21 December 2010

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

Article printed in "OF SUBSTANCE".

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

Commentary on Addiction editorial on benzodiazepine maintenance.

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

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

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

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

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

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

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


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

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

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

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

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

17 December 2010

More drop-outs with buprenorphine in pregnancy.

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

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

Dear Colleagues,

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

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

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

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

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

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

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

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

Comments by Andrew Byrne ..


15 December 2010

French study shows torsade rare to vanishing.

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

Dear Colleagues,

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

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

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

14 December 2010

QT changes in babies aged one day uncertain relevance.

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

Dear Colleagues,

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

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

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

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

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

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

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

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

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

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

Comments by Andrew Byrne ..


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

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

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

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

22 October 2010

Three articles addressing problems with buprenorphine treatment.

Dear Colleagues,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

Full citations:

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

Vicknasingam B, Mazlan M, Schottenfeld RS, Chawarski MC. Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia. Drug and Alcohol Dependence 2010 111;1/2:44-

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

7 July 2010

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

29 June 2010

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

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

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

Dear Colleagues,

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

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

7 May 2010

Pain and addiction conference New York City March 2010

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

Newman RG. "Maintenance" treatment of addiction: To whose credit, and why it matters. International Journal of Drug Policy (2009) 20;1:1-3

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

4 May 2010

Advice to stop methadone could be dangerous.

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

Dear Readers,

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

9 April 2010

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

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

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

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

16 February 2010

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

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

Dear Colleagues,

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

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

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

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

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

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

Comments by Andrew Byrne ..

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


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

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

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

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