Opioid-induced hypogonadism in opioid use disorder, its role in negative reinforcement, and implications for treatment and retention

ABSTRACT

Hypogonadism is a highly prevalent complication of chronic opioid use associated with a constellation of affective, algesic, and cognitive symptoms as well as decreased quality of life. Given that the mainstays of pharmacologic opioid use disorder (OUD) treatment – methadone and buprenorphine – are themselves agonists or partial agonists at the mu opioid receptor, opioid-induced hypogonadism (OIH) remains an underappreciated clinical concern throughout the course of OUD treatment. Prominent theoretical frameworks for OUD emphasize the importance of negative reinforcement and hyperkatifeia, defined as the heightened salience of negative emotional and motivational states brought on by chronic opioid use. In this perspective article, we highlight the striking parallels between the symptom domains of hyperfakifeia and hypogonadism in males, who comprise the vast majority of existing clinical research on OIH. By extension we propose that future research and ultimately clinical care should focus on the identification and treatment of OIH in OUD patients to help address the longstanding paradox of poor treatment retention despite efficacious therapies, particularly in the setting of the current opioid overdose epidemic driven by high potency synthetic opioids such as fentanyl. We then review evidence from chronic pain patients that testosterone replacement provides clinically significant benefits to men with OIH. Finally, using this framework, we compare extant OUD therapeutics and discuss critical gaps in the clinical literature—including the relative dearth of data regarding hypothalamic-pituitary-gonadal function in females who use opioids—where future study should be focused.

KEYWORDS:

• Opioid use disorder
• hypogonadism
• testosterone
• hyperkatifeia
• androgen insufficiency
• treatment retention

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Columbia University Vagelos College of Physicians, Doris Duke Charitable Foundation COVID-19 Fund to Retain Clinical Scientists, and the American Heart Association [Grant # 923718, Brezing, 2022–2023].