According to the Centers for Disease Control and Prevention (CDC), in 2019, 20.4% of adults in the United States (US) suffered from chronic pain, and 7.4% reported their chronic pain interfered with daily activities.1 Prescription opioids are frequently used to treat chronic pain. Although the total number of opioid prescriptions dispensed each year in the US has steadily decreased in the past decade, CDC data confirms that in 2019 Americans filled more than 153 million opioid prescriptions or 46.7 prescriptions per 100 individuals.2 Coupled with the exponential increase in opioid use disorder, opioid adverse effects have become well recognized. The most common effects discussed with patients upon prescribing are constipation, nausea, vomiting, dry mouth, and somnolence.³
A lesser-known adverse effect associated with long-term opioid use is opioid-induced endocrine dysfunction. Opioid-induced endocrinopathies occur primarily as a result of hypothalamic-pituitary suppression. Opioid-induced hypogonadism (OIH) and opioid-induced adrenal-insufficiency (OIAI) are the 2 primary subsets.4 Chronic use of opioids has been reported to suppress gonadal function by 21% to 86% in both genders.5 These conditions are often underdiagnosed in clinical practice due to patients under-reporting symptoms, limited clinician awareness, and the lack of clinical guidelines for diagnosis and treatment.4
Opioid-induced hypogonadism (OIH)
The hypothalamic-pituitary-gonadal (HPG) axis is a complex feedback loop system that controls primary sex hormone production.5 The hypothalamus produces gonadotropin-releasing hormone (GnRH), which in turn stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH) into the bloodstream. In males, LH stimulates the Leydig cells in the testes to produce testosterone and FSH promotes sperm cell production and growth. In females, LH and FSH act on the ovaries to produce estrogen and develop ovarian follicles. These sex hormones then exert negative feedback on the hypothalamus and pituitary to control GnRH, LH, and FSH secretion.
Opioids exert their effects primarily through μ, δ, and κ opioid receptors.5,6 Evidence suggests opioids modulate gonadal function by binding to μ receptors present in the hypothalamus, which decreases the release of GnRH. The reduction in GnRH causes a reduced release of LH and FSH from the pituitary, resulting in a fall in gonadotropin levels.
Persistently low testosterone levels in males can have the following effects:7
-musculoskeletal - decreased muscle bulk, low bone mineral density
-metabolic - increased body fat
-neuropsychiatric - decreased energy, depression
-reproductive - decreased libido, erectile dysfunction.
Persistently low estrogen levels in females can have the following effects:4
-musculoskeletal – osteoporosis
-neuropsychiatric - depression
-reproductive – decreased libido, irregular menstrual cycles, anovulation.
In a review of 13 studies evaluating the effect of opioid treatment on androgen levels in men with chronic non-cancer pain, Coluzzi et al found the prevalence of opioid-induced androgen deficiency ranged from 19% to 86%, depending on the testosterone level used to define hypogonadism.8 Most studies reported an overall prevalence of opioid-induced androgen deficiency greater than 50%, affirming the significant impact opioids have in reducing testosterone levels. A meta-analysis of 15 studies, conducted by Vries et al, examined the effects of opioid use on pituitary function in 3,250 subjects (99.5% male) with chronic opioid use.9 The number of patients with hypogonadism ranged between 36% to 100%, with a weighted mean percentage of 63% (95% confidence interval [CI]: 55% – 70%).
Studies evaluating the impact of chronic opioid treatment in women are less abundant, but support opioids' role in reducing gonadotropins in females. A systematic review including 165 women, 18 to 55 years of age, receiving opioids for chronic non-cancer pain revealed that 23% to 81% had oligomenorrhea or amenorrhea. Another study evaluating data from a large United Kingdom primary care database of women aged 18 to 55 years also demonstrated that opioid use for ≥90 days for chronic non-cancer pain was associated with a higher risk of oligomenorrhea and amenorrhea (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.05–1.21) and of menopause (HR 1.16, CI 1.10–1.23) compared with short-term opioid use of < 90 days.4
Few studies have examined the impact of opioid dose, duration of action (short-acting vs. long-acting), and type (synthetic vs. natural) on the severity of hypogonadism. However, limited data suggest that androgen deficiency is more likely with long-acting opioids and higher morphine milligram equivalent (MME) doses.4 In equivalent doses, long-acting opioids are significantly more likely than short-acting opioids to cause hypogonadism in men.8 Additionally, patients taking fentanyl, methadone, and oxycodone have been shown to have a higher risk of androgen deficiency.4,8
Opioid discontinuation reverses OIH in males and females. However, discontinuing opioid therapy is not always an option.4 The need for chronic pain management may only allow for reducing the opioid dose, switching to another opioid, or adding non-opioid options such as behavior therapies, nerve stimulation, or non-opioid drugs.10 The Endocrine Society Clinical Practice Guidelines on testosterone therapy in men with hypogonadism address opioid-induced testosterone deficiency in men. They recommend considering testosterone replacement therapy in men with OIH experiencing sexual symptoms who are unlikely to discontinue the opioid.7 Currently, there are no accepted standards for the management of OIH in women. Replacement therapy for women may consist of estrogens, progestin, or oral contraceptives.5
Opioid-induced adrenal-insufficiency (OIAI)
Long-term opioid use is also associated with hypothalamic–pituitary–adrenal (HPA) axis suppression. Opioids exert their effects through opioid receptors present in the hypothalamus and the pituitary gland. Corticotropin-releasing hormone (CRH) and antidiuretic hormone (ADH) secretion are inhibited, resulting in decreased adrenocorticotropic hormone (ACTH) and cortisol release.4 It is interesting to note that high doses of intravenous naloxone, an opioid receptor antagonist, increase cortisol levels and augment corticotropin's response to CRH stimulation, providing further evidence of the effects of opioids on the HPA axis.11</p>
<p>Individuals with adrenal insufficiency may present with nausea, vomiting, anorexia, weight loss, fatigue, hypotension, postural dizziness, and loss of consciousness.11 These nonspecific signs and symptoms may overlap with other coexisting conditions, making the diagnosis easy to miss on initial evaluation.
An OIAI prevalence of 8.3% to 33% has been reported in a review of 5 small studies in patients receiving long-term opioid therapy.11 Adrenal suppression and crisis occurred with various opioid dosage forms: oral, transdermal, and intrathecal. Some studies suggest that higher daily MME doses and long-acting opioids may increase the risk of developing OIAI. One study revealed that OIAI occurred in participants who took more than 60 MME and that the incidence increased with higher doses (50%, when taking >200 MME). These studies' limitations include small sample size and the limited assessment of other possible factors contributing to adrenal insufficiency.
Another cross-sectional study examined patients, admitted to the Pain Rehabilitation Center at Mayo Clinic from 2016 to 2018, who had periodic or regular opioid use for at least 90 days.12 Participants' morning cortisol, dehydroepiandrosterone sulfate (DHEAS), and ACTH levels were measured. Of the 102 patients enrolled, 11 patients (10.8%) had abnormal adrenal lab results and were referred for endocrine evaluation. Of these individuals, 9 patients (9%) were diagnosed with OIAI. Patients diagnosed with OIAI were taking a higher daily MME dose than those without adrenal insufficiency (median, 140 [20-392] mg vs. 57 [3-840]mg; P = 0.06). Cumulative opioid exposure was significantly higher in those with OIAI compared to those without (median cumulative opioid exposure, 13,440 mg*months [range 120-36,000] vs 3,120 mg*months [30-21,240]; P = 0.03).
Specific guidance regarding the management of OIAI is not currently available. Opioid discontinuation results in the resolution of OIAI.11 Therefore, treatment should include tapering with the goal of discontinuing the opioid, coupled with glucocorticoid replacement until HPA axis recovery. The 2016 Endocrine Society guidelines for diagnosing and treating primary adrenal insufficiency recommend replacing with physiologic doses of glucocorticoids; hydrocortisone is most commonly used. Doses ranging from 15 to 25 mg/day are given in divided doses 2 to 3 times a day, with the majority of the dose given in the morning.13 The guidelines also stress the importance of patient education about increasing the glucocorticoid dose during times of illness, fever, and stress, and developing an adrenal insufficiency action plan.11, 13
OIH and OIAI have multiple endocrine and metabolic effects, which may result in serious medical consequences. Healthcare providers' early recognition of the causal link between chronic opioid use and endocrinopathies can facilitate appropriate monitoring, early treatment, and improvement in patient outcomes. Large prospective studies are needed to help identify patients at most significant risk, along with the development of evidence-based guidelines for the diagnosis and optimal management of opioid-induced endocrinopathies.
- Zelaya CE, Dahlhamer JM, Lucas JW, Connor EM. Chronic pain and high-impact chronic pain among U.S. adults, 2019. National Center for Health Statistics; 2020. NCHS Data Brief390. Accessed February 3, 2021. https://www.cdc.gov/nchs/data/databriefs/db390-H.pdf
- Centers for Disease Control and Prevention. U.S. Opioid Dispensing Rate Maps. December 7, 2020. Accessed February 3, 2021. https://www.cdc.gov/drugoverdose/maps/rxrate-maps.html
- Wehbeh L, Dobs AS. Opioids and the hypothalamic-pituitary-gonadal (HPG) axis. J Clin Endocr Metab.2020;105(9). doi:10.1210/clinem/dgaa417
- Fountas A, Van Uum S, Karavitaki N. Opioid-induced endocrinopathies. Lancet Diabetes Endocrinol. 2020 Jan;8(1):68-80. doi: 10.1016/S2213-8587(19)30254-2
- Marudhai S, Patel M, Valaiyaduppu Subas S, et al. Long-term opioids linked to hypogonadism and the role of testosterone supplementation therapy. Cureus. 12(10): e10813. doi 10.7759/cureus.10813
- Baillargeon J, Raji MA, Urban RJ, et al. OpioidiInduced hypogonadism in the United States. Mayo Clin Proc Innov Qual Outcomes. 2019;3(3):276-284. doi:10.1016/j.mayocpiqo.2019.06.007
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. doi:10.1210/jc.2018-00229
- Coluzzi F, Billeci D, Maggi M, Corona G. Testosterone deficiency in non-cancer opioid-treated patients. J Endocrinol Invest. 2018;41(12):1377-1388. doi:10.1007/s40618-018-0964-3
- Vries FD, Bruin M, Lobatto DJ, et al. Opioids and their endocrine effects: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2019;105(4):1020-1029. doi:10.1210/clinem/dgz022
- Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009;25(2):170-175. doi: 10.1097/AJP.0b013e3181850df6
- Donegan D. Opioid induced adrenal insufficiency. Curr Opin Endocrinol Diabetes Obes. 2019;26(3):133-138. doi:10.1097/med.0000000000000474
- Li T, Cunningham JL, Gilliam WP, Loukianova L, Donegan DM, Bancos I. Prevalence of opioid-induced adrenal insufficiency in patients taking chronic opioids. J Clin Endocrinol Metab. 2020;105(10): e3766-e3775. doi:10.1210/clinem/dgaa499
- Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. doi:10.1210/jc.2015-1710
Kathy Kasiurak, PharmD
Clinical Pharmacist, Academic Detailer
University of Illinois Chicago College of Pharmacy
The information presented is current as of June 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
Posted on Aug. 27, 2021
Last updated on Aug. 30, 2021