Managing Opioid-Induced Androgen Deficiency

Although the overall trend of illicit drug use has decreased in the United States, the abuse of prescription opioids has increased by 81% since the 1990s.¹ The opioid epidemic has become a national crisis, bringing with it a myriad of complications, including the rise of opioid-induced androgen deficiency (OPIAD). Although OPIAD can significantly impact men’s sexual function and quality of life, it is thought to often be overlooked and poorly understood by the medical community.

Understanding Androgen Deficiency

The increased opioid use has been associated with a rising incidence of opioid-induced endocrinopathy, most commonly in the form of androgen deficiency.¹ In a recent review of research on the topic, it was estimated that sexual dysfunction rates range from 34% to 85% in heroin addicts, from 14% to 81% in men on methadone maintenance treatment, and from 36% to 83% in individuals on buprenorphine maintenance treatment.²

Chronic opioid use inhibits the hypothalamic pituitary gonadal (HPG) axis, resulting in a secondary testosterone deficiency known as OPIAD.³ Activation of opioid receptors in the hypothalamus and the pituitary is associated with inhibition of the HPG axis, leading to hypogonadotropic hypogonadism.³ Persistently low levels of testosterone can affect the musculoskeletal, metabolic, and neuropsychiatric functions and reduce sexual function in men.^1,3

The true incidence of OPIAD is difficult to evaluate, as associated symptoms are often nonspecific, if present at all.¹ However, small-scale studies have estimated the prevalence of OPIAD at approximately 90% and 53% and at 53% in symptomatic and asymptomatic men on chronic opioid therapy, respectively.¹ The risk for androgen deficiency increases with opioid doses, usually when the morphine-equivalent dose exceeds 60 mg and to a greater extent when the dose exceeds 100 mg.³  In addition, the effect of opioids on the HPG axis differs with the type and preparation of the opioid.³ Among opioid users, men taking hydrocodone and hydromorphone were found to be the least affected by androgen deficiency, while men taking fentanyl, methadone, or oxycodone (long- and short-acting formulations) were found to have higher odds of being androgen-deficient, particularly those taking fentanyl.³

“Because of the scale of the opioid epidemic, the concomitant rise in OPIAD, and its effects on the quality of life of patients, the urologic and sexual health communities need to be aware of this condition and how to treat it,” explained Alan Hsieh, MD, a cardiologist in Morristown, New Jersey.¹

Diagnosing OPIAD

Hypogonadism, perhaps the least known and investigated effect of chronic opioid use, has been increasingly reported in both men and women on chronic opioid treatment.¹ Hypogonadism is traditionally categorized as primary, secondary, or tertiary. As OPIAD origninates at the hypothalamic level, it is classified as tertiary hypogonadism. Testosterone levels have been found to drop within hours of opioid administration, with effects last for weeks after opioid discontinuation, but eventually returning to baseline levels.³

According to researchers, there are no definitive guidelines for diagnosing OPIAD. During the history and physical examination, patients with hypogonadism may complain of increased fatigue, reduced sense of vitality, depression, weight gain, and decreased muscle mass.

However, these symptoms may be attributed to reasons for using opioid medications, such as underlying chronic pain or aging.¹ Sexual side effects are not often reported by patients due to feelings of inadequacy, so direct inquiry by the physician is recommended. Careful questioning can establish the patient’s baseline levels of desire, arousal, and orgasmic function, in an effort to determine whether the symptoms of sexual dysfunction began with the use of opioids.² Determining whether sexual dysfunction is a side effect of chronic opioid use may be easier for clinicians when it is reported as a new symptom after treatment initiation, noted investigators.² The more specific symptoms of low testosterone, which patients may be hesitant to discuss, include  erectile dysfunction, difficulty achieving an orgasm, lower intensity of orgasm, diminished ejaculatory volume

As many of the symptoms associated with OPIAD are nonspecific, it is essential to measure serum testosterone levels, particularly in the early morning hours, in order to diagnose the condition. The lower limit of total testosterone should range from 300 to 350 ng/dL, and studies indicate that approximately 50% of men on chronic opioid treatment have testosterone levels approximately 165 ng/dL compared with men not on the medication. When serum testosterone levels are found to be low, measurements should be repeated. Measuring the levels of other hormones (eg, hormone-binding globulin, luteinizing hormone, follicle-stimulating hormone, and prolactin) can help determine the level of the lesion on the HPG axis as well as help determine whether hypogonadism is the result of another etiology. Some studies suggest that the rates of sexual dysfunction can be affected by comorbid depression and other psychological symptoms, but are contradicted by other studies.²

Treating OPIAD

Modifying diet and lifestyle as well as reducing opioid doses or replacing opioids with nonsteroidal anti-inflammatory drugs or other non-narcotic painkillers are key for an effective treatment of OPIAD. However, because many patients require opioids to manage their pain, tapering or eliminating opioids may not be an option. As the incidence of OPIAD may be higher in individuals taking long- vs short-acting opioids, alternating these types of opioids or avoiding long-acting opioids may be preferable.

In patients who are persistently symptomatic and hypogonadal, androgen replacement therapy should be considered. Testosterone replacement therapy with transdermal gels, patches, or injections can provide varying degrees of symptom relief in men with hypogonadism. A study in which men who were taking opioids for chronic noncancer pain had hypogonadism indicated that treatment with 5 g transdermal testosterone gel was associated with improved sexual desire.¹ Other studies in which men with OPIAD were treated with testosterone replacement therapy, found associated increases in testosterone levels and improvements in sexual function.  Adverse events associated with testosterone replacement therapy include polycythemia, sleep apnea, reductions in high-density lipoprotein, azoospermia, gynecomastia, priapism, worsening of benign prostatic hyperplasia, and an increased risk for cardiovascular events. Men should be screened for osteoporosis (ie, measurements of bone mineral density and vitamin D levels) before initiating testosterone replacement therapy.³

“Fundamental management of OPIAD should be lifestyle therapies and tapering of opioids, with the goal of weaning off completely. There should be a low threshold for checking testosterone levels in opioid users, especially if they are receiving potent opioids and on high doses,” noted the investigators.³

References

1. Hsieh A, Digiorgio L, Fakunle M, Sadeghi-Nejad H. Management strategies in opioid abuse and sexual dysfunction: A review of opioid-induced androgen deficiency. Sex Med Rev. 2018;6(4):618-623.

2. Grover S, Mattoo SK, Pendharkar S, Kandappan V. Sexual dysfunction in patients with alcohol and opioid dependence. Indian J Psychol Med. 2014;36(4):355-65.

3. O’rourke TK, Wosnitzer MS. Opioid-induced androgen deficiency (OPIAD): prevalence, consequence, and efficacy of testosterone replacement. Curr Urol Rep. 2016;17(10):76.

This article originally appeared on Clinical Pain Advisor