Addiction and tolerance are well-known risks of long-acting opioid use. However, despite initial recognition of opioid-induced androgen deficiency (OPIAD) as a possible consequence of opioid use more than four decades ago, “few studies have systematically investigated hormonal changes induced by long-term opioid administration or the effects of testosterone replacement therapy (TRT) in patients with OPIAD,” a study has found.

In 1973, compared to non-abusing peers, males who abused opioids were observed to have lower sexual function and libido and lower levels of serum sex hormones.

The study focused on the pathophysiology, diagnosis, and management of OPIAD, a condition that frequently remains undiagnosed despite “widespread and increasing rates of opioid prescription and abuse.” Also summarized was the literature that evaluated TRT treatment in men with OPIAD.

The systemic effects of long-acting opioids such as morphine sulfate, oxycodone, fentanyl, and methadone include nausea, itching, and constipation as well as hypogonadotropic hypogonadism, believed to be induced “through direct inhibitory action of opioids on receptors within the hypothalamic pituitary gonadal [HPG] and hypothalamic pituitary-adrenal axes” and with “testosterone production within the testes.” Consequently, testosterone is depleted, leading to central and peripheral effects. Central effects include decreased attention, decreased libido, fatigue, and depressive state, while peripheral effects manifest as muscle hypotrophy, osteoporosis, anemia, erectile dysfunction, and delayed ejaculation. 

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Among patients with chronic opioid use, incidence of hypogonadotropic hypogonadism ranges from 21% to 86%, with prevalence of OPIAD as high as 90%, or more than 5 million US men with non-malignant pain.

Following treatment initiation at doses greater than 100 to 200mg oral morphine equivalents/day, hypogonadism can occur within several hours to weeks, with castrate testosterone levels observed “in a dose dependent manner,” the authors reported. Within 24 to 72 hours of opioid cessation, testosterone levels may recover; however, depending on “chronicity of opioid use,” hypogonadism “may persist for months or even years.”

For that reason, clinicians should monitor patients treated with opioids for OPIAD and associated sequelae as well as provide education about the potential effects of opioids on the endocrine system; specifically, androgen deficiency.