Opioid-induced Sexual Dysfunction
Sexual dysfunction is a common problem among patients with chronic pain. Yet, many of these patients suffer in silence, healthcare providers rarely ask about patients’ sexual concerns, and guidance literature on the subject is relatively scarce. Ironically, in many of these cases the long-acting opioid medications prescribed to relieve patients’ pains may be causing or contributing to their sexual problems.
Since the 1990s, prescriptions written for opioid medications have significantly and steadily increased.1 Along with that, there have been increasing concerns about adverse consequences of opioid treatment, and opioid-induced endocrine deficiency leading to sexual dysfunction is one the most common yet most frequently undiagnosed problems with opioids.
Considerable evidence through the years has suggested that long-acting opioids used on a daily basis for more than a month can have a number of adverse effects on human endocrine function. The most common and clinically significant effects are androgen deficiencies and menstrual cycle abnormalities.2-11
These hypogonadal and androgen-inhibiting effects, which are a “class effect” of all opioids to some extent, can lead to sexual dysfunctions in both men and women. Therefore, potential endocrine deficiencies should be considered in all patients taking daily opioids equivalent to, or greater than, 100mg morphine. If present, opioid-induced sexual dysfunction can be treated, but approaches are quite different for men versus women.
This article examines the causes and diagnosis of endocrine dysfunction related to opioid therapy. Recommended clinical approaches for treatment of this disorder are discussed and, it is hoped that through a better understanding of these issues, opioid therapy can be more effectively used in the treatment of pain.
Disrupting HPG Processes
Opioid medications can exert a number of effects that alter the normal functioning of hormones found in hypothalamic-pituitary-gonadal (HPG) pathways which are depicted in the Figure 1. HPG processes controlling the production of sex hormones begin with secretion by the hypothalamus of gonadotropin-releasing hormone (GnRH). In turn, GnRH stimulates the pituitary gland to secrete the gonadotropins LH and FSH. These stimulate production in the testes and ovaries of gonadal hormones—testosterone, estrogens, and progesterone.
As gonadal hormone levels rise, they signal back to the hypothalamus to decrease production of GnRH which, in turn, decreases pituitary gonadotropin secretion. Thus a feedback control loop is formed.
Both endogenous (eg, endorphins) and exogenous opioids (eg, analgesics) exert an inhibitory effect on GnRH, thus decreasing LH.12 In women, blunting of the normal pulsatile release of LH interferes with the menstrual cycle, often causing irregular or absent menses that also may result in decreased ovarian testosterone secretion. In men, decreased LH causes the testes to produce less testosterone.3
Testosterone deficiency in both men and women results in adverse effects such as weight gain, fatigue, depression, and sexual dysfunction. This effect of opioids in reducing production of sex hormones from the gonads—testes in men, ovaries in women—is referred to as hypogonadism.
Adrenal Androgen Deficiency
Opioid Interference with Adrenal Androgen Production
Opioids also exert a negative influence on adrenal androgen production. In women, both the ovaries and adrenal glands play important roles in overall androgen production. The adrenal hormones dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione are weakly androgenic in and of themselves, and they are precursors of testosterone. Serum DHEAS levels are used to determine adrenal function in general and, more specifically, adrenal androgen production. Daily use of opioids decreases adrenal androgen production as measured by DHEAS levels.
Daniel (2006) assessed DHEAS levels in patients treated with sustained-action oxycodone, sustained-action morphine, continuous transdermal fentanyl, or methadone and found decreased DHEAS levels in over half of those studied. The exact mechanism by which opioids reduce DHEAS and, consequently, interfere with adrenal androgen production is not known; however, the resultant deficiency is of clinical importance in women.
Opioid-Induced Endocrine Deficiency in the Clinical Setting
It appears that all opioids cause endocrine deficiencies at least to some degree, which may influence sexual problems. A significant proportion of men treated with sustained action opioids, estimated at 5 million in the U.S. and Canada, are testosterone deficient.13,14
Deleterious opioid effects on endocrine function and sexual health were first noticed decades ago in sexual dysfunction associated with intravenous heroin use.15-17 Decreased libido is common among addicts in general, but erectile dysfunction in men and menstrual cycle disturbances in women are especially common in those with opioid dependence.
For example, studies have shown that about two-thirds of patients entering methadone maintenance treatment for opioid addiction complain of some form of sexual dysfunction and about one-third continue to have symptoms while receiving treatment. Researchers recognized that both heroin and methadone were associated with decreased serum testosterone levels in men.12-22 This results predominately in decreased libido and erectile dysfunction, and men may also commonly complain of fatigue, hot flashes, weight gain, or increased sweating. In addition to those effects, women in methadone maintenance treatment often have menstrual cycle abnormalities.
Despite the fact that hypogonadism has been a well-known adverse effect of methadone treatment for many years, it never became common practice to screen for this disorder; perhaps because methadone treatment takes place in single purpose clinics that do not routinely diagnose or treat conditions other than opioid dependence. Inadequate clinic staff education regarding the adverse endocrine effects of methadone treatment may be another factor. Therefore, thousands of individuals receiving methadone for addiction have not been treated for symptomatic endocrine deficiencies.
Of even greater importance, metha-done’s ability to disrupt normal endocrine function is a “class effect” shared with other opioids. With the dramatic increase in the use of sustained-release oxycodone, morphine, and oxymorphone for chronic noncancer pain, these drugs are the most common cause of opioid-induced endocrine deficiency.