Effect of Opioids on Sexual Function
Selective Serotonin-Reuptake Inhibitors

The following sections describe the effects of various commonly used medications on sexual function in people with cancer. People undergoing cancer treatment are often treated with multiple medications that can cause diminished desire or other difficulties in sexual functioning, which can add to the impact of surgery, radiation, and chemotherapy on sexuality. Medications may adversely affect one or more of the physiologic mechanisms (i.e., vascular, hormonal, neurologic) that underlie normal sexual function. Drug therapy may also affect sexual functioning indirectly through concomitant effects on mental alertness, mood state, and/or social interactions. The evaluation of sexual problems in people with cancer must, therefore, be comprehensive and attuned to the multiple etiologies of these difficulties. The following sections may be helpful in identifying some of the possible medication side effects, though more than one may play a role in an individual.

Reduced libido is a well-known phenomenon for those using heroin or participating in a methadone maintenance program. Unfortunately, this effect is poorly understood by clinicians prescribing opioids for pain. Animal studies confirm that opioids lower testosterone levels and suppress sexual function in males.[1] Early case studies of persons using heroin or methadone described diminished libido, sexual dysfunction, reduced testosterone levels in men, and amenorrhea in women.[2-7] Two mechanisms are thought to be responsible for the reported reduction in libido associated with opioid use. Opioids inhibit the production of gonadotropin-releasing hormone, subsequently decreasing the release of luteinizing hormone (LH), thus decreasing the production of testosterone. Opioids also produce hyperprolactinemia, which causes negative feedback on the release of LH and decreases the production of testosterone.[8] Opioids are known to alter the normal function of the hypothalamic-pituitary-gonadal axis.[9] These effects resolve after the opioid has been discontinued. Other case reports of patients receiving opioids for relief of chronic pain suggest these same findings.[10-12] Another case-control study examined the effects of chronic oral opioid administration in survivors of cancer and, consistent with the research on intrathecal administration, found marked central hypogonadism among the opioid users with significant symptoms of sexual dysfunction, depression, and fatigue.[12] Although the limited research that has examined the relationships among sexual functioning, chronic pain, opioid therapy, and testosterone levels has been predominantly evaluated in men, anecdotal clinical experience supports similar relationships in women. Empirical support has been documented for women in a study that examined the endocrine consequences of long-term intrathecal administration of opioids. Reduced libido was reported in 95% of the men and 68% of the women, with significant reduction in serum LH for both groups and in serum testosterone for the men. All of the premenopausal women (n = 21) developed either amenorrhea or an irregular menstrual cycle, with ovulation in only one woman.[13]

The long-term effects of reduced testosterone and amenorrhea are not well known. Sexuality is an important component of one’s quality of life, especially for cancer survivors, but also for some people with advanced disease. Patients may report a history of changes in libido and sexual dysfunction. If these changes are distressing to the patient, serum total- and free-testosterone levels and prolactin levels may be obtained.[14] Should the patient seek improvement in libido and performance, treatment is often empirical, keeping in mind that there are many potential causes of changes in sexual function. Treatment options may include using nonopioids for pain, adding adjuvant analgesics in the hope that the opioid dose may be reduced, or replacing testosterone through injections, a patch, or gel if not contraindicated.[15] More research is needed to understand the relationship between opioids and sexual function, as well as the most effective treatment strategies.

Decreased sexual desire is a frequent symptom of depression, and sexual impairment in depressed patients has been consistently confirmed in controlled studies.[16,17] Continued recognition of the difficulty in discerning the subjective complaints that are a part of the depressive syndrome, the consequences of treatment, a pre-existing sexual dysfunction, or a combination of these factors is needed. Approximately one third of depressed patients without medication treatment report reduced sexual desire, anorgasmia, delayed ejaculation, or erectile dysfunction.[18] Selective serotonin-reuptake inhibitors (SSRIs), tricyclics, monoamine oxidase inhibitors, and lithium have all been associated with sexual dysfunction.[19,20]

Sexual desire is mediated through the central nervous system by the reception of sensory stimuli and the subsequent interpretation through the limbic system and prefrontal cortex.[21] Additionally, the hypothalamic and preoptic nuclei contribute to the mediation of this process. Serotonin inhibits hypothalamic arousal postsynaptic receptors resulting in the release of excitatory neurotransmitters. These neurotransmitters are responsible for the activation of the erectile centers of the spinal column. Upon activation of the erectile centers, subsequent erection, orgasm, and detumescence occur in males, whereas genital vasocongestion, vaginal lubrication, and clitoral enlargement occur in females.[22] Physiologically, serotonin is stored in synaptosomal vesicles awaiting another impulse for release. SSRIs inhibit this uptake mechanism, which results in the pooling of serotonin in the synaptic space.[21,23] The excess serotonin causes the postsynaptic receptors to down-regulate, resulting in decreased stimulation of the lower erectile centers. It is this action that is thought to be the principal mechanism for SSRI-induced sexual dysfunction.

There are no well-controlled studies that evaluate the effects of SSRIs on sexual function within the oncology patient population. There are several studies, however, that have examined the effects of fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft) on sexual function in patients being treated for depression or obsessive-compulsive disorder. There are few data regarding the prevalence of sexual dysfunction with the use of citalopram (Celexa) in the treatment of depression. Sexual dysfunction from SSRIs has generally been reported to affect approximately 1% to 15% of patients in clinical trials of these medications in physically healthy depressed patients. Other studies, however, report significantly higher rates of sexual dysfunction that may more accurately reflect the incidence typical of clinical practice. A large-scale retrospective nonrandomized comparison trial of 596 psychiatric outpatients (167 men, 429 women) treated for at least 6 months with sertraline (n = 170), fluoxetine (n = 298), venlafaxine (n = 36), or paroxetine (n = 265) found that symptoms of sexual dysfunction were spontaneously reported by approximately 20% of patients overall and were more common in men (23.4%) and married individuals of both genders. The rates of sexual dysfunction associated with each of the SSRIs were the following: sertraline (16%), fluoxetine (20%), paroxetine (22%), and venlafaxine (38%). For this sample, the most common sexual symptoms reported were orgasmic delay or anorgasmia, followed by decreased desire and arousal difficulties.[24] A prospective multicenter study of 344 patients (152 men, 192 women) with mixed psychiatric disorders treated with SSRIs and systematic inquiry of sexual dysfunction by the physician found the frequency of sexual side effects was highest for paroxetine (65%), followed by fluvoxamine (59%), sertraline (56%), and fluoxetine (54%).[25] Paroxetine produced significantly greater delay of orgasm or ejaculation (48%) and more frequent erectile dysfunction and vaginal lubrication difficulties than sertraline (37% and 16%), fluvoxamine (31% and 10%), or fluoxetine (34% and 16%). Loss of libido and anorgasmia were more severe in women, though men reported a greater frequency of sexual dysfunction. The effects of SSRIs are dose related and may vary among the group. The incidence of sexual dysfunction obtained by patient self-report does not appear to reflect the true incidence of sexual dysfunction associated with antidepressant therapy, and systematic inquiry by providers is needed as sexual dysfunction may be an unrecognized cause of noncompliance.[26] Two critical reviews of the effects of SSRIs on sexual function are available.[26,27]

For individuals with premature ejaculation, SSRIs provide an effective treatment. In a recent double-blind placebo-controlled trial of men with lifelong rapid ejaculation, paroxetine delayed ejaculation the most, and fluvoxamine delayed ejaculation the least. Daily doses of 20 mg of paroxetine and 20 mg of fluoxetine may be regarded as effective treatments for lifelong rapid ejaculation.[28] Cancer patients treated with these medications in clinical situations may have higher rates of anorgasmia, decreased sexual desire, and other problems, possibly because these medications compound the difficulties cancer patients encounter from multiple etiologies. There are several possible interventions in the management of SSRI-induced sexual dysfunction. An obvious, though not always appropriate, possibility is to decrease the dosage of the SSRI. Altering the timing of SSRI administration, either by delaying doses until after intercourse or dosing immediately before intercourse,[29] may be an effective intervention. There are published data to suggest a drug-holiday intervention over the weekend can improve the sexual dysfunction induced by SSRIs.[30] Another possibility is the addition of another medication to help in the control of SSRI-induced sexual dysfunction or consideration of another antidepressant with less known sexual side effects. In a randomized, double-blind, multicenter trial comparison of sustained-release bupropion (bupropion SR) and sertraline, both were found to be similarly efficacious in the treatment of outpatients with moderate-to-severe depression. There was a significantly greater percentage of sertraline-induced sexual dysfunction (63% and 41% of men and women, respectively), however, compared with bupropion SR–induced sexual dysfunction (15% and 7%, respectively).[31]

A definitive treatment has not been established for SSRI-induced sexual dysfunction in males or females. The oncology patient population presents with significantly more obstacles in the management of sexual dysfunction, as compared with patients whose symptoms are being managed with SSRIs for depression alone. The etiology of sexual dysfunction in cancer patients is multifactorial and complex. The above data are intended to provide practitioners and patients with possible options in the management of SSRI-induced sexual dysfunction.

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