The acceptability, safety, and tolerability of methadone/naloxone in a 50:1 ratio.

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 pharmacodynamics 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 appeared 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 precipitated 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 challenges. 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.