To The Editor: In the May 2007 issue of the Journal, Johan Kakko, M.D., et al. reported on an excellent randomized controlled trial of “stepped” buprenorphine versus methadone therapy for heroin dependence (1). However, nearly two-thirds (65%) of the subjects were transferred to methadone because of continuing illicit drug consumption or cravings. Therefore, this study suggests that methadone should be the drug of first choice for maintenance treatment, and buprenorphine should be reserved for patients who do not respond well to methadone.
Most trials to date have reported that methadone provides superior retention (2). Methadone is also less expensive and easier and faster to administer than buprenorphine and is accepted as a safe treatment during pregnancy.
Dr. Kakko et al. reported a nonsignificant difference in their primary outcome of 6-month treatment retention, with 77% for buprenorphine and 79% for methadone. Such high retention is unusual for trials of this kind. In addition, the high buprenorphine retention may have been partly achieved by a more rapid dose escalation and a higher mean dose (29 mg/day) than usual.
Before the findings of Dr. Kakko et al. are accepted, there should be confirmation of the “noninferiority” of a standardized buprenorphine regimen in a community rather than clinic setting.
Methadone is more toxic than buprenorphine. This finding may not have been apparent in the study conducted by Dr. Kakko et al., since most of their patients ultimately received methadone. In some jurisdictions, buprenorphine is already the most frequently prescribed maintenance therapy for opioid addiction. It is undoubtedly an excellent second-line treatment.
Another important finding in this study was the average dose of 29 mg/day, which is more than double the average in most other studies and almost the manufacturer’s maximum recommendation of 32 mg/day. Such a large dose often takes more than 15 minutes to administer. Dr. Kakko et al. speculated that the inclusion of naloxone (not naltrexone as stated in the editorial accompanying the article) in the combination product may have contributed to the need for such an unusually high dose. Other studies have reported higher doses required for the buprenorphine-naloxone combination (3). However, we are not aware of any rigorous “equivalence” studies comparing buprenorphine with the combination product.
The recommendation by Dr. Kakko et al. that buprenorphine should be considered as the first-line medication, despite 65% of patients being transferred to methadone, is difficult to accept. While industry support is often integral to the development of new intervention strategies, it has also been shown that studies funded by the pharmaceutical industry have a greater likelihood of reporting favorable conclusions (4).
1.Kakko J, Grönbladh L, Svanborg KD, von Wachenfeldt J, Rück C, Rawlings B, Nilsson L-H, Heilig M: A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial. Am J Psychiatry 2007; 164:797–803
2.Mattick RP, Kimber J, Breen C, Davoli M: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. The Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD002207
3.Bell J, Byron G, Gibson A, Morris: A pilot study of buprenorphine-naloxone combination tablet (Suboxone) in treatment of opioid dependence. Drug Alcohol Rev 2004; 23:311–318
4.Jørgensen AW, Hilden J, Gøtzsche PC: Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review. BMJ 2006; 333:782. Epub 2006 Oct 6
Dr. Byrne owns and runs a private clinic that dispenses methadone, buprenorphine, and other drug treatment. Dr. Wodak is the director of a public clinic (free to patients and government funded) that dispenses both methadone and buprenorphine.
This letter (doi: 10.1176/appi.ajp.2007.07071058) was accepted for publication in July 2007.