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Internal Medicine and then withdrawn, only to be re-published three months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, Wedam’s 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.
References:
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
http://www.ncbi.nlm.nih.gov/pubmed/24500948?dopt=Abstract
