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QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP.

Dr Andrew Byrne & Associates
A Harm-Minimisation Research Perspective

Issue 72: June 2008
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Editor's Note:Dr Byrne (and his associates) advocate for better policies which are proven to reduce risks for drug users and the general community under a framework in parallel with Australia's official policy of harm minimization. The findings of the New South Wales Drug Summit recommend better access to methadone, detoxification and other dependency treatments. It also advised investigating alternative services such as supervised injecting centres, leading to the opening of the Sydney Medically Supervised Injecting Centre in 2001. Dr Andrew Byrne has been involved in opioid treatments from a primary care background for 20 years at the same site in Redfern, an inner suburb of Sydney. He is recognised worldwide as a specialist in the addiction field and was involved in the seminal stages of the Chapter of Addiction Medicine, Royal Australasian College of Physicians. He received the Dole-Nyswander award from the American Association for the Treatment of Opioid Dependence in April 2006. In this edition of i2P, Dr Byrne comments on an article in Arch Intern Med 2007 167;22:2469-2473.

QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP.

Dear Colleagues,

This is the latest salvo in a cavalcade of papers on the supposed cardiac associations of methadone in addiction treatment.  Readers might assume from the title that this is a randomised trial looking at cardiographic changes from a new perspective.  In fact it is a re-examination of study performed in the 1990s, this time with old analogue cardiograph traces salvaged and corrected QT estimations attempted.  I have repeatedly written to the corresponding author over some apparent discrepancies in the methadone “rescue” group but without any resolution.  Some heroin addicted patients received placebo-equivalent (20mg methadone daily) which I believe would be unethical under today’s standards. 

These authors report an average corrected QT interval increased of up to 23 milliseconds 4 months into methadone treatment.  However, we are not told what proportion actually met clinical criteria for cardiac risk (eg. QTc > 500ms or increase >40ms after treatment). 

It appears that no patient developed tachycardia during the trial which is consistent with the literature.  Torsades arrhythmia in methadone clinic patients seems to be a very rare event as I could not find a single clinician in New York recently who had ever seen a case out of tens of thousands of MMT subjects.  The finding of lengthened QT timings in this trial is consistent with Lipsky’s study from 1973. 

The clinical significance in causing arrhythmias is still unclear, but according to Martell, Gourevitch and colleagues: “… an increase in QTc interval of greater than 40 milliseconds [is] the generally accepted threshold for an increase that should prompt clinical concern (4).  Similarly, … a QTc interval of more than 500 milliseconds is considered a definite risk for torsade de pointes regardless of sex (5) …”.  By these criteria, the findings of Wedam and colleagues are consistent with the almost complete lack of cardiac symptoms in methadone patients generally, except for those on very high doses (>300mg daily) and nearly all other such reported cases who were also prescribed other strong drugs, had pre-existing heart disease and/or had documented metabolic problems. 

Far from conceding this conclusion, the authors find that methadone is far more likely to involve risks which can be avoided by the use of buprenorphine which they state should be considered in its place.  This is a most naïve deduction, and seems to show a lack of insight into the current state of dependency treatment (see Kakko’s trial from Sweden; Ling; Strang and others showing the limitations of buprenorphine in addiction treatment). 

Having stated in the first sentence that bup and meth are equivalent (which they are not), they state further: “Levomethadyl and methadone each have had reports of notable clinical adverse events, including TdP [refs 9-15 see below].”  On closer examination, these references do not generally involve methadone maintenance cases which is what they address in their conclusions, but rather, they are complex medical and overdose cases. 

The mean daily dose in Krantz’ original study was 397mg (n=17); Walker >600mg (n=3); Sala (n=4) mean 365mg daily; Mokwe – street methadone dose unknown (n=1); de Bels blood levels 3500mg/L and 1740mg/L (n=2) overdose cases (therapeutic range 100-1000mg/L). 

Martell, who is not cited for some reason: (n=132) doses 30-150mg had “a small QT interval prolongation of uncertain significance” [average 12ms, mostly in males taking 110-150mg daily]. Also not cited is the world’s largest and most authoritative series from FDA reports: Pearson’s mean dose was 410mg (n=56).

The Wedam report concludes: “We know of no published cases of TdP with the use of buprenorphine” [they omit that there are virtually no reports of TdP in methadone maintenance patients either]. Then: “Physicians must use their judgment in choosing the appropriate therapy for opioid dependence; failure of therapy results in considerable mortality. However, given that buprenorphine has previously been proven to be equally efficacious in the treatment of opioid addiction [this is not referenced and is incorrect in my view], buprenorphine may be a safe alternative for treatment of this common and life-threatening problem.”  As drug guru Walter Ling has written, finding no significant difference between treatments does NOT prove that they are equivalent.  

The paper states: “Financial Disclosure: Dr Johnson is currently an employee of Reckitt-Benckiser Pharmaceuticals Inc, the manufacturer and distributor of buprenorphine. Dr Bigelow has received, or anticipates receiving, research support, through his institution, from Purdue Pharma LP, Biotek Inc, and Titan Pharmaceuticals Inc for studies of other buprenorphine formulations.”

Comments by Andrew Byrne ..  http://www.redfernclinic.com/  (who is an enthusiastic prescriber of both buprenorphine and methadone in addiction medicine).  

 

References:

 1. Johnson RE, Chutuape MA, Strain ED, Walsh SL, Stitzer ML, Bigelow GE.  A Comparison of Levomethadyl Acetate, Buprenorphine, and Methadone for Opioid Dependence. NEJM (2000) 343;18:1290-1297

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

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

 4. Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557

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

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

 7. Walker PW, Klein D, Kasze L. High dose methadone and ventricular arrhythimias: a report of three cases. Pain 2003 103:321-4

 

 


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