Buprenorphine trial patients mostly end up needing methadone: Swedish RCT

Am J Psychiatry 2007 164;5:797-803

A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Kakko J, Gr�nbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, Heilig M.

This Swedish group may have done the field another service without realising it. A previous buprenorphine trial by Kakko et al. (Lancet 2003) had a placebo group with so many deaths (25% within a year) that they unintentionally demonstrated the life saving benefits of buprenorphine treatment (for the first time to my knowledge). They also showed that, at least in the Swedish environment with restricted access to alternative maintenance treatments, even second line treatment can yield a high retention rate of 75% at one year.

In the present study, half of 96 addicted subjects received standard methadone treatment (mean dose 111mg daily) while the rest received buprenorphine with transfer to methadone if needed. The latter occurred according to defined criteria of drug use or cravings, but only after a buprenorphine dose escalation to 32mg daily if this was tolerated. The final mean dose of buprenorphine was 29mg daily (�5). Consistent with previous research, only a third of buprenorphine patients remained on the treatment (42% transferred to methadone while 21% dropped out, most notably in the first 3 weeks). Treatment was daily in the first month when the trial was still double-blinded, in what these authors themselves describe as the �sensitive initial month of treatment�. After documented stability, there was graduation to twice and even once weekly attendance with the remaining doses given as �take-away� or dispensed doses.

The authors claim that retention rates in the two groups were �virtually identical� yet their decay graph clearly shows an excess of buprenorphine drop outs in the first three weeks of treatment, which is consistent with the reported experience of others. There were only one or two early drop outs in the methadone group yet in those randomised to start with buprenorphine, one in eight appear to have departed the trial. Methadone had about the same number of people leaving treatment overall (22% in six months), but they did so at a more constant rate over the 6 months of the trial. Overall 80% of methadone patients remained in treatment at 6 months, a commendable result, probably partly due to the good treatment given and lack of alternatives in this community.

Both groups had approximately 80% clear urine tests for opiates, also consistent with the adequacy of doses and high quality psychosocial treatment provided these Swedish subjects.

Despite these predictable findings, the authors initially state in the article�s abstract: �strategies using buprenorphine as a first line treatment should be considered�. This is changed, without additional explanation or references to a much stronger conclusion in the text that buprenorphine �should generally be used as the first-line treatment in heroin dependence, with provisions for rapid progression to methadone when needed�. It seems bizarre to recommend a drug with a known failure rate of over 50%, especially when there was an acceptable, cheaper and more effective alternative. The methadone in this very trial showed a failure rate of 20%. In addition, methadone is considered the drug of choice in pregnancy.

The only reason given for using the combination buprenorphine/naloxone drug was that it has been approved in the United States. From a pure science point of view, this clouds the issue since most research is on the pure product with very little on the combination product. The authors speculate that the addition of naloxone might have caused the high average dose of buprenorphine at 29mg daily (�5mg). The reference cited for dose equivalence (Johnson RE 2000) reports no such comparison from my reading of the original paper. The finding of high doses required is consistent with Bell et al 2004 (which is not cited by these authors, despite being the only clinical comparison to date as far as I know). In this, patients needed approximately 50% more buprenorphine when transferred from pure buprenorphine to the combination product. They detail the low primary toxicity of buprenorphine yet their case is not helped by a majority of their patients needing methadone in the long run and mean doses of buprenorphine being so much higher than other reports.

We are informed that the trial was partly funded by Schering-Plough Sweden. Four of the authors have received funds from drug companies. Three of these were from the manufacturer of buprenorphine and one author received funds from this source in three separate countries (Estonia, Sweden and Australia).

These authors quote the term �non-inferiority� four times in their article regarding their customised �stepped care strategy� based on retention rates and toxicology. In this comparison, however, they do not take into account several other important factors including dose, costs and patient satisfaction. They state that �no patients commented on transitioning� (is that English?) from buprenorphine/naloxone to methadone. Yet such patients must have been doing poorly on buprenorphine and must have had some views on finally being prescribed a more effective drug. Some might also possibly have had some views at being given the less effective drug initially in the trial, despite the consent process. Have any of these �transitioning� patients been asked to comment on the authors� suggestion relating to first line buprenorphine, I wonder? One may worry that some needle sharing or overdose might have occurred in the interim period, not to mention the 12.5% who appear to have dropped out altogether in this early period from the stepped care group.

It would also be interesting to know how many of the methadone patients may have needed to transfer to buprenorphine (we find it is between 10 and 30% in our own practice). This may well have applied to some of the drop-outs and possibly some of those retained in the treatment, who may be preferred to have buprenorphine for a variety of reasons.

Comments by Andrew Byrne ..