2 December 2013

Poor retention buprenorphine/nxn vs. methadone. Also NYT article on bupe.

Hser YI, Saxon AJ … Ling W. Treatment Retention among Patients Randomized to Buprenorphine/Naloxone Compared to Methadone in A Multi-site Trial. Addiction. 2013 Aug 20
Dear Colleagues,
Over 1000 opiate dependent patients were randomised to methadone or Suboxone and then followed for 24 weeks.  Retention in the methadone group was 74% compared with 46% (p<.01) for those taking buprenorphine with naloxone.  The buprenorphine retention was so poor, more than half dropping out, that they had to recruit more subjects to allow a meaningful comparison of liver function tests, the primary purpose of this Phase IV study (see ref 1 for original report).  There were 24 cases of extreme elevations of liver enzymes but reassuringly, no difference between the groups.  There was no discussion of harm reduction measures since American doctors are banned from such interventions so that harm maximisation can co-exist with an ‘ethical’ trial.  Seroconversions among treated individuals in the community should be exceptional even with the most rudimentary public health services.  Men did better on buprenorphine for some reason. 
While the authors say that the retention rates are ‘in the range’ of other studies, the low buprenorphine retention rate would seem to be well out of step with the several RCTs comparing pure buprenorphine with methadone, each finding either no difference or a modest difference between the groups (see Cochrane summary on the subject - ref 2, also refs 3, 4 and 5).  To my reading none found such a substantial difference in retention.  The present authors make the rather hopeful speculation that doses higher than 32mg daily might improve the poor retention rates, despite the basic pharmacology being against this (not to mention the undignified dosing and enormous cost, as well as the fact that most had dropped out long before such doses were achieved).  Inadequate induction protocols might also apply to methadone.  And without routine supervised doses in America, induction in community treatment with buprenorphine in America is hard to determine. 
Another possible explanation for the poor results on combination buprenorphine might be that the added naloxone reduced the efficacy of buprenorphine, something which has not been formally tested to my knowledge.  Most RCT have involved pure buprenorphine, including the recent MOTHER study (with all its faults).  There is still no cogent evidence for the thesis that the combination reduces abuse, despite the attractiveness of the concept empirically (ref 6 and see Wiki quote at ref 8). 
The possibility that adding naloxone changes the characteristics of buprenorphine is supported by a small but well conducted pilot study from Sydney, funded by the NSW Health Department.  Bell et al. transferred 17 stable (pure) buprenorphine patients to the combination formulation, finding that most needed a higher dose with a mean of just over 50% of the original dose (ref 7). 
This present trial was not blinded and we are not informed how patients attending clinics were consented and randomised.  It is possible that incentives such as free treatment might have induced previously successful methadone patients to take a chance on buprenorphine, causing a falsely high drop-out rate for buprenorphine.  However, until there is a valid comparison of pure buprenorphine with the combination product we are forced to rely on indirect evidence and imperfect studies, few if any of which support the use of combination buprenorphine.  Today’s New York Times quotes of the US FDA: “Early this year, it [FDA] approved generic tablets and asked the Federal Trade Commission to investigate potentially anticompetitive business practices by the company.” See link below for very wide-ranging article on buprenorphine. 
I still find no cogent reason to use combination buprenorphine.  It is possible that large numbers of opiate dependent patients in Australia and elsewhere are taking naloxone for reasons which are more related to good marketing than good medicine.  I remain a fervent supporter of (pure) buprenorphine as a maintenance treatment and would recommend it as an excellent alternative to methadone with some major benefits as well as some shortcomings. 
Written by Andrew Byrne ..
STOP PRESS – I highly recommend this detailed front page item in the New York Times http://www.nytimes.com/2013/11/17/health/in-demand-in-clinics-and-on-the-street-bupe-can-be-savior-or-menace.html?partner=rss&emc=rss&_r=0  They still omit the ‘elephant in the room’ which is clinic-type treatment.  Monthly dispensed pills without some structure (counselling, urine testing and/or supervised doses etc) have never been shown to be safe or effective yet that is exactly what many French and American patients receive.  
1. Saxon AJ, Ling W, Hillhouse M, Thomas C, Hasson A, Ang A, Doraimani G, Tasissa G, Lokhnygina Y, Leimberger J, Bruce RD, McCarthy J, Wiest K, McLaughlin P, Bilangi R, Cohen A, Woody G, Jacobs P. Buprenorphine/Naloxone and methadone effects on laboratory indices of liver health: A randomized trial. Drug Alcohol Depend 2013;128:71-76
2. Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002207
3. Schottenfeld RS, Pakes JR, Olivento A, Kosten TR, Zeidonis D. Buprenorphine vs Methadone Maintenance Treatment for Concurrent Opioid Dependence and Cocaine Abuse. Arch Gen Psychiatry. 1997 54:713-720
4. Schottenfeld RS, Pakes JR, Kosten TR. Prognostic factors in Buprenorphine- versus methadone-maintained patients. J Nerv Ment Dis. 1998 186;1:35-43
5. Pani PP, Maremmani I, Pirastu R, Tagliamonte A, Gessa GL. Buprenorphine: a controlled clinical trial in the treatment of opioid dependence. Drug Alcohol Depend. 2000 60;1:39-50
6. Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Am J Drug Alcohol Abuse 2009 Feb 12:1
7. Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318

8. Wiki page on buprenorphine excerpt: http://en.wikipedia.org/wiki/Buprenorphine
"There is a common misconception that naloxone, a potent opioid antagonist included in the Suboxone formulation, is active and responsible for this blockade effect. This is not true. Instead, Buprenorphine alone is responsible for the blockade effect due to its high binding affinity at the brains opioid receptors, a higher affinity than that of naloxone. The naloxone is in effect not active regardless of the route of administration."