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 Krantz et al 2009 is the Editorial’s main supporting reference yet this piece was so problematic that it was withdrawn and republished with an altered list of contributors, new conflict statement and changed title (see my review Click here).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-
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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”