Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins K. Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958
Dear Colleagues,
This study randomised consenting heroin dependent subjects to receive one month’s treatment with (i) buprenorphine, (ii) buprenorphine/naloxone or (iii) placebo. For a further 11 months, surviving (sic) patients were followed in an open-label manner for primary outcome measure of 'percentage of urine drug screens negative for opiates' as well as for safety.
The double blind treatment was given for one month, supervised for weekdays with take-home doses for weekends. Doses were fixed at 16mg buprenorphine, 4mg naloxone. In the open label study there were more liberties with up to 10 consecutive doses being dispensed for home consumption.
The authors seem to have been surprised that results (retention and drug screens) for the placebo group quickly became more than 3 standard deviations away from those in the active treatment groups. Under their agreed protocol this triggered abandonment of the placebo arm of the trial, but not before a substantial excess of treatment drop outs and relapses to illicit drugs.
The paper leaves many questions unanswered. What was the 12 month retention rate? Significant numbers of late drop-outs must have occurred as there is a shortage of urine drug screens reported from the open label study. We are not told whether the patients with abnormalities to liver function tests thought to be ‘possibly’ or ‘probably’ related to the treatment (7 cases) were prescribed pure buprenorphine or the combination product.
These subjects were presumably told that they had a one in three chance of being given no active drug and would thus may have had to face opiate detoxification.
The ethics of researchers offering placebos for serious conditions has been dealt with in detail since this paper’s genesis in 1996. These authors may be reluctant to be associated with such a practice today.
This trial is only of very limited relevance since it did not compare office based practice with standard US clinic treatment. Nor were the conditions the same as current licence arrangements in the US (no supervised doses are required!). In essence, the trial patients on bup/naloxone combination showed slightly more side effects (?significance) but comparable reductions in illicit drug use .. and similar early retention rates compared with those taking the pure sublingual tablet without the naloxone. Hence the combination drug conferred no particular advantage for the patient and, being a mixed drug, may have some disadvantages over the pure drug. Thus there would seem to be no proof that the combination drug is either better for the patient, nor that it is necessarily better for the public health situation in America. This lack of good scientific evidence favouring the use of the combination product provides yet another challenge for American doctors. It is to be hoped that this trial will, however, give strong support for allowing more unsupervised buprenorphine doses in Australian settings where such dispensed doses are still the exception. For 8 years in France most doses of the pure drug buprenorphine have been unsupervised and most indications are positive.
Comments by Andrew Byrne ..
