Is methadone too dangerous for opiate addiction?

The case for using a safer alternative, buprenorphine, is strong

Methadone is an effective treatment for heroin addiction, and it remains the mainstay of drug treatment for opiate dependence in the United Kingdom.1 The lethal dose of methadone is estimated at 50 mg for an opiate-naive adult.2 Nevertheless, many authorities recommend that methadone doses should be gradually increased to maintenance doses of 80-120 mg¹—that is, twice the lethal dose for non-users. The greatly increased risk to users from methadone, particularly black market methadone, thus remains a major concern. Buprenorphine is a partial agonist that has a lower potential for causing respiratory depression than many other opioids, including methadone and heroin.3 It is increasingly used in the United Kingdom to treat opiate dependence, with guidelines for clinical management in primary and secondary care summarised by Ford et al4 and Taikato et al.5 It is time it replaced methadone as the mainstay of drug treatment for opiate dependence.

A long running debate continues between proponents of long term maintenance treatment with methadone and the proponents of detoxification (in which the dose of a substitute drug is reduced over time to achieve abstinence from all agents). An expert US panel concluded, “although the drug free state represents an optimal treatment goal, research has demonstrated that the state cannot be achieved or sustained by the majority of persons dependent on opiates.”6 Without digressing further into this debate, we point out that that buprenorphine is at least as effective as methadone in both maintenance and detoxification.7^–9

One mechanism to reduce the diversion of methadone on to the black market is to insist that these drugs are taken in the presence of a pharmacist rather than being given “to take away.” Repeated advice to this effect is provided by the UK Department of Health and the Home Office.1 10 We have recently contacted 120 of the 140 community drug teams in England and Wales to ask what proportion of new patients on methadone undergo supervised consumption. We found that at least 25% of people who start prescriptions for methadone are still prescribed methadone to take away. This proportion is likely to be much higher in people who remain on methadone in the long term. Historical practice, and the reluctance of many pharmacies to provide supervised consumption facilities, make routine supervised consumption of methadone difficult to provide.

In 2003 there were 167 drug related deaths in Britain where methadone was solely or partly involved.2 Just over half of these deaths were due to diverted methadone—that is, methadone that had been sold to the victim on the black market. A total of 1 486 800 prescriptions for methadone were issued in 2003 (www.ppa.org.uk/). This translates into an annual death rate of 112 deaths per million methadone prescriptions. In contrast, the risk of death from overdose of tricyclic antidepressants is estimated at 30 per million prescriptions.11 Clearly, opiate dependent people are likely to have much higher levels of risk taking behaviour than recipients of antidepressants, but these figures indicate the relative risk of methadone compared with other drugs that are regularly cited in fatal overdose.

In 2003 310 700 prescriptions were issued for buprenorphine (www.ppa.org.uk/). Buprenorphine has not been cited in any drug related deaths reported to coroners in England and Wales since it was licensed for the treatment of opiate dependence in 1999. The Medicines Control Agency adverse drug reactions database has received reports of seven deaths involving buprenorphine, (www.mca.gov.uk/), although to what extent these cases were related to buprenorphine or to other factors (such as intercurrent cardiac illness or continued illicit drug use) is unknown.

The maximum licensed dose of buprenorphine is 32 mg, with a suggested maintenance dose of 16 mg/day. Trials have shown that even opiate-naive individuals can tolerate doses of 32 mg of buprenorphine while “experiments on rhesus monkeys proved that buprenorphine does not cause any respiratory depression that requires intervention, even at very high doses (10 mg/kg).”3 Pirnay et al reported a series of 34 deaths involving buprenorphine in France,12 but buprenorphine was “clearly” responsible for only four of these; most deaths involved its intake with other drugs, especially benzodiazepines and antipsychotics.

Buprenorphine is as prone as methadone to diversion to the black market and it may have a higher propensity to be injected than oral methadone.5 8 This is probably the main reason for the reluctance to use this drug in preference to methadone in some areas. Cost may be another reason; although buprenorphine has clearly been shown to be cost effective,13 it is about four times more expensive than methadone (www.bnf.org/). Nevertheless, the safety of buprenorphine in overdose is a significant advantage over methadone, especially considering the continued failure to prevent diversion of these agents on to the black market.