Exogenous Opioids and the Human Endocrine System: An Endocrine Society Scientific Statement

An 8-month aerobic gymnastics training program in young opioid-addicted women failed to show any effects on bone quality, as assessed by quantitative ultrasound.

“An 8-month aerobic gymnastics training program in young opioid-addicted women failed to show any effects on bone quality, as assessed by quantitative ultrasound (253).”

• cites [253] Ding, 2021, Effect of eight-month exercise intervention on bone outcomes of young opioid-dependent women, Int J Environ Res Public Health sourceDisputed

  The Abstract reports that bone quality was assessed by quantitative ultrasound and that the exercise group's stiffness index increased significantly after eight months, while the control group's did not. The Conclusions likewise describe a positive effect on bone quality, contrary to the claim of no effect. (LLM, conf=0.95)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Less common but well-recognized manifestations of cortisol deficiency include hypercalcemia and hypoglycemia.

“As well as common symptoms of cortisol deficiency, such as fatigue, nausea/vomiting, musculoskeletal pain, weight loss, headache, and light-headedness (119), less common but well recognized manifestations, such as hypercalcemia (123) and hypoglycemia (124) have been described.”

• cites [123] Lee, 2015, Opioid-induced secondary adrenal insufficiency presenting as hypercalcaemia, Endocrinol Diabetes Metab Case Rep sourceSupported
• cites [124] Tabet, 2019, Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia, BMJ Case Rep sourceNot checked — no full text of the source

Other studies have reported secondary adrenal insufficiency in people on lower opioid doses, including a cross-sectional study of 102 patients on various opioids.

“However, other studies have reported secondary adrenal insufficiency in people on lower opioid doses, including a cross-sectional one examining the hypothalamic-pituitaryadrenal axis function of 102 patients on various opioids (117).”

• cites [117] Li, 2020, Prevalence of opioid-induced adrenal insufficiency in patients taking chronic opioids, J Clin Endocrinol Metab sourceSupported

In a case report of a 61-year-old man with chronic intercostal neuropathic pain managed with methadone, GH treatment with daily doses up to 0.3 mg led to improvement of cognitive capacity.

“Interestingly, in a case report of a 61-year-old man with chronic intercostal neuropathic pain managed with methadone, GH treatment with daily doses up to 0.3 mg led to improvement of cognitive capacity (140).”

• cites [140] Rhodin, 2014, Recombinant human growth hormone improves cognitive capacity in a pain patient exposed to chronic opioids, Acta Anaesthesiol Scand sourceSupported

The limited number of included reports and the different protocols used to assess GH deficiency did not allow definite conclusions to be obtained in a systematic review of opioids' effects on the GH axis.

“The limited number of included reports and the different protocols used to assess GH deficiency did not allow definite conclusions to be obtained (72).”

• cites [72] de Vries, 2020, Opioids and their endocrine effects: a systematic review and meta-analysis, J Clin Endocrinol Metab sourceSupported

In a systematic review of 6 studies evaluating long-term effects of opioids on PRL secretion among 346 patients with cancer pain or noncancer pain, the results were variable.

“In a systematic review of 6 studies evaluating the long-term effects of opioids on PRL secretion among 346 patients with either cancer pain or noncancer pain, the results were variable (72).”

• cites [72] de Vries, 2020, Opioids and their endocrine effects: a systematic review and meta-analysis, J Clin Endocrinol Metab sourcePartly supported

  The Results section (page not provided) reviews opioid effects on prolactin secretion and reports differing findings. However, it counts seven studies and 354 patients, not six studies and 346 patients; it does not identify that group as exclusively patients with cancer or noncancer pain. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

High PRL levels were found in 2 of 20 (10%) noncancer pain patients on intrathecal morphine.

“In addition, high PRL levels were found in 2 of 20 (10%) noncancer pain patients on intrathecal morphine (147).”

• cites [147] Duarte, 2013, Hypogonadism and low bone mineral density in patients on long-term intrathecal opioid delivery therapy, BMJ Open sourceSupported

In a report of 14 patients on opioids for cancer pain, serum PRL levels were above the reference range in 6 (43%) of them.

“In a report of 14 patients on opioids for cancer pain, serum PRL levels were above the reference range in 6 (43%) of them.”

• cites [75] Merdin, 2016, Opioid endocrinopathy: a clinical problem in patients with cancer pain, Exp Ther Med sourceSupported

A data mining study from the US FDA Adverse Event Reporting System demonstrated that in patients with OUD, there was a positive association with hyperthyroidism (adjusted odds ratio, 1.46; 95% CI, 1.43-1.49).

“A data mining study from the US Food and Drug Administration Adverse Event Reporting System demonstrated that in patients with OUD, there was positive association with hyperthyroidism (adjusted odds ratio, 1.46; 95% CI, 1.43-1.49)and hypothyroidism (adjusted odds ratio, 1.45; 95% CI, 1.42-1.48)(162).”

• cites [162] Pan, 2022, Mining comorbidities of opioid use disorder from FDA adverse event reporting system and patient electronic health records, BMC Med Inform Decis Mak sourcePartly supported

  The Results section, under “Positive associations between hypothyroidism, hyperthyroidism, type 2-diabetes and OUD,” reports the stated hyperthyroidism association (AOR 1.46; 95% CI 1.43–1.49). However, the Discussion says the study identified potential associations from FAERS and tested them using patient electronic records; the quoted adjusted odds ratio comes from that EHR validation, not directly from FAERS data. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

A data mining study from the US FDA Adverse Event Reporting System demonstrated that in patients with OUD, there was a positive association with hypothyroidism (adjusted odds ratio, 1.45; 95% CI, 1.42-1.48).

“A data mining study from the US Food and Drug Administration Adverse Event Reporting System demonstrated that in patients with OUD, there was positive association with hyperthyroidism (adjusted odds ratio, 1.46; 95% CI, 1.43-1.49)and hypothyroidism (adjusted odds ratio, 1.45; 95% CI, 1.42-1.48)(162).”

• cites [162] Pan, 2022, Mining comorbidities of opioid use disorder from FDA adverse event reporting system and patient electronic health records, BMC Med Inform Decis Mak sourcePartly supported

  The Results section, “Positive associations between hypothyroidism, hyperthyroidism, type 2-diabetes and OUD,” reports the stated positive association and exact adjusted odds ratio for hypothyroidism. However, the Abstract Results and Discussion identify those odds ratios as coming from an independent EHR-based validation, not from the FAERS data mining itself. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Fentanyl increased AVP release in both surgical patients and healthy volunteers.

“Fentanyl increased AVP release in both surgical patients (166) and healthy volunteers (167).”

• cites [166] Boulton, 1986, Haemodynamic and plasma vasopressin responses during high-dose fentanyl or sufentanil anaesthesia, Can Anaesth Soc J sourcePartly supported

  The Results report increased plasma AVP in fentanyl-treated surgical patients during cardiopulmonary bypass. The Discussion says AVP remained normal before bypass and describes the rise as occurring during bypass, not as an effect caused by fentanyl itself. The healthy-volunteer claim is attached to citation (167), not this source. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [167] Weiskopf, 1987, Effects of fentanyl on vasopressin secretion in human subjects, J Pharmacol Exp Ther sourceNot checked — no full text of the source

Data from in vitro experiments on animal and human cells, as well as in animal models, indicate that opioids can reduce BMD by directly influencing osteoblast activity.

“Data deriving from in vitro experiments on animal and human cells, as well as in animal models indicate that opioids can reduce BMD by directly influencing osteoblast activity (205-210).”

• cites [205] Carvalho, 2022, Sustained morphine delivery suppresses bone formation and alters metabolic and circulating miRNA profiles in male C57BL/6J mice, J Bone Miner Res sourceNot checked — no full text of the source
• cites [206] Holan, 2018, The impact of morphine on the characteristics and function properties of human mesenchymal stem cells, Stem Cell Rev Rep sourceNot checked — no full text of the source
• cites [207] Marczak, 2009, Orally administered H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2), a potent mu/delta-opioid receptor antagonist, regulates obese-related factors in mice, Eur J Pharmacol sourceSupported
• cites [208] Pérez-Castrillón, 2000, Expression of opioid receptors in osteoblast-like MG-63 cells, and effects of different opioid agonists on alkaline phosphatase and osteocalcin secretion by these cells, Neuroendocrinology sourceNot checked — no full text of the source
• cites [209] Saeidinezhad, 2021, Effects of maternal consumption of morphine on rat skeletal system development, BMC Musculoskelet Disord sourcePartly supported

  The Discussion (page unavailable) reports that morphine disturbed bone formation in rats and mentions a possible adverse effect of opioids on osteocalcin synthesis by osteoblasts. It does not establish a reduction in BMD or present in vitro evidence from both animal and human cells. Its proposed mechanisms are also more tentative than a demonstrated direct effect on osteoblast activity. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [210] Tanaka, 2019, Systemic administration of low-dose naltrexone increases bone mass due to blockade of opioid growth factor receptor signaling in mice osteoblasts, Life Sci sourceNot checked — no full text of the source

Acute administration of the kappa-opioid receptor agonist asimadoline in normal subjects at doses 1, 5, and 10 mg reduced plasma AVP during 2.5% saline infusion in 6 of 8 participants receiving the highest dose of 10 mg, compared to placebo.

“It has also been shown that acute administration of the kappa-opioid receptor agonist asimadoline in normal subjects at doses 1, 5, and 10 mg reduced plasma AVP during 2.5% saline infusion in 6 of 8 participants receiving the highest dose of 10 mg, compared to placebo (180).”

• cites [180] Kramer, 2000, Influence of asimadoline, a new kappa-opioid receptor agonist, on tubular water absorption and vasopressin secretion in man, Br J Clin Pharmacol sourceSupported

In a recent study measuring copeptin before, during, and after electrophysiological stimulation in healthy volunteers, after administration of opioids there was no visible effect on copeptin values.

“A recent study measured copeptin levels before, during, and after electrophysiological stimulation in healthy volunteers, initially before and then during opioid delivery; after administration of opioids, there was no visible effect on copeptin values (185).”

• cites [185] Blum, 2022, Relevance of cortisol and copeptin blood concentration changes in an experimental pain model, Sci Rep sourceSupported

Opiate-dependent patients on diacetylmorphine (heroin) maintenance treatment had reduced AVP levels compared with controls.

“Finally, opiate-dependent patients on diacetylmorphine (heroin) maintenance treatment had reduced AVP levels compared with controls (181).”

• cites [181] Glahn, 2013, Atrial natriuretic peptide, arginine vasopressin peptide and cortisol serum levels in opiate-dependent patients, Neuropsychobiology sourceSupported

Two additional experimental studies indicated a pro-osteogenic effect of naltrexone in a murine model of osteoporosis induced by liver cirrhosis.

“Two additional experimental studies indicated a pro-osteogenic effect of naltrexone in a murine model of osteoporosis induced by liver cirrhosis (211, 212).”

• cites [211] Hosseini-Fard, 2024, Exploring the impact of naltrexone on the THBS1/eNOS/NO pathway in osteoporotic bile duct-ligated rats, Sci Rep sourcePartly supported

  The Conclusion reports a possible positive effect of naltrexone on bone tissue at the molecular level in bile-duct-ligated rats. The Results report no significant improvement in bone histomorphometry or radiographic density, so the evidence for a pro-osteogenic effect is limited; the experimental animals were rats, not mice. This verdict assesses only this source, not the other study cited in the sentence. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [212] Moradi, 2019, The influence of TRAIL, adiponectin and sclerostin alterations on bone loss in BDL-induced cirrhotic rats and the effect of opioid system blockade, Life Sci sourceNot checked — no full text of the source

In a rat fracture model, morphine administration inhibited callus strength at 8 weeks.

“In a rat fracture model, morphine administration inhibited callus strength at 8 weeks (226)”

• cites [226] Chrastil, 2013, Postoperative opioid administration inhibits bone healing in an animal model, Clin Orthop Relat Res sourceSupported

Among those hypogonadal patients, 10 had osteopenia or osteoporosis.

“whereas 10 of hypogonadal patients had osteopenia or osteoporosis (147).”

• cites [147] Duarte, 2013, Hypogonadism and low bone mineral density in patients on long-term intrathecal opioid delivery therapy, BMJ Open sourceSupported

In a prospective longitudinal nationwide study of mid-life women, opioid users had a more pronounced BMD decline over 5 years compared with users of acetaminophen and NSAIDs.

“A prospective longitudinal nationwide study of mid-life women assessed the impact of different analgesics (acetaminophen, nonsteroidal anti-inflammatory drugs, and opioids] on bone mass and reported a more pronounced BMD decline over 5 years in opioid users (237).”

• cites [237] Yoshida, 2018, Effects of analgesics on bone mineral density: a longitudinal analysis of the prospective SWAN cohort with three-group matching weights, Pharmacoepidemiol Drug Saf sourcePartly supported

  The Methods describe a prospective cohort of mid-life women recruited at eight U.S. sites. The Results and Discussion say the on-treatment analysis suggested greater BMD decline in opioid users after five years of continuous use, but the group differences were not statistically significant; the initial-treatment-group analysis showed similar trajectories. The claim overstates this tentative finding as an observed greater decline in opioid users generally. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

The most common indications for opioid prescription in that study were musculoskeletal disorders, including vertebral osteoporotic fractures, degenerative spinal disorders, and osteoarthritis.

“Most common indications for prescription were musculoskeletal disorders (ie, vertebral osteoporotic fractures, degenerative spinal disorders, and osteoarthritis)”

• cites [232] Mörttinen-Vallius, 2021, The prevalence of and exact indications for daily opioid use among aged home care clients with and without dementia, Aging Clin Exp Res sourceSupported

Low doses of naloxone enhanced bone mineralization and callus formation of a cortical defect induced in a sheep model.

“In contrast, low doses of naloxone enhanced bone mineralization and callus formation of a cortical defect induced in a sheep model (228).”

• cites [228] Petrizzi, 2007, Preliminary study on the effect of parenteral naloxone, alone and in association with calcium gluconate, on bone healing in an ovine “drill hole”? model system, BMC Musculoskelet Disord sourceSupported

In older nursing home residents, opioid use in the immediate 14-day period post-hip fracture was associated with a lower likelihood of death and functional decline.

“Of interest, a study assessing opioid use in the immediate 14-day period post-hip fracture in older nursing home residents found that opioid use in that period was associated with a lower likelihood of death and functional decline (234).”

• cites [234] Zullo, 2018, Pain treatments after hip fracture among older nursing home residents, J Am Med Dir Assoc sourcePartly supported

  The Methods describe opioid use within 14 days after hip fracture in older nursing home residents. The Results report a significantly lower likelihood of death, but the lower estimate for functional decline was not statistically significant after adjustment. The claim omits that uncertainty. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In a population-based cohort of opioid-naive community-dwelling US citizens, continuous opioid use was reported in 6.4% of patients one year after an index hip fracture.

“Similarly, a population-based cohort study of opioid-naive community-dwelling US citizens reported continuous opioid use in 6.4% of patients one year after sustaining an index hip fracture (233).”

• cites [233] Torchia, 2019, Patterns of opioid use in the 12 months following geriatric fragility fractures: a population-based cohort study, J Am Med Dir Assoc sourcePartly supported

  The Results (Opiate prescriptions after fracture; page unavailable) report that 6.4% of hip-fracture patients continued to fill opioid prescriptions at 12 months. The Abstract (Setting and Participants; page unavailable) identifies the cohort as opioid-naïve, community-dwelling US Medicare beneficiaries. The study measured prescription fills by month, not uninterrupted opioid use throughout the year, and describes beneficiaries rather than establishing citizenship. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

In a small observational study of 20 males receiving long-term intrathecal opioid treatment for nonmalignant bone pain, 17 patients displayed biochemical hypogonadism.

“In a small observational study comprising 20 males receiving long-term intrathecal opioid treatment for nonmalignant bone pain, 17 patients displayed biochemical hypogonadism”

• cites [147] Duarte, 2013, Hypogonadism and low bone mineral density in patients on long-term intrathecal opioid delivery therapy, BMJ Open sourcePartly supported

  The Methods (Patients; page not provided) describe an observational study of 20 men receiving intrathecal opioids for chronic non-cancer pain. The Discussion (page not provided) reports that 85% were biochemically hypogonadal, matching 17 of 20. The paper does not characterize their condition as “bone pain”; it describes nociceptive, neuropathic and mixed pain syndromes. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Vertebral augmentation procedures, such as balloon kyphoplasty and vertebroplasty, were associated with decreased or discontinued opioid prescription fills in a significant proportion of 8845 patients undergoing these procedures.

“vertebral augmentation procedures, such as balloon kyphoplasty and vertebroplasty, were associated with decreased or discontinued opioid prescription fills in a significant proportion of 8845 patients undergoing these procedures (235).”

• cites [235] Ni, 2022, Trends in opioid use following balloon kyphoplasty or vertebroplasty for the treatment of vertebral compression fractures, Osteoporos Int sourceSupported

Some data highlight a high incidence of falls and fractures in long-time opioid users.

“some data including time-to-event analyses, highlight a high incidence of falls and fractures in long-time opioid users”

• cites [251] Silverman, 2022, Risk factors associated with falls and fractures following prescription of opioids among privately insured patients with osteoarthritis, J Health Econ Outcomes Res sourcePartly supported

  The Abstract reports that 3,886 of 16,663 patients (23%) had a fall or fracture during 36 months of follow-up, and the Discussion describes time-to-event analyses. However, the study was limited to privately insured patients with hip or knee osteoarthritis who had at least 90 days’ opioid supply; it does not establish that incidence for long-time opioid users generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Meta-analyses using mostly cohort and case-control studies reported an increased risk for major osteoporotic fractures in opioid-treated patients.

“major osteoporotic fractures (246, 248) in opioid-treated patients.”

• cites [246] Teng, 2015, Opioids contribute to fracture risk: a meta-analysis of 8 cohort studies, PLoS One sourcePartly supported

  The Results report increased fracture risk with opioid use, and the Discussion reports increased risk for hip fractures. But the paper does not analyze major osteoporotic fractures as a defined outcome. The Results and Discussion also state that all eight included studies were cohorts, not a mix of cohort and case-control studies (page numbers unavailable in our copy). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [248] Yue, 2020, An updated analysis of opioids increasing the risk of fractures, PLoS One sourcePartly supported

  The Abstract (Results; page unavailable) reports a meta-analysis of 12 cohort and 6 case-control studies and an increased overall fracture risk with opioid therapy. The Results (Subgroup meta-analysis; page unavailable) report increased risks for hip, nonspine, and any fractures, but do not report an outcome defined as major osteoporotic fractures. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In non-tramadol opioid users with osteoarthritis, fractures occurred in a median time of 14 months after opioid initiation.

“as reported for example in non-tramadol opioid users with osteoarthritis experiencing fractures in a median time of 14 months after opioid initiation (251).”

• cites [251] Silverman, 2022, Risk factors associated with falls and fractures following prescription of opioids among privately insured patients with osteoarthritis, J Health Econ Outcomes Res sourcePartly supported

  The Time to Event section reports a median of 13.9 months to fracture after the index date, approximately 14 months. But the study population includes both tramadol and non-tramadol opioid users; it does not report this median specifically for non-tramadol users. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In a cross-sectional analysis of the Third National Health and Nutrition Examination Survey, opioids were associated with significantly reduced BMD after adjustment for several common causes of secondary osteoporosis.

“Last, in a cross-sectional analysis of Third National Health and Nutrition Examination Survey, opioids were associated with significantly reduced BMD after adjustment for several common causes of secondary osteoporosis (240).”

• cites [240] Kinjo, 2005, Bone mineral density in subjects using central nervous system-active medications, Am J Med sourceSupported

Use of exogenous opioids has been associated with an increased risk of fractures in several meta-analyses.

“Use of exogenous opioids has been associated with an increased risk of fractures in several meta-analyses (245-248).”

• cites [245] Ping, 2017, Opioids increase hip fracture risk: a meta-analysis, J Bone Miner Metab sourceNot checked — no full text of the source
• cites [246] Teng, 2015, Opioids contribute to fracture risk: a meta-analysis of 8 cohort studies, PLoS One sourceSupported
• cites [247] Yoshikawa, 2020, Opioid use and the risk of falls, fall injuries and fractures among older adults: a systematic review and meta-analysis, J Gerontol A Biol Sci Med Sci sourceNot checked — no full text of the source
• cites [248] Yue, 2020, An updated analysis of opioids increasing the risk of fractures, PLoS One sourceSupported

The variable prevalence of opioid-induced secondary adrenal insufficiency may in part relate to the number of poor metabolizers in the generally small cohorts.

“The variable prevalence of opioid-induced secondary adrenal insufficiency may in part relate to the number of poor metabolizers in the generally small cohorts.”

Acute IV administration of endogenous opioids and pharmacological opioids demonstrates an acute inhibitory effect on ACTH and cortisol levels in humans.

“Acute IV administration of endogenous opioids, such as betaendorphin (104), enkephalin analogues (105), and pharmacological opioids, such as morphine (106), demonstrates an acute inhibitory effect on ACTH and cortisol levels in humans.”

• cites [104] Taylor, 1983, beta-endorphin suppresses adrenocorticotropin and cortisol levels in normal human subjects, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [105] Stubbs, 1978, Hormonal and metabolic responses to an enkephalin analogue in normal man, Lancet sourceNot checked — no full text of the source
• cites [106] Rittmaster, 1985, Morphine inhibits the pituitary-adrenal response to ovine corticotropin-releasing hormone in normal subjects, J Clin Endocrinol Metab sourceNot checked — no full text of the source

The interaction between drug concentration and opioid receptor expression determines the extent of hormonal suppression.

“The interaction between drug concentration and opioid receptor expression then finally determines the extent of hormonal suppression.”

Buprenorphine, a partial opioid receptor agonist, is associated with milder effects on the hypothalamic-pituitary-gonadal system.

“Buprenorphine, a partial opioid receptor agonist, is associated with milder effects on the hypothalamic-pituitary-gonadal system (91,92).”

• cites [91] Bliesener, 2005, Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [92] Varma, 2018, Impact of opioid therapy on gonadal hormones: focus on buprenorphine, Horm Mol Biol Clin Investig sourceNot checked — no full text of the source

No patient on an MME dose below 60 mg per day showed a suboptimal response.

“No patient on an MME dose of below 60 mg per day showed a suboptimal response (116).”

• cites [116] Lamprecht, 2018, Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain, Eur J Endocrinol sourceNot checked — no full text of the source

There is unlikely to be a simple relationship between drug dose, plasma drug concentration, and hypothalamic-pituitary-adrenal axis inhibition across a broader cohort of patients because of individual differences in absorption and metabolism.

“The key point is that there is unlikely to be a simple relationship between drug dose, plasma drug concentration, and hypothalamic-pituitary-adrenal axis inhibition across a broader cohort of patients because of individual differences in absorption and metabolism.”

• AssumptionRests on an assumption: Opioid plasma concentration depends on drug dose, absorption, and metabolism.

Common symptoms of cortisol deficiency include fatigue, nausea/vomiting, musculoskeletal pain, weight loss, headache, and light-headedness.

“As well as common symptoms of cortisol deficiency, such as fatigue, nausea/vomiting, musculoskeletal pain, weight loss, headache, and light-headedness (119), less common but well recognized manifestations, such as hypercalcemia (123) and hypoglycemia (124) have been described.”

• cites [119] Li, 2020, Clinical presentation and outcomes of opioid-induced adrenal insufficiency, Endocr Pract sourceNot checked — no full text of the source

There are data indicating that the overnight metyrapone test is a more sensitive test for secondary adrenal insufficiency than the ACTH1-24 stimulation test.

“There are data indicating that the overnight metyrapone test is a more sensitive test for secondary adrenal insufficiency than the ACTH1-24 stimulation test (129).”

• cites [129] Soule, 2000, The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

In a study with cortisol sampling every 10 minutes for 2 hours between 7 AM and 9 AM, there was a median difference of 6.4 mcg/dL (177 nmol/L) between an individual's highest and lowest cortisol across the 2-hour window.

“In a study in which cortisol sampling was undertaken every 10 minutes for 2 hours between 7 AM and 9 AM, there was a median difference of 6.4 mcg/dL (177 nmol/L) between an individual's highest and lowest cortisol across the 2-hour window (130).”

• cites [130] English, 2021, The relationship between early post-operative ACTH / cortisol following pituitary surgery and long-term glucocorticoid requirement—do ultradian rhythms matter?, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

In a study of long-term oral or transdermal opioids in patients with noncancer pain, overall rate of secondary adrenal insufficiency was 22.5% (9/40) defined as failing either ACTH1-24 stimulation test or overnight metyrapone test.

“In a study assessing the effects of long-term oral or transdermal opioids in patients with noncancer pain, an overall rate of secondary adrenal insufficiency of 22.5% (9 out of 40) was reported (defined as failing either an ACTH1-24 stimulation test or an overnight metyrapone test) (116).”

• cites [116] Lamprecht, 2018, Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain, Eur J Endocrinol sourceNot checked — no full text of the source

The heterogeneity in diagnostic criteria for opioid-induced secondary adrenal insufficiency, cortisol assay variability, and a wide sampling window make direct comparison of morning cortisol levels between studies difficult.

“The heterogeneity in the diagnostic criteria for opioid-induced secondary adrenal insufficiency, cortisol assay variability, and a wide sampling window make direct comparison of morning cortisol levels between studies difficult.”

There was a clear relationship between steady-state drug concentration and degree of analgesia.

“There was a clear relationship between steady-state drug concentration and degree of analgesia, and 80% of those reporting side effects had impaired CYP2D6 metabolism (121).”

• cites [121] Jannetto, 2009, Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management, Pharmacogenomics sourceNot checked — no full text of the source

In a landmark study using the insulin tolerance test, 15% (9/61) of patients on intrathecal opioids for nonmalignant pain had secondary adrenal insufficiency.

“A landmark study published 3 years later, investigating the effects of intrathecal opioids using the insulin tolerance test (ITT) (the gold standard for the diagnosis of secondary adrenal insufficiency), showed that 15% (9/61) of the patients on intrathecal opioids for nonmalignant pain had secondary adrenal insufficiency (74).”

• cites [74] Abs, 2000, Endocrine consequences of long-term intrathecal administration of opioids, J Clin Endocrinol Metab sourceNot checked — no full text of the source

There is evidence that secondary adrenal insufficiency in the context of pituitary disease itself impacts aspects of health-related quality of life, including pain, which may be alleviated by increased glucocorticoid doses.

“Nevertheless, there is evidence that secondary adrenal insufficiency (in the context of pituitary disease) itself impacts aspects of health-related quality of life, including pain, which may be alleviated by increased glucocorticoid doses (125).”

• cites [125] Werumeus Buning, 2016, Hydrocortisone dose influences pain, depressive symptoms and perceived health in adrenal insufficiency: a randomized controlled trial, Neuroendocrinology sourceNot checked — no full text of the source

The concentration threshold variability reported for opioid-induced secondary adrenal insufficiency may be explained by factors such as drug dose, absorption, and metabolism.

“This potentially explains some of the variability in dose threshold that has been reported to be associated with opioid-induced secondary adrenal insufficiency.”

• AssumptionRests on an assumption: Opioid plasma concentration depends on drug dose, absorption, and metabolism.

In a study of cancer patients, there was a 2-fold difference in steady-state oxycodone concentration among 10 patients taking an identical oral dose.

“In a study of cancer patients, there was a 2-fold difference in the steady state oxycodone concentration among 10 patients taking an oral identical dose (120).”

• cites [120] Leow, 1992, Single-dose and steady-state pharmacokinetics and pharmacodynamics of oxycodone in patients with cancer, Clin Pharmacol Ther sourceNot checked — no full text of the source

The significance of opioid inhibitory actions on the HPA system and the occurrence of clinically relevant adrenal insufficiency is not fully elucidated.

“the significance of their inhibitory actions on the hypothalamic-pituitaryadrenal system and the occurrence of clinically relevant adrenal insufficiency is not fully elucidated.”

80% of those reporting side effects had impaired CYP2D6 metabolism.

“There was a clear relationship between steady-state drug concentration and degree of analgesia, and 80% of those reporting side effects had impaired CYP2D6 metabolism (121).”

• cites [121] Jannetto, 2009, Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management, Pharmacogenomics sourceNot checked — no full text of the source

Poor metabolizers had the highest steady-state drug concentrations.

“Poor metabolizers had the highest steady state drug concentrations.”

• cites [121] Jannetto, 2009, Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management, Pharmacogenomics sourceNot checked — no full text of the source

The finding of a possible but inconsistent dose-dependent effect is compatible with the pharmacodynamics, pharmacokinetics, and pharmacogenomics of opioids.

“The finding of a possible but inconsistent dose-dependent effect is compatible with the pharmacodynamics, pharmacokinetics, and pharmacogenomics of opioids.”

A prospective study comparing the diagnostic accuracy of the ACTH1-24 stimulation test, overnight metyrapone test, and ITT to diagnose secondary adrenal insufficiency after pituitary surgery found no significant differences between them when requirement for glucocorticoid replacement at 6 months was the critical end point.

“However, a prospective study comparing the diagnostic accuracy of the ACTH1-24 stimulation test, overnight metyrapone test, and ITT to diagnose secondary adrenal insufficiency after pituitary surgery found no significant differences between them, when requirement for glucocorticoid replacement at 6 months was the critical end point (130).”

• cites [130] English, 2021, The relationship between early post-operative ACTH / cortisol following pituitary surgery and long-term glucocorticoid requirement—do ultradian rhythms matter?, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

There is a considerable diurnal decrease in cortisol concentrations across the morning time frame.

“There is a considerable diurnal decrease in cortisol concentrations across this time frame.”

Inherited polymorphisms in the CYP2D6 enzyme determine opioid metabolism.

“In another study examining pharmacogenomics, it was shown that inherited polymorphisms in the CYP2D6 enzyme determined opioid metabolism (121).”

• cites [121] Jannetto, 2009, Utilization of pharmacogenomics and therapeutic drug monitoring for opioid pain management, Pharmacogenomics sourceNot checked — no full text of the source

Both opioid use and pain syndromes may result in a broad spectrum of symptoms and signs that impact health-related quality of life, including physical function, sexual function, mental health, and fatigue, hindering interpretation of the relationship between health-related quality of life and hormonal data.

“Both opioid use and the pain syndromes may result in a broad spectrum of symptoms and signs that impact health-related quality of life, including physical function, sexual function, mental health, and fatigue hindering the interpretation of the relationship between health-related quality of life and hormonal data (116, 124).”

• cites [116] Lamprecht, 2018, Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain, Eur J Endocrinol sourceNot checked — no full text of the source
• cites [124] Tabet, 2019, Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia, BMJ Case Rep sourceNot checked — no full text of the source

In another study of 39 noncancer pain patients on different oral opioids and 20 controls, mean serum IGF-I was lower in the opioid-treated group, although statistical significance was not attained.

“Another study evaluated 39 noncancer pain patients who received different oral opioids and 20 controls (118); GH stimulation test was not performed but mean serum IGF-I was lower in the opioid-treated group, although statistical significance was not attained.”

• cites [118] Rhodin, 2010, Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment, Clin J Pain sourceNot checked — no full text of the source

Therefore, although participants in that trial had low morning cortisol and a reduced hypothalamic-pituitary-adrenal axis response to a cold pain stimulus, most did not have adrenal insufficiency as defined by the ACTH1-24 stimulation test.

“Therefore, although the participants had low morning cortisol and a reduced hypothalamic-pituitary-adrenal axis response to a cold pain stimulus, most did not have adrenal insufficiency as defined by the ACTH1-24 stimulation test.”

• cites [132] Nenke, 2015, Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial, Psychoneuroendocrinology sourceNot checked — no full text of the source

Because the Li et al study was uncontrolled and these symptoms/signs are common in patients on opioids with normal adrenal function, it is not possible to definitively attribute any clinical improvement to glucocorticoid replacement.

“Because this was an uncontrolled study and these symptoms/signs are common in patients on opioids with normal adrenal function, it is not possible to definitively attribute any clinical improvement to the glucocorticoid replacement.”

• cites [119] Li, 2020, Clinical presentation and outcomes of opioid-induced adrenal insufficiency, Endocr Pract sourceNot checked — no full text of the source

In the same study, the opioid-treated group had lower IGF-I SD score (-0.53 ± 1.45) compared to controls (0.57 ± 1.00; P = .002).

“The opioid-treated group had lower mean serum IGF-I (138.5 mcg/L ± 64.1) in comparison to the controls (162.0mcg/L ± 55.3; P = .045),as well as lower IGF-I SD score (-0.53 ± 1.45 and 0.57 ± 1.00; P = .002).”

• cites [74] Abs, 2000, Endocrine consequences of long-term intrathecal administration of opioids, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Single dose administration of opioids has a dose-dependent stimulatory action on the GH axis.

“Single dose administration of opioids has a dose-dependent stimulatory action on the GH axis (133).”

• cites [133] Bhansali, 2005, Effect of opiates on growth hormone secretion in acromegaly, Horm Metab Res sourceNot checked — no full text of the source

Studies reporting on outcomes of patients with opioid-induced secondary adrenal insufficiency following glucocorticoid replacement are scarce.

“Studies reporting on outcomes of patients with opioidinduced secondary adrenal insufficiency following glucocorticoid replacement are scarce.”

In the Li et al study, relevant but nonspecific symptoms such as headache, abdominal pain, nausea, vomiting, and light-headedness were improved in less than 25% of those presenting with them.

“Relevant but nonspecific symptoms, such as headache, abdominal pain, nausea, vomiting, and light-headedness, were improved in less than 25% of those presenting with them (119).”

• cites [119] Li, 2020, Clinical presentation and outcomes of opioid-induced adrenal insufficiency, Endocr Pract sourceNot checked — no full text of the source

When a Met-enkephalin analogue G-DAMME was administered with a maximally stimulatory dose of a GHRH analogue in healthy men, an enhancing effect of GHRH-induced GH release was observed.

“Other mechanisms may also be implicated, as when a Met-enkephalin analogue G-DAMME was administered in combination with a maximally stimulatory dose of a GHRH analogue in healthy men, an enhancing effect of the GHRH-induced GH release was observed (135).”

• cites [135] Delitala, 1989, Opioids stimulate growth hormone (GH) release in man independently of GH-releasing hormone, J Clin Endocrinol Metab sourceNot checked — no full text of the source

The acute stimulatory effect of opioids on the GH axis seems to be mediated through GHRH.

“This acute effect seems to be mediated through the GHRH (134).”

• cites [134] Wehrenberg, 1985, Pituitary secretion of growth hormone in response to opioid peptides and opiates is mediated through growth hormone-releasing factor, Neuroendocrinology sourceNot checked — no full text of the source

Li et al reported some improvement in possible manifestations of adrenal insufficiency in 70% of those evaluated.

“They reported some improvement in possible manifestations of adrenal insufficiency in 70% of those evaluated; however, analyzing the individual symptoms, none demonstrated more than 50% of patients improving with glucocorticoids.”

• cites [119] Li, 2020, Clinical presentation and outcomes of opioid-induced adrenal insufficiency, Endocr Pract sourceNot checked — no full text of the source

These actions have been confirmed in subsequent studies with various types of opioids.

“These actions have been confirmed in subsequent studies with various types of opioids (143-146).”

• cites [143] Hoehe, 1988, Human studies on the mu opiate receptor agonist fentanyl: neuroendocrine and behavioral responses, Psychoneuroendocrinology sourceNot checked — no full text of the source
• cites [144] Mendelson, 1989, Naloxone suppresses buprenorphine stimulation of plasma prolactin, J Clin Psychopharmacol sourceNot checked — no full text of the source
• cites [145] Saarialho-Kere, 1989, Psychomotor, respiratory and neuroendocrinological effects of a mu-opioid receptor agonist (oxycodone) in healthy volunteers, Pharmacol Toxicol sourceNot checked — no full text of the source
• cites [146] Zis, 1984, Morphine inhibits cortisol and stimulates prolactin secretion in man, Psychoneuroendocrinology sourceNot checked — no full text of the source

Currently, there is inadequate evidence to underpin recommendations for monitoring, diagnosis, and management of GH deficiency in long-term opioid users.

“Overall, currently, there is inadequate evidence to underpin recommendations for monitoring, diagnosis, and management of GH deficiency in long-term opioid users.”

These results suggest that up to 17% of patients treated with intrathecal opioids may develop GH deficiency.

“These results suggest that up to 17% of the patients treated with intrathecal opioids may develop GH deficiency (74).”

• cites [74] Abs, 2000, Endocrine consequences of long-term intrathecal administration of opioids, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Twelve opioid-treated patients (17%) had an IGF-I SD score below -2 SD, as opposed to no such case in the control group.

“Twelve opioid-treated patients (17%) had an IGF-I SD score below -2 SD, as opposed to no such case in the control group.”

• cites [74] Abs, 2000, Endocrine consequences of long-term intrathecal administration of opioids, J Clin Endocrinol Metab sourceNot checked — no full text of the source

In male heroin addicts, the mean peak GH was similar in controls, methadone-treated patients, heroin-addicted patients, and former heroin addicts.

“The mean of peak GH was similar in all groups.”

• cites [138] Cushman, 1972, Growth hormone in narcotic addiction, J Clin Endocrinol Metab sourceNot checked — no full text of the source

Normalization of hypothalamic-pituitary-adrenal axis function can occur rapidly following opioid dose reduction.

“Normalization of hypothalamic-pituitary-adrenal axis function can occur rapidly following opioid dose reduction.”

• cites [112] Oltmanns, 2005, Chronic fentanyl application induces adrenocortical insufficiency, J Intern Med sourceNot checked — no full text of the source
• cites [124] Tabet, 2019, Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia, BMJ Case Rep sourceNot checked — no full text of the source

In the study with the largest number of cases, the opioid-treated group had lower mean serum IGF-I (138.5 mcg/L ± 64.1) compared to controls (162.0 mcg/L ± 55.3; P = .045).

“The opioid-treated group had lower mean serum IGF-I (138.5 mcg/L ± 64.1) in comparison to the controls (162.0mcg/L ± 55.3; P = .045),as well as lower IGF-I SD score (-0.53 ± 1.45 and 0.57 ± 1.00; P = .002).”

• cites [74] Abs, 2000, Endocrine consequences of long-term intrathecal administration of opioids, J Clin Endocrinol Metab sourceNot checked — no full text of the source

In a report comparing intrathecal and oral morphine, serum IGF-I range was not different between the groups.

“Serum IGF-I range was not different between the groups.”

• cites [136] Valverde-Filho, 2015, Chronic spinal and oral morphine-induced neuroendocrine and metabolic changes in noncancer pain patients, Pain Med sourceNot checked — no full text of the source

The peak GH during the ITT was significantly lower in the opioid group (n = 62; 14.5 mcg/L ± 12.7) compared to controls (n = 18; 20.9 mcg/L ± 11.5; P = .010).

“The peak GH during the ITT was significantly lower (P = .010)in the opioid group (n = 62; 14.5 mcg/ L ± 12.7) compared to controls (n = 18; 20.9 mcg/L ± 11.5).”

• cites [74] Abs, 2000, Endocrine consequences of long-term intrathecal administration of opioids, J Clin Endocrinol Metab sourceNot checked — no full text of the source

There are no data to underpin a consensus on the need for daily physiological glucocorticoid replacement in opioid-induced secondary adrenal insufficiency.

“There are no data to underpin a consensus on the need for daily physiological glucocorticoid replacement but for those who are unable to discontinue their opioids or wean to a dose below the threshold that results in opioid-induced secondary adrenal insufficiency, physiological glucocorticoid replacement may be considered.”

Opioid type, dose, and route of administration are potential parameters influencing the effects of opioids on the GH axis.

“Opioid type, dose, and route of administration are potential parameters influencing these effects; more methodologically robust studies would provide definitive conclusions.”

Data on the long-term impact of opioids on the somatotroph axis are contradictory.

“In contrast, data on the long-term impact of opioids on the somatotroph axis are contradictory.”

Taken together, the scarce published literature suggests that long-term use of opioids may compromise the GH axis.

“Taken together, the scarce published literature suggests that long-term use of opioids may compromise the GH axis.”

In the Li et al study, none of the individual symptoms demonstrated more than 50% of patients improving with glucocorticoids.

“They reported some improvement in possible manifestations of adrenal insufficiency in 70% of those evaluated; however, analyzing the individual symptoms, none demonstrated more than 50% of patients improving with glucocorticoids.”

• cites [119] Li, 2020, Clinical presentation and outcomes of opioid-induced adrenal insufficiency, Endocr Pract sourceNot checked — no full text of the source

Unlike classical glucocorticoid-induced axis suppression, which can take months or even years to fully recover, normal ACTH and cortisol parameters may occur within days to weeks of reducing opioid doses.

“Unlike the classical scenario of glucocorticoid-induced axis suppression, which can take months or even years from which to fully recover, normal ACTH and cortisol parameters may occur within days to weeks of reducing opioid doses (112, 124).”

• cites [112] Oltmanns, 2005, Chronic fentanyl application induces adrenocortical insufficiency, J Intern Med sourceNot checked — no full text of the source
• cites [124] Tabet, 2019, Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia, BMJ Case Rep sourceNot checked — no full text of the source

In a UK population-based cohort study, use of tramadol was related to a 2-fold increased risk of hospitalization for hyponatremia when compared to codeine.

“In a UK population-based cohort study, the use of tramadol was related with a 2-fold increased risk of hospitalization for hyponatremia when compared to codeine; the authors postulated that hyponatremia developed because of stimulation of AVP and/or through inhibition of central reuptake of serotonin, leading to increased AVP release and syndrome of inappropriate antidiuresis (174).”

• cites [174] Fournier, 2015, Tramadol for noncancer pain and the risk of hyponatremia, Am J Med sourceNot checked — no full text of the source

In a group of 39 noncancer pain patients on oral opioids, hyperprolactinemia was detected in approximately 40% of them.

“In a group of 39 noncancer pain patients on oral opioids, hyperprolactinemia was detected in approximately 40% of them (118).”

• cites [118] Rhodin, 2010, Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment, Clin J Pain sourceNot checked — no full text of the source

IV or epidural morphine administered to children undergoing surgery led to an increase in AVP levels.

“It has also been shown that IV or epidural morphine administered to children undergoing surgery had led to an increase in AVP levels (165).”

• cites [165] Bozkurt, 2003, Effects of systemic and epidural morphine on antidiuretic hormone levels in children, Paediatr Anaesth sourceNot checked — no full text of the source

Studies with dynamic thyrotropin-releasing hormone test performed in chronic opioid users have demonstrated conflicting results with enhanced, blunted, or no TSH response.

“Studies with dynamic thyrotropin-releasing hormone test performed in chronic opioid users have demonstrated conflicting results with enhanced (118), blunted (136, 155, 156), or no (74, 157) TSH response.”

• cites [118] Rhodin, 2010, Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment, Clin J Pain sourceNot checked — no full text of the source
• cites [136] Valverde-Filho, 2015, Chronic spinal and oral morphine-induced neuroendocrine and metabolic changes in noncancer pain patients, Pain Med sourceNot checked — no full text of the source
• cites [155] Brambilla, 1980, Effects of chronic heroin addiction on pituitary-thyroid function in man, J Endocrinol Invest sourceNot checked — no full text of the source
• cites [156] Vescovi, 1984, Effect of methadone on TSH and thyroid hormone secretion, Horm Metab Res sourceNot checked — no full text of the source
• cites [74] Abs, 2000, Endocrine consequences of long-term intrathecal administration of opioids, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [157] Spagnolli, 1987, Prolactin and thyrotropin pituitary response to thyrotropin releasing hormone in young female heroin addicts, Drug Alcohol Depend sourceNot checked — no full text of the source

In patients on methadone or buprenorphine maintenance treatment, PRL has been found to be reduced, similar, or higher when compared with controls.

“In patients on methadone or buprenorphine maintenance treatment, PRL has been found to be reduced, similar, or higher when compared with controls (91,150,151).”

• cites [91] Bliesener, 2005, Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence, J Clin Endocrinol Metab sourceNot checked — no full text of the source
• cites [150] Kley, 1977, The effect of methadone on hypophyseal and peripheral glandular hormones during withdrawal, Horm Metab Res sourceNot checked — no full text of the source
• cites [151] Vescovi, 1985, Effects of dopamine receptor stimulation on opiate-induced modifications of pituitary-gonadal function, Horm Res sourceNot checked — no full text of the source

The data on the impact of opioids on thyroid function in humans are inconsistent.

“The data on the impact of opioids on thyroid function in humans are inconsistent.”

Acute administration of opioids in healthy volunteers has led to increased serum TSH concentrations.

“Acute administration of opioids in healthy volunteers has led to increased serum TSH concentrations (153, 154).”

• cites [153] Devilla, 1985, Morphine-induced TSH release in normal and hypothyroid subjects, Neuroendocrinology sourceNot checked — no full text of the source
• cites [154] Pende, 1986, Evaluation of the effects induced by four opiate drugs, with different affinities to opioid receptor subtypes, on anterior pituitary LH, TSH, PRL and GH secretion and on cortisol secretion in normal men, Biomed PharmacotherNot checked — no full text of the source

In a report of 40 patients on oral or transdermal opioids for chronic pain (for more than 6 months on an MME dose ≥25 mg), no difference in prolactin values was found compared with 25 controls not taking opioids.

“In a report of 40 patients on oral or transdermal opioids for chronic pain (for more than 6 months on an MME dose ≥25 mg), no difference in the prolactin values was found when compared with 25 controls not taking opioids (116).”

• cites [116] Lamprecht, 2018, Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain, Eur J Endocrinol sourceNot checked — no full text of the source

DAMME, a long-acting analogue of met-enkephalin, produced water diuresis in dehydrated or hypertonic saline-loaded subjects by inhibiting AVP release.

“DAMME, a long-acting analogue of metenkephalin, produced water diuresis in dehydrated or in hypertonic saline-loaded subjects by inhibiting AVP release (177); in this study, the effect of opioids on AVP seemed to be dependent on the hydration status, as DAMME infused into water-deprived healthy volunteers produced diuresis that was attenuated by naloxone, whereas when subjects were hydrated, there”

• cites [177] Grossman, 1980, Inhibition of vasopressin release in man by an opiate peptide, Lancet sourceNot checked — no full text of the source

Copeptin has emerged as a surrogate marker for AVP because, unlike AVP, it can be measured reliably in clinical routine by commercially available assays with high-standard technical performance.

“In recent years, copeptin has emerged as a surrogate marker for AVP because, in contrast to AVP, it can be measured reliably in clinical routine by commercially available assays with high-standard technical performance.”

• cites [183] Land, 1982, Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor, Nature sourceNot checked — no full text of the source

Only very limited data on the effect of exogenous opioids on copeptin are available to date.

“However, only very limited data on the effect of exogenous opioids on copeptin are available to date.”

Morphine and naloxone have no impact on oxytocin levels during pregnancy.

“It has been shown that morphine and naloxone have no impact on oxytocin levels during pregnancy (193) and that morphine administration to the mother has no effect on fetal oxytocin levels (194).”

• cites [193] Lindow, 1993, The effect of morphine and naloxone administration on maternal oxytocin concentration in late pregnancy, Clin Endocrinol (Oxf) sourceNot checked — no full text of the source

Women treated with IV opioids did not show oxytocin augmentation compared to those on epidural analgesia.

“Women treated with IV opioids did not show oxytocin augmentation compared to those on epidural analgesia ( 200).”

• cites [200] Anim-Somuah, 2018, Epidural versus non-epidural or no analgesia for pain management in labour, Cochrane Database Syst Rev sourceNot checked — no full text of the source

Studies on the effects of opioids on oxytocin in humans have primarily focused on women, particularly investigating the effect of analgesics during pregnancy and labor.

“Studies on the effects of opioids on oxytocin in humans have primarily focused on women, particularly investigating the effect of analgesics during pregnancy and labor.”

Treatment with the opioid antagonist naloxone reversed the effect of morphine with regards to osteocalcin expression.

“In addition, treatment with the opioid antagonist naloxone reversed the effect of morphine with regards to osteocalcin expression (208).”

• cites [208] Pérez-Castrillón, 2000, Expression of opioid receptors in osteoblast-like MG-63 cells, and effects of different opioid agonists on alkaline phosphatase and osteocalcin secretion by these cells, Neuroendocrinology sourceNot checked — no full text of the source

Morphine administration to the mother has no effect on fetal oxytocin levels.

“It has been shown that morphine and naloxone have no impact on oxytocin levels during pregnancy (193) and that morphine administration to the mother has no effect on fetal oxytocin levels (194).”

• cites [194] Lindow, 1998, Effects of morphine administration on the fetal production of oxytocin in labour, Clin Sci (Lond) sourceNot checked — no full text of the source

Pivotal experiments confirmed the expression of three types of opioid receptors, namely MOR, delta-opioid receptors, and kappa-opioid receptors, in the human osteoblast-like cell line MG-63 via reverse transcription-polymerase chain reaction and immunohistochemistry.

“Pivotal experiments from two decades ago confirmed the expression of three types of opioid receptors, namely MOR, delta-opioid receptors, and kappa-opioid receptors in the human osteoblast-like cell line MG-63 via reverse transcription-polymerase chain reaction and immunohistochemistry (208).”

• cites [208] Pérez-Castrillón, 2000, Expression of opioid receptors in osteoblast-like MG-63 cells, and effects of different opioid agonists on alkaline phosphatase and osteocalcin secretion by these cells, Neuroendocrinology sourceNot checked — no full text of the source

Naltrexone, an antagonist of canonical opioid receptors and opioid growth factor receptor, administered daily intraperitoneally to mice for 28 days increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when compared with control animals.

“Conversely, naltrexone, an antagonist of canonical opioid receptors and opioid growth factor receptor, administered daily intraperitoneally to mice for 28 days increased their femoral bone mass, bone formation ratio, and osteoblast number/bone surface values when compared with control animals (210).”

• cites [210] Tanaka, 2019, Systemic administration of low-dose naltrexone increases bone mass due to blockade of opioid growth factor receptor signaling in mice osteoblasts, Life Sci sourceNot checked — no full text of the source

The results of many studies on opioids and AVP are difficult to interpret because changes in patients' hemodynamic status or side effects of opioids such as hypotension or nausea, which could secondarily stimulate AVP release, were not controlled.

“It should be noted, however, that the results of many of these studies are difficult to be interpreted, as changes in patients' hemodynamic status or side effects of opioids (such as hypotension or nausea), which could secondarily stimulate AVP release, were not controlled.”

The inhibiting effect of DAMME on AVP has been confirmed in further reports.

“The inhibiting effect of DAMME on AVP has been confirmed in further reports (178, 179).”

• cites [178] Brownell, 1980, Inhibition of vasopressin secretion by a met-enkephalin (FK 33-824) in humans, Acta Endocrinol (Copenh) sourceNot checked — no full text of the source
• cites [179] Lightman, 1980, The effect of the methionine enkephalin analogue DAMME on the vasopression response to tilt in man, Clin Sci (Lond) sourceNot checked — no full text of the source

In a case report of a 19-year-old female with complete AVP deficiency since age 6, the patient developed hyponatremia on treatment with hydrocodone after wisdom teeth extraction.

“Indeed, in a case report of a 19-year-old female with complete AVP deficiency since the age of 6 years, the patient developed hyponatremia on treatment with hydrocodone offered after the extraction of her wisdom teeth (182).”

• cites [182] Bhat, 2017, Opioid-induced hyponatremia in a patient with central diabetes insipidus: independence from ADH, J Pediatr Endocrinol Metab sourceNot checked — no full text of the source

Chronic use of tramadol, which has a lower affinity for MOR, led to a less pronounced osteoporotic phenotype in adult female rats compared to morphine or fentanyl.

“For example, chronic use of tramadol, which has a lower affinity for MOR, led to a less pronounced osteoporotic phenotype in adult female rats compared to morphine or fentanyl (214).”

• cites [214] Boshra, 2011, Evaluation of osteoporosis risk associated with chronic use of morphine, fentanyl and tramadol in adult female rats, Curr Drug Saf sourceNot checked — no full text of the source

A number of studies have reported indirect effects on osteoclastogenesis and osteoclast function through modulation of osteoblast-derived factors.

“A number of studies have reported indirect effects on osteoclastogenesis and osteoclast function through modulation of osteoblast-derived factors.”

Long-term opioid therapy is a risk factor for low BMD, as shown in various groups of patients.

“Long-term opioid therapy is a risk factor for low BMD, as has been shown in various groups of patients.”

This study also identified potential mediating miRNAs in the suppression of bone formation in male mice.

“Of interest, this study also identified potential mediating miRNAs in the suppression of bone formation in male mice (205).”

• cites [205] Carvalho, 2022, Sustained morphine delivery suppresses bone formation and alters metabolic and circulating miRNA profiles in male C57BL/6J mice, J Bone Miner Res sourceNot checked — no full text of the source

No up-regulation of C-terminal telopeptide was found in another cohort of men on methadone substitution therapy.

“Conversely, no up-regulation of C-terminal telopeptide was found in another cohort of men on methadone substitution therapy (224).”

• cites [224] Grey, 2011, Decreased bone density in men on methadone maintenance therapy, Addiction sourceNot checked — no full text of the source

Female sex was associated with an increased likelihood of opioid prescription.

“Female sex was associated with an increased likelihood of opioid prescription”

• cites [231] Al-Qurain, 2020, Prevalence and factors associated with analgesic prescribing in poly-medicated elderly patients, Drugs Aging sourceNot checked — no full text of the source

Fentanyl caused immature spinal fusion in a rabbit model.

“whereas fentanyl caused immature spinal fusion in a rabbit model (227).”

• cites [227] Jain, 2018, Opioids delay healing of spinal fusion: a rabbit posterolateral lumbar fusion model, Spine J sourceNot checked — no full text of the source

Traditional opioids have been found to impair bone healing in some animal models of bone trauma.

“Traditional opioids have been found to impair bone healing in some animal models of bone trauma (225).”

• cites [225] Coluzzi, 2020, The effect of opiates on bone formation and bone healing, Curr Osteoporos Rep sourceNot checked — no full text of the source

Most studies suggest differential effects on humans and preclinical models.

“Moreover, most studies suggest differential effects on humans and preclinical models.”

Different opioid categories, depending on affinity for the respective opioid receptors, exert differential effects on bone cells.

“Nonetheless, it appears that different opioid categories, also depending on their affinity for the respective opioid receptors, exert differential effects on bone cells.”

Some evidence of direct effects of opioids on osteoclasts exists.

“On the other hand, some evidence of direct effects of opioids on osteoclasts exists.”

Data on the impact of opioids on bone remodeling and bone healing are discordant.

“In conclusion, data on the impact of opioids on bone remodeling and bone healing are discordant (225).”

• cites [225] Coluzzi, 2020, The effect of opiates on bone formation and bone healing, Curr Osteoporos Rep sourceNot checked — no full text of the source

An older Danish cohort study with a 10-year follow-up period failed to identify such a trend, albeit with a very small number of opioid users.

“In contrast, an older Danish cohort study with a 10-year follow-up period had failed to identify such a trend, albeit the number of opioid users in that study was very small (238).”

• cites [238] Vestergaard, 2012, Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS), Osteoporos Int sourceNot checked — no full text of the source

In that study, osteopenia was detected in 50% of men and 21% of women.

“osteopenia was detected in 50% of men and 21% of women”

• cites [158] Fraser, 2009, Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women, Exp Clin Endocrinol Diabetes sourceNot checked — no full text of the source

In men treated with oral opioids for chronic pain for at least one year, the prevalence of hypogonadism was 75%.

“found high prevalence of hypogonadism in men (75%)”

• cites [158] Fraser, 2009, Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women, Exp Clin Endocrinol Diabetes sourceNot checked — no full text of the source

Patients with continuous opioid use remain at high risk for falls and fracture.

“Thus, it appears that patients with continuous opioid use remain at high risk for falls and fracture.”

In men on methadone maintenance therapy for a median of 11 years, testosterone levels were lower than in controls.

“confirmed lower testosterone levels in men on MMT compared to controls”

• cites [224] Grey, 2011, Decreased bone density in men on methadone maintenance therapy, Addiction sourceNot checked — no full text of the source

In all age groups in that study, BMD was significantly lower than in age- and BMI-matched controls.

“In all age groups, BMD was significantly lower than in age-and BMI-matched controls”

• cites [223] Gotthardt, 2017, Bone mineral density and its determinants in men with opioid dependence, J Bone Miner Metab sourceNot checked — no full text of the source

A previous cross-sectional study in a mixed population (36% men) described decreased BMD in 83% of people enrolled in a methadone maintenance program compared to a gender and race/ethnicity-matched young adult reference population.

“A previous cross-sectional study in a mixed population (36% men) had described decreased BMD (compared to a gender and race/ethnicity-matched, young adult reference population) in 83% of people enrolled in a MMT program”

• cites [242] Kim, 2006, Low bone density in patients receiving methadone maintenance treatment, Drug Alcohol Depend sourceNot checked — no full text of the source

The increase in falls and fractures is accentuated in new opioid users with cognitive impairment, as seen in a study of patients with Alzheimer disease.

“Of note, such an increase in falls and fractures is accentuated in new opioid users with cognitive impairment, as seen in a study of patients with Alzheimer disease (250).”

• cites [250] Taipale, 2019, Incident opioid use and risk of hip fracture among persons with Alzheimer disease: a nationwide matched cohort study, Pain sourceNot checked — no full text of the source

Meta-analyses using mostly cohort and case-control studies reported an increased risk for falls in opioid-treated patients.

“falls (247)”

• cites [247] Yoshikawa, 2020, Opioid use and the risk of falls, fall injuries and fractures among older adults: a systematic review and meta-analysis, J Gerontol A Biol Sci Med Sci sourceNot checked — no full text of the source

In that study, decreased BMD was predominantly on the axial skeleton in 73% of participants.

“predominantly on the axial skeleton in 73% of participants (223).”

• cites [223] Gotthardt, 2017, Bone mineral density and its determinants in men with opioid dependence, J Bone Miner Metab sourceNot checked — no full text of the source

In a small cohort of male patients developing hypogonadism under intrathecal opioid treatment, testosterone substitution restored gonadal status and BMD after two years.

“Of interest, in a study evaluating the effect of testosterone substitution in a small cohort of male patients developing hypogonadism under intrathecal opioid treatment, restoration of gonadal status and BMD after two years of testosterone therapy was reported (239).”

• cites [239] Finch, 2015, Effects of testosterone treatment on bone mineral density in hypogonadal men receiving intrathecal opioids, Pain Pract sourceNot checked — no full text of the source

Scarce data exist on the effects of sex hormone substitution on bone health in hypogonadal patients on opioids.

“Scarce data exist on the effects of sex hormone substitution on bone health in hypogonadal patients on opioids.”

Meta-analyses using mostly cohort and case-control studies reported an increased risk for hip fractures in opioid-treated patients.

“reported an increased risk for hip fractures (245)”

• cites [245] Ping, 2017, Opioids increase hip fracture risk: a meta-analysis, J Bone Miner Metab sourceNot checked — no full text of the source

In premenopausal women treated with oral opioids for chronic pain for at least one year, 21% reported oligo- or amenorrhea indicating hypogonadism.

“whereas only 21% of the women reported oligo-or amenorrhea indicating hypogonadism”

• cites [158] Fraser, 2009, Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women, Exp Clin Endocrinol Diabetes sourceNot checked — no full text of the source

These findings suggest a potential sexual dimorphism in long-term effects of opioids regarding gonadal status and bone health.

“suggesting a potential sexual dimorphism in long-term effects of opioids regarding gonadal status and bone health (158).”

• cites [158] Fraser, 2009, Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women, Exp Clin Endocrinol Diabetes sourceNot checked — no full text of the source

That study identified male gender, low BMI, heavy alcohol use, and HIV infection as significant predictors of low BMD.

“identified male gender, low BMI, heavy alcohol use, and HIV infection as significant predictors of low BMD”

• cites [242] Kim, 2006, Low bone density in patients receiving methadone maintenance treatment, Drug Alcohol Depend sourceNot checked — no full text of the source

In that study, methadone maintenance therapy was associated with bone loss.

“but also indicated that MMT was associated with bone loss (243).”

• cites [243] Sharma, 2011, Prospective evaluation of bone mineral density among middle-aged HIV-infected and uninfected women: association between methadone use and bone loss, Maturitas sourceNot checked — no full text of the source

In a Swiss cross-sectional study of 144 men receiving opioid substitution therapy, BMD was decreased compared to age- and BMI-matched healthy controls.

“reported a decreased BMD compared to compared to age-and BMI-matched healthy controls”

• cites [223] Gotthardt, 2017, Bone mineral density and its determinants in men with opioid dependence, J Bone Miner Metab sourceNot checked — no full text of the source

Free testosterone was an independent predictor of bone mass in that study.

“whereas free testosterone was shown to be an independent predictor of bone mass (223).”

• cites [223] Gotthardt, 2017, Bone mineral density and its determinants in men with opioid dependence, J Bone Miner Metab sourceNot checked — no full text of the source

In middle-aged women, rates of BMD decline were similar between HIV-infected and HIV-uninfected women.

“reported similar rates of decline in BMD between HIV-infected and HIV-uninfected women”

• cites [243] Sharma, 2011, Prospective evaluation of bone mineral density among middle-aged HIV-infected and uninfected women: association between methadone use and bone loss, Maturitas sourceNot checked — no full text of the source

Opioid use can have negative impact on bone homeostasis and metabolism.

“Opioid use can have negative impact on bone homeostasis and metabolism”

Acute administration of opioids increases prolactin secretion.

“Acute administration of opioids increases prolactin secretion.”

Data on the impact of long-term use of opioids on the GH axis are not consistent.

“data on the impact of long-term use of opioids on the GH axis are not consistent”

Opioids inhibit the hypothalamic-pituitary-adrenal axis.

“Opioids inhibit the hypothalamic-pituitary-adrenal axis”

Chronic use of opioids can lead to hyperprolactinemia.

“Chronic use of opioids can lead to hyperprolactinemia.”

Data on the effect of exercise interventions on the bone quality of opioid-dependent individuals are limited.

“but data on the effect of exercise interventions on the bone quality of opioid-dependent individuals are limited.”

The scarce published literature suggests that long-term opioid use could possibly impact negatively on the GH axis in humans.

“The scarce published literature suggests that long-term opioid use could possibly impact negatively on the GH axis in humans.”

Acute administration of opioids has a stimulatory effect on GH secretion.

“Acute administration of opioids has a stimulatory effect on GH secretion”

Opioids have variable and inconsistent effects on the hypothalamic-pituitary-thyroid axis.

“• Opioids have variable and inconsistent effects on the hypothalamic-pituitary-thyroid axis.”