6 October 2011

1 October 2011

First publication on Suboxone film gives little clinical information.

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.

13 September 2011

Launch of Suboxone Film - Sydney Olympic Site - August 2011

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.

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.



17 June 2011

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

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 ..


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

15 June 2011

Buprenorphine wafer/film inductions confusing.

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 bears 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”

17 May 2011

German hep C study reports excellent results.

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

10 April 2011

Eric Strain talks about the buprenorphine film.

“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.

9 April 2011

“Prescription Opiate Dependence” - John Mendelson

“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 ..

8 April 2011

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

“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 ..

6 April 2011

Letter from New York ...

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 ..

11 March 2011


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 ..


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

22 February 2011

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

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.