Kill or cure?

Is it time for us to reappraise our relationship with the ‘life-saving’ drug methadone? Dave Marteau discusses the evidence

Since the early 1970s, methadone has been the predominant opioid prescribed in the UK for the ongoing treatment of heroin addiction. It has proved extremely useful in the fight to contain HIV among injecting heroin users, and there is strong evidence that longer-term methadone treatment of heroin addiction reduces death rates by as much as 50 per cent. Moral objections have been voiced by many about a treatment that swaps addiction to one drug (heroin) for dependence on another (methadone), but perhaps we can all agree on the primacy of life itself: it trumps any argument.

In 2007 the National Institute for health & Clinical Excellence (NICE) positively evaluated methadone and buprenorphine. In circumstances where assessments had suggested that both drugs were equally suitable, NICE recommended that ‘methadone should be prescribed as the first choice’.

However, in a review of drug-related deaths in France between 1994 and 1998, Marc Auriacombe found that, set within the context of numbers of prescriptions issued, methadone was at least three times more lethal than buprenorphine in respect of overdose deaths within the French population as a whole (ie, among patients and the wider public).

On the subject of the relative toxicity of methadone and buprenorphine, NICE had this to say:

‘Comparison of data from population cross-sectional studies suggests that the level of mortality with BMT [buprenorphine maintenance] may be lower than that with MMT [methadone maintenance], although other authors have commented that these data were unlikely to capture all related deaths.’

This was a cursory summary of an important matter in 2007; it would be insufficient to the point of negligence now. In 2009 James Bell and colleagues in New South Wales found that, per prescription, methadone was 4.25 times more lethal than buprenorphine. This year Rebecca McDonald, Kamlesh Patel and I carried out a similar but larger study in England and Wales. We found that between 2007 and 2012, 57 death certificates mentioned buprenorphine, and 2,366 death certificates mentioned methadone.

Allowing for a calculation that seven methadone prescriptions were issued for every buprenorphine prescription, methadone emerged as six times more dangerous across the population as a whole. The picture in Scotland appears no prettier. Between 2011 and 2013, heroin and its metabolite morphine were implicated in 538 drug poisoning deaths; methadone was found to be implicated in 663 deaths.

So how is it that a drug with the potential to halve a patient’s risk of dying ends up killing so many people? The answer is horribly simple: while most patients are safer on methadone, the wider population are at continued risk from diverted supplies of the drug. The National Programme on Substance Abuse Deaths found that of 1,117 UK deaths that involved methadone alone or in combination with other drugs, only 36 per cent occurred among individuals who were known to be receiving methadone treatment.

To be fair to NICE, their methodology was designed to determine the cost-effectiveness of a drug, not its safety. That same methodology, based solidly on randomised controlled trials, compares the outcomes for a patient group on drug A with those for members of a patient group on drug B. No persons outside of these two groups are considered. This is a very good means to evaluate antibiotics or chemotherapy, but altogether less suitable for drugs intended to treat people with a drug-taking problem. No one on antibiotic ‘A’ would be likely, for instance, to consider trading their medication with a non-patient, or to be put under duress to hand over their medication outside the pharmacy.

There is another stark statistic: of all drugs detected at post-mortem over the past three years in Scotland, methadone has, at 93 per cent, the highest degree of implication in the unfortunate person’s death. So, if you were to die from a drugs overdose, and methadone was among the substances found in your body, there is a 93 per cent chance that it had been wholly or partly responsible for your death. This makes methadone significantly more toxic than heroin, (which had an implication rate of 83 per cent), buprenorphine (65 per cent) and cocaine (63 per cent). Put simply, methadone is the most dangerous drug out there.

Methadone has the capacity to retain more people in treatment than buprenorphine, but the evidence is now overwhelming that it is significantly more lethal. Hundreds of our fellow UK citizens are dying every year from methadone poisoning. If we agree with the premise at the start of this article that the value of life prevails over any other argument, then we have now to relegate methadone to a secondary option for the substitute treatment of opioid dependence, behind buprenorphine and buprenorphine-naloxone. Failure to change would indicate that we are less courageous than our clients in confronting a dangerous pattern of our own behaviour.

For the record, I have never taken nor will ever take a penny from a drug company.

Dave Marteau is research fellow at the University of London

References

Auriacombe M, Franques P, Tignol J. Deaths attributable to methadone vs buprenorphine in France. JAMA. 2001 Jan 3;285(1):45. PubMed PMID: 11150107.

Bell JR, Butler B, Lawrance A, Batey R, Salmelainen P. Comparing overdose mortality associated with methadone and buprenorphine treatment. Drug Alcohol Depend. 2009 Sep 1;104(1-2):73-7. PubMed PMID: 19443138.

Cornish R, Macleod J, Strang J, Vickerman P, Hickman M. Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database. BMJ. 2010; 341.

Corkery J, Claridge H, Loi B, Goodair C, Schifano F. Drug-related Deaths in the UK, National Programme on Substance Abuse Deaths (np-SAD), UK Annual Report 2012. London: St George’s University; 2013.

Heinemann A, Iwersen-Bergmann S, Stein S, Schmoldt A, Puschel K. Methadone-related fatalities in Hamburg 1990-1999: implications for quality standards in maintenance treatment? Forensic science international. 2000 Sep 11;113(1-3):449-55. PubMed PMID: 10978661.

Kimber J, Copeland L, Hickman M, Macleod J, McKenzie J, De Angelis D, et al. Survival and cessation in injecting drug users: prospective observational study of outcomes and effect of opiate substitution treatment. BMJ. 2010;341:c3172. PubMed PMID: 20595255. Pubmed Central PMCID: 2895695.

Marteau D, McDonald R, Patel K. The relative risk of fatal poisoning by methadone or buprenorphine within the wider population of England and Wales. BMJ Open 2015; 5: e007629

National Institute for health & Clinical Excellence (NICE), Technology appraisal guidance 114, Methadone and buprenorphine for the management of opioid dependence 2007 [April 25 2014]. Available from: www.nice.org.uk/TA114

ONS. Statistical bulletin: Deaths related to drug poisoning in England and Wales, 2012 2013 [May 30, 2014]. Available from: http://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drug-poisoning/2012/stb—deaths-related-to-drug-poisoning-2012.html

NHS Scotland Information Services Division. The National Drug Related Deaths Database (Scotland) Report 2013. Available from: http://www.isdscotland.org/Health-Topics/Drugs-and-Alcohol-Misuse/Publications/data-tables.asp?id=1386#1386