Important and novel findings from Suboxone� study in Sydney

Drug Alcohol Rev (2004) 23;3:311-318

A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Bell J, Byron G, Gibson A, Morris A.

Dear Colleagues,

These researchers are to be congratulated on one of the first studies of its kind. They report on responses in 17 consenting 'stable' buprenorphine patients who were offered transfer to the combination product containing naloxone which, after the first week, was dispensed once weekly and taken by the patient unsupervised rather than daily dispensing as previously.

Most research I have read on buprenorphine employs the drug for new patients presenting for treatment, measuring illicit drug use and treatment retention. However, very useful clinical evidence is also derived from comparing existing practice with the experimental condition. The combination buprenorphine and naloxone product ('Suboxone®') was approved for unsupervised use in the US over 2 years ago despite most of the existing research being on supervised dosing. We are told that the combination drug is equally effective and has theoretically less prospect for diversion as it contains an antagonist which if injected will cause withdrawals in those dependent on heroin or methadone.

The most surprising finding in this pilot study was that when transferred to the combination drug, nearly all patients required substantially higher doses of buprenorphine. Of the 15 successful cases, 4 needed double or more of the original dose of buprenorphine. One needed triple while the rest required more modest increases averaging about 50% at the transfer time.

"The switch from buprenorphine (Subutex®) to the combination product (Suboxone®) was associated with mild withdrawal symptoms for 24 hours in the first subject. Thereafter, 13 subjects had about a 50% increase in dose when switching (from an average dose of 8.5 mg Subutex® to day 1 Suboxone® average of 12.2 mg); in no cases were there complaints of either intoxication or withdrawal."

The possible 10% quoted absorption of naloxone may be responsible for antagonising the opioid effects, at least temporarily. Three patients reported withdrawals when starting the combination product. One of them chose to withdraw from the study altogether rather than taking increased doses offered. Thus it would appear that the combination drug may not be bio-equivalent and therefore not 'equally effective' as pure buprenorphine, especially for high-dose patients since 32mg is the current maximum recommended dose. Another explanation might be that the subjects in this trial were originally taking inadequate doses of the pure drug. Yet, since they were 'stable' such doses must have been associated with positive outcomes at the time.

Those intent upon eventual abstinence may have been disappointed that after six months in these 'stable' patients the mean buprenorphine dose were still significantly higher than at the start of the trial (up from 9 to 11mg daily [22%]). Apart from the withdrawals, there were some major events with one patient suffering a stroke and another becoming pregnant despite the strict protocol (Suboxone® is contraindicated in pregnancy). It must also be a concern that despite only enrolling stable, employed patients, by the end of the study four of the fifteen were unemployed. In spite of being chosen for their stability, there was still use of illicit drugs in about 6 patients according to urine toxicology reported. At least one patient was using such drugs frequently.

Since doses were dispensed unsupervised, in order to check for compliance, patients agreed to random call-back arrangements. Despite this, four patients (27%) failed to do so, claiming they had work commitments. Yet it appears that they were still permitted to continue with unsupervised medication. This reported finding could mean that some of the four patients had already consumed or even on-sold their medication.

It is puzzling that these patients had not been receiving any take-home doses despite being long-term and 'stable'. Nor do the authors address second daily administration of buprenorphine in these cases as recommended by the manufacturer. They write at length on the benefits of take-away doses and of the difficulties with daily attendance. Indeed, Australian Commonwealth guidelines on opioid maintenance point out that retention rates are reduced when take-away doses are not available. Even the original strict NSW buprenorphine prescribing guidelines allowed stable patients 2 take-away doses weekly with certain conditions. Most Australian jurisdictions now permit up to 5 take-away buprenorphine doses per week with few reports of problems. The use of strict 7-day dosing should be exceptional and dispensed doses used judiciously as an added incentive to normalise the dependent life style.

It is clear that opioid maintenance can be very successful with twice (or even once) weekly supervision. The researchers' final statement is that 'using access to unsupervised dosing to promote abstinence from heroin probably limits the potential benefits of unsupervised administration to a very small proportion of patients.'

comments by Andrew Byrne ..