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Intermittent naloxone attenuates the development of physical dependence on methadone in rhesus monkeys
J H Krystal1, M W Walker, G R Heninger
1Abraham Ribicoff Research Facilities, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
Abstract:
Rhesus monkeys that received 15 daily injections of methadone (2 mg/kg i.m.) exhibited a characteristic opiate withdrawal syndrome after injection of naloxone (0.5 mg/kg i.m.) on the 16th day. In comparison, injection of naloxone (0.5 mg/kg i.m.) once every 2 days during a similar 15 day methadone treatment period in these same monkeys significantly attenuated the severity of the opiate withdrawal syndrome exhibited after naloxone injection on the 16th day. Each naloxone administration during the 15 day methadone treatment period elicited an opiate withdrawal syndrome that did not significantly differ on each of the 7 days it was given and was less severe than the syndrome precipitated by naloxone following 15 days of methadone without intermittent naloxone. The lack of increments in the withdrawal response to the seven naloxone injections during the 15 days of methadone treatment and the attenuation of the withdrawal response to naloxone on day 16 after intermittent naloxone administration during the 15 day methadone treatment period support the hypothesis that naloxone modifies opiate receptor mechanisms so that they revert to an agonist-naive state following antagonist exposure. These findings suggest that various agonist and antagonist opiate drug combinations or mixed agonist-antagonist drug could be clinically useful in the management of situations where physical dependence on opiates is a problem.
Insights
Administering naloxone intermittently during methadone treatment in rhesus monkeys attenuated opiate withdrawal syndrome. This suggests naloxone modifies opioid receptors, potentially aiding in managing opioid dependence.
Area of Science:
- Pharmacology
- Neuroscience
- Addiction Medicine
Background:
- Opioid dependence is a significant public health issue.
- Managing physical dependence often involves complex pharmacological strategies.
- Understanding opioid receptor dynamics is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the effect of intermittent naloxone administration during methadone treatment on opioid withdrawal severity.
- To explore the hypothesis that naloxone exposure modifies opioid receptor mechanisms.
Main Methods:
- Rhesus monkeys received daily methadone injections for 15 days.
- One group received naloxone on day 16, while another received intermittent naloxone every two days during the treatment period.
- Withdrawal syndrome severity was assessed after naloxone challenge.
Main Results:
- Daily methadone followed by naloxone precipitated a significant opiate withdrawal syndrome.
- Intermittent naloxone administration during methadone treatment significantly attenuated the severity of the withdrawal syndrome.
- Withdrawal responses to intermittent naloxone did not increase over time and were less severe than in the control group.
Conclusions:
- Intermittent naloxone administration may reset opioid receptors to an agonist-naive state.
- This suggests potential clinical utility for opioid agonist/antagonist combinations or mixed agonist-antagonist drugs in managing opioid dependence.
- Findings support novel therapeutic strategies for opioid use disorder.