22 October 2010

Three articles addressing problems with buprenorphine treatment.

Dear Colleagues,

Three interesting articles (citations below) have come out recently each addressing a limitation of buprenorphine in clinical practice. Last week’s JAMA has a description of a trial using a depot form of buprenorphine in America. There is also a supporting editorial from Patrick O’Connor from Yale University who points out the restrictions of current opioid treatments and the need for alternatives.

Unsurprisingly, the implant patients had more opiate-free urine tests (40%) than placebo patients (25%) and better retention (60% versus 30%). Just over 50% of the recipients reported significant local reactions at the implant sites, both active and placebo groups but none had to be removed early. One developed frank cellulitis. The blood levels of buprenorphine were found to be in the low range yet it is pointed out that retention rate is about double that of trials of sublingual buprenorphine.

I find it hard to understand how the disadvantages of a fixed dose and surgical insertion of implants could outweigh the high patient acceptability and modest cost of custom dosing of sublingual buprenorphine.

Rather than comparing the buprenorphine 80mg implants with evidence based methadone maintenance treatment (O’Connor calls it the ‘gold standard’ in his editorial) these veteran researchers used placebo implants and ‘rescue’ sub-lingual buprenorphine as a control group. Nor was there any third group for comparison with existing treatments. In my experience this is what is commonly seen in drug company funded trials aimed at marketing approval rather than scientific investigations to determine clinically important questions (see below). O’Connor states that criticism of the use of a placebo group is moderated to some degree by the need for a definitive assessment of a new delivery method and the fact that the placebo group was smaller than the active cohort (55 versus 108) with supplemental sub-lingual buprenorphine available under certain circumstances. While this design may improve the statistical power of the findings, it lowers the credibility of the researchers involved in my view, like the HIV cases in Africa who were denied treatment ‘in the interests of science’. It must be said, sadly, that it is consistent with the much quoted statistic that up to 6 out of 7 American drug addicts are denied appropriate treatment.

The reader is informed that the study was funded by a pharmaceutical company whose personnel collected and monitored data and were involved in the design of the study, management, analysis, and interpretation of the data and preparation, review, and approval of the manuscript. One is left wondering just what the named authors did by comparison with the anonymous ones. The researchers’ financial disclosure statement runs to 33 lines of small print. This may be a record in my own reading.

Another report comes from Malaysia where the combination buprenorphine/naloxone tablet replaced the pure product which was being widely abused, including injecting. While there was a reduction in some harmful behaviour, the focus group reports make fascinating reading. They would appear to confirm James Bell’s finding that the combination product is significantly weaker than the pure product it replaced (a 50% increase was required on average). Malaysian patients here reported the need for double the dose for the same degree of effect when the antagonist was added, despite claims that its absorption is clinically insignificant.

The present researchers, who had previously investigated HIV transmission in Kuala Lumpur, state: “ … the results of the second wave survey suggest a continuing widespread [intravenous use buprenorphine/naloxone], at least in Kuala Lumpur.” “The introduction of BNX and withdrawal of BUP may have helped to reduce, but did not eliminate the problems with diversion and abuse.” Some addicts reported that the combination pill was not as desirable.

These findings accord with Robinson’s report from New Zealand 20 years ago when injecting of buprenorphine combination was so prevalent that it was withdrawn from the market completely. They also quote Bruce et al who concluded in 2009 that introduction of combination buprenorphine to Malaysia ‘did not reduce BNX injection or associated risk behaviors’. His group also found that the change to combination buprenorphine was associated with increased quantities injected in about half of the patients interviewed. Their informants also reported that injecting smaller quantities of the combination product or using additives of benzodiazepines or heroin could avoid withdrawal reactions. Paradoxically, the change to a combination drug had made buprenorphine generally less attractive, more expensive and less available to addicts than street heroin in many cases. It is surprising that such a study has not been performed in Australia where both forms of the drug are available and widely used.

The third report is from a group in New York which found high rates of precipitated withdrawal in commencements onto buprenorphine treatment (17%). Such reactions were more common with lower initial doses, recent methadone use and concurrent benzodiazepine use. To her great credit, Dr Whitley reported in 2007 on the co-locating of buprenorphine and methadone treatments. While she called this ‘novel’, for the rest of the world it is just normal. The American legislative requirement to isolate methadone prescribed patients is indeed bizarre and counter-productive.

One problem with the high rate of precipitated withdrawals may have been due to the use of combination product containing the antagonist naloxone. This is contrary to the original American treatment guidelines which advised stabilising patients on pure buprenorphine before transferring to the combination product.

Equivalence studies have still not been performed despite such research being relatively simple and cheap. Furthermore, despite 0.4mg pure product being marketed in Australia for ten years, there is still no low-dose combination product available (eg. 0.4mg or 0.2mg increments for those taking less than, say, 4mg daily). 40 years of experience with methadone have shown that carefully graduated dose reductions are often necessary to achieve abstinence.

It was the low potency preparations, both pure and combination, which became subject to wholesale abuse 20 years ago in New Zealand (Robinson, D&A Dependence 1993 13;1:86). I understand that in America the smallest tablet available is a non-bisectable 2mg pill, making reductions towards abstinence extremely challenging for patient and clinician alike. It would be like the lowest dose of methadone available being around 20mg daily in my estimation. Some ultimately successful abstinence patients have taken very low doses for a long period before eventually ceasing their pharmacotherapy.

Our own practice experience with buprenorphine inductions has been similar to what one might expect from the literature. We have had a very low rate of precipitated withdrawal reactions (<5%) but a failure rate for inductions of approximately 20-40%, mostly due to the drug not abolishing withdrawals. This is about double our failure rate with methadone. Our impression is that there are also excess early dropouts in those successfully inducted onto buprenorphine, as also reported by others.

Personal disclosure: I first prescribed buprenorphine (off-label) in 1986 and have been an enthusiastic supporter of its use for dependency ever since. While methadone is the ‘gold standard’ it does not suit everyone with opioid dependency. For many years our dispensary has had about 20% of our opioid pharmacotherapy patients taking (pure) buprenorphine. I personally do not prescribe the combination product due to the lack of safety and equivalence data as well as a lack of the 0.4mg preparation allowing low-dose titration. Our Concord Dependency Seminar group receives sponsorship for refreshments by Reckitt Benckiser who have also generously donated a data projector.

Comments by Andrew Byrne ..

Full citations:

Ling W, Casadonte P, Bigelow G, Kampman KM, Patkar A, Bailey GL, Rosenthal RN, Beebe KL. Buprenorphine Implants for Treatment of Opioid Dependence A Randomized Controlled Trial. JAMA 2010 304;14:1576-1583

Vicknasingam B, Mazlan M, Schottenfeld RS, Chawarski MC. Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia. Drug and Alcohol Dependence 2010 111;1/2:44-

Whitley SD, Sohler NL, Kunins HV, Giovanniello A, Li X, Sacajiu G, Cunningham CO. Factors associated with complicated buprenorphine inductions. J Subst Abuse Treat. 2010 39;1:51-57