Opioids are a treatment option for a variety of chronic pain conditions. But long-term opioid use can be associated with side effects, including hypogonadism. Opioid-induced hypogonadism (OIhG) is associated with the alteration of the hypothalamic-pituitary-gonadal axis (HPG). In males, hypogonadism can result in erectile dysfunction, reduced libido, fatigue, worsening mood, and increased risk of osteoporosis; in females, it can result in changes in the menstrual cycle and reduced libido, among other effects. A current treatment option for these patients is hormone replacement therapy. In this report, we discuss the problem of opioid-induced hypogonadism, and the therapeutic approach and the potential complications of treating pain patients using hormone replacement therapy.
Manchikanti, L., Vallejo, R., Manchikanti, K.N., Benyamin, R.M., Datta, S. and Christo, P.J. (2011) Effectiveness of Long-Term Opioid Therapy for Chronic Non-Cancer Pain. Pain Physician, 14, E133-E156. https://www.ncbi.nlm.nih.gov/pubmed/21412378
Furlan, A.D., Sandoval, J.A., Mailis-Gagnon, A. and Tunks, E. (2006) Opioids for Chronic Noncancer Pain: A Meta-Analysis of Effectiveness and Side Effects. Canadian Medical Association Journal, 174, 1589-1594. https://www.ncbi.nlm.nih.gov/pubmed/16717269 https://doi.org/10.1503/cmaj.051528
Benyamin, R., et al. (2008) Opioid Complications and Side Effects. Pain Physician, 11, S105-S120. https://www.ncbi.nlm.nih.gov/pubmed/18443635
Ceccarelli, I., De Padova, A.M., Fiorenzani, P., Massafra, C. and Aloisi, A.M. (2006) Single Opioid Administration Modifies Gonadal Steroids in Both the CNS and Plasma of Male Rats. Neuroscience, 140, 929-937. https://www.ncbi.nlm.nih.gov/pubmed/16580783 https://doi.org/10.1016/j.neuroscience.2006.02.044
Ceccarelli, I., Rossi, A., Maddalena, M., Weber, E. and Aloisi, A.M. (2009) Effects of Morphine on Testosterone Levels in Rat C6 Glioma Cells: Modulation by Anastrozole. Journal of Cellular Physiology, 221, 1-4. https://doi.org/10.1002/jcp.21830 https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.21830
Amini, H. and Ahmadiani, A. (2005) In Vivo Evidence for an Increase in 5 Alpha-Reductase Activity in the Rat Central Nervous System Following Morphine Exposure. International Journal of Developmental Neuroscience, 23, 621-626. https://kundoc.com/pdf-in-vivo-evidence-for-an-increase-in-5alpha-reductase-activity-in-the-rat-central.html https://doi.org/10.1016/j.ijdevneu.2005.07.001
Abs, R., et al. (2000) Endocrine Consequences of Long-Term Intrathecal Administration of Opioids. Journal of Clinical Endocrinology and Metabolism, 85, 2215-2222. https://www.ncbi.nlm.nih.gov/pubmed/10852454 https://doi.org/10.1210/jcem.85.6.6615
Aloisi, A.M., et al. (2005) Gender-Related Effects of Chronic Non-Malignant Pain and Opioid Therapy on Plasma Levels of Macrophage Migration Inhibitory Factor (MIF). Pain, 115, 142-151. https://www.ncbi.nlm.nih.gov/pubmed/15836977 https://doi.org/10.1016/j.pain.2005.02.019
Daniell, H.W. (2002) Hypogonadism in Men Consuming Sustained-Action Oral Opioids. Journal of Pain, 3, 377-384. https://doi.org/10.1054/jpai.2002.126790 https://www.ncbi.nlm.nih.gov/pubmed/14622741
Daniell, H.W. (2008) Opioid Endocrinopathy in Women Consuming Prescribed Sustained-Action Opioids for Control of Nonmalignant Pain. Journal of Pain, 9, 28-36. https://www.ncbi.nlm.nih.gov/pubmed/17936076 https://doi.org/10.1016/j.jpain.2007.08.005
Fraser, L.A., et al. (2009) Oral Opioids for chronic Non-Cancer Pain: Higher Prevalence of Hypogonadism in Men than in Women. Experimental and Clinical Endocrinology & Diabetes, 117, 38-43. https://www.ncbi.nlm.nih.gov/pubmed/18523930 https://doi.org/10.1055/s-2008-1076715
Azizi, F., Vagenakis, A.G, Longcope, C., Ingbar, S.H. and Braverman, L.E. (1973) Decreased Serum Testosterone Concentration in Male Heroin and Methadone Addicts. Steroids, 22, 467-472. https://doi.org/10.1016/0039-128X(73)90002-0
Mendelson, J.H., Ellingboe, J., Judson, B.A. and Goldstein, A. (1984) Plasma Testosterone and Luteinizing Hormone Levels during Levo-Alpha-Acetylmethadol Maintenance and Withdrawal. Clinical Pharmacology & Therapeutics, 35, 545-547. https://doi.org/10.1038/clpt.1984.75
Woody, G., McLellan, A.T., O’Brien, C., Persky, H., Stevens, G., Arndt, I. and Carroff, S. (1988) Hormone Secretion in Methadone-Dependent and Abstinent Patients. NIDA Research Monograph, 81, 216-223.
Roberts, L.J., Finch, P.M., Pullan, P.T., Bhagat, C.I. and Price, L.M. (2002) Sex Hormone Suppression by Intrathecal Opioids: A Prospective Study. Clinical Journal of Pain, 18, 144-148. https://www.ncbi.nlm.nih.gov/pubmed/12048415 https://doi.org/10.1097/00002508-200205000-00002
Vestergaard, P., Rejnmark, L. and Mosekilde, L. (2006) Fracture Risk Associated with the Use of Morphine and Opiates. Journal of Internal Medicine, 260, 76-87. https://www.ncbi.nlm.nih.gov/pubmed/16789982 https://doi.org/10.1111/j.1365-2796.2006.01667.x
Moffat, S.D., et al. (2004) Free Testosterone and Risk for Alzheimer Disease in Older Men. Neurology, 62, 188-193. https://www.ncbi.nlm.nih.gov/pubmed/14745052 https://doi.org/10.1212/WNL.62.2.188
Straub, R.H. and Cutolo, M. (2001) Involvement of the Hypothalamic-Pituitary-Adrenal/Gonadal Axis and the Peripheral Nervous System in Rheumatoid Arthritis: Viewpoint Based on a Systemic Pathogenetic Role. Arthritis & Rheumatology, 44, 493-507. https://www.ncbi.nlm.nih.gov/pubmed/11263762 https://doi.org/10.1002/1529-0131(200103)44:3 3.0.CO;2-U
Vuong, C., Van Uum, S.H., O’Dell, L.E., Lutfy, K. and Friedman, T.C. (2010) The Effects of Opioids and Opioid Analogs on Animal and Human Endocrine Systems. Endocrine Reviews, 31, 98-132. https://www.ncbi.nlm.nih.gov/pubmed/19903933
Osran, H., et al. (1993) Adrenal Androgens and Cortisol in Major Depression. American Journal of Psychiatry, 150, 806-809. https://doi.org/10.1176/ajp.150.5.806
Seidman, S.N. and Walsh, B.T. (1999) Testosterone and Depression in Aging Men. The American Journal of Geriatric Psychiatry, 7, 18-33. https://www.ncbi.nlm.nih.gov/pubmed/9919317 https://doi.org/10.1097/00019442-199902000-00004
Zarrouf, F.A., Artz, S., Griffith, J., Sirbu, C. and Kommor, M. (2009) Testosterone and Depression: Systematic Review and Meta-Analysis. Journal of Psychiatric Practice, 15, 289-305. https://www.ncbi.nlm.nih.gov/pubmed/19625884 https://doi.org/10.1097/01.pra.0000358315.88931.fc
Daniell, H.W., Lentz, R. and Mazer, N.A. (2006) Open-Label Pilot Study of Testosterone Patch Therapy in Men with Opioid-Induced Androgen Deficiency. The Journal of Pain, 7, 200-210. https://www.ncbi.nlm.nih.gov/pubmed/16516826 https://doi.org/10.1016/j.jpain.2005.10.009
Aloisi, A.M., et al. (2011) Hormone Replacement Therapy in Morphine-Induced Hypogonadic Male Chronic Pain Patients. Reproductive Biology and Endocrinology, 9, 26. https://doi.org/10.1186/1477-7827-9-26