Monday, July 7, 2008

Opiate-substitution therapy quadruples treatment success in Malaysian heroin users: authors urge adoption in non-western countries

A study from Malaysia published in the June 28th edition of The Lancet has found that substitution therapy with the opiate drug, buprenorphine, tripled the length of time heroin users were able to stay “clean” compared with individuals on a placebo, and nearly quadrupled the proportion of participants who completed the trial without relapse.

An accompanying editorial states that, given these results, “the preferred oral pharmacological treatment for opioid dependence should be agonist maintenance with either methadone or buprenorphine,” and says that concerns that dispensing these drugs could swell black-market use should not outweigh “the major public-health effects of untreated opioid dependence”. Buprenorphine, like methadone, is currently illegal in Malaysia and many other countries with serious injecting drug use problems, such as Russia.

Four times as many individuals given buprenorphine completed the six-month treatment trial without relapse as individuals given naltrexone or placebo; individuals on buprenorphine took on average nearly three times as long to resume heroin use as those on placebo, and twice as long as those on naltrexone. Furthermore individuals provided with buprenorphine were able to stay completely abstinent from heroin for twice as long as those on either naltrexone or placebo.

Substitution therapy using the oral drugs methadone or buprenorphine has been standard practice as a way of trying to wean heroin users off injecting and off street drugs for years in most developed countries. However, in other parts of the world the idea of substituting one opioid for another is still seen as just substituting one addiction for another and adding more drugs into the black market. More recently the opioid antagonist naltrexone – a drug that blocks opioid receptors and so enforces a state of physiological withdrawal from heroin – has been permitted, but although some naltrexone trials report positive results, others have been neutral or negative.

This study was the first ever study in Malaysia to use an opiate agonist – a direct substitute – rather than an antagonist. In the event, the superiority of that agonist, buprenorphine, over both naltrexone and placebo was so marked that the study was terminated before time, when 70% of participants had completed their six month course.

The study involved dependent heroin users. A total of 44 were provided with buprenorphine plus a naltrexone placebo, 43 with naltrexone plus a buprenorphine placebo, and 39 with two placebos. The patients were initially given a fast six-day detox and then provided with substitution therapy or placebo. Urine tests were performed three times weekly to see if they had taken heroin.

Three primary outcome measures were used: time without any heroin use; time to relapse (being defined as three or more consecutive positive heroin tests or a positive test followed by withdrawal from the study); and time remaining on the treatment regime. One other outcome was a global score of HIV risk behaviours, which was split into drug-use and sex-related behaviours.

Patients had a mean age of 37 and were consistent heroin users, with an average of 27 days’ use in the last 30. Only a minority (approximately 41%) were current injectors, though 80% had injected at some point. Twenty-four per cent had shared needles in the last month. Twenty-two per cent were HIV-positive (with fewer in the placebo group, 13%), and the vast majority (95%) had hepatitis C. Only 7% reported consistently using condoms and a third reported having had multiple concurrent sex partners at some point.

At the time the study was terminated, individuals taking the placebo had stayed in treatment for an average of 70 days (out of a maximum possible 168); those on naltrexone for 84 days; and those on buprenorphine for 117 days. Retention was 2.15 times higher amongst buprenorphine users than those taking the placebo and some 1.55 times higher for those randomised to buprenorphine compared to naltrexone; it was 32% higher on naltrexone than placebo, but this was not statistically significant.

Patients on buprenorphine took 2.17 times longer on average to relapse than patients in the placebo arm and 1.56 times longer than patients taking naltrexone. By the end of the study, eleven out of 44 buprenorphine users were still in the study and still abstinent compared with four of those taking naltrexone and three in the placebo arm.

As indicated above, occasional one-off heroin use did not count as ‘relapse’; the mean time subjects manages to remain completely heroin free was 24 days on placebo, 42 days on naltrexone and 59 days on buprenorphine.

Sexual risk behaviours did not change at all during the study; drug-related risk behaviours (i.e. needle sharing) declined throughout the study but did not differ between treatment arms.

The authors report that their results “lend support to dissemination of maintenance treatment with buprenorphine or methadone…as an important component of an effective public-health approach for reduction of problems associated with heroin dependence.”

Schottenfeld R. et al. Maintenance treatment with buprenorphine and naltrexone for heroin dependence in Malaysia: a randomised, double-blind, placebo-controlled trial. The Lancet 371: 2192-2200, 2008.

Hall W. et al. Oral substitution treatments for opioid dependence. The Lancet 371: 2150-2151, 2008.