September is National Pain Awareness Month. This article is the conclusion of a weekly series on pain-related topics to commemorate the pharmacist's role in pain management.
Opioid-induced androgen deficiency (OPIAD) is a common yet under diagnosed adverse effect of chronic opioid use.1, 2
Hypogonadism is frequently seen with opioid use and can occur quickly; however, it is generally considered reversible.1-3
Up to 100 million Americans experience chronic pain, which affects their quality of life and ability to perform daily activities.4
Opioids are highly effective analgesics frequently used to treat various chronic pain syndromes.
From 1991 to 2013, the total number of opioid prescriptions increased by 172% in the United States.4
Associated with this surge in opioid use is an increase in incidence of OPIAD.
Before we discuss the OPIAD phenomenon, let’s explore how testosterone and estrogen are produced and regulated by the body.
Synthesis of testosterone and estrogen
Synthesis of testosterone and estrogen is regulated by the hypothalamic-pituitary-gonadal (HPG) axis.
The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which in turn stimulates the anterior pituitary gland to secrete follicular stimulating hormone (FSH) and luteinizing hormone (LH).
In men, LH travels to the leydig cells in the testes and stimulates testosterone production and release, whereas FSH stimulates sperm production and maturation by the Sertoli cells. In women, FSH stimulates the production of estrogen by ovarian cells, while LH stimulates ovulation.
The HPG axis is regulated by a negative feedback loop. Testosterone and estrogen exert an inhibitory effect on the hypothalamus and pituitary gland, thereby reducing the production of GnRH, LH, and FSH.3
Opioids exert their activity by binding to the mu opioid receptor, which is expressed in the central nervous system (CNS), peripheral nervous system (PNS), and other areas such as the hypothalamus and pituitary gland.3
Opioids indirectly inhibit secretion of GnRH by the hypothalamus, thereby reducing downstream production of gonadal hormones in both sexes.3
Conversely, the mu-receptor antagonist naloxone increases LH and gonadal hormone secretion.5,6
Therefore, OPIAD is considered a form of secondary (hypogonadotropic) hypogonadism.1,3,5
Opioids may also cause adrenal insufficiency, reducing androgen production by the adrenal glands. Deficiency in dehydroepiandrosterone (DHEA), an adrenal precursor to testosterone production, was documented in patients on opioid therapy.7
Opioids were also found to induce apoptosis of leydig cells, which is thought to directly inhibit testosterone synthesis.8
It is thought that down-regulation of noradrenergic neurons and up-regulation of GABAergic neurons plays a role in transmitting the indirect effects of opioids on GnRH neurons in the hypothalamus. One study found that morphine could interact with a neuropeptide called Kisspeptin, which in turn down-regulates the HPG axis.9
Another possible mechanism is increased production of sex hormone-binding globulin, which reduces the levels of free testosterone. Studies in rats have found that morphine increased the conversion of testosterone to estradiol and dihydrotestosterone (DHT) by increasing aromatase and 5-alpha-reductase mRNA production.3
Various studies have reported rates of hypogonadism between 54% and 64% in men using chronic opioids.2
Hypogonadism with opioid use is dose-dependent and occurs quickly. Patients receiving 100 mg to 200 mg of morphine equivalent for 1 month are 50% to 100% likely to develop some degree of OPIAD.3
In one study, HPG axis suppression was found to occur as soon as 1 week after opioid use and was sustained for 12 weeks.5
However, hypogonadism associated with opioid use is generally considered reversible.3,5
It should be noted that both sexes are affected, as females also experience hypogonadism and may have decreased libido when taking opioids.1,2,3
Signs and symptoms of hypogonadism1,2,3
Fatigue and decreased energy and vitality
Depression and irritability
Decreased lean muscle mass
Increased visceral fat
Decreased bone density
Decline in cognitive skills: concentration and memory
Some OPIAD symptoms of hypogonadism could be easily confused with adverse effects of opioids (fatigue), comorbid psychiatric conditions associated with chronic pain (depression/low self-esteem), or a normal part of aging (low libido and erectile dysfunction).
For instance, a male patient started on an opioid returns for a follow-up appointment and reports “dizziness and fatigue”; the clinician may conclude that dizziness and fatigue are common side effects of opioids and overlook that it could be OPIAD.
Besides affecting quality of life, decreased hormone levels can be associated with decreased life expectancy. Hypogonadism is linked to other chronic conditions, including decreased bone density with resultant osteoporosis, hyperlipidemia and weight gain leading to metabolic syndrome, and sleep apnea.2,3
Therefore, a male patient taking a chronic opioid for spine degeneration could develop osteoporosis, which would cause further spinal degeneration and worsening of his pain. Dual-energy X-ray absorptiometry (DEXA) scans should be routinely performed in patients on chronic opioids who develop hypogonadism, in addition to ensuring adequate calcium and vitamin D levels. 10
Inter-opioid variability in OPIAD incidence
The risk of OPIAD depends in part on the opioid dose and formulation.
Some evidence suggests that short-acting opioids have a lower risk of androgen deficiency compared with long-acting opioids, purportedly because of a rest period between doses.11,12
A retrospective cohort of 1585 men demonstrated that androgen deficiency occurred in 57% of men on long-acting opioids compared with 35% of men on equivalent daily doses of short-acting opioids.12
The study also noted a dose-related incidence of OPIAD with a 1.16 increase in adjusted odds ratio (OR) for every 10-mg increase in morphine standardized equivalent dose.
Interestingly, the increased risk of androgen deficiency with increased opioid dose is more strongly associated with short-acting opioids than long-acting ones.11
There is some evidence that certain opioids have a decreased risk of causing hypogonadism. One study found that patients taking buprenorphine had significantly higher levels of testosterone and a lower frequency of reported sexual dysfunction compared with methadone.13
This could be because buprenorphine is a partial agonist/antagonist for the opioid receptor compared with methadone, which is a pure agonist.
Although tapentadol (Nucynta) is a pure agonist with norepinephrine reuptake-inhibiting properties, there is also some evidence that it is less likely to cause hypogonadism.14
A randomized, placebo-controlled, double blind study found that tapentadol had a lower effect on diminishing serum testosterone compared with morphine and oxycodone.
These findings suggest that tapentadol has a decreased risk of hypogonadism, which may be due to the fact that tapentadol is 18 times less potent for the opioid receptor than morphine.14
The role of the pharmacist
Pharmacists should be aware that androgen deficiency is a common complication of opioid use. They should be able to identify patients on opioids who have symptoms of hypogonadism and recommend that they contact their health care provider.
This might include a male patient who fills opioids regularly, presents to the pharmacy with a new sildenafil prescription for erectile dysfunction, and mentions that this is a new occurrence, or a female patient who presents similarly with a prescription for flibanserin (Addyi), which might also be cause to consider OPIAD.
Other take-home points for pharmacists include:
This article was collaboratively written with Daralyn A. Morgenson BS, PharmD, and Mena Raouf, PharmD candidate 2016.
Dr. Morgenson received her BS from the University of Nebraska-Lincoln, and her PharmD from the University of Nebraska Medical Center College of Pharmacy. Dr. Morgenson is currently completing a PGY1 Pharmacy Residency at the Stratton VA Medical Center, with a focus on ambulatory care.
Hypogonadism could worsen pain, affect patients’ quality of life, and lead to further health complications.
Some symptoms of androgen deficiency may be confused as side effect of opioids or as a comorbidity of chronic pain. For example, fatigue may be considered a side effect of an opioid associated with drowsiness, and depression may be considered a normal complication of chronic pain.
Patients who develop OPIAD should be counseled on osteoporosis risk, along with having DEXA scan performed and ensuring adequate calcium and vitamin D.
Buprenorphine and tapentadol have a lower incidence of OPIAD.
Mena Raouf is a 2016 PharmD Candidate at the Albany College of Pharmacy and Health Sciences, with a concentration in Nephrology. He hopes to complete a PGY1 and PGY2 Pharmacy Residency and practice as a clinical pharmacist specialist.
Both co-authors were under the mentorship of Dr. Fudin at the time of this publication.
This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers, employee affiliates. It was not prepared as part of the authors' duty as federal employees.
Demarest SP, Gill RS, Adler RA. Opioid endocrinopathy. Endocr Pract. 2015;21(2):190-8.
Valverde-filho J, Da cunha neto MB, Fonoff ET, Meirelles Ede S, Teixeira MJ. Chronic spinal and oral morphine-induced neuroendocrine and metabolic changes in noncancer pain patients. Pain Med. 2015;16(4):715-25.
Smith HS, Elliott JA. Opioid-induced androgen deficiency (OPIAD). Pain Physician. 2012;15(3 Suppl):ES145-56.
Volkow ND. National Institute on Drug Abuse. America’s addiction to opioids: heroin and prescription drug abuse. Testimony to the Senate Caucus on International Narcotics Control. May 14, 2014
Roberts LJ, Finch PM, Pullan PT, Bhagat CI, Price LM. Sex hormone suppression by intrathecal opioids: a prospective study. Clin J Pain. 2002;18(3):144-8.
Mendelson JH, Ellingboe J, Kuehnle JC, Mello NK. Heroin and naltrexone effects on pituitary-gonadal hormones in man: interaction of steroid feedback effects, tolerance and supersensitivity. J Pharmacol Exp Ther. 1980;214:503-506.
Daniell HW, DHEAS deficiency during consumption of sustained-action prescribed opioids: evidence for opioid-induced inhibition of adrenal androgen production.
Yin D, Mufson RA, Wang R, Shi Y. Fas-mediated cell death promoted by opioids. Nature. 1999;397:218.
Mahmoudi F, Khazali H, Janahmadi M. Interactions of morphine and Peptide 234 on mean plasma testosterone concentration. Int J Endocrinol Metab. 2014;12(1):e12554.
Daniell H. Opioid osteoporosis. Arch Intern Med. 2004;164(3):338.
Rubinstein AL, Carpenter DM, Minkoff JR. Hypogonadism in men with chronic pain linked to the use of long-acting rather than short-acting opioids. Clin J Pain. 2013;29(10):840-5.
Rubinstein A, Carpenter DM. Elucidating risk factors for androgen deficiency associated with daily opioid use. Am J Med. 2014;127(12):1195-201.
Bliesener N, Albrecht S, Schwager A, Weckbecker K, Lichtermann D, Klingmüller D. Plasma testosterone and sexual function in men receiving buprenorphine maintenance for opioid dependence. J Clin Endocrinol Metab. 2005;90(1):203-6.
Eichenbaum G, Göhler K, Etropolski M, et al. Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency. J Opioid Manag. 2015;11(3):211-27.