia and Analgesia 2009 109;5:1395-1402

Borg L, Broe DM, Ho A, Kreek MJ. Cocaine abuse sharply reduced in an effective methadone maintenance program. Journal of Addictive Diseases 1999 18:63-75 http://www.informaworld.com/smpp/content~db=all~content=a903861825~frm=abslink

Paulus I, Halliday R. Rehabilitation and the Narcotic Addict: Results of a Comparative Methadone Withdrawal Program. CMAJ 1967 96:655-659 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936075/pdf/canmedaj01207-0020.pdf

Halliday R. Management of the Narcotic Addict. 1963 British Columbia Medical Journal 5(10):412-414 http://www.redfernclinic.com/c/2007/11/management-of-narcotic-addict-halliday_4512.php4

Newman RG. "Maintenance" treatment of addiction: To whose credit, and why it matters. International Journal of Drug Policy (2009) 20;1:1-3
http://www.ijdp.org/article/S0955-3959(08)00165-5/fulltext

Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965 193:646-50 http://jama.ama-assn.org/cgi/content/abstract/193/8/646

Advice to stop methadone could be dangerous.

2010-05-04T08:30:00.010+10:00

Methadone-associated Q-T interval prolongation and torsades de pointes. Stringer J, Welsh C, Tommasello A. American Jour Health System Pharmacy 2009 1;66(9):825-833 [*see new conflict statement]

Dear Readers,

This review examines the literature on cardiac events in methadone patients. ‘Torsade de pointes’ arrhythmia and its accompanying prolonged, rate-corrected ’QTc’ interval are discussed in detail. The abstract states “A thorough patient history and ECG monitoring are essential for patients treated with [methadone], and alterations in treatment options may be necessary.” Despite the extensive literature review, they give no specific justification for the controversial advice about ECG and ‘altered treatment options’. Their own references would seem to indicate the futility of ‘screening’ ECG.

The authors quote 33 published torsade events in dependency subjects from 2002-2008. My review of these indicates that 24 of the 33 give QTc interval information away from the torsade episode (and therefore away from the precipitating factor/factors which are usually involved). Of the known 24 QTc intervals, 19 are ‘normal’ (460ms or less when enumerated) while only 3 are over 500ms, the interval where risk is thought to be significant. Hence, according to the case reports quoted by Stringer et al. screening ECG could not possibly detect or prevent cases of torsade de pointes in the great majority of such cases. This is consistent with Justo’s literature review which also found precipitating events in 85-100% of published torsade cases he examined. Krook questions the use of screening ECG as being the ‘wrong priority’.

Stringer and colleagues also discuss in some detail two studies (Fanoe and Chugh), each of which concluded that large numbers of methadone patients may develop torsade. Surprisingly, Fanoe also reported syncope, much of which he ascribed to torsade, in about 10% of his buprenorphine subjects. Both studies used indirect and ‘circumstantial’ methodologies to implicate methadone. Neither presented any actual cases of torsade de pointes. Nor did Wedam’s important RCT, another plank of this paper’s discussion, report any cases of torsade, despite high rates of QT prolongation (he is quoted here incorrectly as ‘Wedman’ on three occasions).

The conclusions of Chugh and Fanoe must now be in serious doubt after publication of Anckersen’s large national mortality series from Norway. This showed that despite prolonged QT intervals being common, their analysis of 90 deaths over seven years found that none was reportedly due to arrhythmia. Unexplained deaths were rare with positive coronial findings available for all but four cases (in 2 of the 4 autopsy was not performed). Even if all four of these were due to torsade de pointes, an unlikely event, the incidence would still be extremely low. Contrary to the claims of Krantz and colleagues (2009), the finding in Norway of so few unexplained deaths in methadone patients (<5%) is also consistent with other reports (Ballesteros 2003; Sorg 2002; Gagajewski 2003; Shah 2005).

From my reading on the subject over the years, I could find no confirmed deaths due to torsade de pointes in a patient being treated with methadone for addiction or pain. When this serious tachycardia does occur, it appears to be in older individuals with more than one risk factor, and, at least in methadone patients, appears to be non-fatal and treatable in most or all reported cases.

Anckersen’s findings from Norway are also consistent with 40 years of research on methadone treatment showing that it reduces mortality substantially when used according to established guidelines (using adequate doses, supervision and psychosocial supports).

Stringer, Welsh and Tommasello seem to ignore the potentially fatal consequences of their recommendations about “alterations in treatment options” based on ECG findings alone. Without any detailed explanation they blandly advise that buprenorphine ‘should be used’ in addiction subjects who develop prolonged QTc on methadone, despite the often impractical nature of such advice. Most such patients will be taking dose levels of methadone at which buprenorphine transfer is not recommended by the manufacturer. And this rather controversial advice is supported by just one single case report!

Good therapeutics dictates that successful treatment should only be change based on sound clinical evidence … and this is not produced in this paper. It is clear that for a substantial proportion of the opioid-using population there is simply no treatment that comes close to methadone maintenance regarding attracting, retaining and benefiting opioid dependent patients. And buprenorphine remains an excellent alternative for appropriate subjects.

*Please note also the up-dated conflict statement published in January 2010 edition:

Correction
Am J Health Syst Pharm 2010 67:94
Methadone-associated Q-T interval prolongation and torsades de pointes (May 1, 2009, Clinical Consultation). On page 825, the author identification section should contain the following statement: Dr. Tommasello is Field Medical Advisor, Reckitt Benckiser Pharmaceutical Company, Parsippany, NJ, which manufactures buprenorphine–naloxone (Suboxone).

I hope this summary is of interest to readers. [NOTE RESPONSE LETTER June 2010] http://byrnehallinanpubs.blogspot.com/2010/06/blog-post.html

Clinic web page: http://www.redfernclinic.com/c/
Concord Seminar blog: http://www.redfernclinic.com/concord/
Opera blog: http://www.redfernclinic.com/opera/critique/blog/

References:

Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395

Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy 2005 25:611-614

Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71

New York City public lecture on HIV medicine and public health.

2010-04-09T01:05:00.010+10:00

Public Lecture at NYC Health Department under auspices of Mayor Bloomberg. 2pm Thursday 18th March 2010

This City Department of Health public lecture started with some rather complex statistical formulae of how to deal with missing data in studies of the natural history of HIV seroconversions. Michelle Shardell PhD had ‘inherited’ a job on a long term project (ALIVE or AIDS Linked to the Intra-Venous Experience) which started, she said, while she was still in school (1988). It enrolled 3000 HIV negative injectors and ordered twice yearly blood testing to determine ‘natural’ rates of seroconversion.

Professor Shardell described the problems of having reams of data but where much was incomplete and how best to draw the correct conclusions by approximating missing data. She discussed the conflicting possible biases of those who miss blood test appointments, some because they may have been well and busy with life … while others may have been unstable and unhappy, using drugs and alcohol, being unemployed and/or engaging in high-risk behaviours and thus missed their blood test.

We were introduced to a complex set of sigma formulae which were supposed to account for missing periods in otherwise long-term data. It was a little disappointing that we were given virtually no outcome data of the study, some details of which I looked up later on an internet search.

On the other hand, Dr Don Des Jarlais quoted HIV prevalence figures for several American cities, Miami, New Orleans and Washington DC were amongst the worst with near 30% of injectors estimated to be HIV positive. In other cities, I understand, including Tucson, Seattle and St Louis, the figure was much lower, some even as low as 1% amongst injectors. In several major centres, the figure was not available.

The message was emphasised that good research from New York had shown that for injectors who began injecting before 1995 the rates of HIV was substantially higher than for those who started afterwards, in just about every category of risk. New York, unlike the rest of the country, had reasonably good access to opioid maintenance treatments as well other harm reduction services such as needle “exchange”, as it is still quaintly termed here. And it largely functions in the US as just that – ‘exchange’ new for old (imagine if we did that for condoms!). We were reminded that the proportion of dependent individuals currently on opioid maintenance treatment (OMT) was calculated to have risen from 6 to 8 percent in America, showing only a modest improvement over ten years. We were reminded also that “secondary needle exchange” (pass-it-on) was vital to the success of the intervention wherein non-addicts (sometimes called ‘alcoholics’) would make small profits by returning used needles and obtaining clean supplies to be sold/distributed at a later time for money.

Dr Des Jarlais is far too experienced to lecture Americans about foreign findings yet he subtly dropped two pearls into the mix towards the end of his presentation in lower Manhattan. He had discussed and described some of the needle services here in American cities and then told the audience that (‘tiny’) New Zealand had over 600 needle exchanges while there were only about 300 in the whole of America. He alluded to the changes in federal funding for such preventive interventions but pointed out that it will take some years for such policy change to filter down to ‘street level’. In a reference to Australia our speaker also pointed out that most of the few drug injectors who contract HIV do so from sexual exposure rather than from needles (while up to 7000 Americans do so annually from contaminated needles if we are to believe the figures).

The correlation between past genital herpes simplex infection and HIV was reiterated, pointing out the behavioural and physical reasons involved. This was clarified further during question time.

While Don Des Jarlais did not quote the HIV rates in New Zealand I had done so privately with the City Health Department official Lucia Torian before she opened the session - which was delayed slightly due to new and inordinate security introduced (all visitors were photographed and ‘branded’!). She had responded to my comment that a number of countries had avoided the HIV plague, saying that I must be referring to Russia, Ukraine and North Korea where there is still denial of the existence of the epidemic in some circles. I said that in fact I was referring to Hong Kong, Australia and New Zealand. Following another off-hand remark she made, I told her that each time I mentioned this to Americans I was either disbelieved or derided, just as she was doing.

Dr Samuel Friedman acted as discussant and in half an hour elaborated some details of the presentations. He commended Dr Shardell on her study but commented that rather than only seeking views of academic experts the team might do better to include the views of knowledgeable drug users. Such folk are readily available and many have a lot to contribute. On that subject, I once asked Professor Vincent P. Dole his opinion about a new secure medicine container. He said that before giving his views he would rather hear the views of a few drug use patients.

Dr Friedman pointed out the large number of major US states and cities which no longer publish official figures on HIV cases. His personal greatest worry in epidemiology was when data was not being collected so that knowledge of the public health issues could be swept under the carpet.

Further, we were told of a study done by Dr Friedman, Des Jarlais and colleagues which showed that the different modes of transmission depending upon the infected pool involved in a given population. Where the prevalence in injectors was >20% already, some behaviours (eg. needle sharing) were directly correlated with seroconversion. Where rates of HIV were <9% risk behaviours were not statistically associated with seroconversion but rather the predictors reflected whom they injected among. We learned that the New York rate was between 9 and 20%. There was also some discussion of arrest rates, socio-economic areas and seroconversions and some research linking them.

I mentioned to Dr Des Jarlais that Hawai’i appears to have the best organised and most widespread needle availability in the US, some of which I saw on a recent visit. Dr Des Jarlais told me he was aware of that since in fact he was the official evaluator for the State’s harm reduction project! That man is everywhere! I recall that he spoke at one of the first Methadone Conferences in Sydney almost 20 years ago, warning us about the threat of HIV and the means to prevent a second wave in drug users. His advice was timely and his campaign to implement better public health strategies continues unabated. More strength to him - and his colleagues! And thanks to the New York City Health Department for sponsoring these public lectures, and allowing strays like me in.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/c/

Opera blog: http://www.redfernclinic.com/opera/critique/blog/

New York in spring: http://ajbtravels.blogspot.com/

Fatal torsade tachycardia due to methadone either rare or non-existent finds Norwegian study.

2010-02-16T01:55:00.007+11:00

Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Addiction 2009 104;6:993-999

Dear Colleagues,

This study is another high quality research paper from Scandinavia, a region which has been informing our field for decades. Because of complete citizen registers and comprehensive national health systems, such population studies can yield very meaningful results. These authors investigated the issue of QT prolongation, torsade de pointes tachycardia (TdP) and possible related cardiac mortality from two different vantage points.

One component of the study examined mortality data relating to all registered opiate maintenance treatment (OMT) patients in a seven year period to 2003 (n=2382 in 6450 years in treatment). These showed 90 deaths during the period (0.20-0.54% crude annual mortality: my own back-of-envelope calculations). Careful examination of death certificates and post mortem reports showed that only in four of the ninety could sudden cardiac death not be excluded. Thus the authors found compelling and credible non-cardiac causes of death in all but four cases. Two of the four were included purely because they did not have an autopsy performed. While there was nothing to suggest that any of these final four were in fact due to arrhythmia, the authors made a conservative calculation of the mortality as a maximum figure in the unlikely event that all were of this origin (0.06 per 100 patient years). Like most such papers, there were no reports of confirmed or suspected cases of TdP in either the death statistics or the sample of maintenance patients from Oslo. Hence the official mortality rate due to torsade de pointes was zero.

Another important finding was that there were only two deaths in the first 4 weeks from nearly 4000 ‘starts’ during the study period. One of the two was a brain haemorrhage and the other unknown causes. This is reassuring both that inductions in that country are apparently well managed and that the fear of early deaths due to TdP in predisposed individuals does not occur at a significant rate, if at all.

As the second component to their study, to re-assess prevalence of QT prolongation 200 OMT patient volunteers had an ECG performed. This group represented about 20% of the total registered OMT patients attending pharmacies and clinics in the Oslo metropolitan area. The authors state that their findings are parallel to previous studies. Buprenorphine patients had no cases of QTc > 500ms cf. 8 out of 173 (4.6%) of the methadone patients with prolonged QTc, each of them taking 120mg daily or more. They recommend ECG in those prescribed more than 120mg.

The authors state that they agree with Schmittner & Krantz (2006) in a paper entitled “QTc prolongation in methadone maintenance: fact and fiction” in which they state: “screening electrocardiography is probably unwarranted and creates a barrier to accessing care.” Anchersen and colleagues continue: “We found no evidence to suggest that the risk of QTc prolongation or TdP is especially elevated during the initial period of methadone treatment. Additionally, mortality attributable to QTc prolongation in OMT as a whole was found to be very low. We do not believe that implementation of routine ECG prior to OMT initiation would have any significant impact on mortality.”

This also casts serious doubts on the two studies of Chugh and Fanoe which both implicated TdP in fatal and non-fatal events respectively using ‘circumstantial’ methodologies. The high rates of TdP predicted by these authors are not consistent either with this Norwegian study nor have other studies provided corroboration of their deductions. Furthermore, Anchersen’s findings of low mortality in early treatment is inconsistent with Wedam’s RCT finding that prolonged QTc in early methadone treatment (>10% in their group) lead to extremely high risk of TdP in such patients. Indeed, such younger opioid dependents in early treatment seem to be almost immune from TdP considering the 100 or more reports in the literature. No cases of tachycardia were reported in any of these three studies - somthing which would also seem to confirm Anchersen’s findings.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/c/

References:

Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71

Schmittner J, Krantz MJ. QTc prolongation in methadone maintenance: fact and fiction. Heroin Addict Relat Clin Probl 2006 6:41-52

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Does methadone cause QT problems or is it often viral?

2009-11-16T20:30:00.002+11:00

HIV and Long QT syndrome - Cause or coincidence? Puri R, Roberts-Thomson KC, Young GD. International Journal of Cardiology 2009 133;1:e9-e10

Dear Colleagues,

This may be the first article to formally describe the link between HIV and torsade de pointes tachycardia and at the same time to question the role of methadone. Their single case report has much in common with others in the literature: the 36 year old female with HIV was taking long term methadone for dependency and presented with recurrent syncope. The dose was only 70mg daily at the time of the torsade but importantly, had been 190mg daily 18 months previously – at which time ECG showed the QTc to be normal - and there were no cardiac symptoms. The authors proposed that their patient did not have methadone induced QT changes, but HIV-induced long QT (LQT) syndrome. The QTc was 540ms around the time of the torsade.

These authors go on to discuss the effects of HIV on the heart. Up to 60% apparently have positive cardiac findings at autopsy and 30% of cases may have asymptomatic prolonged QTc, largely in the absence of ‘culprit’ medications (citing Kocheril 1997). “Minor repolarisation abnormalities in HIV infecteds may therefore become clinically overt in the setting of concomitant predisposing drug therapies.”

The authors state in their introduction: “Methadone use has been associated with prolongation of the QTc and an increased risk of sudden cardiac death.” In fact after 40 years of widespread use there has been no such association with sudden cardiac deaths. Yet this statement well exemplifies the current popular mythology around the subject. Since Krantz and colleagues wrote the original case series (but not the first case) in 2002, there have been no confirmed or strongly suspected deaths due to torsade tachycardia from my reading. The only 2 or 3 deaths were either remote from the period of the torsade and/or else were due to another reported cause such as myocardial infarction. French reports from over 30 years ago quote a mortality from ‘torsade de pointes’ of around 16%. Since this was before modern mobile resuscitation and pacing technologies were widespread, the survival rate of 84% might have increased to something over 95%.

It is now clear that ‘torsade de pointes’ tachycardia rarely if ever occurs in new entrants to methadone treatment. The 103 reports in the literature and Justo’s excellent summary of the field in the Addiction journal inform us that simple clinical features can highlight risk and indicate the need for ECG monitoring where appropriate. Almost 50% of the ~100 reported cases in the literature had HIV infection. The author of the original FDA report, Ellen Pearson, has postulated that QT prolongation and torsade are ‘threshold events’ with numerous contributors based on the known risk factors.

The risk factors (not in order) are:

(1) long term methadone maintenance for addiction
(2) female sex
(3) age over 40
(4) doses over 150mg daily
(5) HIV infection
(6) concomitant use of drugs which either increase methadone levels and/or prolong QT interval
(7) metabolic disturbance
(8) structural heart disease
(9) alcohol

When used with supervision and adequate supports methadone treatment for heroin addiction reduces mortality substantially. It should be used with confidence as the benefits far outweigh even the most pessimistic views of the possible side effects.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/c/
Refs:

Kocheril AG, Bokhari SAJ, Batsford WP, et al. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997 20:2810-6

Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. 2002 137:501-504

Dessertenne PF. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 1966 59:263-72

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Safety. 2005 14;11:747-753

Methadone safe in cancer patients - minor QT problems went away after 4-8 weeks methadone

2009-11-16T20:28:00.007+11:00

The Effect of Oral Methadone on the QTc Interval in Advanced Cancer Patients: A Prospective Pilot Study. Reddy S, Hui D, El Osta B, de la Cruz M, Walker M, Palmer JL, Bruera E. Journal of Palliative Medicine, October 13, 2009 E-pub ahead.

Dear Colleagues,

These authors have done a great service by following serial ECGs prospectively on 100 patients who were being considered for methadone treatment for advanced cancer pain. ECG was ordered at baseline, 2, 4 and 8 weeks. Due to altered medication, hospice transfers, community discharges and one death (non-cardiac) in this palliative patient population the follow up results were available for 64, 41, and 27 patients at 2, 4 and 8 weeks.

Perhaps the most interesting and unexpected findings of this study were that even before starting the medication, over a quarter of patients (28%) had QT prolongation (>430 ms in males; >450 ms in females) and this dropped. The proportion of subjects was *lower* at each of the follow-up periods with only 8-11% of patients having QT prolongation.

At two weeks 11 patients (17%) had QTc>10% above baseline. However, by 4 and 8 weeks this had dropped to one single patient (3%). There was only one ECG in one single patient where QTc increased beyond 500ms (1.6%). This was asymptomatic and not associated with any tachycardia episode. Furthermore, that patient’s prolonged QT resolved spontaneously in subsequent ECG tracings. The authors express their surprise at these unexpected findings which they ascribed partly to the high baseline occurrence of QT prolongation and/or possibly a reduction in other drugs prescribed or improvements in electrolyte disturbances.

The doses of methadone were relatively low compared to the dose levels used for addiction (median at 2 weeks 23mg daily and maximum was 90mg daily).

The authors conclude: “clinically significant QTc prolongation rarely occurred … our preliminary findings are encouraging. … we believe that methadone should be prescribed without reservations … . For patients with significant risk factors … monitoring with ECGs at baseline and at subsequent intervals may be reasonable.”

This should give doctors and patients confidence that methadone is still a safe and effective analgesic and that concerns regarding cardiac side effects may have been exaggerated out of keeping with the literature. When I contacted the study’s author I was told that they had seen no cases of torsade tachycardia in relation to methadone treatment at the MD Anderson Cancer Center to date.

Comments by Andrew Byrne ..

Safe and effective opioid prescribing in addiction treatment. Article written for UK psychiatry journal.

2009-11-01T11:47:00.009+11:00

Safe and effective opioid prescribing in addiction treatment.

Author Dr Andrew Byrne

Abstract:

A large body of research supports the prescribing of maintenance opioids for heroin addiction yet poor quality treatment in the UK has limited the potential benefits. This in turn has caused many to become disillusioned about addiction treatment generally. Inadequate dose levels without the necessary supervision and psychosocial supports have both contributed to this state of affairs in the UK. By failing to address this situation, the National Addiction Centre in London has actually perpetuated it. While some progress has been made in recent years, psychiatry trainees in the UK are ideally placed to help improve the quality of pharmacotherapies in line with other European countries in moving towards an evidence base.

Article:

The principles linking opioid maintenance treatment and behavioural therapies were defined in Dole and Nyswander’s classic paper which is now one of the most quoted in the medical literature [ref 1]. Psychiatrist Marie Nyswander had noted limited success treating heroin addicts in New York using psychoanalytic techniques alone. With Dr Dole, she reported a cohort of ‘hopeless’ New York street addicts responding favourably to a trial of strictly supervised, ‘high-dose’ methadone treatment (mean 100mg/d, range 15-180) with intensive psychosocial supports. They found dramatic reductions in illicit drugs use, excellent retention in treatment along with vocational, social and other demographic improvements. The trial was radical at the time as it placed social functioning as its primary goal, rather than abstinence from all opiates. Patients received daily supervised medication and their drug use was monitored by regular urine tests as part of treatment. Many rigorous studies since have further refined ‘best practice’ and also documented safety data. These were especially important in long-term patients, pregnancy and in those with coexisting mental illness.

Over four succeeding decades, methadone and other maintenance treatments have become just one component of a more complex therapeutic repertoire for addiction including the anti-craving drugs, mood altering medications, detoxification, brief interventions, CBT, formal psychotherapy and other strategies. These are all aimed primarily at reducing the harms from drug addiction while also encouraging engagement in normal social activities. Contrary to popular opinion, the natural history of opiate use, like smoking and alcoholism, in fact moves towards abstinence, with or without treatment [ref 2].

British perspective – historical background of opioid treatment in the UK.

Due to an unwillingness of the dependency establishment to accept methadone as a valid maintenance treatment, a majority of heroin users in treatment in the UK have been subjected to a ‘culture of abstinence’. This is akin to Nancy Reagan’s retort of “just say no to drugs!” Like smokers, drug addicts are generally well aware of the dangers they are taking. Even by 1989 when methadone maintenance was being introduced into many other countries, UK treatment practise was only for short term reduction prescribing. We knew then as now that this leads to relapse in over 90% of cases.

At a time when needle sharing was still common, this caused many otherwise preventable cases of HIV. To this day, many doctors in the UK will only condone short-term, low dose methadone. Others continue to implement a punitive policy of enforced dose reductions when drug use, even non-opiate drug use, is found on urine testing. Some NHS clinics refuse to readmit their own old discharged patients for arbitrary periods, raising further barriers for those most needing assistance.

In the 1980s two forward thinking doctors introduced a more evidence based type of maintenance treatment into Scotland using GP ‘shared care’. Pharmacists were instructed (and paid) to witness the administration of liquid doses and an emphasis on rehabilitation replaced a priority of dose reductions to abstinence [ref 3]. High quality, clinic-based services were also developed in some centres in England (eg. Sheffield, Portsmouth, Manchester). Nevertheless, a large proportion of methadone in the UK was still prescribed ‘on demand’ in general practice using doses which were often inadequate and ineffective, and in settings where there was no dose supervision, little urine testing and no check on compliance. The poor outcomes led predictably to a cycle of negative attitudes towards methadone treatment which persists to the present day [ref 4]. With the unrealistic goal of short term abstinence, it is not surprising that many informed citizens, parents, police and even health workers held little confidence in methadone treatment, despite its glowing record in public health circles when properly implemented.

Uniquely in the UK, methadone and other opioid prescriptions are at least theoretically available to all addicts through the NHS. This would utilise GPs and/or specialist clinics with other health workers giving counselling and psycho-social supports which are known to improve outcomes [ref 5]. Pharmacists or clinic nurses would administer (supervised doses) and dispense (give out medication for later consumption) the medication. Guidelines were finally introduced in 1999 which incorporated what Dole in New York and others around the world had been doing for decades [ref 6]. These advised maintenance treatment and also the use of supervised dosing for new and unstable patients as well as adequate dose schedules. Yet even four years later Strang et al report that most methadone is given without supervision and in doses which are still inadequate for most to curtail injecting behaviour [ref 7].

Some jurisdictions which introduced methadone maintenance propitiously have avoided the HIV epidemic almost completely in their injecting population (Hong Kong, Australia, New Zealand). Unfortunately, for reasons which are still being elucidated, this did not extend to hepatitis C which continues to spread even where new HIV cases had almost ceased.

What is opioid maintenance treatment? What can it do? What can’t it do?

Who needs treatment? When do they need it? The first dose.

Who is best placed to provide such treatments?

So what is needed for the future?

What is opioid maintenance treatment? What can it do? What can’t it do?

Opioid maintenance treatment involves the legal prescribing of a drug of dependence to an addicted patient within a defined therapeutic framework, involving goals, support, supervision and regular review. Short term opioid abstinence is usually considered secondary to other goals such as reduced risk taking behaviour, better general health, work, education and family responsibilities.

Many things change in an addict’s life when starting opioid maintenance treatment. Studies have shown mortality declines from over 2% per years to less than 0.5% [refs 8,9]. Since there is less injecting, viral disease is less likely to be passed on by those who are already infected. As well as less injecting, employment, legal and financial matters have all been shown to improve substantially for those in treatment (Ref 9b). And the longer treatment lasts, the greater these improvements. This is not to say that everyone needs treatment indefinitely and a large proportion do successfully withdraw from maintenance opioids [refs 2, 12].

Only a very small proportion of patients will successfully withdraw from the opioid treatment in the short term and still remain opiate abstinent [ref 9b]. This is probably less than 10% of the total, even though many more express a desire for such an outcome. Hence all opioid dependent patients should have access to continuing prescribed opioids and those who discontinue should be encouraged to seek supports which seem appropriate for the individual.

Who needs treatment? When do they need it? The first dose.

A careful assessment is essential in any patient presenting with drug or alcohol problems. This involves a thorough history, physical examination (pupils, mental state and injecting sites as a minimum) and usually a supervised urine test and blood tests including liver function, hepatitis B/C, HIV status, etc. As for other medical prescribing, the necessary minimum includes both a clear diagnosis and, usually, the failure of non-drug treatments. In practice, the need for opioid maintenance is relatively easy to establish, except in the very young or in those with concurrent medical or psychiatric illness. The diagnostic criteria for opiate dependence involve compulsive self administration, escalating doses, withdrawal effects and usually, documented adverse health and social consequences. It is important to document all of these clearly in the patient record before prescribing any medication. In addition, the patient’s identity and some aspects of their past treatment history needs to be confirmed.

To make our job easier, patients may have ‘self-selected’ by seeking out a doctor or clinic where dependency services are available. Some may not want methadone but seek other medications to assist with detoxification. Such patients should be informed of the benefits of maintenance therapies in case their detox episode is unsuccessful. All patients should be informed about self help groups including AA, NA and the new SMART Recovery movement [ref 10].

Most patients will have a substantial history of heroin or other opioid use, often by injection and with documented complications, end-organ damage, legal, financial and social consequences. Venous scarring is the most obvious sign of long term history. The drug use may take the form of injected heroin, black market methadone, codeine, morphine, opium or even poppy seeds in rare cases. As long as the use is consistent and compulsive with tolerance and withdrawal symptoms/signs the criteria of dependency are fulfilled. It is helpful to use the DSM-IV definition although it must be remembered that this was devised for use by private American psychiatrists and there may be occasional deviations in ‘normal’ countries.

In patients who are very young (under 18 years) or who have unstable mental illness, it is important to ascertain that opiate opioid maintenance therapy is indeed the most suitable option at the time. Some such patients may develop a mistaken notion that they need prescribed opiates opioids. They may also give a credible history of dependence. This always needs to be carefully corroborated with physical examination and urine testing. This is especially so if there are no venipunctures, no history of hepatitis C, overdose, financial, legal or other consequences of opiate dependence. In such sensitive cases it is prudent to seek a written opinion from a colleague to ensure that other forms of treatment may not be more appropriate. This may be the patient’s own GP or consultant who has been involved. In some jurisdictions parental permission may be required at this age. Health authorities or family services may also have to be involved in under-age cases, with details varying between jurisdictions.

As with other major treatment decisions, the patient should fully informed about its nature. This essential information should be given verbally, allowing for questions, as well as in writing. Various documents are available on the internet for patient education. Some documentation of consent should also be obtained in the patient records. Patients need to know that both methadone and buprenorphine have benefits and also certain side effects such as headache, constipation and sweating. The issue of cardiac conduction defects has never been shown to be a problem in patients being treated under dependency guidelines. However, for those taking higher doses (>150mg daily) or with other risk factors a cardiograph is a prudent step [ref 11].

Although many patients do attain opiate abstinence, methadone and buprenorphine treatments are not ‘cures’ for addiction. Patients should be aware that this is a treatment which requires regular attendance for medication, medical reviews, counselling and urine testing. They should also be informed that this treatment often lasts for months and sometimes for years. The myth of methadone being “for life” has been disproved by longitudinal studies with acronyms NTORS, ATOS, etc [ref 12]. Gossop points out that because clinics see successful patients less often than others, staff may develop the incorrect impression that few ever successfully withdraw from treatment.

Patients often arrive in distress and dismay, wanting to get into treatment urgently. It is still essential to ascertain who needs opioids and who may be more appropriate for detoxification services. Just because a patient says that they are in withdrawals does not mean that a doctor must write a prescription for opioids, although this should always be seriously considered as an option. Prescribing always has more predictable outcomes than detoxification. The doctor takes responsibility for the former and the patient the latter. Vincent Dole, the co-inventor of methadone treatment, said that “detoxification is an experiment in the life of the patient”
Who is best to provide such treatments? How is it done?

The delivery of methadone can occur in either the specialised clinic setting or in existing community facilities. There are advantages and disadvantages to both types, but ideally, new and unstable addiction cases would be treated in a specialised clinic. This allows close supervision for a period, after which stable and longer term patients could be referred back to GPs and pharmacists for community treatment. In practice there are usually more patients than services available so any treatment opportunity will have immediate applicants, most of whom are assessed as appropriate for maintenance treatment.

As with other acute presentations, one cannot do everything in the first consultation. However the basics need to be organized and a decision taken promptly as to whether or not the patient is to be prescribed opioids in a treatment ‘program’. At that point, one can afford to put off certain other matters until the patient feels better and has more confidence and familiarity with the staff and treatment setting. Another essential detail at this point is whether the patient has adequate housing considering they may be dispensed bottles of strong medicine. Also one needs to find out if there are children in the house and stress the importance of safe drug storage out of their reach.

The first dose.

The patient should usually be given a starting dose of 30mg with small increases in subsequent days up to the usual effective dose of 60 – 120mg. If given too quickly, drug accumulation can cause fatal toxicity so vigilance is needed in the first two weeks when this can occur. An additional 5 to 10mg every 2 to 3 days is usually a safe increase. On the other hand, if doses are kept too low, some patients will drop out while others may continue to use street drugs and/or alcohol. In some clinical settings it may be possible to give supplementary doses later the same day but only if the prescribing doctor has examined the patient 2 to 4 hours after the first dose. Where supplements are given, the second day’s dose should normally be the sum of the first day’s doses as long as there is no sign of toxicity.

Inductions onto buprenorphine are not as critical since early overdose is not a problem owing to the “ceiling effect” for respiratory depression. Most start with 4 to 8mg as a supervised sublingual dose, increasing only after 3 to 4 days when steady-state levels are achieved in this very long acting drug. Supplements may also be given, but these should be considered ‘loading doses’ and may only be needed in the first few days. The usual effective dose is 6 to 16mg daily with only a small proportion requiring more or less than this level. 32mg is the maximum daily dose.

Patients often know from previous experience how much they need and which drug suits them best. About a third of heroin addicts treated with buprenorphine will continue to feel drug cravings even when doses have been raised to the maximum of 32mg daily [ref 13]. Such patients usually do well on methadone using standard doses. For this and other reasons, methadone is probably still the best first line drug. A smaller proportion of methadone patients report unacceptable side effects such as sedation, sexual dysfunction, constipation or sweating and a transfer to buprenorphine can be very rewarding. However this can only be done ideally when the methadone dose has been reduced below 40mg daily due to the potential for a precipitated withdrawal episode as the partial opioid agonist buprenorphine replaces the full agonist methadone. This can be very unpleasant although it is usually short lived, in most cases less than one hour.

The first month of treatment is crucial to long term success. Hence it is essential to engage with the patient and establish a confident and professional relationship. This will involve all health care workers from reception staff to nursing, medical and pharmacists.

As with other conditions, management involves educating our patients, prescribing medications judiciously and supervising and monitoring progress. As with diabetes, depression or blood pressure, there is wide variation in views about how frequently patients may need to see a doctor, counsellor, pathology service or pharmacist. But the general principle is that new and unstable patients need more frequent and intensive involvement than long-term stable patients. Where there are psychologists, counsellors and other staff medical visits may be less frequent after the first month of treatment. There should be a formal interview each week until the patient shows signs of stability, then 2 to 4 weekly consultations should suffice for a year. Even very long term patients should probably see their prescriber every two months at a minimum.

Urine testing.

All patients who have come to the attention of dependency services should probably have urine testing at some frequency. This is essential at the initial assessment and twice yearly urine toxicology is probably a minimum for any person prescribed take-home doses of opioids, probably including pain management cases. Tests should be ‘supervised’ to some degree. The most useful tests for research or legal purposes will be directly witnessed and done at random. This is not always practical, nor is it necessary in most cases in clinical practice, unless the patient needs to prove their status for legal, family, sporting or sensitive employment matters. It is usually sufficient to ask for a urine test on a particular consultation day and have the staff test the temperature of the specimen. This may be done manually or using adherent temperature sensitive strips.

The interpretation of urine testing involves distinguishing non-specific ‘opiate’ positive tests from ‘morphine’ which is the breakdown product of heroin. One must take into account the half-lives of the cannabinoids, benzodiazepines, cocaine, amphetamine, etcetera. There should be no punitive outcomes from urine tests and these should only be used as a clinical indicator.

Dose supervision.

For new and unstable patients, as with other areas of medical practice, outcomes are directly related to compliance. The treatment of malaria, TB and HIV have each been shown to improve with directly observed treatment [refs 14,15]. Likewise with opioid therapies, witnessed doses improve outcomes and reduce the scope for diversion. In practice, most patients can be successfully treated by attending one to three times weekly depending on time in treatment, stability and dose level. The uniquely British practice of attendance at the pharmacy every one of two days to take bottles of medicine home is not based on any research and should be abandoned.

Cardinal rules for methadone:

The effective dose is generally 60-120mg daily with a small proportion needing more or less that this range due to unusual metabolism or tolerance. No more than 30mg should be given as a starting dose with increases of 5-10mg every 2-3 days, more rapidly only where close medical supervision is possible. Methadone should be avoided with fluvoxamine (inhibits metabolism), phenytoin or carbamazepine (induce metabolism) or pentazocine (may precipitate withdrawal, like buprenorphine). Special precautions are also necessary with various anti-HIV and TB drugs which may increase or decrease blood levels of methadone. Even grapefruit juice, with its effect on the cytochrome P450 enzymes can reduce methadone metabolism and raise levels. The principle is to carefully monitor any patient who is prescribed other drugs and be prepared to raise or lower the dose as appropriate – an examination 3-4 hours post-dose for signs of intoxication, and 24 hours afterwards for signs of withdrawal is generally more useful than measuring methadone blood levels [ref 16]. Patients should be warned not to drive, operate machinery or look after children until they are stable.

So what is needed for the future?

Treating addictions can be enormously rewarding and one does not have to wait for years to see the fruits of interventions. Many of these patients are ‘survivors’ who have enormous energy and resources which they often use to turn their lives around while in treatment. A ‘lapse’ back to drug use does not imply failure, but may mean that more attention needs to be paid to treatment. In cases of ‘relapse’, a second attempt at treatment is more likely to be successful than the first, especially if depression and anxiety are correctly dealt with.

All psychiatrists should be comfortable with treating dependency problems. There are some parallels between the management of nicotine, alcohol, opiate and stimulant addictions. Each has a behavioural and a chemical component. We should be aware of the differences and the similarities, each requiring appropriate interventions when required. Addictions are still inadequately covered in most undergraduate and family medicine training. Indeed, there was a time when some considered substance dependency not to be an area for doctors, nurses and pharmacists at all!

It is essential that consultant psychiatrists know how to set up and run a dependency unit within a community hospital setting. These will have the ability to take referrals with a view to assessments and a range of treatments, both medicated and non-medicated, based on rational, practical and cost-effective principles. As with general psychiatry, the great majority of such cases can be handled as out-patients but a small sub-set will need hospital admission. As with alcoholism, needs may vary from just brief respite care to acute care and intensive treatment. All the same principles of good medical practice should apply just as in every other medical specialty. While in treatment special attention needs to be paid to other areas of risk such as hepatitis C and other communicable diseases [ref 17].

Opioid maintenance treatment should be considered for all those who are addicted to either street heroin or pharmaceutical opioids and who are unable or unwilling to cease using such drugs. The same could be said for nicotine or, indeed, many medical situations where prescribing is only appropriate when non-drug approaches have failed or are inappropriate (eg. diabetes, hypertension, hyperlipidaemia).

For reasons which would be unacceptable in other fields, deficiencies in dependency treatments in the UK have undoubtedly contributed to the epidemics of HIV, hepatitis C, overdose and other consequences of addiction. It may take many years to turn these deficiencies around. Conceding them would be a great starting point. Methadone treatment has long been treated with great suspicion by the addiction ‘establishment’ in the UK. Indeed, Professor John Strang of the Maudsley Hospital has revealed his own misgivings about methadone by claiming that, despite its known benefits, it may have a ‘bitter final pathological twist’ (ref 18). Such personal reservations stand in stark contrast to 40 years of positive research findings, much published in the high rating journal, Addiction, of which he is an assistant editor.

References:
1. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. JAMA 1965 193:646-50
2. Thorley A. Longitudinal Studies of Drug Dependence. In: Drug Problems in Britain: A review of ten years. Eds: Edwards G, Busch C. 1981, Academic Press. p162
3. Greenwood J. Six years' experience of sharing the care of Edinburgh's drug users. Psychiatric Bulletin 1996 20:8-11
4. Stevenson RJ. Drug misusers are likely to abuse the system. BMJ 2007 335:317
5. McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The Effects of Psychosocial Services in Substance Abuse Treatment. JAMA 1993 269:1953-1959.
6. Drug Misuse and Dependence - Guidelines on Clinical Management. 1999 HMSO Department of Health. Working Group Chair: Strang J.
7. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. Brit J General Practice 2005 55;515:444-451
8. Caplehorn JRM, Dalton MSYN, Cluff MC, Petrenas A. Retention in methadone maintenance and heroin addicts' risk of death. Addiction 1994 89:203-7
9. Grönbladh L, Öhlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand 1990 82:223-227
9b Gossop M, Marsden J, Stewart D, Treacy S. Outcomes after methadone maintenance and methadone reduction treatments: two-year follow-up results from the National Treatment Outcome Research Study. Drug and Alcohol Dep 2001 62;3:255-264
10. Self management and Recovery Training. http://www.smartrecovery.co.uk/ (accessed on 13/2/08).
11. Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366
12. Gossop M. The clinical fallacy and treatment outcomes. Addiction 2007 103:89
13. Kakko J, Grönbladh L, Svanborg KD, von Wachenfeldt J, Rück C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803
14. Babudieri S, Aceti A, D'Offizi GP, Carbonara S, Starnini G. Directly Observed Therapy to Treat HIV Infection in Prisoners. JAMA 2000 284;2:179-180
15. Garner P, Volmink J. Directly observed treatment for tuberculosis. BMJ 2003 327:823-824
16. Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug Alc Dep 2006 81:129-136
17. Hallinan R, Byrne A, Dore G. Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated HCV-specific harm reduction. Drug Alc Rev 2007 26:437-443
18. Strang J. Looking beyond death: paying attention to other important consequences of heroin overdose. Addiction 2002 97:927-928

Declaration of interest:
Dr Byrne’s addiction clinic charges a fee for dispensing methadone and buprenorphine.

Torsade rarity: Annals responses argue ECG ineffective and unnecessary before MMT.

2009-09-08T20:40:00.004+10:00

Krantz et al, Annals of Internal Medicine March 17: letters in reply, Aug 4 2009.

http://www.annals.org/cgi/content/full/151/3/216
http://www.annals.org/cgi/reprint/151/3/216

Dear Readers,

Each of four responses to this item was strongly critical of the position or Krantz et al. regarding cardiac safety in methadone patients. Apart from my own small contribution, there were considered responses from physicians and alumni of Johns Hopkins, Harvard and Rockefeller University as well as the medical director of a network of private addiction clinics treating 5000 methadone patients in California. There was no letter in support of Krantz et al and their “guidelines”.

Despite my written requests to Drs Krantz, Stimmel, Haigney and Martin, there is still no indication from these authors on the proposed means whereby regular ECG tracings would or could prevent torsade tachycardia from occurring in MMT patients. It would seem incumbent on Dr Krantz and colleagues to explain just how they anticipate the published recommendations might reduce cardiac side effects, and further, what might be the downside of the recommendation in terms of barriers to methadone treatment for those who want and need it both in developed and developing countries.

Krantz has written that cardiac safety in methadone treatment is a ‘national priority’ and that torsade is ‘potentially fatal’. Yet in 40 years there has still not been one confirmed death due to this complication in a methadone patient I can find in the literature. Out of ~100 case reports the great majority had complex medical scenarios including HIV, existing heart disease, metabolic disturbance and/or taking exceedingly high doses (mean 400mg daily in Krantz’s original report). These would only represent a small minority of those being assessed in addiction clinics around the world.

It is difficult to accept these guidelines in their present form when the main authors simply deflect criticism from senior colleagues rather than responding to it - see their response to the four letters.

Two original panel members declined to be associated with the publication and its recommendations. Their names were on the original internet version published around 1 Dec 2008 and now withdrawn. To my knowledge their dissenting views have not been published although the Annals editors took the rather unusual step of writing their own rapid response pointing out some of the facts following my initial communications: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1 (‘Putting the cart before the horse’). They also published a balanced and well considered editorial in the same hard-copy edition by Gourevitch.

I am still persuaded by the advice given by Dr Mori Krantz consistently from 2002 up until his Annals article this year that ECG is unnecessary before starting methadone treatment unless there is a specific indication (*see his quotes below). This is parallel with the views of other respected authors such as Krook, Athanasos, Gourevitch, Kreek, Bart and others.

We need a high level of awareness for numerous diseases and complications in older addiction patients. Cardiac conduction disturbance is just one of many such areas that we need to deal with. Although cardiac problems are dwarfed in scope by many other problems such as blood borne infections and hormonal imbalance, they should not be overlooked in known high risk groups.

In our own practice we generally order an electrocardiogram when the methadone dose exceeds 150mg daily and/or when there are other risk factors such as HIV, older age or other drug prescription known to affect methadone metabolism or cardiac conduction.

Comments by Andrew Byrne .. http://www.redfernclinic.com/c/

REFERENCES:
Original article: http://www.annals.org/cgi/content/full/0000605-200903170-00103v1

Krantz on cardiac health in MMT patients (2001): http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml#anchor1222388

Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1

Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5

Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients - a cross-sectional study. Addiction 2007 102;2:289-300

Gourevitch MN. First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;417-8

*Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368;9535:556-557 (quotes herewith from page 557)
“… we do not believe that routine ECG screening is warranted for heroin addicts entering treatment.”
“… we believe that the decision for ECG screening should not only be informed by the patient’s arrhythmia risk factors but also by the dose of methadone received.”

Possibly the last word: Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4. http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml#anchor1222388

Cardiac complications in long-term methadone patients seem to be due to diverse factors.

2009-06-30T00:38:00.008+10:00

Methadone induced long QTc and "torsade de pointe". Bittar P, Piguet V, Kondo-Oestreicher J et al. Swiss Medical Forum 2002 S4;P244:36S

Dear Colleagues,

This instructive case history which pre-dates Krantz’s report by several months, describes a long term methadone patient aged 39 developing ‘torsade de pointes’ a few days after starting triple therapy for HIV in the context of opioid withdrawal symptoms/signs and low blood levels. The patient also had chronic hepatitis C and epilepsy. As well as valproic acid for the latter, benzodiazepines, cannabis and alcohol were also involved in this seminal case.

The patient presented to the emergency room in opioid withdrawal. There was no electrolyte disturbance but methadone level was found to be ‘sub-therapeutic’ despite daily doses of 115mg administered by suppository (this is routinely used by some doctors in Switzerland). The QTc interval was available from a month before the episode at 480ms (normal less than 450mg).That cardiograph may have been ordered as part of a ‘work-up’ prior to starting anti-retroviral therapy but this is not detailed in the text.

While in hospital, 15 minutes following the daily rectal methadone dose the patient developed bradycardia, bigeminy and then torsade tachycardia. He was successfully resuscitated despite major seizures occurring simultaneously. The methadone was replaced by morphine 200mg twice daily which was associated with QTc interval reduction from 480 to 430ms.

Subsequent challenge a few days later with just 40mg methadone saw the QTc interval increase to 520ms and so the trial was abandoned due to the perceived risk. A cardiograph two weeks later showed the QTc interval to be still slightly elevated at 460ms despite the methadone having been long ceased. These observations are consistent with other evidence that methadone causes some modest prolongation of the QT interval and that this effect alone is generally of little clinical significance.

This patient took methadone, valproic acid, alcohol, cocaine and cannabis for at least 7 years without reported cardiac problems and so the onset of torsade during a period when the methadone level was low is hard to ascribe as a direct and dose-related effect. Rather, a combination of factors including possibly some myocardial ‘priming’ may be occurring.

This appears to be the very first of over 100 case reports in the literature of torsade de pointes in patients taking methadone maintenance for addiction. In nearly every case where details are available there were other drugs, extremely high dose, overdose, HIV and/or electrolyte disturbance reported. Pearson has called this a ‘threshold’ effect. Since methadone levels are sometimes in the low range it is possible that the drug is sometimes a ‘bystander’ while other drugs and/or the HIV virus itself might be responsible for the electrical instability in the heart.

Like others, these authors give some details of the management given to the patient. Even 7 years later, there still appears to be little agreement about an approach to treatment as cardiologists, intensivists and emergency physicians describe quite diverse approaches. These have included (1) efforts to maintain heart rate, (2) restoring electrolyte balance, (3) removal of triggering factors and (4) supportive measures. Magnesium and potassium infusions, administration of isoprenaline, atenalol, quinidine, lignocaine, amiodarone (!), glucoheptonate; implantable cardioverter-defibrillator (ICD); reducing methadone; continuing methadone; changing to morphine or buprenorphine. A review of such clinical manoeuvres by a cardiologist would be highly desirable in my view.

Instead of this logical step, Krantz and his panel have advised ‘discussions of risk’ (which are still largely unknown), pre-treatment ECG and continued QT interval monitoring. This is in the context of a lack of evidence for the effectiveness of such a strategy to prevent arrhythmias. Krantz’s group, in their extensive literature review of almost 100 papers left out numerous seemingly relevant articles (eg. Justo, Athanasos, Krook and Cruciani). It is hard to understand how the CSAT panel of experts could have completely overlooked these crucial papers, each of which is available on a simple internet search.

Further, despite the clear association with HIV infection (40% according to Justo), HIV is not even mentioned in the entire Annals paper from March 2009. The drugs gabapentin and ciprofloxacin come up in numerous reports, including 5 of Krantz’s original series of 9 pain management cases. Likewise, the issue of targeting strategies to those taking such medication is not emphasised by the CSAT panel report.

This early report from Switzerland contains some vital but conflicting evidence concerning causation. Like others, these authors find evidence of multifactorial causes for their patient’s torsade tachycardia. Yet there seems to be QT prolongation in relation to methadone dose levels, despite torsade occurring only very rarely in such cases. The cautious trial to reintroduce methadone caused QT prolongation but no arrhythmia. At the same time, it is questionable that a purported side effect of methadone would occur when the blood level was low and the patient was in a drug-induced withdrawal state.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/c/

References:

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1

Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5

Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552

Drug decriminalisation in Portugal successful after 8 years.

2009-05-22T11:12:00.002+10:00

Greenwald G. Drug Decriminalization in Portugal: Lessons for Creating Fair and Successful Drug Policies. Cato Institute. 2009

Dear Colleagues,

It has taken a long time, but finally we have convincing evidence, even proof, that decriminalising drugs helps drug users and society in practice. Like alcohol before it, the banning of drugs with criminal sanctions against users is a counter-productive and dangerous ‘experiment’ which should be abandoned in favour of more logical and effective ways to control drugs in society.

As a response to burgeoning drug use, the Portuguese government decriminalised all personal drug use, possession and cultivation from July 2001. The history of this goes back to at least 1996 and involved support from two successive Prime Ministers, a popular Portuguese media personality and some key legal figures at Lisbon University. There were also apparently New York and Californian connections in the lead-up to decriminalisation.

The approach taken by the Lisbon government removes legal sanctions for any adult detected with up to ‘ten days average use’ for any drug, psychoactive plant or ‘preparation’. Rather than a court, drug users who come to attention can still be dealt with by a ‘drug dissuasion commission’ (an imperfect translation I suspect). Set up in each health region, these are boards of three members including a health professional. They take into account whether the person is addicted or not and how much drug/drugs were involved. They can theoretically mandate treatment but in fact they have no power to enforce their advice, rather like medical advice for voluntary mental health cases.

Despite my best efforts to be informed, little solid evidence had emerged in the years following the removal of criminal sanctions for drug use and observers have speculated on the outcomes. Now Dr Greenwald and the Cato Institute have put together a comprehensive review which demonstrates from every aspect they examined, the exercise was beneficial. Dire predictions of mayhem from some quarters simply failed to occur. It appears that even in staunchly Catholic Portugal there is strong support for the policy and only a fringe group of activists opposes the current law.

Rather than a surge in drug use predicted by some, there were significant reductions in most types of drug use in Portugal each year following decriminalisation. While the UK topped most of the statistics for the periods covered by the report, by 2006 Portugal had some of the lowest drug use, HIV, overdose and other statistics in the entire EU. They reported no ‘drug tourism’ which some had predicted.

Holland and the state of South Australia both decriminalised cannabis use about 30 years ago and the results have been reportedly positive with few serious moves to reverse the decision. Two neighbouring jurisdictions, Belgium and Northern Territory have apparently done the same thing some years later.

Substantial resources have been redeployed from policing to treatment. I know from experience of patients who have visited that Portugal has an efficient system of well run opiate addiction clinics, for example, something which cannot be said of the UK a country which recently reclassified cannabis as being the equivalent of a dangerous narcotic and has some of the worst statistics in Europe regarding drug use and related viral infections.

Governments of all persuasions need to reduce the reliance on prohibitions or else drug related harms will continue to increase. Society generally is now sceptical of the effects of policing and is ready for change, either incrementally as done in Adelaide, but preferably ‘across the board’ as in Portugal. This very policy was proposed for Mexico but was cancelled at the last minute, probably after lobbying from an influential northern neighbour.

I would strongly recommend readers look over this 34 page report.

Comments by Andrew Byrne ..

http://cato.org/pub_display.php?pub_id=10080

http://www.cato.org/pubs/wtpapers/greenwald_whitepaper.pdf

New York addiction conference April 2009

2009-05-20T08:22:00.002+10:00

AATOD meeting, Hilton Hotel, New York City. 26-28 April 2009
American Association for the Treatment of Opioid Dependence.
Brief and selected commentary on this talk-fest, especially cardiac matters.

Dear Colleagues,

I was privileged to attend this conference which is the successor to the long-standing National Methadone Conferences which started in the 1970s. It is essentially the meeting for the American ‘methadone clinic’ sector held every 18 months but it now draws in patient advocates, scientific community, policy makers and even an international connection with ‘EUROPAD’ and occasional delegates from the wide world (I noted several other Australians attending). I had been asked to speak at the session on cardiac consequences of methadone - see below.

After pre-conference sessions on the weekend, the official opening was an address by Karen Carpenter-Palumbo, the Commissioner for the Office of Alcoholism and Substance Abuse Services of New York State. She spoke ‘loud, brash and somewhat arrogant’, as she put it, to emphasise the scope of the problem in her state but also the contribution New York has made to policy, research and funding of drug issues over the years. She answers directly to Governor Patterson who, we were told, had just signed away some of the worst elements of the Rockefeller laws … or ‘dropped the Rock’ as she put it. Further, the Governor had stated publicly that drug users should be ‘treated and not incarcerated’ in New York State. She used many catch-phrases, sounding rather like a campaigning politician, receiving a standing ovation at the end based on her stirring the crowd. “Ladies and gentlemen, methadone IS recovery!!” She spoke so close to her microphone that it was almost painful to the ears.

The Commissioner reminded us that 44% of those entering opiate maintenance treatment now were using prescription drugs and that 33% of entrants had self-injected. To emphasise the shortage of treatment availability, we were told that 15% of Americans in methadone treatment crossed state lines to do so. There are car pools of people travelling long distances, sometimes daily, to access treatment. Some even crossed two state lines to receive medication (and probably a few taking treatment in Canada). A Detroit addiction doctor told me that many of his addicted patients had outstanding legal matters and risked immediate arrest at the border. Hence despite good treatments in Canada, this was not an option for many addicted individuals in America, even those few who might reside close to the border.

There were too many break-out sessions for me to document here but all presentations were put onto a CD which was given to every delegate. I tried to keep abreast of several of the sessions but recommend looking at the program for your own area of interest. Conference abstracts and power point presentations were contained on a CD ROM given to every delegate on registration.

Maternal and neonatal outcomes were discussed in detail by Jack McCarthy, Hendree Jones and Karol Kaltenbach in a well-attended break-out session on the Monday morning. It was pointed out repeatedly that heroin, cocaine and alcohol are all very dangerous for both mother and unborn baby. Methadone treatment can reverse many of the worst consequences of such drug use. Detoxification is still requested by some women and a number of studies were quoted, each showing high rates of relapse (40 - 96%). It was agreed by most that reductions in methadone doses could be affected safely in the middle trimester of pregnancy but that this should be gradual and ONLY if the woman was not using other drugs and/or alcohol at the time. We were reminded that there was a stronger motivation to cease tobacco, alcohol and drugs as in this important period during which so much can be accomplished with adequate support rather than coercion. Of course on the other hand, great damage can also occur when a pregnant woman with drug/alcohol problems has no access to treatment which is still the case in much of America where there are still some areas which might be mistaken for a third world country, so scarce and/or expensive are these services.

Prison systems in Philadelphia have had an experimental pharmacotherapy intervention involving over 500 inmates over a number of years and results are positive, according to John Carroll and Roland Lamb. Similarly, reports from Rhode Island at a previous AATOD meeting had also been positive. However, such reports need to be contrasted with the country’s oldest custodial methadone delivery system at Riker’s Island in New York City which has recently been threatened with de-funding of the ‘KEEP’ program by New York State. Methadone has been available for pre-existing patients prior to sentencing but not in up-state regular jails where most sentences are served. As might be expected, the experience of methadone treatment in the custodial system report positive results. The main benefit to the community we were told were the dramatically lower recidivism rates in those receiving treatment when compared to addicted folk in jail who did not receive treatment (see power point presentations for exact figures). The lack of treatment in jails is yet another American tragedy where careful research has been ignored to the detriment of the entire society.

Many of these prisoners were victims of unfair and discriminatory laws and should not have been in jail at all. The severity of sentences was discussed at another forum later that week on the Upper West Side. The Voluntary Committee of Lawyers (VCL) honoured Federal District Judge Robert W Sweet for his stance in refusing to hear drug cases in his New York District court 20 years ago. In his acceptance speech he said that he had found that 80% of the work in his jurisdiction was related to minor or personal drug use/possession which he found completely unproductive. We were reminded of the cruel sentences still handed out in some states. In Alabama, for example, it was mandatory for the third cannabis offence to receive a virtual life sentence. Fortunately many states are now coming to terms with the enormous cost of all of this futile ‘war on drugs’ due to the economic crisis forcing every aspect of state expenditure to be reviewed. There are now many instances of early release of low-security prisoners to save money. Some optimistic commentators at the AATOD conference were now saying that “the stars are lining up” for change to the punitive American approach to drug/alcohol use.

A lunch meeting was held for about 200 clinic managers, researchers and policy makers on the Monday. This was addressed by ex-marine and now Washington DC Senior Public Health Advisor - Substance Abuse, Office of Public Health, Gregory Goldstein MPH. He spoke about the competing areas and priorities for his office in Washington, starting with a briefing on the latest issue, the influenza H1N1 outbreak.

In questions from the audience Dr Mary Jeanne Kreek made a brief tribute and commentary in response to the address reminding us of her 44½ years in the field and her work on opiate receptors. She stated that we now had two ‘marvellous’ drugs for opiate addiction but that current work may well turn up other medications for amphetamine, cocaine and other addictions. She sounded more hopeful than others in the room. One wonders whether stimulant users would care to take a pill which made their stimulants inactive. Equally would those who enjoy coffee, tobacco or alcohol take an experimental vaccine to negate the effects of their drug of choice?

The final question/comment was from the conference chair Ira Marion which was to ask if President Obama might be persuaded to make a visit to a ‘methadone clinic’ [sic] to show his administration supports such services. This was taken on notice by Mr Goldstein. In response, AATOD president Mark Parrino mentioned an anecdote about such a request under a previous administration in which the person making the request was simply told that they would only ask such a question if they did not value their present job!

I was one of four speakers in a workshop and panel discussion on cardiological status of methadone patients. Dr Mori Krantz gave his case for methadone being the causative agent for QT interval prolongation and torsade tachycardia which is potentially fatal. He has stated that methadone safety is a ‘national priority’. One by one he re-quoted the numerous studies which he believes conclude that, despite no actual cases, methadone may be a cause of torsade tachycardia. Chugh, Fanoe, Martell, Peles, Lipsky and Wedam were all studies without, as far as I can gather, any documented cases of torsade de pointes tachycardia. Krantz makes it clear that the Wedam randomised trial takes away doubts about subject selection and thus increases the significance of the findings. Yet this reports relatively high rates of substantial QT prolongation in a group of relatively young, otherwise healthy ‘street heroin addicts’ (some with chronic or mental illnesses were excluded). Yet this is the very group which appears to be almost immune from ‘torsade de pointes’ judging by their absence from the detailed reported cases. Krantz was careful to point out that without actual cases of torsade de pointes, some of these studies had limitations regarding causation.

I pointed out that with so few documented torsade cases in so many cited studies, one interpretation might be that in methadone treated patients, QT prolongation does not seem to induce torsade at all (cardiologists often cite amiodarone as being in this same category). It is surprising that Dr Krantz did not cite the only literature review of torsade in addiction cases. Justo, in the Addiction journal, reported several risk factors affecting virtually all 40 documented cases he identified in the literature up to 2006. These included high dose, co-medication, HIV, electrolyte disturbance, cirrhosis and structural heart disease.

Dr Krantz and Dr Barry Stimmel described the processes of their expert panel and its decision to publish recommendations, including cardiograph tracings before treatment, at three months and annually thereafter … with additional ECGs in those taking 100mg or more daily or with positive medical histories. Neither speaker explained why their advice was contrary to that given by Krantz consistently since 2002 that routine ECG was not necessary in MMT patients. The first three speakers, Stimmel, Martin and Krantz, were all co-authors on the Annals article proposing mandatory ECGs.

Dr Krantz contends that torsade will prove to be a major contributor to the death toll of those taking methadone, despite only one report in the literature in over 40 years. He stated that deaths were increasing significantly in both addiction treatment programs and the pain management field. This is not consistent with the reference he has quoted (Ballesteros) which shows 96% of such deaths in one state were treated for pain rather than addiction. Despite Krantz’s contention, I have read no evidence suggesting increased sudden deaths in the clinic treated population.

San Francisco doctor Judy Martin said that she has been performing ECGs in all her patients for over a year. Despite this precaution, she still reported two of her patients developed torsade in the twelve month period, both apparently complex medical cases. It was hard to understand her continued staunch support for routine cardiographs for all new and continuing patients on methadone (I had a long talk with her afterwards). She stated that in her own clinic it was simple and cheap to get these tests organised. It is fortunate that her employers in California are so accommodating. In many American clinics it is still difficult to obtain even simple hepatitis C, HIV and other testing.

In the formal Q&A afterwards some simpler alternatives were raised such as ‘two finger’ tracings and automated versus manual calculations. One audience member pointed out the difficulties obtaining an accurate QTc measurement and asked whether the timing of cardiographs mattered in relation to methadone dose, meals, diurnal variation, lead placement, posture and other factors. It would seem that Dr Stimmel’s contention of “why not just do a cardiograph to define the risk?” could create a mine field for the unwary (and we now know that a cardiograph does not ‘define’ the risk of torsade to any useful degree. See Viskin et al 2005 below. Dr Martin’s final slide summarised her own clinic’s experience although did not bode well: “Doing the ECG is the least of it: evaluating and addressing contributing factors took the most time.”

In my own presentation I was at pains to point out that there were now over 70 cases of torsade in the literature and we can learn from them who is at risk (and perhaps even what to do to prevent such cases). There is no evidence that wholesale ECG tracings will prevent this complication since QTc is often normal before and after the precipitating event(s). There are many similarities in the reported cases, including very high doses (Krantz reported a mean dose of 400mg daily; Pearson 410mg), concomitant drug/alcohol use, older age groups (Krantz’s series had mean age of 49; Pearson 46) and co-existing viral infections (Justo found 16 of 40 (40%) cases were HIV positive). I could not find any cases reported from standard methadone treatment programs and there was only one single death, despite Dr Krantz’s slide stating that 8% died in Pearson’s series of 43 cases of torsade related to MMT. By my reading it was 1 of 43 (2%), not 5 of 59 (8%). Many of the latter had QT prolongation but no torsade and thus cannot be deemed ‘torsade’ deaths as Krantz has apparently done here.

I pointed out that in different ways, each of the case reports lent support to the contention, first proposed by Ellen Pearson after her FDA report, that there is a ‘threshold effect’ of methadone blood levels in which age, sex, electrolyte aberrations, structural heart disease, viral infections and alcohol can, when combined, can together cause torsade de pointes to occur.

Dr Stimmel indicated that one of the patients from 1973 with long QT had died. However, he failed to mention or include on his slide that his original report stated that the patient in question had an ‘impressive barbiturate habit as well as a sporadic history of parenteral cocaine use’ and further, that the coroner had found a fresh injection site (Lipsky). While discussing torsade and QT prolongation, Dr Krantz also put up another slide which may have been misinterpreted. It stated that Peles et al. reported 3 patients with long QT and that two of them died. Fortunately the author was actually present in the room, so Dr Peles herself was able to clarify to the audience (and the speaker) that neither of these two patients died from cardiac causes (both had confirmed non-cardiac causes of death) and hence should not be considered in the discussion on torsade de pointes.

None of the speakers alluded to the possibility that lengthened QT, high dose methadone and medical illnesses may just be ‘fellow travellers’ rather than a direct causative effect. It is clear that even significantly prolonged QTc in some groups appears to yield little or no risk of torsade in the absence of other factors, as with amiodarone, a drug which is apparently still used by cardiologists despite its propensity to cause significant QT prolongation.

Dr Gourevitch, who wrote the Annals editorial dealing with Krantz et al (2009) also addressed the workshop in question time with some clarifications. He had stated that the ‘expert panel’ had gone well beyond the research evidence in their recommendations. He emphasises that the issue is not as clear cut as the proponents had been saying in the session.

The remainder of the conference had many interesting sessions, workshops, plenaries and discussion groups on every aspect of addictions except the elephant in the room, decriminalisation of drugs for personal use which seems off limits. Medical cannabis (called “medicinal marijuana” by Americans) was mentioned frequently, as were drug courts and other moves away from law enforcement towards treatment.

Comments by Andrew Byrne ..

References:

Viskin S, Rosovski U, Sands AJ, Chen E, ... Zeltser D. Inaccurate electrocardiographic interpretation of long QT: The majority of physicians cannot recognize a long QT when they see one. Heart Rhythm 2005;2: 569-574 [Byrne commentary: http://www.redfernclinic.com/c/2009/03/inaccurate-electrocardiographic.php4

Peles E, BodnerG, Kreek M, RadosV, AdelsonM. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study. Addiction. February 1 2007;102(2):289-300

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in Deaths Due to Methadone in North Carolina. JAMA 2003 290:40

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395

Gourevitch MN. First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;417-8

Editor’s response on Krantz et al: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1#112632

Andrew Byrne response to Krantz et al: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1#112623

AATOD conference link: http://www.aatod.org/pdfs/2009/Conference_Glance.pdf

Clinic web page: http://www.redfernclinic.com/c/

Opera blog: http://www.redfernclinic.com/opera/critique/blog/

New York in spring: http://ajbtravels.blogspot.com/

Measuring QT interval: more complex than you may think!

2009-05-11T03:52:00.007+10:00

Inaccurate electrocardiographic interpretation of long QT: The majority of physicians cannot recognize a long QT when they see one. Viskin S, Rosovski U, Sands AJ, Chen E, ... Zeltser D. Heart Rhythm 2005 2;6:569-574

Dear Colleagues,

In this well conducted study from Israel 4 cardiograph tracings (2 with long QT syndrome vs. 2 normal controls) were sent to about 1000 doctors in several countries, including Australia for their assessments. Clinicians included QT interval specialists, electro-physiology experts, cardiologists and ‘other physicians’.

Correct classification of all four ECGs was gratifyingly 96% in QT specialists and their results were used as the expected ranges. Only 62% of arrhythmia experts and less than 25% of other physicians (including cardiologists) were correct in all four cases.

More than 80% of arrhythmia experts but less than 50% of regular cardiologists and less than 40% of non-cardiologist physicians calculated the QTc interval correctly in all four trial subject ECGs. Much of the inaccuracy occurred in the correction for rate - clearly many doctors did not know how to do this important step. The most common errors were underestimating the QTc of patients with long QT syndrome and overestimating the QTc of healthy patients.

While there is talk about alleged dangers of heart rhythm disturbances in association with methadone treatment, the QTc interval is often discussed as if it were a constant. Automated calculations are not dealt with in this article but their use is becoming widespread in advanced centres but is apparently rare in the developing world where most dependent individuals live. Even so, abnormal automated results are also subject to certain difficulties, needing the human touch … which from this study would still appear to be far from perfect, even in specialist hands.

This interesting report should remind us that the QT interval issue in methadone treatment needs to be looked at from a practical standpoint related to patient safety and treatment effectiveness. To date few if any young, new or uncomplicated patients treated with standard induction protocols have been reported to develop torsade. And this is despite many such patients being reported to have substantial QT interval prolongation (Wedam found >10% had over 500ms at some stage in the first three months of standard treatment).

In our own practice we have faced numerous challenges in obtaining a confirmed corrected QT (QTc) interval in those who may be at risk of torsade - largely those needing methadone doses in excess of 150mg daily. In New South Wales since 2002 there has been a requirement for a cardiograph with detailed QTc interval before patients are permitted to exceed 200mg daily dose of methadone. Our difficulties have included (1) specified QT request ignored by cardiologist, (2) a bland response: “normal tracing, including QTc”, (3) some approximate figures: eg. “QTc around 0.3ms” and (4) some results which were just wrong when checked by us. We have become reasonably adept at doing these measurements simply because of the variable results we have obtained from cardiology reports.

Of the growing number of torsade reports in the literature, nearly all are of patients with (1) multiple medical illness and/or (2) multiple drug/alcohol use and/or (3) taking very high doses of methadone (>150mg). Fortunately only one death was reported amongst about 80 such cases I found in the literature. See Justo’s review in Addiction for 40 such detailed cases up to 2006: he found virtually all had co-existing contributors over and above standard methadone treatment.

Thus we can define a sub-group of methadone patients in whom torsade may be a credible risk and act accordingly. These would include those prescribed the drug in very high dose, those over 40 years of age, female gender, co-prescribed medications, HIV infected, continued use of illicit drugs and/or those with structural heart disease. The most obvious is the co-prescription of drugs known to prolong the QT interval such as erythromycin, droperidol and cisapride.

Just doing an ECG in such cases on its own has limited if any likelihood of avoiding torsade. Most of the reported cases in the literature had a normal ECG before and/or after the torsade episode where one was available. Thus an ECG tracing in such cases is only a starting point or baseline. At best it would detect most cases of familial long QT syndrome (Smith) should this occur in a methadone patient (some may have died during exposure to illicit drugs such as cocaine or amphetamine).

Torsade has also been reported with normal and shortened QT intervals, so this is by no means a yes or no situation - like most other situations in medicine it is a continuum. This is why diagnosis should always be individual and why clinical guidelines should be reserved for particular public health priorities, and only when they are evidence based and known to do more good than harm.

Fortunately, the majority of methadone dependency patients are not in a risk category and do not need cardiography. On the other hand, most should probably be recommended hepatitis testing since this is a major public health issue and a communicable disease.

Thus, despite talk about supposed dangers of high doses, there are in fact far more dangers by using inadequate doses. This is especially so in high risk individuals such as during pregnancy, those with co-existing mental illness and/or continuing drug use. We should be confident to prescribe higher doses for those who need them, based on clinical factors with no arbitrary maximum cut-off. There are major benefits in using adequate doses as shown by many controlled comparative studies. The side effect profile is relatively low as long as patients are properly assessed. Many well run clinics have mean doses around 100mg daily which is about the same as the original report by Dole and Nyswander in 1965. Most well run clinics also have a small number of patients taking over 200mg daily due to rapid metabolism and/or high tolerance to the drug. Not all patients do well on methadone and in some countries there has been considerable experience with buprenorphine which suits a substantial minority of opioid dependent individuals.

Nonetheless, we need to remember that some patients on opioid maintenance treatments are now in the age groups which are subject to other illnesses. These include osteoporosis, hypertension, heart failure, cirrhosis, dementia, etc. These are best addressed by a well co-ordinated “shared care” model utilising family physicians and appropriate specialists.

Comments by Andrew Byrne ..

References:

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Smith WM. Cardiac repolarisation: the long and short of it. MJA 2008 188;12:688-689

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

Recommended audio critique of the subject by Dr Gavin Bart: https://umconnect.umn.edu/methadoneqtcscreening/

Does adding an antagonist reduce injecting?

2009-03-20T02:44:00.010+11:00

Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Am J Drug Alcohol Abuse 2009 Feb 12:1

Dear Colleagues,

In this important paper Dr Bruce from Yale University finds no reduction in quantities injected after the widespread change from pure to combination product (Suboxone). Even more worrying is a finding of increased needle sharing in the high proportion who reported withdrawal symptoms following the change.

In a group of 41 recruited illicit buprenorphine injectors in Kuala Lumpur, Bruce and co-workers posed questions about injection of both the pure and combination products after a change in Government policy aimed at discouraging injecting. Pure buprenorphine was banned due to widespread abuse (as it was in New Zealand in 1991) and replaced with a combination product containing naloxone. As in previous experiences, (Robinson 1993), a change to the combination product was not associated with elimination or substantial reduction in abuse.

Half the sample (20) reported experiencing withdrawal symptoms after the change yet this had apparently not discouraged them from injecting. Average daily use increased 30% (from 1.9 to 2.5mg per day). Reported needle sharing was much more prevalent in those who also reported withdrawal symptoms (15 out of 20 or 75% of the ‘withdrawal’ subgroup).

The 41 used other drugs such as methadone (4), ketamine (10), amphetamine (6) or benzodiazepines (13). The authors speculate that this may have been to medicate withdrawals in some cases. They state that none of the subjects appeared to be using the buprenorphine as a recreational drug but to maintain a functional level of opiates in the body.

This paper is not consistent with claims that Suboxone reduces injecting behaviour. While the manufacturer has always been modest in its claims, others have made extravagant statements about the alleged property of combination buprenorphine to prevent diversion. It appears that the drug was approved by the American FDA and marketed without rigorous comparative studies. Combination agonist/antagonists may sound persuasive in theory but this has never been demonstrated in the field despite a long pedigree (methadone and naloxone were first tried together over 30 years ago). Now, 15 years apart and in very different settings, two naturalistic studies on buprenorphine make comparable and consistent findings.

Like Bruce in Malaysia, Robinson in New Zealand took advantage of a similar scenario in which buprenorphine was being widely abused in the community. The government and manufacturer changed to the naloxone-containing product, so Robinson was able to interview patients enrolling in his opioid treatment program in Wellington, NZ. He reported numerous demographic and drug use characteristics before and after, finding that the drug was still widely abused. Indeed, for 59% it was still the drug of choice - and mostly injected.

Interestingly, the Malaysian figures are remarkably close to a published comparison of pure buprenorphine with the combination product. In a small pilot study, Bell and colleagues found that substantial increases (average 50%) in doses were needed by nearly all 17 stable subjects after changing from Subutex to Suboxone. Another factor I learned in my research was that apparently the main driver for injecting in Malaysia was financial since sublingual administration requires a far higher dose due to lower bio-availability and all doses must be paid for by the patient in that country.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/#news

References:

Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6
Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev (2004) 23;3:311-318

Torsade rare in guideline-treated cases: routine ECG not appropriate.

2009-03-07T14:18:00.015+11:00

First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;6 (Annals on line, pre-publication March 17) Gourevitch MN. http://www.annals.org/cgi/content/full/0000605-200903170-00111v1

Dear Colleagues,

With this stentorian editorial Annals of Internal Medicine finally puts the cardiac health of methadone treatment into its correct perspective. Dr Marc Gourevitch questions the utility of routine ECGs to detect or prevent such side effects, countering Krantz and colleagues (Ref 1) who have an article in this issue recommending routine electrocardiography before and during treatment - claiming some sort of professional consensus. In 2006 Krantz had written: “Although QT prolongation associated with higher doses of methadone is an important safety concern, we do not believe that routine ECG screening is warranted for heroin addicts entering treatment” (Ref 2). As Gourevitch points out, no new evidence is presented in this paper to justify a reversal of this widely held view - in fact four important papers are simply omitted by Krantz et al (Ref 3-6). Each of these is reassuring in that torsade is rare and largely occurs in extraordinary clinical circumstances.

After initial pre-publication on Annals-on-line in December 2008, the article by Krantz et al was withdrawn, only to reappear without CSAT endorsement in its title. After originally declaring: “Potential financial conflicts of interest: None declared” fully three primary authors and one panel member subsequently made specific declarations including funding from Reckitt Benckiser, the manufacturer of buprenorphine. All of this should be of some embarrassment to Krantz et al, the Annals editors (they even wrote a rapid response themselves!) and members of an expert panel convened by CSAT, chaired by veteran Dr Barry Stimmel of Mt Sinai Medical School in Manhattan. Two of the panel members declined to be acknowledged in the final version of the paper. It is gratifying that the controversial recommendations in this paper have been countered by an expert editorial by Dr Gourevitch from NYU.

Some major flaws in Krantz’s paper are pointed out. Regarding routine cardiographs before and during treatment, Gourevitch writes: “Unfortunately, this suggested guideline ventures well beyond the evidence presented.” He examines each aspect of Krantz’s ‘case’ for the dangers of QT prolongation and torsade de pointes and the panel’s ‘consensus’ strategy for prevention. We are even told that mandated cardiographs may cause more harm than good, like many other well-intentioned guidelines (ref 7).

Some of the questions raised by Gourevitch are so fundamental that they should have been asked long before in the peer review process or the ‘expert panel’ deliberations. He seems surprised that the panel members were able to (1) discuss 95 detailed references, (2) confer about torsade risk and (3) develop a 5 point plan to address this purported risk in only 2 days at a ‘consensus’ meeting.

Dr Gourevitch implies that ECG testing should be done on those at high risk since overall the rate of torsade is low and cardiac dangers “typically occur in those who receive exceptionally high doses of methadone or who have other risk factors.” [Krantz writes 'relatively high doses' describing an average of 397mg daily.] He also points out that the time frame of ECGs in the article’s recommendations is arbitrary, and there equally seems no rationale behind the 100mg dose level above which the authors say more frequent supervision is needed.

The author points out that the delays involved in getting pre-treatment testing done in this brittle population will inevitably cause some early drop-outs. Further, since torasde is so rare, this could never be balanced by benefits for those remaining in treatment.

The subject of supposed cardiac toxicity from methadone maintenance treatment has taken on a life of its own well beyond the evidence. The contention by Krantz that cardiac safety in methadone maintenance patients is a ‘national priority’ is an overstatement (Ref 8). Those suggesting this have not even determined an approximate incidence (and it may be zero in addiction clinic patients). Amongst ~70 reported cases of torsade, nearly all in older or complex addiction cases, I could only find one which was fatal (a 47 year old female who reportedly also had a myocardial infarction).

This discussion should not allow clinicians to be distracted from the major problems facing our field, notably the hepatitis C epidemic. The overwhelming statistics on this subject put the above minutiae into stark perspective.

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/#news

References:

1. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6: (March 17 issue) http://www.annals.org/cgi/content/full/0000605-200903170-00103v1
2. Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557
3. Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006;101:1333-1338
4. Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1
5. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5
6. Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552
7. Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet. 2002 359:881-4
8. Krantz MJ. Heterogeneous Impact of Methadone on the QTc Interval: What Are the Practical Implications? Journal of Addictive Diseases 2008 27;4:5-9

Close examination finds flaws with Annals article on QT effects from methadone.

2009-03-06T01:26:00.000+11:00

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 (March 17 issue)

Dear Reader,

The title of this article has changed since its original publication and the connection with CSAT has been omitted. I found problems with the methods, processes of ‘consensus’, deductions, conclusions and references.

It is evident (but not stated specifically that I could find) that the main issue being addressed is the occurrence of cardiac arrhythmia in patients being prescribed methadone. Yet the title seems to imply that QT prolongation of itself is a problem, despite 40 years of experience showing it is common (up to 40% of subjects) and yet of unknown clinical significance. Torsade tachycardia has very largely been reported in complex medical cases and those taking extremely high doses of methadone rather than those on standard maintenance treatment.

In my view these authors do not make a logical case for their title: “QTc Interval Screening in Methadone Treatment” but ask readers to accept that there is a problem and that their recommendations form a solution to diagnosing and addressing it. Recommendation 1 involves disclosing the cardiac toxicity to all patients; Recommendation 2 advises a history and physical exam. Serial cardiographs are promoted in Recommendation 3. Recommendations 4 and 5 are a cook-book way of dealing with this difficult and largely uncharted clinical territory. Few clinicians have looked after more than one or two such patients and so a rational approach has not yet been arrived at and it is hard to imagine this is the last word on the subject.

Their first paragraph contains a circular argument since they use the existence of a drug black box warning and FDA safety warning on methadone as support for the case for methadone being dangerous. Yet these measures are a result of the same concerns as Krantz claims to be responding to, so as commercial or regulatory decisions, they are not scientific sources, depending as they do on a variety of factors beyond clinical medicine and public health.

Krantz and colleagues are initially at pains to point out the factors which lead to increased risk of torsade de pointes in relation to prolonged QT interval, sex, heart rate and other factors. The rest of the article lacks clarity and the concise scientific discussion that one normally expects in Annals.

Regular practice would start by describing a clinical or public health problem such as a series of case reports, approximate incidence and evidence of the existence of a recognisable syndrome and a possible causation. They appear unwilling or unable to define the problem and its scope. In proposing these clinical recommendations, some of which are ’motherhood statements’ while others appear arbitrary and untested. In this way Krantz and colleagues deny readers a proposed rationale to demonstrate how known reported cases could have been avoided as a result of their newfound wisdom. They circumvent their subject in numerous ways, drawing quite tenuous conclusions from circumstantial reports with no actual cases of torsade arrhythmias despite being cited as important studies demonstrating its importance (eg. Chugh’s study from Portland, Fanoe from Denmark, Wedam from Baltimore).

Despite torsade de pointes being the complication they are addressing, the article spends most text discussing QT prolongation, something we know happens commonly in methadone patients (up to 40%), and which we know, in methadone clinic patients on ‘normal’ doses, is of little if any clinical significance. Torsade can occur in those with normal QT intervals (Ehret) and in those not taking methadone (Smith). While taking pains to be conservative and conceding the many weak links individually in documenting this subject, these authors still conclude that their advice is based on good science.

As above, it is hard to understand how, from a knowledge of the case reports, such a strategy as proposed by Krantz and colleagues would or could prevent torsade cases. The QT interval is regularly normal before and after the triggering events (Sticherling). I have written to Krantz, Haigney, Stimmel and Martin individually to ask how their strategy could apply to the case reports in the literature. I have been sent no attempts to explain this rather large gap in the logic. My understanding is that few if any reported cases would have been prevented by these measures in Annals.

The authors state that of Pearson’s 59 FDA reported cases there was an 8% mortality (Paragraph 14). They omit to say that only one of the 5 deaths was a torsade case (the others QT abnormalities reported but no torsade). Further, the single death was in a 47 year old female patient who also had a myocardial infarction as well as prescription of azithromycin and droperidol. Both the latter drugs are known to be cardio-toxic. The mean dose of the 59 cases was over 400mg daily. None of the other 4 deaths in Pearson’s FDA series had torsade from their prolonged QT intervals and we are not told any further details of the causes of death. Two of the four had been given methadone intravenously (off-label) at extremely high dose levels (360 and 1680mg daily). Another was a 78 year old woman who had been prescribed cisapride, a drug which is no longer available in some countries. The only patient in this group of five deaths who might have been a standard methadone patient also died from un-stated causes, aged 40 on the unusual dose of 29mg daily (and there was no torsade in her case).

By comparison, Krantz’s series of 17 cases had no deaths (0%), Sticherling’s 5 cases all survived (0% deaths) and Justo’s compilations (including some of the above cases) reported no deaths (0%).

Hence the suggestion that any group of methadone patients had a mortality of 8% is almost meaningless without a denominator. Considering the age and other details of reported cases, these would have little relevance to young people with addiction problems who may be started on opioid maintenance therapy. Few if any of those reported torsade cases come from newly started addiction clinic patients, despite the most worrying trial of QT prolongation (Wedam) finding 12% in the high risk group within 4 months of starting treatment. Even if there were a small incidence of significant QT problems, these would still be outweighed by benefits to patients. Krantz himself proposed that putting a drug injector onto methadone had the scope to reduce rates of endocarditis in the community as a “common sense notion” (2001). Endocarditis is probably more common than torsade de pointes arrhythmia.

Krantz and colleagues argue (paragraph 2) in favor of routine cardiographs by taking examples of findings with two antiarrhythmic drugs (sotalol and dovetailed), “highlighting the importance of pretreatment ECG screening for identifying susceptible patients”. One wonders at this comparison when these cases clearly already had heart disease by definition, in contrast to young people attending for addiction treatment. While it would obviously be inappropriate to treat arrhythmias without a baseline and on-going cardiographs, there can be no parallel here with methadone as the authors attempt. A fairer comparison might be prescribing erythromycin, haloperidol or other such agents to young people without cardiac histories.

The 17% mortality of torsade is based on two old references from the French literature relating to hospitalized torsade cases (Paragraph 16). This rate may now be lower in view of better communications, wider availability of ECG and defibrillators as well as improved specialist care. On the other hand, torsades may have become more readily diagnosed, due in part to the advent of automated digital machinery with QTc print-outs.

In paragraph 21 Krantz and colleagues combine 8 references as supporting a correlation between prescribed methadone dose level and QT interval. In fact, Peles’ trial from Israel (which probably had the highest average doses and largest range of any such report) found no significant correlation between their patients’ dose levels and corresponding QT interval. A sub-group of cocaine users were examined separately and a (significant) correlation was found which may or may not support Krantz and colleagues’ thesis. Further, they quote Martell as supporting the correlation but fail to add (as Cruciani states:) “Martell and co-workers studied heroin addicts during the first two months of induction therapy with methadone and observed a higher increment in the duration of the QTc in those patients receiving 110-150 mg/24 h. The clinical significance of this change is questionable, however, because the increment was only 13.2 ms.”

Further, in paragraph 21 these authors state, or rather understate: “Methadone dosages exceeding 100 mg/d have frequently been noted in published cases of torsade de pointes, and some case reports (43, 47, 55) highlight QTc-interval normalization after methadone discontinuation or dose reduction.” In fact methadone dosages exceeding 200mg, 300mg and 400mg have frequently been noted in reports of Pearson and Krantz (2002). Some of the highest were 1100mg, 1680mg, 1000mg in Pearson’s paper. Further, when QTc interval was available after the torsade event and the triggering factor has been removed, QTc intervals nearly always returned to normal or near normal. Krantz omits this common and important finding while stating “some case reports (43, 47, 55) highlight QTc-interval normalization after methadone discontinuation or dose reduction.” To this one should add the several reports where normalisation of the QT interval was reported after addressing triggering factors (eg. all 5 cases of Sticherling, De Bels’ two cases, one reverting to normal while the other’s QT interval dropped from 736ms to 502ms in 4 days).

This style of writing is much closer to advocacy than careful scientific discourse. While there are caveats and alternatives mentioned at various points, the overall feeling is that there is a case already made and this text is there to support it. The choice of references is another example of a lack of balance. Justo’s prominent literature review from the Addiction journal is omitted. Krook’s item which addresses their exact subject is also surprisingly left out (Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1).

The authors also unfortunately omitted two highly relevant recent items (i) Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5 (ii) Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552. These two address Krantz’s issues directly and each makes enlightening and balanced reading, contributing substantially to the field, yet they are ignored by Krantz and colleagues. Cruciani was available in April 2008 while Athanasos on 12th June 2008. Several of the other 95 references were accessed as late as November 12 2008 according to the text.

With almost 100 other references, some of only tenuous relation to the subject, it is a flaw to have missed other such relevant and contributory sources. In this small field, such documents are usually publicised on the internet, professional list-servers and news-wire services long before they reach formal publication date (as in the case of this very item in Annals which appeared in a previous version in early December 2008). The reader may understand cut-off dates for recent references, but to omit Krook and Justo would seem to show a lack of thoroughness unbefitting a panel which proposes to develop guidelines for physicians who work in this important field.

Derivative internet summaries:
http://www.ncbi.nlm.nih.gov/pubmed/19047020
http://www.tripdatabase.com/spider.html?itemid=801110

Comments by Andrew Byrne ..

Clinic web page: http://www.redfernclinic.com/#news

References:

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

Smith WM. Cardiac repolarisation: the long and short of it. MJA 2008 188;12:688-689

Ehret GB, Voide C, Gex-Fabry M, Chabert J et al. Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone: High Frequency in Hospitalized Patients and Risk Factors. Arch Intern Med 2006 166:1280-1287

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Saf. 2005 14;11:747-753

Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. 2002 137:501-504

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4

Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients - a cross-sectional study. Addiction 2007 102;2:289-300

Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552

Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95:915-8

Other references on request.

"Heterogeneous Impact of Methadone on the QTc Interval" what does this mean?

2009-03-04T09:25:00.006+11:00

Krantz MJ. Heterogeneous Impact of Methadone on the QTc Interval: What Are the Practical Implications? Journal of Addictive Diseases 2008 27;4:5-9

This article is a confusing amalgam of a rehashed set of figures of little relevance to modern treatment practices. Krantz uses the forum to express strong opinions but he fails to back these up with science. In fact he sometimes quotes other opinion pieces as if they were science. He cites himself 8 times and out of 31 references, he chooses to ignore some of the most solid scientific papers, all of which are reassuring to the standard use of methadone in addiction treatment. For example Justo’s literature review in Addiction, Sticherling’s report of 5 torsades cases from Switzerland.

The most useful fact to my mind is that there were no cases of torsades, like every other prospective study of methadone patients ever performed, to my best knowledge.

Krantz misquotes himself as saying “methadone’s effect on QTc is clearly [sic] dose related” (ref 24) yet the reference (to himself) is only an opinion piece which provides no evidence itself but just quotes a retrospective study of Mehler et al. and two other studies which showed ‘modest concentration-dependent effect’ of dose upon QT and one is a study of LAAM and NOT methadone at all! So Dr Krantz does not even manage to argue cogently for his one contention which is probably correct, a methadone dose effect for QT interval.

In the opening paragraph there is a glaring typo: ‘… QTc prolongation defined as *greater than* 470 msec in men and *less than* 490 msec in women’. (my asterisks) In the concluding paragraph of the piece we are told ‘.. the number of patients who developed critical QTc prolongation defined as *less than* 500 msec …’. This should read *greater than* 500 msec I presume and is yet another sign of the imprecision and therefore the inconsequence of this paper.

Why did reviewers not pick up these flaws? Krantz quotes Wedam on two occasions in the paper but calls him Wedman in error. His use of the word ‘heterogeneous’ does not seem to derive from anything in his paper and it is not clear if he is using the term in its strict electrophysiological sense (see Braunwald's text, 7th edition p705) or the common English usage. Likewise, ‘heterogeneous’ does not seem to apply to these findings or opinions, diverse though they be. It is another sign of a lack of clarity in Krantz’s writing. ‘Dispersion’ is another possible example from another paper (Pharmacotherapy 2005). Further, he used the word ‘paradox’ in Lancet in similar ‘disconnected’ and confusing fashion. All medical prescribing involves balancing therapeutic effects with potential side effects. This is not a ‘paradox’ for most doctors but ‘business as usual’.

There is also a faulty reference to Milon et al, presumably from the French literature but without a year of publication. An author’s name is misspelt (Gouffault with a single F) and the year 1982 is omitted.

His 'piece de resistance' is a careful explanation of why nobody has ever seen a case of torsades in a methadone clinic setting. Just read it!! Because it is so rare (one in a thousand he quotes without any specific reference for methadone) and has a mortality of 20% the 'aggregate' [sic] number of methadone related cardiac deaths in the US is 'relatively small' (does he mean vanishingly small or unmeasurable?). He mentions, accepts, but then dismisses Newman’s contention that many such reports are from outside the ‘addiction realm’. Of course the fact remains that there is a dearth of reports of patients entering ‘normal’ addiction treatment and developing torsades as a result. If there are such reports I have not been able to access them.

In the most quoted and seminal paper on the subject from 2002, Krantz and colleagues do not even inform the reader which of the 17 case reports are addiction clinic patients and which are pain cases. And it is important. He has not responded to my requests for clarification.

Krantz has shown himself to be less than objective in talking up this problem in addiction clinics (see his survey of clinic staff) while not showing as much interest in chronic pain cases. For another example, see Lancet in which he misquoted Lipsky et al. His published response not only fails to address the serious error but tries to justify his stance by emphasising increasing methadone related deaths, nearly all of which came from pain management cases in the reference he cites.

Comments by Andrew Byrne ..

References:

Krantz MJ, Mehler PS. QTc prolongation: methadone’s efficacy-safety paradox. Lancet 2006; 368: 556–57

Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366

Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of methadone on QT-interval dispersion. Pharmacotherapy. 2005 25;11:1523-9

Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282–285

APSAD Annual Scientific Conference 2008 [part I]

2008-12-06T17:17:00.009+11:00

APSAD Annual Scientific Conference 2008

Australasian Professional Society on Alcohol and other Drugs.

November 23 - 26, 2008 Part I (Sunday 23 Nov).

Dear Colleagues,

This year's APSAD conference was a fine affair. I must have been to 15 or more of these in most State capitals, Cairns and Canberra. I missed last year’s Fest in Auckland but those who attended said it was excellent. Like national leaders’ meetings with their funny hats, shirts and coats, each APSAD conference is characterised by its own conference attaché bag. This natural-inspired over-the-shoulder model was one of the few I could imagine using in the future.

The venue was splendid, Darling Harbour being just an 8 minutes (downhill) walk from Town Hall station which made me into a commuter again. With medical practice responsibilities I was a part-time conference goer. Thus these notes are incomplete and (as usual) opinionated.

The Sunday afternoon pre-conference session had been booked by the only drug company with a major stake in our field. Reckitt-Benckiser is manufacturer of buprenorphine which is the only registered alternative to methadone, the latter being a generic drug with small bread-and-butter profit lines in comparison. The sponsors began with the topics of pharmaceutical abuse and innovations in addiction management, then ending with two presentations on the potential cardiac complications of methadone before a panel discussion to which I had been invited (and generously funded).

Adrian Dunlop spoke eloquently about the past, present and future of addiction treatments.

Dr Eric Strain covered some historical details of non-medical use of pharmaceuticals in the US, giving some results on prevalence and consequences from household surveys over 25 years. Apparently most users obtained their supplies from one doctor; many from friends or relatives with less only ~1% or less from the internet. Australian figures may be quite different as people are entitled to attend more than one doctor on Medicare. Another speaker quipped that if Australia had a Bill of Rights, it would include being able to attend “as many doctors as you like”. Dr Strain touched on the gap between occasional use and dependent use, something some of us may still forget because of the selected referrals we receive. The other major differences between American street heroin users and those abusing pain killers is that the latter are more likely to be employed, white race and non-injectors. Dr Strain was too modest to mention his own research on buprenorphine abuse and perhaps too polite to mention the reported non-medical use of buprenorphine, including a naloxone combination product which became the drug of choice (mostly injected) by more than half those presenting for treatment in Wellington, New Zealand (see Robinson 1993).

Dr Nick Lintzeris gave some pointers about pharmaceutical abuse in Australia. His talk ending with a plea to put methadone treatment, including side effects, into context both globally, as well as for individual patients. In his rather frequent exposure during the conference, he reminded us that there are much more relevant issues for opioid therapy as patients get older such as testosterone levels, calcium leaching, osteoporosis, dental, viral and bowel problems.

Jason White detailed the rather sparse literature on cardiac complications in methadone recipients. He seemed persuaded that the connection between methadone and torsade is significant and that methadone treatment could be restricted or further regulated as a result. As a demonstration of patients on ‘normal’ methadone treatment coming to torsade, he cited Pearson and Woosley’s report of 59 FDA notifications from 1969 to 2002. While not fully documented, from the limited data 12 could have been on ‘standard’ MMT, 8 of whom were over 40 years of age. This leaves just 4 reported ‘standard’ MMT cases in the USA over a 33 year period in the age group we normally start on MMT. Justo’s more recent literature review found only 6 of 40 cases reported could have been on ‘standard’ MMT cases without other triggering factors (85% had one or more of these known causes of QT prolongation aside from high methadone doses).

QT prolongation on the cardiograph has long been know to occur in about a quarter of methadone patients yet its only serious consequence, ‘torsade de pointes’ tachycardia, hardly ever seems to occur in young patients (<40>40 years of age, electrolyte disturbance, etc.

As our patient population on maintenance treatment gets older so we must be more vigilant about this and other eventualities. As with other related medical issues, close attention should be paid to cardiac status. This may include an ECG in those taking over 150mg, those prescribed other ‘at risk’ medications or those with HIV or personal/family history of unexplained syncope or fainting.

At this session I was delighted to finally learn the origin of the term ‘ether-a-go-go’ which is from the rhythmic dancing induced in the legs of doomed drosophila drones (flies) under the influence of ether in genetic experiments on channel blockers.

We were then shown a 15 minute video ‘interview’ with Colorado cardiologist Dr Mori Krantz detailing blow by blow the now supposedly conclusive case for methadone’s guilt beyond reasonable doubt in causing fatal arrhythmias. The final proof of any medical argument, we are told, involves randomisation of subjects and so the RCT by Wedam is proffered. This trial, a secondary analysis of ECG tracings obtained incidentally in a 1990s RCT, showed very high rates of QT prolongation in the first 4 months of MMT but no cases of torsade. One of the panellists said to me privately that this appears to be rather persuasive of the safety of methadone rather than the opposite.

As above, hardly anyone has ever seen a case except in patients who are already stressed and in highly complex medical circumstances. I note that since his classic description of 17 non-fatal cases in 2002 (8 were pain management cases), Krantz has only reported two other individual cases of torsade, one of which was attributed to cocaine.

In the video, we are told that because one cannot diagnose an electrical disturbance after death, coroners are unable to detect whether the death was due to cardiac arrhythmia or respiratory depression from the drug. In fact many cases are very clear at autopsy as having the classic findings of post mortem sub-acute lung changes and high blood levels as to leave little doubt about the cause of death. So while Krantz’s proposition may be true for a certain minority, with a 20% mortality, there ought to be 4 times as many (80%) torsade survivors. Yet few if any of these ever seem to get to an emergency room (or ambulance) and have their potentially fatal problem diagnosed with a simple cardiograph tracing. Such reports are exceedingly rare or non-existent. I called one of Australia’s busiest casualty departments to be told that their long-time medical director had never seen a case of methadone associated torsade. He also pointed out that for the past several years modern cardiograph machines have given an automated print-out of QTc, making this information much more available than previously. This just might be the single most important cause of the ‘epidemic’ of electrical changes in the absence of actual symptomatic disease.

Further on in the presentation Krantz states the obvious “it’s not to say that there is an epidemic of cardiac events in America”. Yet elsewhere he has written that a large number of patients are at risk of developing torsade. Fanoe’s Copenhagen syncope study was put up as a written question in the video ‘interview’ (there was no interviewer as such) but Krantz failed to comment on it for some reason. Fanoe showed that out of 800 cases (with no torsade reported) that high rates of syncope (over 20% in most dose groups) in methadone patients was at least in part explained by cardiac conduction problems such as torsade. This is hard to understand for a complication known to occur in less than 1% of patients. Krantz then alluded to Chugh’s Portland study suggesting that it lent support to his torsade theory, yet like so many of the other quoted references, this is another report which does not document any torsade cases at all.

Do I belabour the point? If this is a serial killing, Miss Marple, where are the bodies?
[more about lives saved in another conference posting shortly]

Comments by Andrew Byrne ..

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr Andrew Byrne MB BS (Syd) FAChAM (RACP)
Dependency Medicine,
75 Redfern Street, Redfern,
New South Wales, 2016, Australia
Email - ajbyrne@ozemail.com.au
Tel (61 - 2) 9319 5524 Fax 9318 0631
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Surgery web page: http://www.redfernclinic.com/#news

References:
Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence 1993 33;1:81-6

Strain EC, Stoller K, Walsh SL, Bigelow GE. Effects of buprenorphine versus buprenorphine/naloxone tablets in non-dependent opioid abusers. Psychopharmacology (Berl) 2000 Mar;148(4):374-83

Justo D. Methadone-Induced Long QT Syndrome vs Methadone-Induced Torsades de Pointes. Arch Intern Med 2006 166:2288

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. 2002 137:501-504

Krantz MJ, Rowan SB, Mehler PS. Cocaine-related torsade de pointes in a methadone maintenance patient. J Addict Dis. 2005;24(1):53-60

Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy 2005 25:611-614

Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71

APSAD Annual Scientific Conference 2008 [part II]

2008-12-05T20:24:00.005+11:00

APSAD Annual Scientific Conference 2008 [part II]
November 23 - 26, 2008

The plenary sessions on Tuesday were excellent, starting out with an American statistician, Rosalie Liccardo Pacula talking about the new generation RAND drug use modelling. This appears to be an enormously detailed, almost 4-dimensional system of looking longitudinally at multiple individual markers as well as societal/drug changes. Already they are able to predict drug trends with far fewer people than household surveys but there is still more work to be done to hone this new tool. Like all statistical models, it is only as good as the information fed into it. [http://www.apsad2008.com/abstract/300.asp]

Next we heard Prof Ross Homel giving a talk about complex family interventions, often involving three generations, with the emphasis on child safety, development and education. He gave numerous examples of what they are doing in a non-Government organisation associated with Mission Australia. There were vastly diverse interventions from group therapies, vocational referrals to literacy programs. Their main aim was to embed such programs into schools where there was a high proportion of disadvantaged children.

It was most appropriate that Prof Ann Roche gave the Rankin Oration this year. She did a broad overview of our field and her involvement in it looking back and then giving some views about the future using many clever and apposite quotes from Woody Allen, Elenor Roosevelt, the Dalai Lama and others. One memorable quote from the conference was a post-modern concept for the single woman to ask of any man she dates: �Is this really the man I want to look after my children on weekends?�

Greg Dore then revealed just what we all needed to know about hepatitis C. He dealt with the progress of the epidemic since it was first formally recognised in our communities around 1990. With no initial symptomatology in most patients, it is hard to determine the true incidence. However, by looking at the prevalence in young age groups one can determine changes from time to time. This would seem to indicate that although there are still many reported new cases each year, fewer of these appear to be true new infections as the prevalence in younger people is dropping more rapidly than in the overall population. [http://www.apsad2008.com/abstract/294.asp]

The range of treatments was detailed, pointing out the major improvements in recent years. We can now expect up to 80% �cure� rates (absent viral PCR at 6 months) in genotypes 2 and 3 with around 50% for genotypes 1 and 4. With several innovations such as closer viral load monitoring, liver "fibro-scans" and treatments for anti-viral side-effects, better results can be expected in the next few years. It is only by combining all of our resources, including GPs, addiction clinics, pharmacies and liver specialists that we will be able to address this epidemic which has a high proportion of patients on opioid therapies.

A talk was then given by Marina Davoli from Rome about the Cochrane Collaboration and internet library. Australia has had a special contribution to several areas and we have the only free access for internet users. Australian and New Zealand have also contributed much more serious research than other comparable western countries by population. This underlines all the evidence based interventions we use today.

I missed the session chaired by Dr Deborah Zador on opioid overdose but happily the conference abstracts are all available on the internet (see below). Dr Zador wrote some of the most important seminal studies on the subject in the 1990s. Two papers were given about naloxone, both its distribution amongst the drug using population and intriguingly by the intranasal route by paramedics in the overdose situation. The �Good Samaritan� provisions and international developments were detailed by Paul Dietze and Simon Lenton. [http://www.apsad2008.com/session/353.asp]

Bethany Butler reported some more results in an on-going study of several thousand NSW cases starting for the first time on methadone (~2500) or buprenorphine (~3500). There was no significant difference in the overall mortality in the groups (~65 subjects in each) but an excess mortality (~5-fold) in the methadone group in the first 2 weeks of treatment (7 versus 2). As well as direct toxicity, this might also be explained by methadone patients being in a higher risk group to start with. Even so, only a randomised trial can scientifically compare the two treatments and this is probably no longer ethical as most patients know which drug they want (see Pinto). It is certainly gratifying that when used in the normal course of practice that patients on each of these drugs have a marked drop in mortality. This study found those who remained in treatment were about three times less likely to die.

Next Louisa Degenhardt gave a paper on her group�s investigations of all deaths in NSW opioid maintenance cases since 1985, showing some differences over time. Overall 0.9% of subjects died each year of follow-up: 0.6% for those in treatment compared with 1.2% for those who had left. There was with a much higher chance of dying in the first two weeks of treatment when rate was 4.2%. This latter has dropped significantly since the early 1990s and does not apply at all to buprenorphine cases. The authors state that the treatments have the same mortality rates since those on buprenorphine have a lower retention rate, consistent with the comparative literature.

Finally, the session was given information about significant reductions in local ambulance attendances during the opening hours of the Sydney injecting centre (MSIC) as well as comparisons with the 2 years prior to its opening.

On the Wednesday morning we heard a plenary talk by Nicholas Lintzeris on the directions of treatment in the 21st century. He alluded to the shortage of doctors working in the field, the use of new medications requiring less supervision and models of treatment from elsewhere such as France. His subtext seemed to be individualising treatments rather than having rules and one-size-fits-all. He quoted the average age of methadone prescribers approaching the average daily dose! [Which is now about 75mg!] The speaker also did a study with Adam Winstock regarding attitudes towards withdrawal from treatment.

Next, those of us nursing a headache from the previous night�s dinner at L�Aqua Restaurant were given a fascinating talk by Sharon Walsh who is working in Kentucky on the effects of non-medical use of pharmaceuticals. She reminded us that in some areas there is now as much or more such abuse as for heroin. [This was also reported recently from inner Sydney in an ABC radio story which was nominated for a Walkley Award.] The emergence of prescription drug abuse may mean that we need to alter our approach and will increase the need for treatment services. Despite street and prescription drug use having essentially the same dependency diagnosis, these occur in quite different demographics (see Dr Strain�s talk from Sunday). The new RACP Policy on Prescription Opioids and Chronic Non-malignant Pain was introduced in another session, mapping out a plan for problematic use of prescription opioids in Australia and New Zealand [http://www.apsad2008.com/session/374.asp].

Dr Walsh reported on her results in human laboratory studies on oxycodone (Oxycontin; Prolodone), hydromorphone (Dilaudid) and hydrocodone. The latter is not available in Australia but is a constituent of Vicodin, a commonly abused drug in America. While hydromorphone is thought to be about 7 times stronger than morphine for its analgesic effects, in experiments on recreational users the differences between these three drugs were only marginal. [http://www.apsad2008.com/session/380.asp]

Despite running short of time, the next speaker Mark Tyndall spent some minute or two giving a hilarious description of the harm reduction aspects of pedestrians running red �WALK� signs. Next the hapless visiting Canadian described his shock at being taken to a surf beach where crashing waves buffeting swimmers who risked life and limb against the elements which were anything but �pacific� of late. His implication, I think, was that life savers are the equivalent of harm reduction services for drug users.

Returning to his subject, a square kilometre of western urban Canada, there were an estimated 6000 drug users, mostly injectors, of whom 25% had already contracted HIV and 90% hepatitis C. Services were and are grossly inadequate despite statistics which show disastrous rates of just aboot everything one would not want in one�s neighbourhood (crime, public injecting, overdose, deaths, hospital admissions, HIV cases, infections, etc). The Vancouver injecting centre is slightly larger in scale and opening hours, but shares all the essential characteristics of the Sydney injecting centre at Kings Cross (on which some say it was modelled). It has registered over 10,000 Canadian drug users (not all injectors as in Sydney). There are moves to close down this centre despite a wealth of public health research showing benefits to drug users and the community generally at modest cost (or even a net saving to the health system). Its closure would be a most pointed and poignant natural experiments in public health, comparable perhaps with the Broad Street pump exposure in London in the 1800s.

Next I attended a break-out session in which Carla Treloar spoke about the impressions people had about hepatitis C (http://www.apsad2008.com/session/388.asp). The myths were myriad. Defeatist misconceptions abounded. Some of her quotes were classics. Clearly our first job with hepatitis C is to inform people about the truth. Yes, the disease is still difficult and poorly understood. But we now have simple ways of determining the stage of the disease (�fibroscans�, risk criteria, etc) and we have reasonable and tolerable treatments with success rates up to 80%.

Nick Lintzeris reported some findings of an excellent intervention started some years ago in western Sydney in which OTP patients were offered a rapid vaccination program for hepatitis B. The results and a literature review showed that people at risk should probably be given a booster just about any time they are prepared to take one when it is available, even in quite short succession or as a booster down the line. Strict and appointment based regimens are perhaps not best suited to our patient group and so haphazard inoculations are probably more effective than no inoculations at all.

Some 9 cases of bacterial endocarditis in Newcastle area were reported next by Andrew Taylor. These formed a small minority of the total number of such cases in the region. Candida and staphylococcus aureus were common pathogens. The costs of such treatment to the health care system were high and the savings in prevention substantial.

The final segment of the conference for me at least was our own pet topic, hepatitis C outcomes. Carolyn Day, Paul Haber and colleagues reported on the barriers to addressing this public health priority (http://www.apsad2008.com/abstract/263.asp). From the low rates of assessment and treatment, even some prominent and well run clinics seem not to have effective strategies for testing and referring their patients. Some have no idea what proportion of their patients have been tested. Where resources allow, this can be pro-active, �on-site� and direct to hepatology services. Alternatively, referral to the individual patient�s GPs may be the best way to handle such matters in some situations. It is no longer acceptable to do nothing as advocated by some, claiming that �the treatment is worse than the disease�(!!). Some clinic practices seem so calcified that they have not even managed the change from methadone syrup (containing alcohol, caramel, sorbitol, gum, etc) to the safer �pink� methadone, despite majority patient support where the transfer was done some years ago (eg. NSW prisons; Rankin Court, Langton Centre, Clinic 36, Regent House, etc). At a recent health department forum at North Sydney some senior salaried clinicians described every barrier to improved treatment except themselves!

Next I moved to the session on intervention outcomes where Richard Hallinan reported our own 6 year experience prioritising hepatitis C assessments in OTP cases in Redfern (http://www.apsad2008.com/abstract/270.asp). We used some simple criteria devised by Greg Dore to indicate the likelihood of disease progression with liver fibrosis or cirrhosis. Some findings were given from 315 consecutive assessments with follow-up results for 30 cases having anti-viral treatment. Pegylated interferon alpha plus ribavirin were monitored in a shared care model with specialist hepatology services, with encouraging results thus far showing an overall 74% sustained viral response.

Comments by Andrew Byrne ..

Surgery web page: http://www.redfernclinic.com/#news

Opera blog: http://www.redfernclinic.com/opera/critique/blog/

New York in 2008: http://ajbtravels.blogspot.com/

New York diaries 1922: http://bpresent.com/harry/code/10b_bowery.php

Travel log: http://www.redfernclinic.com/c/2007/10/lord-howe-island-naturalists.php4

Vincent Dole in Nepal Diary: http://vincentdolehimalaya.blogspot.com/

Old photos of Sand Souci: http://sanssouciphotos.blogspot.com/

Reference:
Pinto H, Rumball D, Maskrey V, Holland R. A pilot study for a randomized controlled and patient preference trial of buprenorphine versus methadone maintenance treatment in the management of opiate dependent patients. Journal of Substance Use 2008 13;2:73-82

�Current policy puts too much emphasis on protecting society from methadone, and not enough on protecting society from the epidemic of addiction, violence and infections that methadone can help reduce.�

Institute of Medicine 1995

Tiny tobacco "tea-bags" commonly used in USA, unregulated!

2008-12-05T17:23:00.005+11:00

http://www.nytimes.com/aponline/health/AP-Reinventing-Tobacco.html

Dear Readers,

This contains some information which is quite interesting. In some American states there are currently significant numbers of tobacco �suckers� compared with traditional smokers (eg. West Virginia 16% vs. 27%). Apparently these products have not been formally approved yet they were never banned and thus are legal and marketable. We await some good research on their use but most believe that they are probably safer than smoking.

Comment by Andrew Byrne .. (see excerpt below). http://www.redfernclinic.com/#news

MORGANTOWN, W.Va. (AP) -- They're discreet, flavorful and come in cute tin boxes with names like ''frost'' and ''spice.'' And the folks who created Joe Camel are hoping Camel Snus will become a hit with tobacco lovers tired of being forced outside for a smoke.

But convincing health officials and smokers like Ethan Flint that they're worth a try may take some work.

Snus -- Swedish for tobacco, rhymes with ''noose'' -- is a tiny, tea bag-like pouch of steam-pasteurized, smokeless tobacco to tuck between the cheek and gum. Aromatic to the user and undetectable to anyone else, it promises a hit of nicotine without the messy spitting associated with chewing tobacco. Just swallow the juice.

Publications from Byrne Surgery in Redfern, New South Wales.

2008-11-21T20:18:00.005+11:00

Byrne A, Hallinan R. HIV seroconversion. [letter] ANZ J Pub Health 2002 26;2:182

Byrne A, Hallinan R, Love A. Administration of a lighter-coloured methadone liquid. D&A Review 2002 21;4:405

Byrne A, Hallinan R. The introduction of buprenorphine into a medical practice treating addiction. Monograph Byrne Surgery March 03

Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus incidence among injecting drug users on opioid replacement therapy. ANZ Journal Public Health 2004 28;6:576-578

Byrne A, Hallinan R. Evaluation of accreditation of methadone clinics in NSW - Survey of clinics. Poster presentation 29;112 APSAD conference November 2004, Perth WA.

Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy. J Gastro Hepatology 2005 20;7:1082-1086

Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug Alc Dep 2006 81:129-136

Byrne A, Graham G, Hallinan R, Murnion B. Naltrexone implants as treatment for heroin dependence: Part I. Addiction Biology 2005 10:201

Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug and Alcohol Dependence 2006 81;2:129-136

Byrne A, Hallinan R. Methadone is still needed in addiction treatments. BMJ 2006;332:53
http://www.bmj.com/cgi/content/extract/332/7532/53-a

Hallinan R, Byrne A, Dore G. Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated HCV-specific harm reduction. Drug Alc Rev 2007 26:437-443
http://www.redfernclinic.com/c/2007/06/harm-reduction-hepatitis-c-and-opioid_9756.php4

Byrne A. Safe and effective opioid prescribing in addiction treatment. Monograph of article commissioned, accepted and rejected by Advances in Psychiatric Treatment journal 2008
http://www.redfernclinic.com/c/2009/11/safe-and-effective-opioid-prescribing.php4

Hallinan R, Byrne A, Agho K, Dore GJ. Referral for chronic hepatitis C treatment from a drug dependency treatment setting, D&A Dependence 2007 88;1:49-53
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T63-4M69JK7-1&_user=10&_coverDate=04%2F17%2F2007&_rdoc=1&_fmt=high&_orig=browse&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=d58ea170adbb9c060472366c8f9fc696

Methadone safe in young uncomplicated patients; check QT in older folk and those taking other drugs or alcohol, or with HIV.

2008-11-12T16:40:00.011+11:00

Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Journal of Addictive Diseases 2008 27;3:31-35

Dear Colleagues,

These authors from Adelaide, South Australia report a relevant and reassuring ECG study from a 'normal' addiction clinic setting.

We are presented with a comparison of 35 methadone maintained patients, 19 on buprenorphine and 17 controls. Methadone doses varied from 15-145mg daily, being in the common range used clinically around the world. Most subjects were in their 30s and 28 of 71 subjects (39%) were female.

They report no significant difference between the mean corrected QT interval (QTc) of the three groups (407, 407 and 397 milliseconds). There was also no correlation found between methadone dose and QT interval. The QTc in those taking more than 60mg daily were slightly longer (405ms or 6.3%) than for those taking less than 60mg (381ms) (p=0.02). There were also some 'U' waves reported in the methadone patients. Two methadone patients and one control had prolonged QTc when defined as 430ms or longer for males (450 for females). No result was over 475ms. The threshold above which risk of torsade rises significantly is believed to be 500ms.

These findings are all consistent with the report of Lipsky et al. 35 years ago linking methadone prescription with QT prolongation and U waves. The clinical significance of these findings is still uncertain. These authors report no cases of torsade arrhythmia.

They conclude: 'Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.'

As a further exercise I contacted two prominent addiction experts in Adelaide (pop 1.2 million) on this subject. One had seen no cases and the other was aware of one possible case some years before. This is on a long background of good quality methadone treatment, both private and public, in that city.

It may be timely to examine the evidence for claims that methadone prescription in addiction treatment is accompanied by a significant risk from arrhythmias, including death. Despite there being no body of case reports in such guideline-treated subjects (or perhaps because of it) a number of authors have attempted to assess methadone's role in cardiotoxicity by using indirect and unconventional methods.

For example, Fanoe (ref below) prefers QT/torsade as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen. Since the incidence of torsade is certainly less than 1% annually, this explanation is not credible, especially coming from a country with extremely high alcohol statistics.

Chugh (ref below) used a methodology looking at post mortem structural heart disease in those dying suddenly with or without therapeutic levels of methadone in the blood. Their deduction for QT changes without a single case report seems hard to understand.

Wedam (ref below) wrote 'To compare the effects of [methadone] on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid addicted subjects.' In fact they performed a retrospective re-analysis of old analogue ECG tracings from a 1990s RCT, finding more than 10% had QTc over 500ms. This is not consistent with other reports on the subject. No torsade cases were reported in the study groups.

A review of the world literature by Justo (ref below) found only 40 documented cases, 85% of whom had two or more risk factors. Few of these reported cases bear much similarity to those commencing 'normal' clinic or community addiction treatment. The QT/torsade cases tend to be significantly older, female sex, and to involve co-medications, very high methadone doses (up to 1200mg daily or ten-fold 'normal' doses) as well as certain metabolic (potassium or magnesium deficiencies) and genetic states (familial long QT syndrome).

I believe that it is now possible to restate unequivocally that 'normal', guideline-based methadone treatment is safe and effective. The cardiac arrhythmia issue appears to be based on a combination of factors rather than a consequence of standard methadone treatment. Knowing the other risk factors, most cases could probably be avoided using good clinical practice (see Sticherling). Routine pre-treatment cardiographs would have been unlikely to have detect any of these latter cases.

Even in the face of a dearth of relevant case reports, some have given advice to avoid methadone without due consideration of its benefits and the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko). While methadone-induced torsade clearly can occur, the numbers appear to be exceedingly low and would probably be swamped statistically by reductions in endocarditis cases alone in those taking methadone (these and other benefits are eloquently reported by Krantz in 2001 - ref below).

In practical terms, this means that existing methadone patients needing other strong medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should be recommended a cardiograph, just as they should have electrolytes, liver function tests, etc performed as a matter of clinical course.

We need to ensure that as clinicians we continue to ask the question: what is the evidence?

Comments by Andrew Byrne ..

http://www.redfernclinic.com/#news

References:

Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006;101:1333-1338

Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282-285

Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml

Dr Mori Krantz on cardiac protections in methadone treatment. 2001.

2008-11-08T16:53:00.008+11:00

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml (Archive accessed on 25/10/08 excerpt herewith)

A.T.F. Volume X #4 Fall 2001

Clinical Concepts- Cardiovascular Health in MMT Patients

By Mori J. Krantz, MD*

According to current estimates nearly 61 million Americans have one or more types of cardiovascular disease, including coronary artery disease (CAD), congestive heart failure, and hypertension.[1] Methadone maintenance treatment (MMT) patients are clearly part of this larger demographic, and there are unique clinical characteristics in this group warranting special attention.

High Risk, Less Access

Patients entering MMT are a very high-risk population from a general health maintenance standpoint. As a rule, patients who use illicit drugs expose themselves to a number of health risks, and are less likely to regularly interface with the healthcare system. An increased reliance on emergency services and a lack of integration into healthcare delivery systems create a backdrop for poor outcomes.

The literature confirms that barriers to high quality care for cardiovascular disease are greater in vulnerable patient populations, such as minorities and the poor. A great many MMT patients fall into both of those categories.

For example, African Americans and low-income patients are less likely to receive care by a cardiologist. In contrast, white race, higher income, and college education independently predict care by a cardiologist.[2]

Available data suggest that the gap in cardiovascular disease mortality between the poor and uneducated versus the wealthy and well educated has not lessened and may be widening. The National Conference on Cardiovascular Disease Prevention concluded that to attain the goals set forth by the U.S. Surgeon General�s Healthy People 2010 initiative, we should focus on reducing disparities in health status on the basis of race, ethnicity, and socioeconomic status.[3]

To make matters worse, mainstream physicians often stigmatize MMT patients. This further distances these patients from regular, preventive health care services.

Some Specific Cardiac Risks

Endocarditis

Intravenous drug users (IVDUs) are at high risk for developing infections of their heart valves (infective endocarditis). These infections are a direct result of bacteria entering the bloodstream at the skin site of injection.

Acute infection accounts for the majority of hospital admissions among IVDUs and endocarditis is found in 10% of these episodes.[4] Most of these patients have no pre-existing cardiovascular disease.

The symptoms of this disorder may include persistent fever, chills, sweats, muscle and joint aches, malaise, and back pain.[5] These symptoms are invariably preceded by an episode of intravenous drug use.

Endocarditis has very high morbidity and mortality. It can necessitate extended intravenous antibiotic therapy and in many patients will require complex heart valve surgery or even valve replacement. Other consequences of endocarditis include brain abscess, kidney failure, and death.

MMT offers substantial protection from this deadly disease by eliminating or dramatically reducing the amount of illicit drug use. In our local hospital experience during 2000-2001, practically none of the heroin-abusing patients admitted with endocarditis were in methadone treatment programs.

Furthermore, in my oversight of hundreds of MMT patients during nearly a decade, I have encountered only 3 cases of endocarditis in that population. This evidence is anecdotal and retrospective, but supports the common sense notion that methadone treatment dramatically reduces the risk of endocarditis in IVDUs.

Coronary Artery Disease (CAD)

CAD is the number one cause of death in the Western world [1] and MMT patients are no exception. These patients may be at particularly high risk given that as many as 90% of them smoke tobacco, which is a known risk factor for CAD.[6]

Additionally, cocaine abuse is seen with some frequency in this population. Cocaine use has been linked to the development of arrhythmias, CAD, heart attack, and death.[7]

Despite the uses of tobacco and cocaine in MMT patients there have been no published reports documenting a higher overall incidence of cardiovascular disease in these patients. In my MMT practice, there are very few patients with established CAD. This is remarkable, given the fact that a significant proportion are beyond 50 years of age and many continue to smoke cigarettes.

Is there a possible explanation for this relatively low incidence of CAD in MMT patients?

The evidence is not clear. However, there is some pharmacologic data suggesting that methadone may exert a calcium channel blocking effect.[8] Calcium channel-blocking medications lead to slower heart rates and reduced cardiac work, and these agents are effectively used to treat CAD patients who develop symptoms of angina (chest pain).[9]

Also, opiates, including methadone, are known to reduce blood pressure and slow the heart rate. Morphine, for instance, is a commonly used medication to treat hospitalized patients who experience a heart attack.

Thus, due to these properties, methadone is theoretically protective in preventing or reducing cardiac ischemia (lack of blood supply to the heart).

Cardiac Arrhythmias

There is no compelling evidence in the literature to suggest that methadone treatment is a direct cause of sudden cardiac death or fatal heart rhythm disturbances.

In clinical practice, the risk of cardiac arrhythmias attributable to these treatments currently appears to be quite small. Future research and accurate incidence data will help clarify any contribution of opioid-agonist therapies to arrhythmia risk.

MMT Minimizes Cardiac Risks

Ongoing participation in MMT affords patients many heart health benefits. For one thing, these patients have significantly greater access to preventive cardiac-health services than opioid-dependent persons not in treatment.MMT patients are provided periodic monitoring of their blood pressure and pulse. Vital signs are obtained upon admission, during yearly physical exams, and during dose changes.

In my experience, this has offered a tremendous opportunity to screen patients for hypertension and then provide adequate treatment. Hypertension afflicts 50 million Americans; it is a leading contributor to CAD and the number one cause of stroke.

In my practice, a full lipid panel is obtained annually in all patients to check cholesterol levels. Those with elevated levels can be offered effective treatment with cholesterol-lowering medications, which have clearly been shown to reduce the risk of heart attack and death in patients who are at high risk.[10-12]

Finally, patients in MMT have access to frequent professional counseling, which presents ideal opportunities for discussing the importance of smoking cessation for long term cardiac health. The most common cause of death in smokers is coronary artery disease (CAD).

Stopping smoking dramatically reduces the risk of future heart attack or death. We regularly counsel patients on tobacco risks and many are able to quit or significantly reduce tobacco consumption as part of comprehensive treatment plans.

In conclusion, from a cardiovascular perspective, methadone is a safe medication and MMT program staff can perform vital roles in providing effective cardiac risk-reduction services.

References:

1. American Heart Association. Heart and Stroke Statistical Update; 1999.

2. Auerbach AD, Hamel MB, Califf RM, et al. Patient characteristics associated with care by a cardiologist among adults hospitalized with congestive heart failure. J Am Coll Cardiol. 2000;36:2119-2125.

3. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke and other cardiovascular diseases in the United States. Findings of the National Conference on Cardiovascular Disease Prevention. Circulation. 2000;102:3137-3147.

4. Murphy JG. Mayo Clinic Cardiology Review. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000:412.

5. Mandell GL. Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone; 1995:748.

6. Practitioner panel: methadone and heart health. Addiction Treatment Forum. 2001;10(3):5.

7. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med. 2001;345:351-358.

8. Lee CH, Berkowitz BA. Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip. J Pharmacol Exper Ther. 1980;215(1):259-265.

9. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina. J Am Col Cardiol. 1999;33:2092-2190

10. Long term treatment with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.

11. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The 4S trial. Lancet. 1994;344:1383-1389.

12. Sacks FM, Pfeffer MA, Moye LA, et al. Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.

*Mori Krantz, MD is Director of the Cardiovascular Risk Reduction Program, Denver Health Medical Center, and Assistant Professor of Medicine and Cardiology, University of Colorado.

More alarmist speculation on QT 'problems' yet still no incidence of actual complications. Smoke and mirrors.

2008-10-06T20:38:00.010+11:00

QTc Interval Prolongation and Opioid Addiction Therapy. Baker WA, Krantz MJ. Archives Internal Medicine (letter) 2008 168;14:1502

Dear Colleagues,

In this letter Baker and Krantz applaud Wedam et al's 'commendable' 'addition to the medical literature' which found QT prolongation in 23% of methadone subjects. In fact these researchers found much the same as Janet Lipski's report from 1973 (34%). Thus it is clear that a substantial minority of methadone patients have modest prolongation of QT intervals of uncertain significance.

Baker and Krantz then express the unsurprising deduction that if a lower cut-off for QT prolongation were used, a correspondingly higher proportion of prolongation subjects will result (up to 50%). The clinical significance of these observations, if any, is not detailed. And none developed tachycardia.

Krantz has wrongly cited Lipski's study as being (at least in part) to investigate sudden deaths in methadone patients. In fact, Lipski and colleagues were concerned about heroin deaths and the QT findings in methadone patients were incidental. When this mistake was pointed out in Lancet, Krantz in reply ignored the matter and turned to increasing deaths of non-addiction treatment (pain) cases in America more recently (Mehler 2007).

Specifically, Krantz writes that Lipski's study was aimed at investigating 'a perceived increase in the risk of sudden death in heroin addicts, even in those successfully treated with methadone' in 1973 in New York (Krantz MJ 2006). From the title and opening lines it is clear that Lipski and colleagues were actually concerned over deaths in heroin users where sometimes blood levels were not particularly high, an issue raised by long time city coroner Dr Milton Helpern (see ref). They performed cardiographs in new methadone applicants who had used street heroin in the previous hours or day(s) to see if there were any electrical disturbances which might explain the sudden deaths in heroin users.

Unlike in his first paper on this subject, Krantz now treats QT prolongation in isolation as if it were a complication in itself, avoiding discussion of torsades or other cardiac events. And like most of the other studies, Wedam and colleagues report no symptomatic heart disease whatever and, most importantly, no sudden deaths. Over a period of 30 years of intensive, supervised prescription of methadone only one single case of arrhythmia was reported to the FDA (Pearson). So while torsades or ventricular fibrillation occur in methadone patients, the prevalence must be very low and possibly near to the rate in the general population (estimated to be 1 in 2000 - see Smith W).

This laudatory letter is just another 'weak link' in the case put by Krantz that due to potential cardiac complications, methadone treatment needs to be reviewed, especially when used in high doses. He recently noted 'with consternation' (hardly a scientific term) that higher doses were being used in addiction clinics in his own state, something most public health specialists would have applauded (D'Aunno). Many rigorous studies indicate that higher doses protect dependency patients from significant and measurable events (overdose, viral disease, criminal behaviour, depression, etc). Dole's seminal study of methadone treatment reported up to 180mg daily with excellent results and no serious side effects.

To my knowledge there have still been no reported series of confirmed case reports of cardiac complications (eg. torsades-de-pointes) in patients receiving methadone treatment for addiction under existing guidelines. Krantz emphasises the proven benefits of MMT yet at the same time questions this established, evidence-based practice, emphasising a difficult therapeutic 'trade-off'. Yet this is before there is documented evidence of a problem existing and despite 30 years of careful research showing safety and effectiveness. Further, there has been no analysis of the costs and benefits of any suggested alternative strategies such as low dose methadone or transfer to buprenorphine. Krantz has also apparently had minimal input from dependency specialists. Few non-cardiologists would be so bold regarding advice on heart treatments.
Dr Krantz's widely publicized views have had the consequence of denigrating methadone as a treatment for both addiction and chronic pain. I can find no evidence suggesting that any cases of cardiac complications resulting from methadone treatment have been avoided as a result. The literature reveals only flimsy and conflicting evidence - most of it retrospective - of an association of methadone and cardiac events. Some have reported a lower cardiac risk (Marmor 2004).

Krantz's articles, letters and personal communications show a clear 'disconnect' between his earlier findings and the sentiments he has expressed more recently. While his earlier findings relate mostly to pain patients, he has strongly targeted an addiction treatment audience for his communications and further research (eg. Krantz 2007). His advice, which has changed over the years, has involved (1) the need (or otherwise) for a cardiograph before starting treatment, (2) the avoidance of methadone where possible and (3) the avoidance of high doses where methadone is used. His other recommendations are purely generic in recommending careful history and physical on each patient and acting on any evidence of cardiac risk. While this is important, it is probably no more important than acting on evidence of infectious disease, overdose risk, liver disease, allergies, mental illness, etc, etc.

The potential risk of cardiac side effects must be balanced against the unequivocal benefits of methadone maintenance to those who need and want it for their condition. There need be no 'competition' with buprenorphine which is an excellent alternative with certain benefit and certain disadvantages in the opiate treatment population.

Comments by Andrew Byrne ..

References:

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557

Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366

Mehler PS, Krantz MJ. Authors' reply. Methadone and QTc prolongation. Lancet 2007 369:366-7

Smith WM. Cardiac repolarisation: the long and short of it. MJA 2008 188;12:688-689

Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Saf. 2005 14;11:747-753

D'Aunno T, Folz-Murphy N, Lin X. Changes in Methadone Treatment Practices: Results from a Panel Study, 1988 - 1995. American Journal of Drug and Alcohol Abuse 1999 25;4:681-700

Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965;193:646-50 '193(8) 80-84'

Helpern M. Fatalities from narcotic addiction in New York City: incidence, circumstances and pathologic findings. Human Pathology 1972 2:13-21

Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Marmor M, Penn A, Widmer K, Levin R, Maslansky R. Coronary artery disease and opioid use. Am J Cardiol. 2004;93:1295-1297

Leavitt S. Methadone: facts and fiction ... http://www.atforum.com/SiteRoot/pages/current_pastissues/2007winter.html

[This summary has been up-dated, omitting an incorrect sentence.]

Subject: Methadone works in American prisoners who are addicted - no surprise.

2008-09-03T21:34:00.007+10:00

A randomized clinical trial of methadone maintenance for prisoners: findings at 6 months post-release. Gordon MS, Kinlock TW, Schwartz RP, O'Grady KE. Addiction 2008 103;8:1333-1342

Dear Colleagues,

These researchers found, predictably, that offering methadone maintenance treatment (MMT) to released prisoners with a history of opiate addiction was feasible, safe and effective, just like it is in the community generally when done according to established guidelines. They compared counselling with/without MMT, finding less heroin use and less criminal activity at 6 months after release in those offered MMT. Treatment retention was also higher.

This is yet another example of American clinical practice which is decades behind other countries. And this is despite heroin addiction has been accepted as a �brain disease� by the White House and methadone/agonist treatments are now approved in every state. However, for those in the US prison system these maxims do not apply for some reason. Note that this study was not published in an American journal.

Almost uniquely, in New South Wales, prisoners have had access to methadone treatment for over 20 years. It was initially introduced in the 1980s as a pre-release measure to address the high rate of overdoses in that group. There is now a copious world literature on the subject, largely very positive. Methadone for prisoners has now been introduced in many other jurisdictions, although rarely �across the board� as occurs in New South Wales.

Thus a trial which gave some subjects no access to such treatment would be unethical, unnecessary and cruel in a �normal� jurisdiction. Yet in America, despite a large drug budget and constitutional protections, denying prisoners appropriate treatment seems to be �business as usual�. These researchers should be commended for trying to buck the trend. They write that there is an �urgent treatment need� and one only hopes that something is done for the sake of the prisoners, their families and the general community where the adverse consequences currently must be enormous.

Comments by Andrew Byrne ..

Surgery web page: http://www.redfernclinic.com/

Lofexidine for withdrawal symptoms works ... (but detoxification usually doesn't).

2008-08-21T20:17:00.013+10:00

A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal. Yu E, Miotto K, Akerele E, Montgomery A, Elkashef A, Walsh R, Montoya I, Fischman MW, Collins J, McSherry F, Boardman K, Davies DK, O�Brien CP, Ling W, Kleber H, Herman BH. Drug and Alcohol Dependence 2008 97;1-2:158-168

Dear Colleagues,
This may be a world record for delays in clinical research. Dr Kleber first wrote about the possible effectiveness of lofexidine for withdrawals in 1981 (ref 1). Now, with a stellar cast of senior American colleagues he has produced a small and unsatisfactory report (n = 68, only 17 completers) in the course of attempting to have the drug registered in the United States. With modest but apparently significant benefits noted in a 4 day regimen using the drug, the trial was dramatically called off just over half way thru. This is normally only done where it is considered unethical to continue to using placebo. However those receiving lofexidine also suffered 4 significant side effects, each probably related to hypotension. The benefit of lofexidine was a reduction in withdrawal symptoms/signs from 30 to 20 and an increase in retention from 15 to 38%. While these differences are substantial, the same or better might have been obtained with clonidine, diazepam or even �hospital brandy�. Additionally we know that this intervention (detoxification from opioids) has a ~90% failure rate and also a substantial mortality in the period following.

Doctors and health workers can recommend established, effective treatments, yet detoxification should only be initiated by the patient in my view � both due to its inherent dangers and the lack of a proven strategy to achieve this noble goal. It is hard to justify detoxification from opioids in pregnancy, for example, and some would say it is unethical. On the other hand, patients are perfectly entitled to request services which doctors would not normally actively recommend (abortion, contraception, euthanasia, circumcision, etc). As long as the detoxification is patient-initiated, and the patients are aware of the alternatives and the relative risks then there can be no ethical problem.

The authors give a comprehensive literature review, pointing out that there is little current evidence favouring lofexidine over clonidine regarding effectiveness yet the former seems to have less hypotensive side effects in some trials. Some quoted trials compared lofexidine with buprenorphine, a ludicrous comparison in my view. It would be like comparing aspirin with penicillin for bronchitis. So after 25 years I am still not convinced that lofexidine is a sure-thing in detoxification. One might also think that if it were indeed effective that there might be more anecdotal evidence as well as a possible black market in the drug (at least in the UK).

Comments by Andrew Byrne .. http://www.redfernclinic.com/

Washton AM, Resnick RB, Perzel JF, Garwood J, Gold MS, Pottash AC, Annitto WJ, Extein I, Kleber HD. Lofexidine, a clonidine analogue effective in opiate withdrawal. Lancet 1981 317;8227:991-993

Concord Seminar summary on Adult ADHD in those with substance use disorder.

2008-08-21T20:17:00.012+10:00

Concord Dependency Seminar Tuesday 22nd July 2008

Adult ADHD & Substance Use Disorders � Dr Julian Trollor

Dr Julian Trollor is Senior Staff Specialist Neuropsychiatrist at the Neuropsychiatric Institute, Prince of Wales Hospital and Senior Research Fellow of the Brain Ageing Program at the University of New South Wales. He established a clinic for the assessment of adults with possible ADHD in 1995. This clinic now operates as a tertiary service, providing second opinions in difficult cases.

Dr Trollor began his presentation by recounting his own experience of filling out a pop-up box which once appeared unbidden on his computer screen. Dr Trollor (who does not have ADHD) was informed...."the responses you have provided indicate that your symptoms may be consistent with Adult ADD. It may be beneficial for you to talk with your healthcare professional about an evaluation.� The pop-up was sponsored by a manufacturer of a pharmaceutical for ADHD.

Dr Trollor pointed to the growing popular awareness of Adult ADHD (A-ADHD), with �self diagnosis� being common, shared controversy with its childhood counterpart, and community fears about treatment with a potential "drug of abuse".

ADHD is a "neurodevelopmental disorder of childhood onset characterised by impairments in cognitive function (inattentiveness), excessive motor behaviour (hyperactivity) and impaired behavioural regulation (impulsivity).� It is common, with high co-morbidity, and it is often overlooked, despite being relatively easily treated, with treatment improving outcomes.

Evidence for the validity of the entity A-ADHD has increased greatly in the last decade and is found in cross sectional, longitudinal and epidemiological studies, family & genetic studies, and neuro-psychological, -physiological, -endocrine and -anatomical studies.

Despite progress in understanding of A-ADHD, clinical diagnosis remains problematic: there is no single criterion marker; the core symptoms are dimensional (or spectrum) rather than categorical; co-morbidity can confound diagnosis; the requirement for retrospective childhood diagnosis may create difficulties; the key descriptors are ubiquitous; and the requirement for �significant impairment� is arbitrary. Diagnostic tests are often used but they lack specificity.

The DSM IV CRITERIA are listed in the appendix (see Redfern Clinic website). Briefly, the person must have (for the primarily inattentive type) six or more inattention symptoms as well as (for the combined type) six or more hyperactivity/impulsivity items for at least 6 months to a degree that is maladaptive. Some symptoms must be present before 7 years of age, impairment must be present in at least two settings, and symptoms do not occur exclusively during the course of a pervasive developmental disorder, psychotic disorder and (as always in DSM-IV) are not better accounted for by another mental disorder.

Symptoms can be grouped in four types:

1. attentional, with difficulty sustaining attention (during lectures, reading, in conversation, at work), easily distractability (eg by extraneous sounds, activity), day-dreaming, making careless mistakes - the primarily inattentional type is more common among women.
2. organisational, often losing things, forgetting day to day activities or appointments, having difficulty organising tasks, following verbal instructions - these may be more pronounced in unstructured settings, and therefore may become more problematic in adults, upon leaving a structured setting like school/college.
3. hyperactivity, being always �on the go� physically, being fidgety or restless, having difficulty relaxing, having racing thoughts or many ideas, taking on multiple tasks at once without finishing many.
4. impulsivity, talking excessively, making tactless comments, interrupting conversations, difficulty waiting turn, taking risks (eg driving, thrill seeking, financial risks), explosive temper, irritated easily by minor frustrations, quick mood changes.

Hyperactivity may be less marked in adults in whom the hyperactivity may be more a phenomenon of mental cluttering, akin to a sense of continuous "noise" - quite distinct from anxiety. A meta-analysis of follow-up studies of children with ADHD showed an age-dependent decline in ADHD symptoms: 65% experienced partial remission in adulthood, with full ADHD diagnosis persisting in approximately 15%. The severity of ADHD symptoms in childhood appears to predict persistence into adulthood.

A large cross-national survey estimated adult ADHD prevalence across ten countries to be 3.4% (range 1.2-7.3%); one US study estimated current prevalence of adult ADHD at 4.4%. As Dr Trollor pointed out, these estimates suggest that A-ADHD is one of the more common mental disorders.

ADHD is a condition with a high genetic loading - family studies suggest 80% of ADHD symptoms can be attributed to genetic factors - with genetic-environmental interactions also playing a role, especially disrupted attachment, early abuse, and chaotic environment. The candidate genes are those involved in motor activity and attentional processes, and include DAT gene (SLC6A3), COMT (Catechol-O-methyltransferase), DBH (Dopamine beta-hydroxylase) and dopamine receptors (especially DRD4), however no single gene accounts for more than 5% of the phenotypic variance of ADHD.

Adult ADHD has major consequences: adults with ADHD are less likely to be employed full-time and more likely to have unstable work records, have significantly lower household income, have fewer close friends, more difficulty sustaining relationships and higher likelihood of having contracted a sexually transmitted disease. They are more accident prone (more traffic violations, severe accidents, more likely to be �at fault�), and have higher medical costs.

Diagnosis

In making a diagnosis, it is important to consider the motive/catalyst for presentation, whether owing to legal & forensic issues, a transition from a more to a less structured environment, or on cessation of substance use. Some adults come forward for assessment following diagnosis of their children. Self diagnosis is not a reliable indicator of the presence or absence of ADHD

The diagnostic pathway is to assess current symptom profile, severity and impact, to establish and corroborate childhood diagnosis (from self-report, parental and school reports, previous psychological or medical assessments) and to evaluate co-morbid (or diagnostically confounding) conditions - people with ADHD have increased risk of a diagnosis of antisocial personality disorder, of anxiety disorders, major depression and substance use disorders.

Bearing in mind the partial remission of ADHD in many or even most adults, it is important to consider the actual impact of symptoms on the patient's social, occupational, educational or family life as well as their current coping strategies. Many people cope well with or are untroubled by having features of ADHD and it is not uncommon for people with ADHD to be less likely to complain than their partners or family.

Establishing a retrospective childhood diagnosis is often a challenge, especially for people with major psychosocial problems including substance use disorder (SUD) who may have chaotic histories and be estranged from family. Where possible, informant interview can provide corroboration of the nature and extent of both current and past symptoms. Evidence can be gleaned from academic records, number and type of jobs, history of impulsive infringements, self esteem and interpersonal problems (resulting from impulsivity, poor anger control and organisational skills), and patterns of drug use which may suggest self-medication of symptoms. Sometimes there is a suggestive �paradoxical response� to street amphetamine - ie a calming effect rather than stimulation.

Further assessment may include the use of rating scales, and require physical examination, bloods testing including thyroid function, urine toxicology, EEG, CT/MRI of the brain (a history of head injury may be common in people ADHD owing to their accident proneness, but brain injury may also sometimes mimic ADHD symptoms), and neuropsychological examination including CPT. Not all of these will be required in every case.

Substance Use Disorders and A-ADHD

The epidemiological relationship between substance use disorders (SUD) and A-ADHD is bi-directional, with increased rates of SUD in ADHD clinic samples (for alcohol 17-45%, other drugs 9-30%) and of ADHD in SUD clinic samples (around 25%).

Relative risk of SUD in follow-up of ADHD cohorts is increased up to five-fold, with earlier and increased use of alcohol, tobacco and other substances in adolescents with ADHD compared to controls, and ADHD in childhood and adolescence a significant predictor for later substance use - the risk is greater if the individual has conduct disorder or mood disorder. The relationship of with childhood ADHD is strongest for tobacco smoking, and it is likely a sub-group of individuals with ADHD self-medicate with tobacco: nicotine has been successfully trialled as an intervention.

People who have both SUD and ADHD have poorer outcomes. However, people treated with stimulants in childhood and/or adolescence have an equivalent or lower incidence of SUD compared to those untreated, and the use of stimulant medication to treat people with ADHD does not increase the risk of developing substance use disorder.

It is preferable to perform diagnostic assessment during long-term abstinence (whereby opioid substitution treatment with abstinence from other problematic substance use can be considered abstinence) and, as with other co-morbidities, active SUD should be addressed prior to specific ADHD treatment. It should be borne in mind that ADHD medications have no demonstrated efficacy for the treatment of ADHD where there is co-morbid SUD, nor have studies been conducted of use of psychosocial interventions.

Dr Trollor recommended (and feedback is welcome about) the Draft Guidelines for the Assessment and Management of Attention Deficit Hyperactivity Disorder (National Health and Medical Research Council and the Royal Australasian College of Physicians) accessible at http://www.racp.edu.au/ ( follow link under �announcements�).

From these guidelines, the following are some key recommendations for best practice for assessment and diagnosis of ADHD in adults when co-morbid SUD is present:

People with personality disorder and/or substance abuse should be referred for evaluation of ADHD if they present with a significant level of hyperactivity / impulsivity accompanied by inattention.
Medication treatment for ADHD co-morbid with substance misuse should only be provided by a medical practitioner with expertise in both conditions.
ATX should be the first medication trialled if there is co-morbid substance abuse.

Management of A-ADHD

Dr Trollor's approach to management is to create a hierarchy for interventions, generally treating pressing co-morbid conditions first, as these may increase the expression of ADHD symptoms, and providing for further observation in cases where the diagnosis is uncertain.

Specific A-ADHD treatments include: education (through internet, books, support groups); drug therapies (methylphenidate 0.3-1.0mg/kd/day; dextroamphetamine 0.2-0.5mg/kg/day, desipramine, imipramine 25-100mg; and others including atomoxetine, buproprion, MAOI, lithium, venlafaxine, SSRI, CBZ, clonidine,); cognitive & other behavioural therapies to increase organisational skills, impulse control, and self monitoring.

Psychostimulants

Against a backdrop of a rapid rise in prescription rates, unease about use of stimulants arises from several considerations. With continuation of treatment from childhood there are potentially decades of exposure to stimulants. Should this be open-ended? What are the risks of psychological dependence, and harmful use/dependence given the high psychosocial and substance comorbidity in adults with ADHD?

Stimulants are effective in adults with ADHD although the number of studies is small. Available efficacy data for adults give response rates between 25 and 78 percent for methylphenidate (MPH), in a similar dose range as for children, and a modest literature suggest similar efficacy for dexamphetamine (DEX) - there is no direct evidence to support use of high or very high doses of MPH or DEX.

Current evidence suggests the use of stimulant medication to treat people, including children, with ADHD does not increase the risk of developing substance use disorder. However, there is evidence of diversion and misuse of prescription medications for ADHD among school students and college students, with between 16 and 29 percent of students on stimulant medication having been asked to give, sell or trade their medication at some time. While some individuals report using diverted stimulants to self-medicate for ADHD symptoms, others use them to enhance performance, or for their euphorogenic effects.

Dr Trollor advises stimulant treatment should be reserved for people with pervasive symptoms causing significant difficulty, and where clear goals can be identified, the patient is motivated to work on broad range of solutions and where adequate follow-up and monitoring is available.

Stimulant treatment is relatively contraindicated where ADHD symptoms are present but are not the primary problem, where the clinical diagnosis conflicts with patient �self-diagnosis�, where there is severe co-morbid psychosis or mood disorder, or continuing problematic substance use. One warning signal is where the patient has many past prescribers of stimulants.

Non-stimulants, long-acting stimulants or anti-depressants are preferred to short acting stimulants, which are strongly reinforcing drugs. Pharmacotherapy should be trialled for effectiveness on an individual basis and carefully monitored for benefits and adverse effects; a contract for stimulant treatment may include regular review (possibly including urine toxicology - a moot point at this seminar) and an ongoing goal of abstinence.

Atomoxetine is a predominantly presynaptic noradrenaline transporter inhibitor without euphorigenic and reinforcing properties, with several studies showing benefit in children and adults. There is also a small number of studies for buproprion (an indirect NA & DA agonist), likewise with a low �abuse potential�.

Stimulant Dose

There are no trials of �high� or �very high� stimulant doses in adults with ADHD, and low dosing appears to be appropriate for most individuals. Dr Trollor recommends cautious titration eg commencing at DEX 0.15mg/kg/day or MPH 0.3mg/kg/day and aiming for DEX < 0.5mg/kg/day or MPH <1.0mg/kg/day. For the stimulant-naive patient, Dr Trollor recommends commencing DEX 5mg mane & midi (or MPH 10mg mane & midi). Smaller doses may also be required if patient on other psychotropics or has comorbid anxiety or sleep disorder.

Animal models demonstrate a biphasic response to DEX: low doses (DEX < 1.0mg/kg) reduce, and higher doses DEX 1.0-5.0mg/kg increase, locomotor activity, which may correspond to a �high� in humans.

As stimulants lower the seizure threshold in animals, are associated with (transient) emergent �tics� in 10% of stimulant treated children, elevate pulse and blood pressure (low dose stimulants increase BP by an average of 3-5mmHg) low doses and close monitoring are indicated where there is co-morbid tic disorder, hypertension or seizure disorder. Although psycho-stimulants can induce paranoid delusions, auditory & visual hallucinations, this is mainly seen with intravenous use.

Inter-individual pharmacokinetic variability (especially for MPH, where peak serum levels vary up to five-fold) provides an argument for a trial of higher doses in some individuals with non response to low doses - monitoring stimulant levels may be helpful, as may a second opinion.

One difficulty is how to monitor response, whether subjectively or using self rating scales, observer rating scales, or neuropsychological/neurophysiological testing. Many people will feel better using low dose stimulants, regardless of whether they have ADHD or not. This conundrum was illustrated in a complex case study presented in the second half (see separate posting).

Some parting questions: how can such a prevalent condition, especially in children, be conceived of as a disorder? In an evolutionary sense, does ADHD confer an individual or collective biological advantage? In an anthropological sense, does it represent a failure of adaptation to modern life?

Summary by Richard Hallinan, based on Dr Trollor's presentation and powerpoint file.

Concord Dependency Seminar Series, Tues 20th May 2008.

2008-07-07T11:28:00.006+10:00

Treating the Addicted Brain: Agonists, Antagonists and Modulators.

Speaker: Stephen Jurd, Psychiatrist, RNSH and RANZCP director of training.

Dear Colleagues,

Dr Jurd commenced by almost stating the obvious: the problem of addiction starts with the brain. The origin of the behaviour does not lie in reasoned thoughts, which are late in evolution, but in reward pathways, organised in the hind-brain. From this ancient part of the nervous system, the responses are transferred to the frontal lobes where conscious thoughts, decisions and deductions are made regarding diverse ways to satisfy the more primitive urges. While most reward pathways are related to survival and procreation, drug use mimics such responses chemically, causing satisfaction, pleasure and desire to repeat the experience. The concept of craving was discussed in depth - it is not easy to define and perhaps best to simply call it ‘the motivation to use the drug’.

Equally, a definition of clinical or behavioural ‘salience’ is difficult, yet it is crucial to understanding and defining addiction, first clearly done by the redoubtable Griffith Edwards. Dr Jurd suggested one way to define ‘salience’ is to look at the person’s ‘top-40’ items of interest which for non-addicted people would range across a variety of things from food to music to work, family and hobbies. For the compulsive drug user or alcoholic, gambler, etc this would be a very short list, largely related to their drug or behaviour of interest. This is the ‘narrowed repertoire’ of drug use behaviour.

We were told of a recent pivotal study by Anne Rose Childress working at Philadelphia with Charles O’Brien’s group. They found significant brain responses on real-time PET scanning from ‘split-second’ projections of drug-related images, despite them not being seen or recognised consciously in a group of 22 long term cocaine users. These were also closely correlated with drug, violence or sexually explicit images shown several days later in relevant cases (and not in controls). So, despite not realizing it at the time, these long-term cocaine users’ brains had registered the brief images unconsciously and committed them to memory. Thus for the first time we have evidence of addiction related cues and/or priming occurring ‘outside awareness’. There was also some corroboration of this remarkable finding from another study involving similar brain responses to cues for ‘‘unseen’’ monetary rewards (Pessiglione). The advertising industry may have known of these matters for years!

Decisions in adolescence are agreed to be most important in learning and memory, and some regard drug addiction as an ‘illness of youth’ [cf Stanton Peele ref below]. We were told that there are maximal numbers of synapses in the adolescent brain which then decrease with age. Synaptic structures are highly dynamic, and adult brains are able to make new cells. Both exercise and stroke can lead to increased neural production and brain cells move towards the injury site. All of this is contrary to traditional teaching about the CNS being unable to repair or replace damaged areas.

Addiction is not simply withdrawal, but craving, the inclination to use, the very nature of dependence and a whole clinical syndrome which persists, sometimes well after drug/alcohol use has ceased. DSM defines ‘early remission’ as up to 12 months. We were told that addiction is common, has social and medical impacts, as well as numerous psychiatric complications.

There must be a system of reward, hard-wired into the mammalian brain where intuitively certain people and/or events are memorable, striking and causing a ‘yearning’. And such a system would just be normal. Dopamine has been identified as the relevant neurotransmitter.

However one defines them, ‘cravings’ lead to the conscious motivation to seek and use the drug, with a euphoric recall, and with often pleasant associations. “This feels sooo … good”. This is the case for both stimulatory and sedating drugs. Dopamine from the nucleus accumbens is crucial for reinforcement and reward; attention, memory and learning. These mesolimbic pathways are not unique to opiates but are similar for nicotine, alcohol, benzodiazepines, stimulants, etc.

The next result is to trigger ‘yearning’ for the experience to be repeated. Drugs excite the reward pathway and this then leads to addiction. At a certain point the individual becomes aware of the dangers and the illogical nature of their behaviour, yet continues with it. Similarly, they may be able to rationalise with a counsellor, doctor or family member that it is harmful to continue (cortical), yet the behaviour persists (driven by limbic pathways).

We were shown a familiar brain diagram from The New England Journal of Medicine: Neural Reward Circuits Important in the Reinforcing Effects of Drugs of Abuse [Cami J, Farre M. 2003 349:975-986].

Stimulants may also cause direct stimulation of dopamine production. On the other hand, sedatives inhibit the production of inhibitors of dopamine and so lead to increased dopamine concentrations. Thus in the reward pathway all drugs lead to increased dopamine at critical points in the hind-brain and so lead to increased learning, attention and focus on the drug use.

Aversive Agents

Disulfiram does not affect the dopamine pathway, but has its action through the frontal lobe using logic and reasoning. With this the person learns that “it is dumb to take alcohol with this”, and so even when cravings are strong the addict may choose not to consume alcohol, knowing the likely consequences.

Agonists/Replacements

Most of these provide a longer acting form of the drug which avoids the cycle of intoxication and withdrawal. For example methadone is a long half life drug, decreasing heroin use and improving quality of life. The person learns that they simply do not need to use additional opiates as there is little gain.

Nicotine is the same drug, with a safer delivery of drug via patches, gums and inhalers. Post-myocardial infarct patients do better on patches.

Dexamphetamine - there is no pharmacological basis to change to this from methamphetamine as the half-life of ‘dex’ is 10-12 hours compared to 9-15 hours for methamphetamine. A longer acting form may be more appropriate for addiction treatment.

Benzodiazepines – theoretically for alcohol but they are not satisfactory, both are disinhibitory agents, acting on GABA receptors.

Partial agonists

Buprenorphine (for opiate dependence).
Varenicline (a nicotine receptor blocker).

Antagonists

Naltrexone – a long acting opioid antagonist, works when taken but does not chemically modulate cravings for opioids (might do so psychologically according to Brewer). For alcohol with time it can modulate cravings but unlike disulfiram the person will not become ill if alcohol is consumed.

Rimonaband – cannabinoid antagonist - not yet available in Australia – used overseas for obesity(?).

Odansetron (Zofran) – serotonin-3 antagonist with promise for alcohol abuse in very low dose [see RCT Bankole Johnson link below].

Modulators

These take time to work, and act less on receptors but modulate other areas which then lead to change in receptors and/or their neurotransmitters.

Acamprosate modulates the balance of GABA. We were reminded that this drug is really only of benefit for those wishing to cease alcohol use completely whereas those on naltrexone are more likely to be able to manage controlled drinking better (although this is not approved under PBS prescribing criteria). In a similar way in depressives, SSRI drugs also take time to have their clinical effects, rather than a chemical effect on receptors which theoretically occurs straight away.

We were then brought back to the traditional in-patient treatment of alcoholism and drug addiction, something which is now rare as authorities have closed down many detox and rehab wards. The justification has often been that they were “not cost-effective”. Dr Jurd quoted the highly reputed “Project Match” which found double the rate of abstinence at one year in those who received an in-patient stay as part of their treatment when compared with those who only received out-patient services. Note that entrants were not randomised so the significance is limited to an non-causal association.

Two case histories were then presented and ‘work-shopped’ in some detail:

Case 1: A youth with excess alcohol use causing serious health, legal, and social problems.

Case 2: A middle-aged set-in-his-ways professional with smoking and alcohol excess with hypertension. He stopped nicotine after 12 months but unable to decrease his alcohol.

Summary written by Judith Meldrum and Andrew Byrne. Further details of the case histories and workshop discussion will be sent as a supplement later when time allows. See our summary of “The neurobiology of addictive behaviours” on web page: http://www.redfernclinic.com/c/2005/12/alcohol-pharmacotherapy-macquarie.php4 Web site: http://www.redfernclinic.com/concord/

References: Childress AR, Ehrman RN, Wang Z, Li Y, Sciortino N,,, O’Brien CP. (2008) Prelude to Passion: Limbic Activation by "Unseen" Drug and Sexual Cues. PLoS ONE 3(1): e1506
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0001506#pone.0001506-Pessiglione1

Johnson BA, Roache JD et al. Ondansetron for Reduction of Drinking Among Biologically Predisposed Alcoholic Patients. A Randomized Controlled Trial. JAMA (2000) 284:963-97

Peele S. The Surprising Truth About Addiction. Psychology Today (2004) May-June: 43-46 http://www.peele.net/lib/surprising.html

Pessiglione M, Schmidt L, Draganski B, Kalisch R, Lau H, et al. (2007) How the brain translates money into force: a neuroimaging study of subliminal motivation. Science 316: 904–906 http://www.sciencemag.org/cgi/content/abstract/316/5826/904

Concord Seminar summary: 'How not to be sued'. Speaker Prof Bob Batey.

2008-07-06T20:09:00.006+10:00

Subject: “Practising in Addiction Medicine: how not to be sued!”
Speaker: Professor Robert Batey.
Concord Seminar Tuesday 18th March 2008 7pm.
Held at Concord Hospital (Western Sydney, Australia), Conference Room No 1.

Professor Batey began by asking his audience to consider why this subject was being covered and also why he had been asked to speak on it. He pointed out that despite doctors being of a certain age and seniority, mistakes and miscalculations could still occur. A prevention strategy was essential using established safeguards. However, when these failed, such errors need to be dealt with appropriately and openly. This applies to doctors, nurses and all allied health professionals.
No amount of renown could avoid this issue. No connection with great physicians, great institutions or fine academic reputation could help when things go wrong. We were told that despite a love of the profession and hitherto keeping out of the way of lawyers, none of us should become complacent or over-confident that it would remain that way.
Connections with great physicians could help in one respect: by following their examples in what they taught about good medical practice.
The art and practice of medicine.
The value of spending time with patients.
The need to be ‘vulnerable’ rather than ‘all-knowing’.
The absolute necessity to know what you are doing while admitting any areas of uncertainty.
The reality that you might appear to be rude while still acting consistently and fairly.
Patients may accept mistakes if you demonstrate that your are sincere and competent.

We can all name some great physicians we have worked with but it would be hard to match Dr Batey’s list of mentors: Allan McGuiness, Charles Ruthven Blackburn, Sheila Sherlock, Mr Michael Stephens, Dr Dick Richards. Those who worked at Sydney’s Prince Alfred Hospital or Sydney University may know three of these.
Some behaviours which patients and colleagues may sometimes overlook include:
Aloofness.
Use of long phrases no one can understand.
Gruffness to the point of rudeness.
Late for rounds but never missing them.
However, this is contingent on the clinician displaying consistent excellence and reliability in the longer term, leading to the earning of respect.
In the field of Addiction Medicine there is another credential needed: A capacity to set boundaries. At this we were shown a slide of the Great Wall of China!
In order to demonstrate some ways NOT to practise we were shown some cases from 2007:
Mr TM
Presents with female partner
Both on methadone: 65mg and 50 mg respectively for >10 yrs
Receiving 4 take away doses.
Neither are employed at present but both had been working in local area 12 months ago.
No children at home

SO far so good but
They want to switch to oral Physeptone (methadone tablets) so they can just pick up scripts for 2 weeks supply.
They also admit to not sleeping well and to using benzodiazepines regularly.
No other major issues.

Main issue is a desire for increased “freedom”
Totally anti-buprenorphine as partner had tried to change and failed miserably
They talk constantly and when one stops to draw breath the other starts up
They have no insight into the issues
It is late in the day

You weaken and write their first script of physeptone tablets, enough for 5 days “to see how they go”.
No no no!
This is dangerous
It is unwarranted
It is indefensible
At this point……
Is there a way forward??
Mr JF:
40 yr old, unemployed hairdresser
Past heavy alcohol intake (120 gm/d as beer) Now nil
Lives alone, no contact with children
Had one admission for pancreatitis 8 yrs ago. Apparently this settled.
Now complains of abdominal pain on a daily basis

Taking:
Oxycontin 10 mg qid
Oxycontin 20 mg tds
Oxycontin 40 mg prn
Asks for proladone suppository twice a day to add to his pain relief program

You give him proladone

You have no idea what his pain is due to or indeed if he has pain at all.
He is dependent, he has a “dog’s breakfast” of a management plan.
BUT HE LOVES YOU for being so ‘caring’ !!!
The state pharmaceutical authorities may not be sympathetic - although after removal of the 2 month rule on opioid prescription in New South Wales in 2006 this may be ‘legal‘ even though it may be ‘poor medicine’.

Ms GG, aged 38.
Admitted to local hospital semi-conscious with signs of pneumonia.
Uncertain what is happening but assessment reveals:
Pneumonia of right lower lobe.
Obtunded with pin point pupils.
Injection marks L ante cubital fossa.
Poor nutrition.
Lives with husband and 3 children 10, 9 and 4.
She does not work, he is a motor mechanic.
No major past medical problems.
Both she and he are on methadone program.
She is on 80 mg/d and he 90 mg/d.
Both get 6 takeaway doses per week.
No safe storage sites at home
No urine drug screens performed in past year.
Pharmacist concerned regarding stability.
Why does she get 6 T/A’s….. “Well, my husband gets them”.
She responds to Narcan injection subcutaneously.
Admits to injecting her doses.
Assessed for HCV and HBV and has both.
1 Child has evidence of exposure to HBV.
Vaccination program not completed.
Is this all OK?? Should there be a full review of their dependency treatment?
Mr BJ had Crohn’s disease for 15 yrs.
Several recurrences when Inflammatory Bowel Disease (IBD) treatment reduced.
Surgery x 3, fistula complicating this.
Intermittent analgesia when in hospital.
Tried heroin from friend “for pain relief”.
Now on methadone program 50mg/d.
Presents wanting pain relief from IBD.
He convinces you of his pain.
He asks for morphine injections prn.
You are convinced of his need for pain relief.
You write script for morphine ampoules and arrange for him to come in for doses when needed.
He is found dead with signs of O/D. Not a good situation.

Ms HT is a 78 year old widow
Dependent on benzodiazepines you commenced years ago for insomnia.
You become convinced benzos are bad for people and discuss trying to withdraw them which she refuses.
Admitted to hospital for an acute surgical problem
She experiences a significant withdrawal as no-one took a medication history. She decides that she was not adequately informed about the risks and sets a litigation process in motion.
Who should have done more?
The next topic was “WHAT AM I DRIVING AT” which reminded us that it is OUR RESPONSIBILITY to ensure that patients are safe to drive, operate machinery and look after children while taking medication. All patients should be warned that new medication and changes in doses of existing drugs, including alcohol, may affect ability to perform adequately.

Professor Batey’s final advice to us was:
Spend time taking a good history and performing a full physical examination.
Communicate appropriately with your patients.
Document findings and management plans in the notes.
Evaluate progress rationally and regularly.
Do not become enmeshed with patient stories rather than reality.
Set boundaries clearly and compassionately.
Seek peer support.
Adhere to good clinical practice guidelines.
Seek second opinions in unusual circumstances where guidelines may not apply.

Heroin addicts turn to pain killers in a big way in Sydney since 2006

2008-06-27T11:28:00.005+10:00

ABC news item Mon 23/6/08

http://www.abc.net.au/news/stories/2008/06/23/2282439.htm

'Hillbilly heroin' makes its mark on Australian streets.

Doctor shopping: dealers rove from surgery to surgery conning doctors.

Audio: Black market booming for prescription painkillers (AM) There are any number of illegal drugs on Australian streets at any one time, but a relative newcomer, known as 'hillbilly heroin', is becoming more popular - subsidised by taxpayers. Audio: http://mpegmedia.abc.net.au/news/audio/am/200806/20080623-am06-oxycodone.mp3

News story:
There are increasing fears that the use of drugs such as oxycodone is growing and becoming a serious problem in Australia.

Oxycodone and similar drugs such as morphine are restricted and only available by prescription, but ABC Radio's AM program has discovered the legitimate market is being rorted by drug dealers.

Twenty-two-year-old Steven - not his real name - moved to Sydney from the United States several years ago.

He brought with him an addiction to the painkiller oxycodone, which is mostly sold under the brand name OxyContin.

In the United States drugs like OxyContin and morphine, usually sold as MS Contin, are widespread. They are called 'hillbilly heroin'.

However when Steven got to Australia, he initially found it hard to find them. But he says that situation changed very quickly.

"I knew that it was prescribed here, but it just wasn't very prevalent. Over the time since getting here, it became more and more, and I heard about it and finally found people selling it down in Melbourne.

"It has become much more prevalent and people do know what it is now and it is definitely growing."

In the United States, the abuse of oxycodone and morphine is rampant and they cause large numbers of overdose deaths.

In Australia, the drugs are restricted and obtainable only with a prescription from a doctor in cases of severe pain.

But there are strong indications the illegal use of these drugs is increasing in Australia. The Australian Crime Commission's recent Illicit Drug Data Report stated morphine use was rising in Queensland and the ACT.

The director of Sydney's Medically Supervised Injecting Centre, Dr Ingrid Van Beek, says she noticed a change about two years ago.

"Of course these medications have always been injected over the years by injecting drug users, but it was about two years ago that we started to see quite a significant increase."

On average around 220 people use the centre each day. Dr Van Beek says now up to 45 per cent of these people report using either oxycodone or morphine.

They get them from people like Sammy, a longtime drug dealer in Sydney's Kings Cross.

He says oxycodone and morphine are more popular than heroin.

"Heroin only holds you for four hours before it starts coming out of your system; where oxycodone or morphine sulphate holds you for 48 hours and one is cheaper than the other," he said.

Sammy gets his supply by what he calls 'doctor shopping' - that is roving from surgery to surgery conning doctors into believing he needs the drugs for medicinal purposes.

"They'd give me what I needed because I looked respectable. If I went in with tracksuit pants and a t-shirt and an Adidas jacket or something like that you know, typical bogan basically, then they would have had second thoughts about prescribing them to me," he said.

Sammy show he has dozens of used packets of OxyContin and MS Contin that he obtained doctor shopping.

These were often bought for less than $5 for a packet of 20 tablets - a price subsidised by the Pharmaceutical Benefits Scheme.

Dr Andrew Byrne is an addiction specialist operating out of Redfern in inner-city Sydney. He says almost all of his patients now report using either oxycodone or morphine, often to the exclusion of heroin.

He says it is far too easy to obtain legal drugs for illegal purposes.

"Given that the doctor doesn't believe that the patient is a drug addict, the doctor is allowed to write a prescription for strong opiate drugs at any quantity and with any number of repeats that they feel is appropriate," he said.

Dr Byrne says it is effectively an illegal drug trade subsidised by the taxpayer.

Based on a report by Michael Edwards for AM.

Tags: drugs-and-substance-abuse, law-crime-and-justice, crime, drug-offences, australia, nsw, sydney-2000, vic, melbourne-3000

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English study shows opiate users knew what they needed.

2008-06-09T11:28:00.007+10:00

A pilot study for a randomized controlled and patient preference trial of buprenorphine versus methadone maintenance treatment in the management of opiate dependent patients. Pinto H, Rumball D, Maskrey V, Holland R. Journal of Substance Use 2008 13;2:73-82

Dear Colleagues,

This pilot study demonstrates the ethical and practical differences between the British and American approach to drug treatment and research. The first author told me that they were trying to prove that they could obtain as good or better results using buprenorphine when compared with methadone in order to force their local NHS formulary to include it. Hence they attempted to randomise subjects applying for opioid prescription to methadone or buprenorphine and then follow progress. However, the first and probably most important finding of this study was that not one single patient of almost 50 presenting to their service over a six month period agreed to this randomisation. Apparently, each patient already had a clear preference for buprenorphine or methadone. Note that combination buprenorphine did not rate a mention in this context despite most doses being non-supervised.

Of those who agreed to be followed for this study, 22 chose methadone and 20 buprenorphine. Of those opting for methadone, 80% had had a previous script for the drug. Only 30% of those choosing buprenorphine had had a previous prescription for that drug (and 40% had tried methadone previously). Thus methadone choice was largely based on previous experience while buprenorphine mostly on second hand information. Consistent with the literature they report: “At 6 months more methadone patients were retained (68 vs. 55% for buprenorphine) …”. There was one ‘cross-over’ patient from each group, each ending the trial on the alternative medication.

Despite no randomisation and no significant differences found between those followed “open-label” over 6 months, these authors make a spectacular reversal of both the above ‘trend’, numerous randomised controlled trials and a Cochrane summary, based on slightly different baselines for methadone against buprenorphine subjects. “As a pilot this study lacked power but the results suggest that, in practice, in the UK, buprenorphine may be more able to retain patients in treatment, suppress illicit opiate use and improve functioning [despite that not happening in RCT elsewhere]. Given the significantly higher cost of buprenorphine a larger study is needed to answer these questions.”

Even if one showed significant differences between methadone and buprenorphine outcomes, this would not “favour” one or other drug, both of which are highly effective in a substantial proportion of heroin addicts presenting for treatment. Further, because patients already know what they want, discussion about which drug has a better retention rate or ability to suppress illicit drug use is almost academic. This may be the first reported series of buprenorphine subjects who had all been offered methadone initially as a choice. The finding of comparable results is greatly reassuring for those of us who prescribe buprenorphine regularly.
These authors take another unreferenced ‘dig’ by stating that methadone “causes a degree of persisting intoxication (which can limit the users’ ability to function) … and has a prolonged abstinence syndrome in withdrawal, leading some to suggest that it prolongs dependence.” Thus they perpetuate the myth that methadone is a sedative drug and buprenorphine is not. They base this purely on anecdotal reports that certain patients feel more energy on buprenorphine after having been on methadone. The reverse may be true for certain patients. It is well known that when stabilised, patients on methadone can drive, operate machinery and look after children perfectly safely. If Dr Pinto has patients reporting sedation on methadone then he might consider lower or split doses as recommended by Payte and others.

We have known for 15 years that buprenorphine can obtain results almost as favourable as methadone. It seems that buprenorphine can lead to increased early drop-outs, possibly due to a lack of agonist reinforcement and/or inadequate doses (Kakko used an average of about 30mg daily). It is hardly surprising that some do better on buprenorphine, even though it is clear that rather more will always do better on methadone in general (see Kakko’s classic study in which most buprenorphine-started patients ended up on methadone ‘rescue’). The lack of toxicity in overdose for buprenorphine must be a major factor in a country like England where more than 90% of opiate maintenance doses are apparently still non-supervised (‘take-aways’).

Regarding price, generic buprenorphine is now available in Europe and at certain dose levels should be comparable in price with methadone. I understand that it is not an expensive drug to manufacture.

In America most research has been performed in a situation where treatment is in extremely short supply and any offer to join funded drug research, even where placebo is a possible offering, is generally taken up promptly by illicit drug users. Many of us have found ethical flaws in this environment, where “choice” is really taken out of the equation, like offering a ‘choice’ of food in a famine, or for prison settings. None can be considered a genuine volunteer when the alternative to being in a trial is to receive no treatment at all (even though this is apparently the norm for 6 out of 7 American addicts currently).

Comments by Andrew Byrne ..

Dr Alex Wodak responds to Ms Miranda Devine.

2008-06-03T19:18:00.005+10:00

An Open Letter to Ms Miranda Devine from Dr Alex Wodak:

A shorter version of this letter (without references) was offered to the Sydney Morning Herald but declined. This commentary is a response to arguments made in an article by Ms Devine published in the Sydney Morning Herald on 15 May 2008. This response was posted on the Update Listserver of the ADCA in Canberra on Monday 2nd June 2008.

REDUCING THE HARMS OF CANNABIS AND CANNABIS POLICIES

In her recent article on cannabis in the Sydney Morning Herald [1], Ms. Miranda Devine expressed three main concerns about taking this drug out of the domain of law enforcement and into the domain of public health. Firstly, that a public health approach will inevitably increase cannabis use in Australia at a time of declining consumption. Secondly, that cannabis increases psychosis. Thirdly, that the Swedish zero tolerance approach demonstrates best how to reduce illegal drug consumption. Some support for each of these views may be adduced from partial quotation of selected research and opinions, including a recent letter [2] to the Sydney Morning Herald by Dr. Don Weatherburn and Professor Wayne Hall. However, a thorough review of research to date does not support Ms. Devine�s case.

Assertions that cannabis use is certain to increase if the drug is taxed and regulated are just beliefs, no doubt strongly held, but unsubstantiated beliefs nonetheless. A European comparative study and an overview of research conducted in the USA and Australia found [3] no convincing relationship between drug policies and prevalence rates of cannabis use. In his evaluation of the effects of the 1987 partial decriminalisation on cannabis use in South Australia, Professor Hall concluded [4] that the increase in consumption in South Australia was not significantly greater than the average increase in the other three states included in the study.

Ms. Devine cited criticism [2] by Weatherburn and Hall of a study by Reinarman, Cohen and Kaal comparing [5] cannabis consumption in San Francisco and Amsterdam as evidence against my views. Weatherburn and Hall argued that differences in demographics may have explained the higher consumption in San Francisco. But it is clutching at straws to believe that the small demographic differences that were found in this study can explain a more than three-fold greater prevalence of smoking cannabis in the city with the more punitive approach. The study also found that the prevalence of use of every other illicit drug was dramatically higher in San Francisco. National surveys in both countries consistently confirm these same differences. If the peer reviewers for the top public health journal in the world had considered demographic differences to be a serious limitation of the study, they would have demanded that the authors indicate this.

Weatherburn and Hall are correct that the samples were not exactly matched. But both were rigorously random, representative samples of experienced users in the household populations of the two cities and the survey instruments and measures used were identical.

The fact that the findings of this study were consistent with virtually all other studies in showing that the great majority of cannabis users clearly reduce use or cease altogether as they get older suggests that the slightly higher average age of the San Francisco respondents was more likely to have reduced use in San Francisco relative to Amsterdam rather than to have increased it. Dr. Weatherburn and Professor Hall have it backwards.

These researchers also appear to cite the comparative study selectively. They did not mention that the slightly higher likelihood of unemployment in the two years before the study was conducted in San Francisco was most likely due to temporary problems of the high technology industry at the time of the study. It is difficult to believe that Weatherburn and Hall could argue that this temporary slightly higher unemployment explains the threefold higher cannabis consumption found in San Francisco.

It is also misleading for these researchers to claim that �consumption increased substantially in the Netherlands after the creation of a de facto legal market�. While cannabis use did increase in the Netherlands at that time, it also increased in almost every other Western country where cannabis prohibition was continued. In some countries, cannabis consumption increased even more than in the Netherlands. Thus, the causal claim that these respected researchers make is too simplistic. Cause cannot be established without proper comparisons and when these comparisons are made, the increase in use cannot be solely attributed to the de facto decriminalization of cannabis in the Netherlands.

Although Dr. Weatherburn and Professor Hall say in their letter that �in research in NSW, most regular cannabis users say they would use it more often if it was legal�, Weatherburn�s own study suggests otherwise. Weatherburn and a colleague concluded [6] �that two-thirds of respondents definitely wouldn't use more cannabis if it were made legal. The remainder, however, would not rule out using cannabis more frequently if it were legal. Four per cent of the sample said they definitely would use more cannabis, about 10 per cent said that they would probably use more and about 19 per cent said that they probably wouldn't use more but, nonetheless, did not rule out the possibility�.

The Police Foundation of the United Kingdom noted [7] in their �Drugs and the Law� report in 2000 that �the consequences of drug use are more important than the numbers of users.� Quite so. The fundamental principle of harm reduction is that reducing harm is more important than a single minded focus on reducing consumption, whatever the cost. Drug law enforcement authorities in Australia have also questioned [8] the wisdom of harsh penalties for cannabis use noting �[cannabis offences] � absorbed a significant proportion of resources dedicated to drug law enforcement. In addition, in contrast to most other illicit drug use, there appears to be a comparatively low rate of associated crime and harm to other individuals and the community. The decriminalisation of personal cannabis use and production may greatly reduce both police and legal resource expenditure�.

Policy determination must include a balancing of benefits and costs. That is why the costs of cannabis prohibition should not be ignored. According to Professor Hall, the costs of cannabis prohibition include �the creation of a large black-market; disrespect for a widely broken law; harms to the reputation of the unlucky few cannabis users who are caught and prosecuted; lack of access to cannabis for medical uses; and an inefficient use of law enforcement resources� [9]. Ms. Devine makes much of my somewhat facetious comments about the realistic options for selling cannabis. But she does not acknowledge the current realities: cannabis is now sold on the black market with no health standards or regulation. Ms. Devine should explain why she prefers cannabis to be sold with no health standards or regulation.

Despite Ms. Devine�s conviction that a causal relationship between cannabis use and mental illness is only questioned by drug law reformers, debate continues among experts. Professor Louisa Degenhardt and colleagues found [10] a �steep rise in the prevalence of cannabis use in Australia over the past 30 years� but �no evidence of a significant increase in the incidence of schizophrenia�. They concluded that �cannabis use does not appear to be causally related to the incidence of schizophrenia, but its use may precipitate disorders in persons who are vulnerable to developing psychosis and worsen the course of the disorder among those who have already developed it.� If cannabis use is associated with a significant risk of causing or worsening serious mental illness, why does Ms. Devine prefer cannabis to be sold only by criminals or corrupt officials?

Ms. Devine�s conviction [1] that Sweden demonstrates �that prohibition is the most certain way to reduce drug use� is shared by few others. What matters more: drug use or drug-related harms? For example, the rate of drug overdose deaths in Sweden (16.9/million) is more than twice that in the Netherlands (7.5/million) [11]. Not so long ago, all Scandinavian countries had the same drug policy. Now Sweden is the last Scandinavian country and among the last countries in Western Europe to reject harm reduction. In 2006, the UN Special Rapporteur on the Right to Health visited Sweden and specifically recommended [12] to the UN General Assembly that: �[T]he Government has a responsibility to ensure the implementation, throughout Sweden and as a matter of priority, of a comprehensive harm reduction policy, including counselling, advice on sexual and reproductive health, and clean needles and syringes�.

But surely if country comparisons with Australia are to be made, we should compare ourselves with a country that shares many of our social, economic, cultural, linguistic and political characteristics: the United States of America. In contrast, Australia has little in common with Sweden. Why does Ms. Devine chose to compare drug outcomes in Australia only with Sweden rather than with the United States of America? After all, Sweden and the United States of America both reject harm reduction and prefer zero tolerance. The US Congress even passed legislation in 1988 mandating that the country would become drug free by 1995. The reason is obvious. Drug-related deaths, disease, HIV, crime and corruption are out of control in the USA. With 737 prisoners per 100,000, the USA has the highest incarceration rate in the world - five times higher than Australia - and more than a third of these inmates are serving sentences for drug related offences. Ms. Devine compares only drug use in countries. But surely drug-related harms count for more than just drug consumption? While the relationship between levels of consumption of legal drugs and drug-related harms is clear both for individuals and communities, the relationship between levels of consumption of illegal drugs and drug-related harms is anything but clear.

Although Ms. Devine quotes Professor Hall approvingly, she should be aware that in 2007, and with important caveats, he advocated [13] �a limited legal cannabis market� accompanied by �grudging tolerance�. Such a system would presumably need to include the same limiting measures I have advocated: taxation, strict regulation of cultivation and sale, health warnings, consumer quality controls, age restrictions on sale and assistance for users when trying to quit. No policy is ever going to be perfect but this approach is surely less costly to the community and less harmful to cannabis consumers than just leaving the market to the Al Capones of this world as Ms. Devine appears to favour.

The wisdom of the decision to include cannabis with the global prohibition of opium poppy and coca plant in the 1961 Single Convention is now being increasingly questioned. The UNODC, the major organization implementing drug policy on behalf of the UN system recently acknowledged [14] �either the gap between the letter and spirit of the Single Convention, so manifest with cannabis, needs to be bridged, or parties to the Convention need to discuss redefining the status of cannabis�.

Is the idea of cannabis taxation really so outlandish? After all, US Congress enacted the Marihuana Tax Act in 1937. This remained legislation until 1970. As recently as 2005, 500 US economists (including Professor Milton Friedman and two other Nobel Prize winners) published [15] an Open Letter to leading politicians including the President and members of Congress calling for the taxation of cannabis.

Ms. Devine is right [1] that Britain recently reclassified cannabis from Class C to Class B (where Class A drugs are considered the most dangerous, Class B intermediate and Class C least dangerous). This was the first time that the British Government had ignored the views of its expert advisory body (the Advisory Council on the Misuse of Drugs). The UK police then announced that they would not change policing practices on cannabis because of this reclassification. Also, cannabis use had declined in the UK after cannabis was classified from Class B to Class C. Does Ms Devine believe that symbolism trumps outcomes or the reverse?

Ms. Devine expressed concern [1] that Australia �ranks in the top 10 drug users of 193 nations in the UN's 2007 World Drug Report�. But the Howard government introduced a �Tough on Drugs� policy in 1997 and continued this policy until it lost office in 2007. Is the high ranking for drug consumption in Australia explained by the Howard government not being tough enough on drugs or does a supposedly tough drug policy have little impact on drug consumption even after ten years?

One of the hallmarks of a poor argument and weak evidence is the use of personal attacks. Ms. Devine shows the weakness of her case by her reliance on gratuitously personal attacks on myself and my 26 years of practice, research and advocacy in this field.

Yours sincerely,

Dr Alex Wodak,
President,
Australian Drug Law Reform Foundation, Darlinghurst, NSW 2010

References:
[1] Ms. Miranda Devine, Puff goes the drug liberalizer, Sydney Morning Herald, 15 May 2008 [2] Dr. Don Weatherburn, Professor Wayne Hall. Mismatch on dope figures (Letters) Sydney Morning Herald, 13 May 2008 [3] V. Maag. Decriminalisation of cannabis use in Switzerland from an international perspective-European, American and Australian experiences. International Journal of Drug Policy. 2003; 14 (3); 279 - 281.
[4] Neil Donnelly; Wayne Hall; Paul Christie. The effects of the Cannabis Expiation Notice system on the prevalence of cannabis use in South Australia: evidence from the National Drug Strategy Household Surveys 1985-95. Drug and Alcohol Review. 2000; 19 (3); 265-269.
[5] Reinarman C, Cohen PD, Kaal HL. The limited relevance of drug policy: cannabis in Amsterdam and in San Francisco. Am J Public Health. 2004; 94(5): 836-42.
[6] Don Weatherburn, Craig Jones. Does prohibition deter cannabis use? Number 58, August 2001. Contemporary Issues in Crime and Justice. Crime and Justice Bulletin. http://www.lawlink.nsw.gov.au/lawlink/bocsar/ll_bocsar.nsf/vwFiles/cjb58.pdf/$file/cjb58.pdf
[7] Drugs and the Law: Report of the Independent Inquiry into the Misuse of Drugs Act 1971. The Police Foundation, London, 2000.
[8] The Australian Bureau of Criminal Intelligence. Australian Illicit Drug Report 1996-97.
[9] Wayne Hall. Reducing the harms caused by cannabis use: the policy debate in Australia. Drug and Alcohol Dependence. 62 (3); 163 - 174.
[10] Louisa Degenhardt, Wayne Hall, Michael Lynskey. Testing hypotheses about the relationship between cannabis use and psychosis. Drug and Alcohol Dependence. 2003. 71 (1); 37- 48.
[11] European Monitoring Centre for Drugs and Drug Addiction, 2007 Annual report, Table DR5 Part (i) http://www.emcdda.europa.eu/stats07/drdtab05a
[12] Report of the Special Rapporteur on the right of everyone to the enjoyment of the highest attainable standard of physical and mental health, Paul Hunt. Addendum: Mission to Sweden.
http://daccessdds.un.org/doc/UNDOC/GEN/G07/111/82/PDF/G0711182.pdf?OpenElement
[13] Wayne Hall. A cautious case for cannabis depenalisation. pp 91-112. Pot Politics. Marihuana and the costs of prohibition. (ed) Mitch Earleywine. Oxford University Press 2007.
[14] United Nations Office on Drugs and Crime, 2006 World Drug Report [15] Open Letter to the President, Congress, Governors, and State Legislatures.
http://economics.about.com/gi/dynamic/offsite.htm?zi=1/XJ&sdn=economics&cdn=money&tm=38&gps=174_306_1008_577&f=00&su=p649.0.147.ip_&tt=2&bt=0&bts=0&zu=http%3A//www.prohibitioncosts.org/endorsers.html

[addition: Hall's response to this on link http://www.crikey.com.au/Blogs/Croakey/Tackling-the-double-standards-on-drugs.html]