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.
References:
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
"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."
