16 August 2006

Community buprenorphine combination study: no control group and limited outcomes

N Engl J Med 2006 355:365-74

Counseling plus Buprenorphine-Naloxone Maintenance Therapy for Opioid Dependence. Fiellin DA, Pantalon MV, Chawarski MC, Moore BA, Sullivan LE, O�Connor PG, Schottenfeld RS.

Dear Colleagues,

Starting in August 2000, these authors prescribed a new and still largely untested buprenorphine combination treatment in three different randomised protocols to 166 community patients who had been on a methadone waiting list. There was no control group given established optimal dependency treatment (supervised �mono�-maintenance therapy).

About a third of subjects had not been on methadone previously (mean age 36; mean 8 years of dependence).

Rather than choosing quite disparate protocols to better contrast different outcomes, these researchers chose two similar levels of counselling (20 vs. 40 minutes per week) and two frequencies of dispensing (1 or 3 times weekly attendance). With these relatively minor differences, the researchers predictably found no significant differences in outcomes, including retention and illicit drug use. This raises the question of why this study was performed.

Unlike nearly all previous American research, there was no direct supervision of doses, even in new or unstable cases. However, the medication was dispensed in a �smart� bottle with a lid which recorded times of opening on a microprocessor. The authors report �adherence� (n�e �compliance�) at 70% � 20% and it would come as no surprise that indeed those with better compliance were more likely to have better drug use outcomes. The sub-optimal maximum dose here of 24mg (usually 32mg) may have limited outcomes to some degree.

In assessing retention rates, we should consider that trial subjects had (1) a comprehensive approach to treatment, (2) gratis treatment, (3) exclusions for those with depression, alcohol/benzo dependence, pregnancy and mental illness and (4) very limited effective alternative treatment options before, during and after the trial. Despite these factors, the 6 month retention rates were nonetheless modest at 39 to 48% (or even less, if we include all drop-outs from entry - see below). These are lower than reports of White (79% at 6 months) or Fudala (55-59% at 6 months).

These researchers also show that even when excluding high risk groups, and after numerous drop-outs, a further 10% fared so poorly in treatment that they needed �protective� transfer to methadone maintenance (with all its uniquely American rigours). Under this provision, after reaching the maximum dose of 24mg daily, patients with three consecutive opiate positive urine tests were automatically advised transfer to methadone. We are not told the subsequent progress of these late failures of buprenorphine combination treatment.

While maintenance opioid treatments have an enormous research base, nearly every rigorous study involved a pure drug (eg. methadone, buprenorphine, LAAM, morphine, heroin) given under direct supervision (at least initially). Thus the use of non-supervised dispensing and a combination drug were two aspects which were experimental in 2000 (as they largely remain in 2006). Thus one must question what these researchers hoped to achieve beyond a prominent peer reviewed publication of an untested treatment against itself of very limited scientific value.

It is also an ethical conundrum that these patients were prescribed a documentedly inferior drug having all been recruited from a waiting list for simple, traditional methadone treatment which is the gold standard. In a �normal� world (eg. Canada, New Zealand, Italy, Switzerland, Scotland, etc) these patients would have been given the option of methadone initially or alternatively, they might have been offered the study protocols in community practice compared to traditional clinic treatment.

In the 6 years since the trial started, the opiate of choice in many American cities has changed from heroin to morphine (which might please drug company shareholders). Buprenorphine may be more of less effective for this group. It is generally believed that buprenorphine is less effective for those with high level opiate use, yet this has never been scientifically tested to my knowledge.

During the 3� year recruitment two thirds of subjects were lost through being excluded, dropping out, etc. This left only one third finally accepted into the trial based in primary care (166 of 497). Hence, treatment retention is really substantially lower than reported if we include those assessed as opioid dependent but never actually starting treatment (208 of 497 lost contact or declined to enroll). This is something Prof James Bell has reiterated from his own trial work: what a small proportion of dependency patients actually prove to be suitable for non-supervised buprenorphine treatment.

The genesis of this study is unclear. It does not address the question about dose equivalence of the new combination buprenorphine, nor does it examine traditional supervised maintenance treatment against fully dispensed (un-supervised) treatment. These are crucial questions which nobody seems prepared to address scientifically (and which one might think would have been answered before approval).

Regarding the different levels of counselling, the first comparison of �bare bones� methadone dispensing with full service management was done in 1973 by Senay and Jaffe in Chicago, finding no significant differences (although some interesting trends were reported).

The improved results of any treatment due to adjuvant supports, both physical and mental, have been known about since the time of Hippocrates. In dependency treatments, McLellan (1993) and Yancovitz (1991) used quite different methods to provide evidence that added supports can make small but significant differences in outcomes.

Comments by Andrew Byrne ..

Yancovitz SR, Des Jarlais DC, Peyser NP, Drew E, Friedmann P, Trigg HL, Robinson JW. A randomised trial of an interim methadone maintenance clinic. (1991) American Journal of Public Health 81:1185-91

Schwartz RP, Highfield DA, Jaffe JH, et al. A Randomized Controlled Trial of Interim Methadone Maintenance. Arch Gen Psychiatry 2006 63:102-109

Senay EC, Jaffe JH, diMenza S, Renault PF. A 48-week study of methadone, methadyl acetate, and minimal services. In: Fisher S. and Freedman AM, eds, Opiate Dependence: Origins and Treatment. New York: Halsted 1973 185-201

Kraft MK, Bothbard AB, Hadley TR, McLellan AT, Asch DA. Are Supplementary Services Provided During Methadone Maintenance Really Cost-Effective? Am J Psychiatry (1997) 154;9:1214-19.

McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The Effects of Psychosocial Services in Substance Abuse Treatment. JAMA. 1993;269:1953-1959.

Fiellin DA, Pantalon MV, Chawarski MC, Moore BA, Sullivan LE, O�Connor PG, Schottenfeld RS. Counseling plus Buprenorphine�Naloxone Maintenance Therapy for Opioid Dependence. N Engl J Med 2006 355:365-74

Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins J, Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958