Narrative Review
Does Naltrexone Therapy Alter the Rewarding Nature of Exercise, Socialization, and Eating? Addressing the Gap in Research on Naltrexone’s Effects in Patients with Opioid Use Disorder.

Caitlin Collier1, Thomas Hilton
Published online: October 2024

1Georgetown University, Washington DC, United States
Corresponding Author: Caitlin Collier, email caitlincollier2018@gmail.com
DOI: 10.26443/mjm.v21i1.1058

Abstract

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 opioid use disorder but some studies on healthy participants show that it may alter the positive endogenous reinforcement associated with recovery promoting activities including exercising, socializing, and eating. No recommendations for treatment duration have been established for naltrexone in treating patients with opioid use disorder. Since studies on naltrexone’s effects on these activities have mostly been conducted on healthy participants, more research is needed to investigate the potential negative impact of naltrexone therapy on recovery-promoting activities in people with opioid use disorder.

Discussion

In this paper, we review medical literature exploring the potential negative effects of naltrexone therapy on eating, exercise, and socializing in healthy individuals. This paper discusses the need for research exploring naltrexone’s effects on these activities in people recovering from opioid use disorder, as these activities are crucial for establishing long-term recovery.

Conclusion

Data on naltrexone’s effects in healthy populations suggests that it may alter the rewarding nature of health-promoting activities, including exercise, eating, and socialization. Research on naltrexone’s effects on these activities in patients with opioid use disorder is lacking. Further research should be conducted to examine whether these effects also occur in people with opioid use disorder undergoing naltrexone therapy, as they may hinder the establishment of positive behaviors essential for long term recovery.

Relevance

Mortality among subjects with opioid 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 in patients with opioid use disorder may be adversely impacted by naltrexone therapy. Further investigation is warranted to determine whether 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 treatment.

Tags: beta endorphin, naltrexone, opioid use disorder


Introduction

Naltrexone is an opioid antagonist with a high affinity to mu-opioid receptors and lower affinity to kappa-opioid receptors. It is a commonly prescribed medication for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). (1) When administered in a 50mg oral dose, naltrexone blocks 95% of the mu-opioid receptors within 8 hours and maintains a greater than 90% blockade in the brain 49 hours post oral administration. (2) In doing so, naltrexone diminishes the positive reinforcing effects of opioids. (3) In addition to the oral version, naltrexone is commonly administered to patients with OUD via a once monthly intramuscular injection, Vivitrol. Prescribing information for both oral naltrexone and Vivitrol do not specify recommendations for the length of treatment. According to Kaiser Permanente’s Opioid Use Disorder Diagnosis and Treatment Guideline, patients with OUD should receive naltrexone therapy for a minimum of 12 months and should be encouraged to continue long-term maintenance treatment. (4) Long-term treatment of OUD with naltrexone for a period of 6 months or longer is not uncommon due to the remitting and relapsing nature of opioid addiction.

The main binding target of naltrexone is the mu-opioid receptor, which also binds endogenous opioids. Beta-endorphin is an endogenous opioid ligand specific to the mu-opioid receptor. (5) When bound to the mu-opioid receptor, beta-endorphin inhibits the release of Gamma-Aminobutyric Acid (GABA) which increases dopamine release. (5,6) Beta-endorphin has been identified as the molecular mediator of the reward effects associated with various healthy behaviors. (5) Most abused substances elicit an increase in beta-endorphin levels, which is considered central to the addictive cycle. Other healthier rewarding activities such as exercising, socializing, and eating also increase levels of beta-endorphin thus creating an endogenous incentive to repeat these activities.

Patients in early recovery from addiction and substance use disorder benefit from a supportive social network, proper nutrition, and activities such as exercise. Antagonism of the mu-opioid receptors for prolonged periods of time could potentially hinder a patient’s ability to establish the behavioral foundation for long-term recovery. In the current manuscript, we explore the concept that the reinforcing nature of certain healthy activities may be altered during naltrexone therapy in healthy individuals and that further research is needed to determine whether these effects are also present in patients with OUD undergoing treatment with naltrexone. We review studies examining the effects of naltrexone on exercising, socializing, and eating to explore whether naltrexone alters the rewarding nature of these activities in healthy patients and patients with opioid use disorder and how this might affect one’s ability to achieve lasting recovery.


Case Description

Selection of articles for this review was conducted through PubMed and Google Scholar using the following terms and abbreviations both separately and in conjunction with one another: ‘naltrexone’, ‘NTX’, ‘low-dose naltrexone’, ‘LDN’, ‘opioid antagonist’, ‘addiction’, ‘alcohol use disorder’, ‘opioid use disorder’, ‘mu-opioid receptor’, ‘kappa-opioid receptor’, ‘endorphins’, ‘beta-endorphin’, ‘endogenous opioids’, ‘dysphoria’, ‘exercise’, ‘effects’, ‘eating’, and ‘socialization’. No date ranges were used during the article selection process. After the selection of articles using keyword searches, additional articles were found through sources listed in the bibliographies of those previously chosen works.


Discussion

Exercise

Exercise and its Importance in Addiction Recovery

Exercise is an underutilized form of treatment for individuals with addiction. Exercise is associated with lower relapse rates, reduced cravings, improved mental health and overall quality of life. (7) Exercise reduces stress and decrease levels of anxiety and depression. Exercise training can suppress drug-seeking behaviors, lessen withdrawal symptoms, and ameliorate brain damage associated with chronic drug exposure. (8) Studies on exercise as a treatment for opioid use disorder have shown restored bone quality, reduced musculoskeletal pain, and overall improvement of physical condition. (9) Due to its benefits on brain health, quality of life, and reduction in anxiety and depression, physical exercise also helps increase commitment to therapy. (10)

Naltrexone Effects on Exercise

Studies examining naltrexone’s effects on exercise induced euphoria, analgesia, and anxiolysis in healthy patients have produced mixed results. (11) Some have demonstrated that naltrexone diminishes the positive mood effects typically observed after exercise. This is consistent with the observation that positive mood effects are mediated by endogenous opioids. (12) Other results show naltrexone did not abolish the euphoric and anxiolytic effects of exercise suggesting that these effects are more likely the result of the endocannabinoid system rather than the opioidergic system. (11) There may be overlap between the opioidergic, endocannabinoid, and dopaminergic systems of the brain. How these systems interact and how mu-receptor blockade may interrupt the rewarding effects of exercise through disruption of endorphin binding remains poorly understood. Additionally, no studies have been conducted to explore the effects of naltrexone on exercise in patients recovering from OUD. Since exercise has been proven to positively modify neural circuits involved in reward, inhibition, and stress in patients with OUD, (9) continued scientific investigation of this subject is needed to determine whether naltrexone may affect this recovery-promoting behavior.

Socialization

Socialization and its Importance in Addiction Recovery

The number of other drug-users in a substance user’s social network has been shown to adversely impact drug use outcomes and treatment. (13) Therefore, the establishment of a new, supportive social network is a crucial component to successful recovery from opioid use disorder. Studies show that people with OUD are at a greater risk of suicide and have increased feelings of social isolation. (14) Involvement in a Twelve Step program such as Narcotics Anonymous (NA) or Alcoholics Anonymous (AA) helps facilitate change in one’s social network and increase social connectedness. (15-17) Regular involvement in NA/AA (once or more a week) is associated with increased abstinence from opioids and alcohol at 4-5 years follow-up when compared to those who did not regularly attend such meetings. (15) These relationships aid people with substance use disorder to connect to a supportive network and establish relationships that reduce risk of relapse. (17)

Naltrexone Effects on Socialization

Research on naltrexone and social connection provides evidence for the Brain Opioid Theory of Social Attachment (BOTSA), which hypothesizes that the positive feelings experienced during social connection are in part due to endogenous opioid release. (18,19) In healthy patients, some studies found that naltrexone reduces the feeling of being socially connected to family, friends, and romantic partners and may negatively impact maintenance of such social relationships over time. (19) Social acceptance is associated with activation of mu-opioid receptors and is predictive of higher social interaction. (20) Research exploring social bonding in healthy participants concluded that mu-opioid receptor activity in humans is associated with feelings of warmth and that naltrexone decreased this feeling. (21, 22). There appears to be preliminary data suggesting unintended consequences of naltrexone therapy in healthy patients, including social isolation and avoidance of salutary social connections. There are currently no studies investigating naltrexone’s effects on social measures in people with OUD. Since decreased feelings of social connectedness may negatively impact recovery, further investigation of naltrexone’s effects on socialization and social network formation in people with OUD seems warranted.

Eating

Eating and its Importance in Addiction Recovery

People with OUD experience metabolic changes as a result of chronic opioid use, often resulting in unhealthy eating patterns. (23) Current research on opioid addiction and its effect on BMI seem to vary. Some studies suggest that the use of certain opioids, specifically heroin, reduces a person’s interest in food, decreases appetite, and increases consumption of sweets and other cheap and convenient foods. (24) Other research suggests that OUD is associated with increased BMI due to exogenous opioids stimulating neuropeptides that promote appetite, specifically for indulgent foods high in sweetness and fat. (25) As a result, malnutrition is common among individuals with severe substance use disorders, especially those with opioid use disorder. Chronic opioid use has been shown to decrease levels of vitamin A, vitamins B6 and B12, vitamin C, vitamin D, thiamine, folate, potassium, calcium, magnesium, zinc, selenium, cholesterol, and iron. (23,26) Both macro and micronutrients are pivotal to the health of people in recovery from OUD. Carbohydrates, fatty acids, proteins, vitamins, and minerals are needed to help restabilize neurotransmitters and mood in people in early recovery. Additionally, amino acids such as tyrosine, phenylalanine, and tryptophan are needed for the synthesis of neurotransmitters including dopamine and serotonin, and therefore may help support mood stabilization during the recovery process. (26) Therefore, eating an appropriate amount of nutritious foods has the potential to aid in addiction recovery by helping to ameliorate the harmful effects undergone as a result of chronic opioid use.

Naltrexone Effects on Eating

The reinforcing properties of eating are partially controlled by opioid-mediated reward mechanisms, and studies have shown that eating may be affected by naltrexone use. (27-30) A meta-analysis examining the effects of naltrexone on eating in healthy patients found a consistent decrease in food intake, with average decreases falling between 11-29%. (27) In another meta-analysis examining opioid antagonism and eating, all but one study on healthy participants demonstrated decreased ratings of food pleasantness when compared to placebo. (28) One study on patients with OUD found that naltrexone therapy led to decrements in food intake and body fat mass. (29) Other research on patients with OUD found naltrexone decreased the rewarding nature of sweet tasting foods. (30) Findings such as these point towards the endogenous opioid system playing an important role in food liking, choice, and consumption. The possibility that naltrexone therapy may elicit an endogenous disincentive to eat in certain patients recovering from OUD with an already low BMI may prove injurious to their ability to recover. For those patients diagnosed with OUD with a higher body fat mass, naltrexone therapy may potentially help to decrease food intake and lower fat mass to healthier levels. Additionally, decreased incentive to consume sweet or rewarding foods may also help these patients to adopt a healthier diet in order to replace the nutrients that their opioid use caused them to lack. Therefore, naltrexone’s effects on BMI and overall nutritional status in patients with OUD may vary and merits further clinical investigation.


Conclusion

In the current manuscript, we review how mu-opioid receptor antagonism may inadvertently negatively motivate adjunctive therapeutic behaviors that have been demonstrated to improve outcomes in subjects recovering from opioid use disorder. Exercising, establishing new supportive social networks, and proper nutrition are key components to a successful recovery. Many of the studies examining the effects of naltrexone on exercising, socialization, and eating have been conducted on healthy participants rather than patients with opioid use disorder. Therefore, researchers should continue to study the effects of naltrexone on patients with opioid use disorder to determine whether it may negatively affect a person’s ability to achieve stable recovery by altering the endogenous reinforcing nature of these and other recovery promoting activities.

Additionally, naltrexone studies often have very low retention rates and researchers are continuing to examine whether this is due to decreased motivation to remain abstinent, lack of reinforcing effects when compared to agonist medications, or adverse effects due to naltrexone therapy itself. One study measuring the self-reported somatic and affective symptoms between individuals with OUD who completed and those who failed to complete a trial of naltrexone therapy found that those who dropped out early experienced increased depression, anxiety, and anhedonia in the weeks prior to dropout. (31) These results point towards the possibility that naltrexone therapy may be eliciting dysphoric effects within some patients and therefore may not be tolerated well by certain individuals with OUD. Despite these potential drawbacks, some studies show that extended release naltrexone therapy decreases opioid cravings and relapse rates in patients with OUD who tolerate it and do not drop out of treatment. (32) Therefore, researchers should further examine the affective symptoms seen in individuals who prematurely stop naltrexone treatment to help determine if they are simply due to protracted withdrawal or potentially due to naltrexone therapy. This information could ultimately help to guide providers on which individuals may tolerate naltrexone therapy well and which patients may need to discontinue naltrexone therapy.

Currently, researchers are studying the use of low dose naltrexone (LDN) to treat disorders characterized by dopaminergic dysfunction including multiple sclerosis, irritable bowel disease, fibromyalgia, and major depressive disorder. (33, 34) At lower doses, naltrexone exhibits different pharmacodynamics than at standard dosages. (33) Due to its demonstrated effects on enhancing mood, decreasing pain, improving immunity, and decreasing neuroinflammation, low-dose naltrexone could potentially be an effective adjunctive treatment for patients with a substance use disorder. (33,34) For these reasons, researchers should consider investigating the effects of alternative dosing schedules of naltrexone for the treatment of OUD, as many of these individuals have concomitant mental and physical health disorders that may potentially benefit from LDN therapy.

Acknowledgments

None.

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