The Acceptability, Safety, and Tolerability of Methadone/Naloxone in a 50:1 Ratio James Bell, James Shearer, Anni Ryan, Robert Graham, Kristy Korompay, and Suzanne Rizzo The Langton Centre Doungkamol Sindhusake The University of Sydney at Westmead Hospital Andrew A. Somogyi University of Adelaide Methadone is an effective therapy for heroin addiction, but the public health benefits are compromised by diversion and injection of prescribed methadone. Combination with naloxone is one way to reduce the risk of diversion and injection. Two studies were conducted. The first ascertained the safety, tolerability, pharmacokinetics, and pharma- codynamics of oral methadone-naloxone in a 50:1 ratio compared with methadone. The second study investigated the effectiveness of intramuscularly injected methadone- naloxone in precipitating withdrawal in methadone-maintained subjects. The first double- blind, crossover study randomized 10 stable methadone-maintained subjects equally to receive either methadone-naloxone or methadone over two alternate 14 day periods. In the second study, 5 subjects received intramuscular injections of methadone-naloxone before their scheduled methadone dose. Oral methadone-naloxone in a 50:1 ratio ap- peared to be well tolerated, although a taste difference between the preparations may have compromised blinding. There were no significant differences between methadone and methadone-naloxone in objective and subjective opioid withdrawal signs, and trough and peak plasma concentrations. Methadone-naloxone in a 50:1 ratio intramuscularly precip- itated mild to moderate signs of opioid withdrawal in 4 out of 5 subjects whereas a 5th subject who did not experience withdrawal at a lower dose refused higher dose chal- lenges. Withdrawal symptoms peaked 15 to 30 minutes postchallenge and returned to baseline levels at 60 minutes. Methadone-naloxone in 50:1 ratio has the pharmacological properties to be a useful combination product for treatment of heroin addiction with reduced risk of injection. Keywords: methadone-naloxone, diversion, pharmacokinetics, pharmacodynamics, precipi- tated withdrawal Methadone treatment has demonstrated positive health outcomes in opiate dependent patients (Mattick, Breen, Kimber, & Davoli, 2003). Diversion and misuse of pre- scribed medication can result in adverse outcomes and is of particular concern when the medication is not administered under supervision (Darke, Topp, & Ross, 2002; Lintzeris, Lenne, & Ritter, 1999). Daily supervised methadone main- tenance is, however, associated with high costs and rigidity that may be a deterrent to treatment for some clients. Di- verted methadone is often injected with attendant health risks (Humeniuk, Ali, McGregor, & Darke, 2003) and has accounted for over half of methadone overdose deaths (Sun- jic & Zador, 1999; Vlahov et al., 2007). On the other hand, takeaway doses are an important feature of opioid substitu- tion therapy as they allow clients to develop activities outside of medication taking. Increased takeaway doses have been associated superior retention in treatment (Grabowski, Rhoades, Elk, Schmitz, & Creson, 1993; Pani, Pirastu, Ricci, & Gessa, 1996). The addition of naloxone to methadone has previously been investigated to discourage the injection of takeaway doses. Naloxone displaces methadone from the microopioid receptor because of a significantly higher affinity (naloxone K i = 1.78  0.25, methadone K i = 4.2  0.61) (Magnan, Paterson, Tavani, & Kosterlitz, 1982) but has a significantly James Bell, James Shearer, Anni Ryan, Robert Graham, Kristy Korompay, and Suzanne Rizzo, The Langton Centre, Sydney, Australia; Doungkamol Sindhusake, Centre for Health Services and Workforce Research, The University of Sydney at Westmead Hospital, Sydney, Australia; Andrew A. Somogyi, Discipline of Pharmacology, University of Adelaide, Adelaide, Australia. We thank Gaye Byron, Nursing Staff, The Langton Centre; Carole Stubley and Donna Brady, Rankin Court, St. Vincent’s Hospital, Sydney; Judith Hampson, May Kwan, Margot Clement, and the Pharmacy Staff, Sydney Hospital; Joel Colville, Depart- ment of Pharmacology, University of Adelaide; and Arlene Wal- lendorf and Graham Hitch, Biomed, New Zealand. Correspondence concerning this article should be addressed to James Shearer, The Langton Centre, 591 South Dowling Street, Surry Hills NSW 2010, Sydney, Australia. E-mail: james .shearer@sesiahs.health.nsw.gov.au Experimental and Clinical Psychopharmacology © 2009 American Psychological Association 2009, Vol. 17, No. 3, 146 –153 1064-1297/09/$12.00 DOI: 10.1037/a0016302 146 This document is copyrighted by the American Psychological Association or one of its allied publishers. This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.