Does Prolonged Naltrexone Therapy Alter the Rewarding Nature of Exercise, Socialization, and Eating? A Narrative Review

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Introduction: Naltrexone is an opioid receptor antagonist prescribed for alcohol use disorder and opioid use disorder. Naltrexone has a high affinity for the mu-opioid receptors, which are the primary binding site of beta-endorphin. Beta-endorphin is an endogenous opioid that functions as the mediator of behavioral reward and reinforcement. Antagonism of the mu-opioid receptors with naltrexone improves certain outcomes in patients with substance use disorder but may alter the positive endogenous reinforcement associated with naturally rewarding and healthy activities including exercising, socializing, and eating. Discussion: In this paper, we review medical literature exploring the potential negative effects of chronic naltrexone therapy on healthy lifestyle modification. Conclusion: Although the data is preliminary, there exists a possibility that naltrexone therapy may adversely impact the endogenous reward system associated with health promoting activities. Relevance: Mortality amongst subjects with substance use disorder has increased to epidemic proportions since fentanyl became widely available. Until relatively recently, behavior modification and Twelve Step programs have been the cornerstones of recovery from substance use disorder. Previous reports have confirmed that exercise, positive social networking, and proper nutrition are important adjunctive therapies in early recovery. The possibility exists that the naturally occurring endorphin mediated reward of these activities may be adversely impacted by naltrexone therapy. Further investigation is warranted to determine whether long-term naltrexone therapy is associated with decreased healthy behaviors and if dose modifications such as low dose or an intermittent dosing scheduling could attenuate this possible unintended consequence of therapy.