3 November 2014

A disappointing 'guideline' on methadone treatment.

Methadone Safety Guidelines. Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society. Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT, Haigney MC, Inturrisi C, Knight JR, Otis-Green S, Marcus SM, Mehta D, Meyer MC, Portenoy R, Savage S, Strain E, Walsh S, Zeltzer L. The Journal of Pain 2014 15;4:321-337
This promising document attempts to give guidelines for the safe use of methadone in pain management, dependency and paediatrics.  With two contributors in common, it appears to be based on an earlier ‘guideline’ initially published on-line in Annals of Internal Medicine and then withdrawn, only to be re-published three months later omitting CSAT in the title (ref 1).  In both these cumbersome and non-evidence based ‘guidelines’ on safe methadone use the reader is first advised to warn individual patients of possible cardiac complications before treatment.  Then, whether for pain or dependency, one is advised to perform ECG before and during treatment. 
After such worrying information some patients may request an alternative medicine which may be less effective and more costly than methadone.  No mention is made of other significant complications such as constipation and hormone disturbances. 
We are told that there is only low-quality evidence for ordering ECG yet a recent Cochrane summary finding ‘no evidence’ for ECG in prevention of cardiac complications is not cited.  So these authors just seem to think ECG is a ‘good idea at the time’ with no suggestion of a cost-benefit analysis or international perspective.  Their call for more research is rather bewildering in a decades old treatment.  Controlled trials are impractical for long-term and very rare events such as TdP [sic].  Mandating ECG in some countries may mean the difference between getting treatment or not getting treatment (for pain or dependency).  This issue is not addressed in this particularly American document. 
Opioid therapy for analgesia and dependency have quite different goals of therapy yet these authors consider the cardiac risk in a parallel fashion.  A reasonable risk for dependency patients may be an unacceptable one in pain management.  These authors do not make this distinction adequately in my view. 
While these authors quote the very low rate of torsade de pointes (TdP) found in a large national study in Norway (Anchesen et al.), they fail to quote a larger and equally reassuring French study by Perrin-Terrin (ref 2).  The latter found extremely low rates of TdP in the national pharmaco-vigilence program in France.  Krantz has written that methadone maintenance substantially improves cardiac safety in several respects (ref 3). 
Twelve years after the first description of TdP in methadone patients there is still no proof that methadone causes this syndrome using strict scientific criteria.  There were no case reports in 35 years of widespread international use of methadone.  Nevertheless, as patients aged and new adjuvant treatments came into use for HIV, hepatitis C and other conditions, substantial evidence has accrued including over 100 published case reports, official adverse event reports, literature summaries and forensic studies on sudden death cases.  These make it clear that when TdP occurs it nearly always has precipitating events in methadone patients, usually when used in high dose over long periods.  It is generally agreed that TdP is multifactorial (ref 4). 
These authors do not appear to be aware of this literature.  For instance, Wedams finding of substantial QTc abnormalities in up to 10% of newly enrolled methadone patients in at odds with an almost complete lack of reports of TdP in patients new to methadone.  Numerous other inconsistencies make these guidelines inappropriate and unduly alarmist.  The authors scarcely mention the consequences of treatment failure, balancing this with the occurrence of side effects.  They also fail to discuss common side effects such as alterations of calcium metabolism which can lead to osteoporosis in later life, not to mention severe constipation which is not always a trivial complication. 
The recommended starting dose of 2.5mg 8th hourly in a patient who is transferring from morphine is highly questionable and almost a recipe for failure (and thus transfer to yet another formulation).  For dependency, 30-40mg starting doses have been the long standing recommendation for most patients.  Yet the US TIP guidelines allow up to 60mg on the very first day (under specific circumstances and in split doses).  They also allow somewhat faster increments than permitted here by these authors where it could take three weeks to reach the common dose of 100mg daily.  Inadequate dose escalation is yet another reason for methadone treatment failure and drop out in the case of clinic patients, and a known high mortality (ref 5), unlike TdP which is “controllable 100% of the time” according to cardiologist Phibbs (ref 6).  Overdose in the first two weeks of treatment is also a risk, hence the need for professional daily supervision. 
Despite a constant theme of cardiac prevention, the reader is not informed that while it is most unpleasant and to be avoided, TdP is exceptionally rare and apparently universally non-fatal in dependency patients.  Furthermore, it usually occurs in patients with more than one risk factor and thus can be predicted up to a point.  TdP should be seen in a balanced context, like all side effects. 
These authors overlook the repeated finding in controlled studies that methadone has better retention and lower intercurrent drug use when compared with buprenorphine at therapeutic doses (ref 7).  We read here instead that they have ‘similar efficacy’ which is less than candid with the reader (and another bonus point to - or from - buprenorphine manufacturers).  And nowhere is cost-effectiveness mentioned even though most medical schools now place this as an important item in therapeutics tuition - and for the third world it is often critical. 
By getting members of pain, dependency and paediatric specialties to agree with previous untested and unproven guidelines these authors have unwittingly allowed themselves to be aligned to the drug industry in its time honoured strategy to denigrate low-profit drugs in favour of expensive and high-profit medications (indeed, that is their duty to their shareholders).  As clinicians we should be able to balance such commercial fervour with common sense in our patients’ interests.  
A national conference side show some years ago entitled Cardiac complications of methadone treatment funded by Reckitt Benckiser brought these tactics into focus.  Their drug, buprenorphine, is the only licensed alternative to methadone for opioid maintenance in Australia so why would they not support publicising alleged problems with methadone?  Despite being over 30 years old buprenorphine still attracts extremely high prices.  Its various formulations combined with naloxone have not been shown to be superior to pure buprenorphine (and remarkably this is not even required under normal TGA regulations for a new pharmaceutical product).  It is unfortunate that thousands of Australian patients are currently taking naloxone every day (1) with no proven benefit and (2) with little long term safety data. 
With new measures attempting to ward off rare complications, these guidelines would be more appropriate for a brand new drug.  However, with decades of safe use worldwide new prescribing restrictions or safeguards should only be added with good reason.  The authors avoid the term ‘drug of choice’ yet with its track record and superiority in retaining patients, reducing high-risk behaviour, methadone may fairly claim this status in opioid maintenance. 
Another area which is studiously avoided by these authors is the supervised administration of methadone in clinics and that uniquely American conundrum that most methadone clinics have been unable or unwilling to prescribe buprenorphine while their private community practice colleagues are not permitted to prescribe methadone for addiction.  So these ‘guidelines’ are of little or no use to a large proportion of American doctors who prescribe for opiate dependence … and should be received with great scepticism by others, such is their narrow clinical message. 
Some might expect methadone treatment guidelines to be written by doctors who prescribing the drug, aided by pharmacologists, public health physicians and/or others with training in therapeutics.  The list of authors shows a quite contrary group, including some serial offenders as being critical of methadone and some have been paid advocates of buprenorphine, the only licensed alternative to methadone for dependency treatment.  The conflict statement would appear to be delinquent in these respects. 
I apologise for bringing such a GIGO* publication to the notice of readers. 
Written by Andrew Byrne ..
* Garbage in, garbage out.
1. Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395
2. 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
3. Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 (copy on request). 
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
5. Grönbladh L, Öhlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand (1990) 82:223-227
6. Phibbs B. Advanced ECG: boards and beyond. 2006 Elsevier p142
7. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2014 Feb 6