Hypogonadism associated with long-term opioid therapy: A systematic review


  • Pravardhan Birthi, MD
  • Vittal R. Nagar, MD
  • Robert Nickerson, MD
  • Paul A. Sloan, MD




chronic pain, opioids, hypogonadism, hypogonadism treatment, long-term opioid therapy, chronic nonmalignant pain


Background: Sexual dysfunction and Opioid-Induced Sexual Hormone Deficiency (OPISHD) have been associated with patients on long-term opioid pain therapy. There have been few comprehensive reviews to establish a relation between hypogonadism with chronic opioid pain management. The OPISHD is often not treated and literature guiding this topic is scarce.

Objective: To investigate hypogonadism associated with long-term opioid therapy based on qualitative data analysis of the available literature.

Study design: Systematic review.

Interventions: The review included relevant literature identified through searches of PubMed, Cochrane, Clinical Trials, US National Guideline Clearinghouse, and EMBASE, for the years 1960 to September 2013. The quality assessment and clinical relevance criteria used were the Cochrane Musculoskeletal Review Group Criteria for randomized control trials and the Newcastle-Ottawa Scale Criteria for observational studies. The level of evidence was classified as good, fair, and poor, based on the quality of evidence.

Main outcome measures: The primary outcome measures were clinical symptoms and laboratory markers of hypogonadism. Secondary outcome measure was management of OPISHD.

Results: Thirty-one studies were identified, of which 14 studies met inclusion criteria. There were no randomized control trials and eight of 14 studies were of moderate quality. The remaining studies were of poor quality. Four studies report most patients on long-term oral opioid therapy have associated hypogonadism and three studies of patients receiving intrathecal opioid therapy suggest that hypogonadism is common.

Conclusions: There is lack of high-quality studies to associate chronic opioid pain management with hypogonadism. At present, there is fair evidence to associate hypogonadism with chronic opioid pain management, and only limited evidence for treatment of OPISHD.

Author Biographies

Pravardhan Birthi, MD

Pain Management Service, Saint Francis Medical Center, Grand Island, Nebraska.

Vittal R. Nagar, MD

Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, Kentucky.

Robert Nickerson, MD

Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, Kentucky.

Paul A. Sloan, MD

Department of Anesthesiology, University of Kentucky, Lexington, Kentucky.


Mehendale AW, Goldman MP, Mehendale BA: Opioid overuse pain syndrome (OOPS): The story of opioids, Prometheus unbound. J Opioid Manage. 2013; 9: 421-483.

Olsen Y, Daumit GL, Ford DE: Opioid prescriptions by US primary care physicians from 1992 to 2001. J Pain. 2006; 7: 225-235.

Sloan PA: Update on extended-release opioids in pain management. Exp Opin Drug Deliv. 2014; 11: 155-158.

Luo X, Pietrobon R, Hey L: Patterns and trends in opioid use among individuals with back pain in the United States. Spine. 2004; 29: 884-890.

Manchikanti L, Singh A: Therapeutic opioids: A ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician. 2008; 11(2): S63-S88.

Vestergaard P, Rejnmark L, Mosekilde L: Fracture risk associated with the use of morphine and opiates. J Intern Med. 2006; 260: 76-87.

Katz NP, Birnbaum HG, Castor A: Volume of prescription opioids used nonmedically in the United States. J Pain Palliat Care Pharmacother. 2010; 24: 141-144.

Elliott JA, Horton E, Fibuch EE: The endocrine effects of long-term oral opioid therapy: A case report and review of the literature. J Opioid Manag. 2011; 7(2): 145-154.

Blank MS, Fabbri A, Catt KJ, et al.: Inhibition of luteinizing hormone release by morphine and endogenous opiates in cultured pituitary cells. Endocrinology. 1986; 118: 2097-2101.

Adams ML, Sewing B, Forman JB, et al.: Opioid-induced suppression of rat testicular function. J Pharmacol Exp Ther. 1993; 266: 323-328.

Lee C, Ludwig S, Duerksen DR: Low-serum cortisol associated with opioid use: Case report and review of the literature. Endocrinologist. 2002; 12: 5-8.

Taylor T, Dluhy RG, Williams GH: Endorphin suppresses adrenocorticotropin and cortisol levels in normal human subjects. J Clin Endocrinol Metab. 1983; 57: 592-596.

Allolio B, Deuss U, Kaulen D, et al.: FK 33- 824, a metenkephalin analog blocks corticotropin-releasing hormoneinduced adrenocorticotropin secretion in normal subjects but not in patients with Cushing's disease. J Clin Endocrinol Metab. 1986; 63: 1427-1431.

Benyamin R, Trescot AM, Datta S, et al.: Opioid complications and side effects. Pain Physician. 2008; 11: S105-S120.

Christo PJ: Opioid effectiveness and side effects in chronic pain. Anesthesiol Clin North America. 2003; 21: 699-713.

Kalyani RR, Gavini S, Dobs AS: Male hypogonadism in systemic disease. Endocrinol Metab Clin North Am. 2007; 36: 333-348.

Dahan A, Kest B, Waxman AR, et al.: Sex-specific responses to opiates: Animal and human studies. Anesth Analg. 2008; 107(1): 83-95.

Birthi P, Sloan PA: Interventional treatment of refractory cancer pain. Cancer J. 2013; 19: 390-396.

Colameco S, Coren JS: Opioid-induced endocrinopathy. J Am Osteopath Assoc. 2009; 109: 20-25.

Moher D, Cook DJ, Eastwood S, et al.: Improving the quality of reports of meta-analyses of randomised controlled trials: The QUO- ROM statement. Quality of reporting of meta-analyses. Lancet. 1999; 354: 1896-1900.

Stroup DF, Berlin JA, Morton SC, et al.: Meta- analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000; 283: 2008-2012.

Liberati A, Altman DG, Tetzlaff J, et al.: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. Ann Intern Med. 2009; 151: W65-W94.

van Tulder M, Furlan A, Bombardier C, et al.: Updated method guidelines for systematic reviews in the Cochrane

Collaboration Back. Review Group. Spine (Phila Pa 1976). 2003; 28: 1290-1299.

Furlan AD, Pennick V, Bombardier C, et al.: 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine (Phila Pa 1976). 2009; 34: 1929-1941.

van Tulder MW, Suttorp M, Morton S, et al.: Empirical evidence of an association between internal validity and effect size in randomized controlled trials of low-back pain. Spine (Phila Pa 1976). 2009; 34: 1685-1692.

Staal JB, de Bie RA, de Vet HC, et al.: Injection therapy for subacute and chronic low back pain: An updated Cochrane review. Spine (Phila Pa 1976). 2009; 34: 49-59.

Chou R, Fanciullo GJ, Fine PG, et al.: Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009; 10: 113-130.

Vandenbroucke JP, von Elm E, Altman DG, et al.: STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. Ann Intern Med. 2007; 147: W163-W194.

Boyd J, Brugger H, Shuster M: Prognostic factors in avalance resuscitation: A systematic review. Resuscitation. 2010; 81: 645-652.

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

Duarte RV, Raphael JH, Labib M, et al.: Prevalence and influence of diagnostic criteria in the assessment of hypogonadism in intrathecal opioid therapy patients. Pain Physician. 2013; 16(1): 9-14.

Deyo RA, Smith DH, Johnson ES, et al.: Prescription opioids for back pain and use of medications for erectile dysfunction. Spine (Phila Pa 1976). 2013; 38(11): 909-915.

Fraser LA, 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(1): 38-43.

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: 1055-1061.

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

Aurilio C, Ceccarelli I, Pota V, et al.: Endocrine and behavioral effects of transdermal buprenorphine in pain-suffering women of different reproductive ages. Endocr J. 2011; 58(12): 1071-1078.

Wells GA, Shea B, O’Connell D, et al.: The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis. Available at http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed July 30, 2013.

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

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

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

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

Daniell HW: Hypogonadism in men consuming sustained action oral opioids. J Pain. 2002; 3: 377-384.

Rhodin A, Stridsberg M, Gordh T: Opioid endocrinopathy: A clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin J Pain. 2010; 26: 374-380.

Wong D, Gray DP, Simmonds M, et al.: Opioid analgesics suppress male gonadal function but opioid use in males and females does not correlate with symptoms of sexual dysfunction. Pain Res Manag. 2011; 16(5): 311-316.

Manchikanti KN, Atluri S, Singh V, et al.: An update of evaluation of therapeutic thoracic facet joint interventions. Pain Physician. 2012; 15(4): E463-E481.

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.

Hallinan R, Byrne A, Agho K, et al.: Erectile dysfunction in men receiving methadone and buprenorphine maintenance treatment. J Sex Med. 2008; 5(3): 684-692.

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

Doleys DM, Dinoff BL, Page L, et al.: Sexual dysfunction and other side effects of intraspinal opiate use in the management of chronic non-cancer pain. AJPM. 1998; 8: 5-11.

Paice JA, Penn RD: Amenorrhea associated with intraspinal morphine. J Pain Symptom Manage. 1995; 10: 582-583.

Tabuchi Y, Yasuda T, Kaneto H, et al.: A case of hypogonadotropic hypogonadism caused by opioid treatment for nonmalignant chronic pain. Case Rep Med. 2012; 2012: 740603.

Bhasin S, Cunningham GR, Hayes FJ, et al.: Testosterone therapy in men with androgen deficiency syndromes: An endocrine

society clinical practical guideline. J Clin Endocrinol Metab. 2010; 95: 2536-2559.

Kapoor D, Aldred H, Clark S, et al.: Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes. Diabetes Care. 2007; 30: 911-917.

Corona G, Mannucci E, Petrone L, et al.: ANDROTEST: A structured interview for the screening of hypogonadism in patients with sexual dysfunctions. J Sex Med. 2006; 3: 706-715.

Morales A, Spevack M, Emerson L, et al.: Adding to the controversy: Pitfalls in the diagnosis of testosterone deficiency syndromes with questionnaires and bio-chemistry. Aging Male. 2007; 10: 57-65.

Wu FC, Tajar A, Beynon JM, et al.: Identification of lateonset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010; 363: 123-135.

De Maddalena C, Bellini M, Berra M, et al.: Opioid-induced hypogonadism: Why and how to treat it. Pain Physician. 2012; 15(3): ES111-ES118.

Aloisi AM, Ceccarelli I, Carlucci M, et al.: Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients. Reprod Biol Endocrinol. 2011; 9: 26-35.

Gurnell EM, Hunt PJ, Curran SE, et al.: Long-term DHEA replacement in primary adrenal insufficiency: A randomized, controlled trial. J Clin Endocrinol Metab. 2008; 9: 400-409.

Kingsberg S, Shifren J, Wekselman K, et al.: Evaluation of the clinical relevance of benefits associated with transdermal testosterone treatment in postmenopausal women with hypoactive sexual desire disorder. J Sex Med. 2007; 4(4): 1001-1008.

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



How to Cite

Birthi, MD, P., V. R. Nagar, MD, R. Nickerson, MD, and P. A. Sloan, MD. “Hypogonadism Associated With Long-Term Opioid Therapy: A Systematic Review”. Journal of Opioid Management, vol. 11, no. 3, May 2015, pp. 255-78, doi:10.5055/jom.2015.0274.



Review Articles