A comprehensive scientific statement detailed the significant impact of exogenous opioids on multiple endocrine systems, with particular emphasis on the hypothalamic-pituitary axes and bone health. The statement, authored by an international panel of experts, provided a critical analysis of existing research while highlighting substantial knowledge gaps in understanding opioid-induced endocrinopathies.
In the review, published in Endocrine Reviews, investigators found that opioid-induced hypogonadism occurred in 40% to 85% of male patients receiving methadone maintenance treatment, with a weighted mean rate of 63% (95% confidence interval [CI] = 55–70) across studies involving 3,250 patients. In female patients, oligo/amenorrhea rates ranged from 23% to 81% among those using oral or intrathecal opioids for chronic noncancer-related pain.
Regarding adrenal function, the analysis revealed that 15% of patients receiving intrathecal opioids developed secondary adrenal insufficiency. Studies examining oral or transdermal opioid users found secondary adrenal insufficiency rates ranging from 6% to 22.5%, with a minimum morphine milligram equivalent (MME) threshold of 60 mg daily identified in several studies.
The statement documented variable effects on growth hormone (GH) secretion, with acute administration stimulating GH release, whereas chronic use potentially suppressed the GH axis. In one study, involving 72 patients receiving intrathecal opioids, 17% of them demonstrated GH deficiency based on insulin tolerance testing.
Bone health emerged as a significant concern, with research demonstrating reduced bone mineral density (BMD) and increased fracture risk among chronic opioid users. A cross-sectional study of 144 male patients receiving opioid substitution therapy found decreased BMD compared with matched controls, predominantly affecting the axial skeleton in 73% of the participants.
The investigators identified several mechanistic pathways for opioid-induced bone loss, including:
- Direct effects on bone remodeling through opioid receptors on osteoblasts
- Increased fall risk caused by central nervous system effects
- Secondary effects from opioid-induced hypogonadism.
The statement emphasized diagnostic challenges, particularly for adrenal insufficiency, where no universally agreed-upon criteria existed. For hypogonadism, the investigators recommended screening patients receiving long-term opioid treatment (> 3 months) and considering hormone replacement therapy when opioid discontinuation was not feasible.
Methodology of the statement included systematic review of published literature, with particular attention to studies examining:
- Prevalence of endocrine dysfunction in various patient populations
- Diagnostic criteria and testing protocols
- Treatment outcomes and management approaches
- Pharmacologic mechanisms of opioid-endocrine interactions.
The investigators noted significant research gaps, including:
- Standardization of diagnostic criteria for opioid-induced adrenal insufficiency
- Long-term safety data on hormone replacement therapy in affected patients
- Prospective studies on bone health interventions
- Clear understanding of dose-dependent effects across different opioid formulations.
This scientific statement was developed by experts from multiple institutions across eight countries, including the University of Birmingham, Harvard Medical School, and the University of Basel, among others. The work represented the most current synthesis of evidence regarding opioid effects on endocrine function while providing a framework for future research priorities.
The investigstors emphasized that the scientific statement was not intended to serve as a clinical guideline but rather to appraise existing research and highlight areas requiring further investigation.
Conflict of interest disclosures can be found in the study.
