Sunday 14th November 2004
Prior to the APSAD conference proper the Reckitt Benckiser drug company had booked the conference centre for a symposium on buprenorphine. For the entire Sunday afternoon those attending discussed, learned, absorbed and almost 'breathed' partial agonists.
Leslie Amass PhD gave a talk on Suboxone versus Subutex, quoting initially from Fudala's NEJM paper from 2003. She showed some outcome markers, including the percentage of clear urine screens at ~22% for the pure drug versus ~18% for the combination with ~6% for 'controls' (actually 'placebo' cases!). While Amass stated that there was 'no difference', someone in the audience pointed to the apparently better results in the pure buprenorphine subjects (I said it looked like a 'trend'). We were told that this difference was not significant, yet such a trend would be consistent with other research presented by Dr Bell regarding the need for higher doses in the combination cases.
All delegates were given copies of the excellent pilot study by Professor James Bell and colleagues from Sydney published in D&A Review. In an expansive presentation he described the 17 stable consenting patients who were transferred from Subutex to Suboxone and also moved from daily to weekly attendance schedules. Most outcome results were gratifying (self report, urine toxicology weekly) as in other trials of stable folk given increased take-home doses (termed 'medical maintenance' in the US). Bell alluded to the random call-back provisions of his trial to count tablets for compliance. It would have been good if we had heard further details of 4 out of 17 who declined to attend when requested, and of the patient who had a stroke during the Suboxone trial, both mentioned in the accompanying published paper. The fact that 4 'stable' patients (25%) could not account for their remaining medication constitutes prima facie evidence of diversion. Professor Bell also told us that one patient "squirreled away" medication for up to 6 months. This is also a form of 'diversion' to my mind as the drug was clearly not taken as prescribed in the trial protocol. I recall an intriguing reference of measures to protect the good standing of a 'new drug', which ideally might have been discussed in more detail. There seemed to be an inconsistency between a projected slide showing dose increases averaging 50%, and the reference to a "slight" increase (needed in those who transferred from pure buprenorphine to the combination product, Suboxone).
As part of the same study, next we had Professor Bell's colleague, Amanda Morris, who spoke about the qualitative effects of changing daily attendances for stable, employed long-term folk into once per week or even fortnight attendances with the combination buprenorphine product. Unsurprisingly, the patients were uniformly grateful. They were almost grovelling in their praise for the new system, rather damning the previous daily attendance. We were shown dozens of quotes in which patients were almost religious in their support for the change wrought upon them. The staff also found it gratifying to have patients attending less often. No real surprises here to my mind. People were given treatment which was almost a 'cruel and unusual punishment' (daily attendance) and then moved to a liberal and tolerable management regimen so there is little surprise that everyone was pleased about it. The exact same would probably have happened using methadone or pure buprenorphine, simply by following established take-away schedules.
Andrea Gordon then spoke about buprenorphine in pregnancy, describing over 40 cases of controls and methadone patients followed from about 19 weeks gestation. She compared these with comparable numbers of women taking the combination product. There were no miscarriages in the methadone or control groups but 3 in the buprenorphine group. She stated that these were 'not significant' without qualifying herself. Even though this was a study in progress, I think more needs to be sought about the miscarriages. Other studies of buprenorphine in pregnancy have mostly be reassuring and many physicians now believe that it is safe to use in pregnancy. I still believe it should be a second line drug, albeit but an excellent one at that.
Andrea Gordon's other figures from Adelaide showed that methadone and buprenorphine patients had slightly smaller babies who were delivered slightly earlier but with few other differences. Some buprenorphine figures appeared to be slightly better on trend regarding neonatal withdrawals. Although buprenorphine is not yet approved for use in pregnancy it appears that some of these women were prescribed the drug as their choice and for others, their doctor's choice.
Walter Ling gave his usual witty and insightful talk, describing pain syndromes versus dependency diagnosis and the intersection of the two. He also covered the very practical subject of what to do for opioid maintained patients with severe pain, acute and chronic. He started by describing simple manoeuvres such as paracetamol and anti-inflammatories to additional methadone/buprenorphine (eg. one sixth dose increase as a start) or a simple addition of morphine which he said was practical and simple, even in inpatients having operations, transferring straight back to the maintenance medication afterwards.
Next (in Italian) we heard Dr Claudio Leonardi speak about the Roman and Neapolitan experience with buprenorphine (pure). He was gregarious and beautifully spoken with a broadly positive impression of their experience. He appeared to be supportive of the use of buprenorphine in preference to methadone in some cases or even more widely but did not give his reasons. He did however quote a paper he heard in Paris recently in which 5000 women on buprenorphine delivered babies apparently with safety. He stated that his group routinely transfers people on as much as 80mg methadone to buprenorphine. He alluded to the use of anti-diarrhoeals, anti-spasmodics and sedatives in such patients who I presume were in-patients. Our experience with high dose (up to 50mg) transfers has been uniformly unpleasant. I was unable to reconcile the difference as the first buprenorphine dose was given at least 24 hours after the last dose of methadone in all cases. Dr Leonardi did make the point that they never given more than 2mg to such high dose transfer cases on the first day, but afterwards they rack up the dose very quickly (eg. 8mg, 12mg, 16mg). He also mentioned much higher doses in some cases as high as 48 or 56mg which would present something of a challenge to consume just because of its bulk, not to mention the extremely high cost.
Fremantle is beautiful at this time of year and we are fortunate thus far to have clear, warm weather also blessed by the afternoon Indian Ocean "doctor" sea breeze each afternoon. The conference venue is the Fremantle Esplanade which is a large old rambling hotel which has been rebuilt with large, modern facilities maintaining the charming old façade facing the park, Norfolk pines, etc. It is a short stroll to the port, station and restaurant area.