Introduction

Opioids remain the current cornerstone for the treatment of pain. An estimated 25 million adult Americans suffer daily from pain, and another 23 million suffer from severe recurrent pain, resulting in disability, loss of work productivity, loss of quality of life, and reduced overall health status [1]. The World Health Organization estimates that chronic pain is present in 22% of primary care patients [2]. Furthermore, up to 42% of emergency room visits are related to pain [3]. Opioids can be classified into three classes—opium alkaloids, semi-synthetic, and fully synthetic. Opium alkaloids are compounds naturally occurring in plants and include morphine, codeine, and thebaine. The semi-synthetic opioids are compounds that are created from naturally occurring opiates including hydromorphone, hydrocodone, oxycodone, buprenorphine, and heroin. Fully synthetic opioids include methadone, fentanyl, and tramadol, among others [4].

The poppy plant was first cultivated in 3400 BC by the Sumerians of Mesopotamia. They were used recreationally and for various medical ailments. In the early 1500s, laudanum or a tincture of opium was thought to be created and promoted by Philippus von Hohenheim, a Swiss physician who is often called the “father” of toxicology. Morphine was first isolated from opium in 1804 by German pharmacist Friedrich Serturner and was widely used as a painkiller during the Civil War, causing addiction among soldiers. The discovery of codeine followed in 1830 to replace raw opium for medical purposes. In an attempt to find a less addictive alternative to morphine, heroin was synthesized by chemist Charles R.A. Wright in 1874 and was initially used as an analgesic and cough suppressant. Subsequent searches for less addictive analgesics led to the discovery of methadone in 1939 [5,6,7,8].

Although opioids are primarily used for pain control, they are also highly addictive. Chronic use of opioids increases the risk for addiction, and treatment of addiction is often with other synthetic opioids, predominantly methadone and more recently buprenorphine. The use of legal and illegal opioids has risen 10–14 times in the last two decades [9]. Since 2000, there has been a 200% increase in opioid-related (pain relievers and heroin) overdose deaths in the USA [10]. According to the Centers for Disease Control, the age-adjusted rates of death from 2013 to 2014 involving natural and semi-synthetic opioid pain relievers, heroin, and synthetic opioids have increased by 9, 26, and 80%, respectively. Given the increase in opioid use and detrimental sequelae of improper usage, it is important to be cognizant of the various health effects of the opioid epidemic.

One of the most common side effects of opioid use is sexual dysfunction (SD). Male SD is known to negatively impact quality of life [11,12,13,14]. SD can be further categorized into erectile dysfunction (ED), hypogonadism, ejaculatory dysfunction, and orgasmic dysfunction. There are many cross-sectional studies demonstrating a high prevalence of SD in men on opioid therapy, and this phenomenon has been corroborated around the world using a variety of scales for quantifying SD [15•, 16•, 17,18,19,20,21, 22•, 23, 24]. However, only a few studies have examined the statistical correlation or causal relationship between opioid use and SD, and currently, there is no guideline for screening, monitoring, or treating opioid-related SD and infertility in men on opioid therapy or with opioid dependence. Additionally, there is limited information on the effects of opioids on orgasmic dysfunction and, therefore, this subcategory of SD was omitted from our review. The goal of this review is to examine the relationship between opioids and SD and infertility in men.

Opioids and Erectile Dysfunction

ED is the inability to achieve or maintain an erection suitable for satisfactory sexual intercourse. The reported prevalence for ED for all ages in the general population is 18–52%. When looking at men on opioid therapy, ED occurs in 21–67% of men 28–49 years old [12, 17, 23, 25,26,27,28].

There are several studies examining the relationship between opioids and ED (Table 1). A recent meta-analysis including ten studies consisting of 8829 men on opioid therapy demonstrated that the use of opioids was positively associated with an increased risk of ED (RR 1.96, P < 0.001) [16•]. Furthermore, a cross-sectional electronic medical record study on men with chronic back pain demonstrated that long-term opioid use is associated with greater use of medications for ED or testosterone replacement (TRT), compared to patients with no opioid use (OR 1.45, P < 0.01) [24].

Table 1 Studies examining the relationship between opioid therapy and erectile dysfunction
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Two common opioid therapies for chronic pain or opioid dependence include methadone and buprenorphine. The first methadone maintenance therapy program was started in the 1960s with buprenorphine approved for treatment of opioid dependence only in 2002 [37]. Some studies have reported a higher prevalence of ED associated with methadone maintenance therapy (MMT) use as compared to the general opioid-naive population [12, 33, 38] Although the studies for buprenorphine maintenance therapy (BMT) alone are sparse, several studies comparing MMT and BMT have demonstrated that men receiving BMT have a lower prevalence of ED compared to those on MMT [17, 23, 39, 40]. A study in China examining men with heroin addiction showed improvements in erectile function after switching to MMT [34]. In contrast, a recent meta-analysis in Iran showed no change in the prevalence of ED after starting MMT in opioid-addicted men [36]. Major predictive risk factors for ED in opioid users include dosage, older age, concurrent depression, and lack of a sexual partner [12, 23, 30, 31, 33, 41].

The underlying pathophysiology for opioid-induced ED remains unknown. One popular theory is the inhibition of gonadotropin-releasing hormone (GnRH) secretion by opioids. While serum testosterone levels are low in opioid users (meta-analysis of 17 studies with mean difference = − 164.78 ng/mL, (P < 0.0001)), there is no significant correlation between testosterone level and ED in opioid users [22•, 23, 28, 30, 42, 43]. While numerous studies have shown an association between ED and testosterone levels in the general population, it is worth noting that others have not [44,45,46,47].

Opioids and Hypogonadism

Male hypogonadism is a clinical syndrome that results from failure of the testes to produce physiological levels of testosterone (androgen deficiency) due to disruption of one or more levels of the hypothalamic-pituitary-gonadal axis [29]. Signs of androgen deficiency may include testicular atrophy, anemia, reduced facial hair growth, infertility, decreases in bone mineral density, and changes in body muscle and fat composition. Hypogonadism has also been associated with the metabolic syndrome [32, 35]. The association between opioids and low testosterone level is well established [22•, 30, 42, 48,49,50]. Hypogonadism associated with opioid use is referred to as opioid-associated androgen deficiency (OPIAD). The proposed mechanism for OPIAD is through direct inhibition of GnRH release by binding of the opioid to the Mu receptor, which leads to reduced production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) at the level of pituitary, and ultimately testicular testosterone (Fig. 1) [51]. Table 2 summarizes studies examining the relationship between opioid use and hypogonadism.

Fig. 1
figure 1

Opioid effect on the hypo-thalamo-pituitary axis

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Table 2 Studies examining the relationship between opioid therapy and hypogonadism
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A recent systematic review and meta-analysis of 17 studies demonstrated a significantly lower level of testosterone in male opioid users by 165 ng/dL (P < 0.0001), independent of the type of opioid and frequency of intake [22•]. Compared with short acting (SA) opioids, men on long acting (LA) opioids were more likely to be androgen deficient (57 vs 35%, P < 0.001). This outcome was dosage dependent, particularly for the SA opioids [50]. The same authors subsequently found that men on fentanyl, methadone, and oxycodone are more likely to be androgen deficient compared to men on hydrocodone (OR 25.7, 7.33, and 3.15, respectively) [49]. A possible explanation of these findings is the “nadir hypothesis.” Because testosterone in men is produced in a pulsatile fashion periodically throughout every 24-h cycle, the nadirs in drug level that occur more frequently between doses of SA opioids may allow some testosterone to be produced during these nadirs, which may be sufficient to maintain normal testosterone levels. In other words, the pharmacokinetics or formulation of the opioid also plays a role in the degree of hypogonadism in addition to the opioid’s direct physiological impact [49].

The relationship between low testosterone level and opioid therapy begs the question of whether men on chronic opioid therapy should be routinely screened for hypogonadism and whether treatment with TRT is beneficial when a diagnosis is made. A prospective study using data from the Testim Registry in the USA showed that hypogonadal men using TRT for 12 months experienced significant changes in total testosterone levels and improvement in sexual function and mood as measured by Brief Male Sexual Function Inventory (BMSFI) and Patient Health Questionaire-9 (PHQ-9) scores, respectively, in both opioid users and nonusers [57]. Similar improvements in sexual function, mood, and body composition were seen in one small open-label pilot study, a small randomized control trial, and a small prospective, pre-post analysis study where TRT was administered to men using opioid therapy for chronic pain [14, 56, 60]. Furthermore, a retrospective pilot study looking at 27 hypogonadal men with chronic non-cancer pain undergoing opioid therapy found that TRT leads to reduced pain levels and decreased opioid requirements [13].

The Endocrine Society recognizes the high prevalence of low testosterone in opioid users and recommends TRT for symptomatic men with classical androgen deficiency syndromes aimed at inducing and maintaining secondary sex characteristics and at improving their sexual function, sense of well-being, and bone mineral density [29].

Opioids and Ejaculatory Dysfunction

The International Society for Sexual Medicine (ISSM) defines premature ejaculation (PE) as “ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration from the first sexual experience (lifelong premature ejaculation), a clinically significant and bothersome reduction in latency time, often to about three minutes or less (acquired premature ejaculation) or the inability to delay ejaculation on all or nearly all vaginal penetration with negative personal consequences such as distress, bother, frustration and/or the avoidance of sexual intimacy” [55]. Several studies have reported high prevalence of ejaculatory dysfunction in men taking opioids. However, most of these studies did not focus solely on ejaculatory dysfunction alone [27, 39, 54]. One study with an emphasis on PE found that the prevalence is three times higher in opiate-dependent males than in the general population. Interestingly, the authors also stated that 63.2% of men with lifelong PE reported that heroin helped their PE, whereas 18.4% thought it worsened their PE. In another study looking at men with opioid addiction, 36.8% felt that MMT helped their PE while 26.3% felt that it worsened their PE [52]. There appears to be a positive correlation between chronic opioid therapy and PE. However, the prevalence or causal relationship has not been specifically studied.

Interestingly, tramadol, a synthetic opioid, is recommended as medical therapy for premature ejaculation due to its ability to delay ejaculation [61]. Pooled results from a systematic review and meta-analysis of randomized controlled trials of tramadol for PE suggest that tramadol is significantly more effective than placebo at increasing intra-vaginal ejaculatory latency time (IELT) over eight to 12 weeks compared to behavioral therapy or placebo (P = 0.0007) [62]. Another systematic review also supports the use of tramadol as an effective treatment for PE, although the maximum study length was only 18 weeks [53]. Two meta-analyses examining the role of tramadol in PE also concluded that tramadol is effective in improving PE [58, 59]. At this point, further studies are needed to characterize the relationship between the various opioids and PE and the potential benefit of tramadol in opioid-related PE.

Opioids and Male Infertility

Recent literature on opioid-related male infertility is limited. There is evidence suggesting that the human body produces endogenous opioid peptides (EOPs) and their receptors are widely distributed throughout the body including the central nervous system and testes. The effect of EOP and their receptors is to decrease testosterone through inhibition of GnRH release [63]. In a case control study of 142 men with opioid addiction, a significant correlation was demonstrated between opioid use and abnormal semen parameters including decreases in sperm count, concentration, motility, normal morphology, acrosome reaction test, seminal plasma antioxidant status, and DNA fragmentation index. This relationship was dependent on the dosage and duration of opioid use [64].

Conclusions

Opioids remain the cornerstone of treatment for both acute and chronic pain. Their frequent usage has, however, led to an opioid epidemic with increasing rates of drug-related deaths. Studies clearly demonstrate a higher prevalence of SD in opioid users, specifically ED, hypogonadism, and ejaculatory dysfunction. TRT in patients taking chronic opioids appears to improve SD and decrease the amount of opioids needed to control pain. These findings suggest that routine screening for SD in men on opioid therapy should be considered.