Open Access Open Access  Restricted Access Subscription or Fee Access

The endocrine effects of long-term oral opioid therapy: A case report and review of the literature

Jennifer A. Elliott, MD, Erica Horton, DO, Eugene E. Fibuch, MD


The negative effects of long-term opioid administration on the body’s endocrine system have been known for decades.1,2 These effects have been observed and studied with the use of intrathecal opioids and in heroin addicts.3-9 However, they have also been noted to occur with the use of oral opioids, especially in those patients who require chronic opioids for the management of nonmalignant and cancer-associated pain.2,10-13 Epidemiologic data in recent years suggest that up to five million men with chronic nonmalignant pain suffer from opioid-induced androgen deficiency (OPIAD) in the United States.14 Therefore, it is important to understand the physiologic impact of chronic opioid administration in patients. In view of the increasing use of opioids for chronic pain, we must anticipate the potential occurrence of hypogonadism during chronic opioid therapy and monitor patients accordingly. If symptoms of endocrine dysfunction are recognized during chronic opioid therapy, appropriate evaluation, treatment, and follow-up should be instituted. This article describes a case report of a patient who suffered from a clinically significant testosterone deficiency and osteoporosis related to the use of long-term oral opioids for chronic nonmalignant pain. It also includes a review of the existing literature regarding OPIAD and provides recommendations regarding the evaluation and management of OPIAD.


endocrine, opioids, hypogonadism, testosterone, osteoporosis

Full Text:



Colamenco C, Coren JS: Opioid-induced endocrinopathy. J Am Osteopath Assoc. 2009; 109(1): 20-25.

Fraser L-A, Morrison D, Morley-Forster P, et al.: Oral opioids for chronic non-cancer pain: Higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009; 117: 38-43.

Finch PM, Roberts LJ, Price LS, et al.: Hypogonadism in patients treated with intrathecal morphine. Clin J Pain. 2000; 16(3): 251-254.

Paice JA, Penn RD, Ryan WG: Altered sexual function and decreased testosterone in patients receiving intraspinal opioids. J Pain Symptom Manage. 1994; 9(2): 126-131.

Abs R, Verhelst J, Maeyaert J, et al.: Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000; 85(6): 2215-2222.

Roberts LJ, Finch PM, Goucke CR, et al.: Outcome of intrathecal opioids in chronic non-cancer pain. Eur J Pain. 2001; 5: 353-361.

Roberts LJ, Finch PM, Pullan PT, et al.: Sex hormone suppression by intrathecal opioids: A prospective study. Clin J Pain. 2002; 18: 144-148.

Bolelli G, Lafisca S, Flamigni C, et al.: Heroin addiction: Relationship between the plasma levels of testosterone, dihydrotestosterone, androstenedione, LH, FSH, and the plasma concentration of heroin. Toxicology. 1979; 15: 19-29.

Daniell HW: Narcotic-induced hypogonadism during therapy for heroin addiction. J Addict Dis. 2002; 21(4): 47-53.

Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al.: Hypogonadism and sexual dysfunction in male cancer survivors receiving chronic opioid therapy. J Pain Symptom Manage. 2003; 26(5): 1055-1061.

Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al.: Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004; 100(4): 851-858.

Daniell HW: Hypogonadism in men consuming sustainedaction oral opioids. J Pain. 2002; 3(5): 377-384.

Daniell HW: Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008; 9(1): 28-36.

Daniell HW, Lentz R, Mazer NA: Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency. J Pain. 2006; 7(3): 200-210.

Katz N: The impact of opioids on the endocrine system. Pain Manage Rounds. 2005; 1(9).

Katz N, Mazer NA: The impact of opioids on the endocrine system. Clin J Pain. 2009; 25(2): 170-175.

Merck Manual Professional: Male hypogonadism: Male endocrinology. Available at Accessed August 30, 2010.

Snyder PJ: Causes of secondary hypogonadism in males. In Martin KA (ed.): Up To Date. Waltham, MA: UpToDate, 2010.

Brydoy M, Fossa SD, Dahl O, et al.: Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol. 2007; 46(4): 480-489.

Hayes FJ, Bubley GJ: Effects of cytotoxic agents on gonadal function in adult men. In Martin KD (ed.): Up To Date. Waltham, MA: UpToDate, 2010.

Pfeilschifter J, Diel IJ: Osteoporosis due to cancer treatment: Pathogenesis and management. J Clin Oncol. 2000; 18(7): 1570-1593.

Kiserud CE, Schover LR, Dahl AA, et al.: Do male lymphoma survivors have impaired sexual function? J Clin Oncol. 2009; 27(35): 6019-6026.

Rivkees SA, Crawford JD: The relationship of gonadal activity and chemotherapy-induced gonadal damage. JAMA. 1988; 259(14): 2123-2125.

Miller KK, Sesmilo G, Schiller A, et al.: Androgen deficiency in women with hypopituitarism. J Clin Endocrinol Metab. 2001; 86(2): 561-567.

Bachmann G, Oza D: Female androgen insufficiency. Obstet Gynecol Clin North Am. 2006; 33: 589-598.

Daniell HW: DHEAS deficiency during consumption of sustained-action prescribed opioids: Evidence for opioid-induced inhibition of adrenal androgen production. J Pain. 2006; 7(12):901-907.

Davis S: Testosterone deficiency in women. J Reprod Med. 2001; 46(3): 291-296.

Daniell HW: Sex hormone deficiency in depressed patients receiving opioids. Arch Intern Med. 2004; 164: 804 (Letter).

Schmidt PJ, Berlin KL, Danaceau MA, et al.: The effects of pharmacologically induced hypogonadism on mood in healthy men. Arch Gen Psychiatry. 2004; 61: 997-1004.

Zarrouf FA, Artz S, Griffith J, et al.: Testosterone and depression: Systematic review and meta-analysis. J Psychiatr Pract. 2009; 15(4): 289-305.

Seidman SN, Orr G, Raviv G, et al.: Effects of testosterone replacement in middle-aged men with dysthymia: A randomized, placebo-controlled trial. J Clin Psychopharmacol. 2009; 29(3): 216-221.

Barrett-Connor E, von Muehlen DG, Kritz-Silverstein D: Bioavailable testosterone and depressed mood in older men: The Ranch Bernardo Study. J Clin Endocrinol Metab. 1999; 84: 573-577.

Pope HG, Cohane GH, Kanayama G, et al.: Testosterone gel supplementation for men with refractory depression: A randomized, placebo-controlled trial. Am J Psychiatry. 2003; 160: 105-111.

Finkelstein JS: Epidemiology and etiology of osteoporosis in men. In Mulder JE (ed.): Up To Date. Waltham, MA: UpToDate, 2010.

Holmes SJ, Whitehouse RW, Clark ST, et al.: Reduced bone mineral density in men following chemotherapy for Hodgkin’s disease. Br J Cancer. 1994; 70: 371-375.

Pedrazzoni M, Vescovi PP, Maninetti L, et al.: Effects of chronic heroin abuse on bone and mineral metabolism. Acta Endocrinol. 1993; 129: 42-45.

Kim TW, Alford DP, Malabanan A, et al.: Low bone density in patients receiving methadone maintenance treatment. Drug Alcohol Depend. 2006; 85: 258-262.

Khosla S, Melton LJ III, Atkinson EJ, et al.: Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab. 2001; 86(8): 3555-3561.

Miller KK: Androgen deficiency in women. J Clin Endocrinol Metab. 2001; 86(6): 2395-2401 (Commentary).

Davis S: Androgen replacement in women: A commentary. J Clin Endocrinol Metab. 1999; 84: 1886-1891.

Amin S, Zhang Y, Felson DT, et al.: Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am J Med. 2006; 119: 426-433.

Fink HA, Ewing SK, Ensrud KE, et al.: Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab. 2006; 91(10): 3908-3915.

Fortin JD, Bailey GM, Vilensky JA: Does opioid use for pain management warrant routine bone mass density screening in men? Pain Physician. 2008; 11: 539-541.

Daniell HW: Opioid osteoporosis. Arch Intern Med. 2004; 164: 338 (Letter).

Vuong C, Van Uum SHM, O’Dell LE, et al.: The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010; 31(1): 98-132.

Bachmann G, Bancroft J, Braunstein G, et al.: Female androgen insufficiency: The Princeton consensus statement on definition, classification, and assessment. Fertil Steril. 2002; 77(4): 660-665.

Arlt W: Androgen therapy in women. Eur J Endocrinol. 2006; 154: 1-11.

Daniell HW: Opioid-induced androgen deficiency discussion in opioid contracts. Am J Med. 2007; 120: e21 (Letter).

American Academy of Pain Medicine: Consent for chronic opioid therapy. Available at Accessed August 30, 2010.

Wierman ME, Basson R, Davis SR, et al.: Androgen therapy in women: An Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. 2006; 91(10): 3697-3710.

Bhasin S, Cunningham GR, Hayes FJ, et al.: Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2010; 95(6): 2536-2559.

Endocrinologist’s Guidelines for the Diagnosis and Treatment of Menopause: Androgen deficiency in postmenopausal women. Available at Accessed August 30, 2010.

Fernandez-Balsells MM, Murad MH, Lane M, et al.: Adverse effects of testosterone therapy in adult men: A systematic review and meta-analysis. J Clin Endocrinol Metab. 2010; 95: 2560-2575.

Basaria S, Coviello AD, Travison TG, et al.: Adverse events associated with testosterone administration. N Engl J Med. 2010; 363(2): 109-122.

Auernhammer CJ, Vlotides G: Anterior pituitary hormone replacement therapyÑA clinical review. Pituitary. 2007; 10: 1-15.

Snyder PJ: Testosterone treatment of male hypogonadism. In Marin KA (ed.): Up To Date. Waltham, MA: UpToDate, 2010.

Lexi-Comp Online: Testosterone. Lexi-Drugs Online. Lexi-Comp, Inc., 1978-2010. Available at

Mazer NA: Testosterone deficiency in women: Etiologies, diagnosis, and emerging treatments. Int J Fertil. 2002; 47(2): 77-86.

Tennant F: Testosterone replacement in female chronic pain patients. Pract Pain Manage. 2009; November/December: 25-27.



  • There are currently no refbacks.