9 June 2008

English study shows opiate users knew what they needed.

A pilot study for a randomized controlled and patient preference trial of buprenorphine versus methadone maintenance treatment in the management of opiate dependent patients. Pinto H, Rumball D, Maskrey V, Holland R. Journal of Substance Use 2008 13;2:73-82

Dear Colleagues,

This pilot study demonstrates the ethical and practical differences between the British and American approach to drug treatment and research. The first author told me that they were trying to prove that they could obtain as good or better results using buprenorphine when compared with methadone in order to force their local NHS formulary to include it. Hence they attempted to randomise subjects applying for opioid prescription to methadone or buprenorphine and then follow progress. However, the first and probably most important finding of this study was that not one single patient of almost 50 presenting to their service over a six month period agreed to this randomisation. Apparently, each patient already had a clear preference for buprenorphine or methadone. Note that combination buprenorphine did not rate a mention in this context despite most doses being non-supervised.

Of those who agreed to be followed for this study, 22 chose methadone and 20 buprenorphine. Of those opting for methadone, 80% had had a previous script for the drug. Only 30% of those choosing buprenorphine had had a previous prescription for that drug (and 40% had tried methadone previously). Thus methadone choice was largely based on previous experience while buprenorphine mostly on second hand information. Consistent with the literature they report: “At 6 months more methadone patients were retained (68 vs. 55% for buprenorphine) …”. There was one ‘cross-over’ patient from each group, each ending the trial on the alternative medication.

Despite no randomisation and no significant differences found between those followed “open-label” over 6 months, these authors make a spectacular reversal of both the above ‘trend’, numerous randomised controlled trials and a Cochrane summary, based on slightly different baselines for methadone against buprenorphine subjects. “As a pilot this study lacked power but the results suggest that, in practice, in the UK, buprenorphine may be more able to retain patients in treatment, suppress illicit opiate use and improve functioning [despite that not happening in RCT elsewhere]. Given the significantly higher cost of buprenorphine a larger study is needed to answer these questions.”

Even if one showed significant differences between methadone and buprenorphine outcomes, this would not “favour” one or other drug, both of which are highly effective in a substantial proportion of heroin addicts presenting for treatment. Further, because patients already know what they want, discussion about which drug has a better retention rate or ability to suppress illicit drug use is almost academic. This may be the first reported series of buprenorphine subjects who had all been offered methadone initially as a choice. The finding of comparable results is greatly reassuring for those of us who prescribe buprenorphine regularly.
These authors take another unreferenced ‘dig’ by stating that methadone “causes a degree of persisting intoxication (which can limit the users’ ability to function) … and has a prolonged abstinence syndrome in withdrawal, leading some to suggest that it prolongs dependence.” Thus they perpetuate the myth that methadone is a sedative drug and buprenorphine is not. They base this purely on anecdotal reports that certain patients feel more energy on buprenorphine after having been on methadone. The reverse may be true for certain patients. It is well known that when stabilised, patients on methadone can drive, operate machinery and look after children perfectly safely. If Dr Pinto has patients reporting sedation on methadone then he might consider lower or split doses as recommended by Payte and others.

We have known for 15 years that buprenorphine can obtain results almost as favourable as methadone. It seems that buprenorphine can lead to increased early drop-outs, possibly due to a lack of agonist reinforcement and/or inadequate doses (Kakko used an average of about 30mg daily). It is hardly surprising that some do better on buprenorphine, even though it is clear that rather more will always do better on methadone in general (see Kakko’s classic study in which most buprenorphine-started patients ended up on methadone ‘rescue’). The lack of toxicity in overdose for buprenorphine must be a major factor in a country like England where more than 90% of opiate maintenance doses are apparently still non-supervised (‘take-aways’).

Regarding price, generic buprenorphine is now available in Europe and at certain dose levels should be comparable in price with methadone. I understand that it is not an expensive drug to manufacture.

In America most research has been performed in a situation where treatment is in extremely short supply and any offer to join funded drug research, even where placebo is a possible offering, is generally taken up promptly by illicit drug users. Many of us have found ethical flaws in this environment, where “choice” is really taken out of the equation, like offering a ‘choice’ of food in a famine, or for prison settings. None can be considered a genuine volunteer when the alternative to being in a trial is to receive no treatment at all (even though this is apparently the norm for 6 out of 7 American addicts currently).

Comments by Andrew Byrne ..