Sexual Dysfunction in Patients with Alcohol and Opioid Dependence

Abstract

There are limited numbers of studies which have evaluated the sexual dysfunction (SD) in patients with alcohol and opioids dependence. This article reviews the existing literature. Electronic searches were carried out using the PubMed, Google Scholar, and ScienceDirect to locate the relevant literature. Subjects addicted to heroin or on methadone maintenance treatment (MMT) or buprenorphine maintenance treatment (BMT) show higher rates of SD in comparison to the general population. SD rates have ranged 34-85% for heroin addicts, 14-81% for MMT, 36-83% for BMT, and 90% for naltrexone maintenance. The rates of SD in alcohol-dependent population have ranged 40-95.2%, with rates being consistently much higher in alcohol-dependent population than in the healthy controls or social drinkers. The common SDs reported have been erectile dysfunction followed by premature ejaculation, retarded ejaculation and decreased sexual desire among men, and dyspareunia and vaginal dryness among women. This review suggests that long-term use of alcohol and opioids are associated with SD in almost all domains of sexual functioning. There is a need to increase the awareness of clinicians about this association as many times SD in patients with substance abuse lead to poor treatment compliance and relapse. Further, there is a need to carry out more number of studies to understand the relationship in a better way.

INTRODUCTION

Sexual dysfunction (SD) is quite common in the community population. Large epidemiological community survey from the United States report >40% of women and 30% of men as suffering from some form of SD, with low sexual desire in women (22%) and premature ejaculation in men (21%) being the most common.[1] These figures are not very different from those of 34% women and 15% men from eight European countries reporting low sexual desire.[2]

Substance abuse is widely prevalent in the community. World Health Report in 2002 reported that 8.9% of the total burden of disease worldwide in 2000 came from the use of psychoactive substances.[3]

People may use alcohol and other substances to tackle sexual performance anxiety, enhance sexual performance, or overcome SD. A World Health Organization cross-cultural study for alcohol and high-risk sexual behavior across eight countries reported that 12% males in the general population consumed alcohol prior to first sexual intercourse due to perceived positive effect of alcohol to improve sexual pleasure.[4] Furthermore, alcohol was commonly used prior to intercourse with commercial sex worker.[4] However, in the long run, substance abuse impacts on sexual functioning negatively and may lead to the onset of sexual disorders.[5] Opioids have also been used as aphrodisiac and to delay ejaculation.[6] However, there is evidence that in the long run, substance abuse including for tobacco smoking impacts on sexual functioning negatively and may lead to the onset of SD or disorders,[5,7] Recovering substance abusers may face continuation or recurrence of SD, while the therapists may be perplexed about addressing the addiction and sexual problems of their clients.[8]

However, very few studies have systematically evaluated the relationship of SD and substances such as alcohol and opioids. This review aims to summarize the available literature on the effect of alcohol and opioids on the reproductive system and the prevalence of SD in males/dependent on alcohol and opioids.

For this review, an Internet search was carried out using the search engines of PubMed, Google Scholar, and ScienceDirect to locate the relevant literature. The keywords used in various combinations were: Alcohol, opioids, sexual function/dysfunction, alcohol dependence, opioid dependence, methadone, buprenorphine, heroin, erectile dysfunction (ED), premature ejaculation, libido, and reproductive hormones etc. Abstract of all the articles was screened, and the relevant articles were selected with a specific focus being effect of alcohol/opioid on the sexual hormones and prevalence of SD in patients with alcohol/opioid dependence. Full text articles were evaluated, and the relevant data were extracted. Cross references from these full-text articles also provided few more relevant articles.

PHYSIOLOGICAL SEXUAL FUNCTIONING: HOW IS IT INFLUENCED BY OPIOIDS AND ALCOHOL?

Endogenous opioids play an important role in the physiological sexual functioning. They act at specific opioid receptors, and contribute to control the release of gonadotropin-releasing hormone and thus, the sex hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Both FSH and LH are secreted by the anterior pituitary and act directly on the testes to stimulate the somatic cells that contribute to spermatogenesis. While FSH stimulates the proliferation of Sertoli cells during puberty, the LH regulates the synthesis of testosterone in the adult testes.[9] Morphine administration suppresses LH release and reduces the levels of testosterone and estradiol, which effects testicular function.[10,11] This is corroborated by an array of evidence. Opioid abuse is linked to the development of hypogonadism, decreased libido, ED, and infertility.[12,13,14] Opioid antagonists like naltrexone can improve symptoms of hypogonadism and erectile function without increasing testosterone or LH levels, suggesting regulation at the central rather than the peripheral level.[15] Opioids also exert a negative influence on adrenal androgen production. The adrenal hormones dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione are weakly androgenic, and they are precursors of testosterone. Serum DHEAS levels are used to determine adrenal function in general and adrenal androgen production in particular. Daily use of opioids decreases adrenal androgen production as measured by DHEAS levels.[16]

Studies on endocrine and other biological effects of alcohol report that long-term use of alcohol leads to inhibition of hypothalamic-pituitary-adrenal axis and reduces the release of gonadotropins from the pituitary. Chronic alcohol abuse has been recorded to cause testicular atrophy, inhibition of testosterone production, and inhibition of spermatogenesis, apart from its direct oxidative toxicity.[17,18]

Animal studies have shown that acute and chronic alcohol exposure affects sex hormones in terms of profound testosterone suppression accompanied by lower or normal LH and FSH levels, when actually elevated levels of these are expected.[19,20] Human studies have shown lower levels of hypothalamic LH-releasing hormone and pituitary LH in adults[21,22] and inhibition of testosterone secretion by the testes[23] by alcohol.

Testicular opioids are messenger molecules similar to morphine within the testes, which suppress testosterone synthesis. An opioid, beta-endorphin has been shown to increase with acute and chronic alcohol consumption and may be a link between alcohol use and testicular damage.[24] Increased level of testicular opioids has been implicated to increase the rate of apoptosis.[25,26] Apoptosis at gonadal level may result in the death of both Leydig and seminiferous cells, which are involved in sperm cell formation and maturation; thus, leading to low testosterone levels and diminished sperm production. Another mechanism postulated for alcohol's harmful effect on testosterone production is the reduced level of nitric oxide (NO) that acts as a local vasodilator.[27] Oxidation of alcohol, part of alcohol metabolism, generates oxidants that can contribute to cell damage and play a role in alcohol-induced tissue damage in the testes. An imbalance between oxidants and antioxidants can create oxidative stress. Alcohol consumption may induce oxidative damage either by enhancing the production of toxic free radicals or by decreasing the levels of antioxidants. Certain oxidants produced by alcohol metabolism are known as reactive oxygen species (ROS). These include anion superoxide, hydrogen peroxide, hydroxyl radicals, and nitrogen reactive species like NO. The metabolism of alcohol and acetaldehyde, which is the principle product of alcohol metabolism, produces highly toxic ROSs. Increased oxidative stress is a well-accepted mechanism of alcohol-induced tissue injury, particularly in the liver,[28,29] heart, and central nervous system, and this also occurs in the testes.[30] There is some suggestion that acetaldehyde is more toxic than alcohol to the production of testosterone, altering the process of testosterone production by inhibiting protein kinase C, a key enzyme in testosterone synthesis.[31] There is research to show that men with chronic alcoholism and hypogonadism actually eliminate alcohol more rapidly, building up less acetaldehyde. Because the build-up of acetaldehyde in the body is nauseating, enhanced clearance of these by-products could lead to reduced gastrointestinal side-effects from drinking (e.g., abdominal discomfort and vomiting) in men with low testosterone levels. This may increase the risk of developing a drinking problem, because a person who does not experience the negative gastrointestinal side-effects of drinking will be more likely to continue to drink, often in larger amounts.[32] Lipid rich testicular membranes being prone to oxidative injury it is reasonable to consider that lipid peroxidation (i.e., damage to the cell membranes) may contribute to the gonadal dysfunction that occurs as a result of chronic alcohol use. Other explanations for alcohol-related gonadal suppression invoke the metabolic cascade of alcohol to toxins lok acetoacetate to salsolinol and others.[33] In alcohol fed animals and chronic alcoholics, when testosterone levels decrease the expected increase in LH levels is not seen. This inability of the pituitary gland to respond appropriately to testosterone decline implies that alcohol has a central effect on the interaction between the nervous system and the endocrine system.[19,20] Studies in alcohol-fed rats have established that the decrease in LH levels results from impairment in both LH production and LH secretion[22] and alcohol's deleterious effects on LH function appear to be both qualitative as well as quantitative. Secretion of FSH also appears to be reduced by alcohol; though, alcohol does not appear to affect FSH synthesis.

SEXUAL DYSFUNCTION ASSOCIATED WITH OPIOIDS AND ALCOHOL

Prevalence of sexual dysfunction in patients with opioid dependence

We identified 24 studies [Table 1] that specifically evaluated prevalence of SD in opioid-dependent patients taking illicit opioids like heroin or opioid substitution therapy like methadone maintenance treatment (MMT) or buprenorphine maintenance treatment (BMT); a few studies included those receiving opioid antagonist naltrexone.

Table 1.

Studies evaluating SD in males receiving/taking opioids

Heroin addiction or MMT or BMT subjects show higher rates of SD in comparison to the general population.[38,41,42,49,52,53] SD rates have ranged 34-85% for heroin addicts,[41,45,46,52] 14-81% for MMT,[35,39,45,51,52,55,56] 36-83% for BMT,[42,43,45,56] and 90% for naltrexone maintenance.[45,56]

Most of the quoted studies did not evaluate SD comprehensively; some focused only on premature ejaculation[34,47] or ED,[41,49,52,55] some evaluated only the frequency of sexual intercourse and masturbatory activity,[38,53] and some did not use a standardized instrument for assessment of SD.[34,35,38,53] Studies that assessed more than one functioning domain suggest the most common dysfunction to be any of the following: ED,[45,49,50,52,55] premature ejaculation,[47,56] orgasmic dysfunction,[51,52,54] and low libido.[38,49,53] However, dysfunction across all the domains has been reported more often.[37,39,52,53,54,56]

Prevalence of sexual dysfunction in patients with alcohol dependence

In clinical population, the relationship between alcohol and SD has been studied from the following point of view: Prevalence and correlates of SD in patients seeking treatment for alcohol problems, prevalence of alcohol use/abuse/dependence in patients seeking treatment for SD, and effect of alcohol on various mechanisms involved in proper sexual functioning.

In one of the first observations, Lemere and Smith[59] reported the prevalence of SD in alcohol-dependent population to be 8%, the dysfunction persisting in 50% patients even into long-term abstinence from alcohol. They postulated the persistent SD to the neurogenic damage caused by alcohol. The research since then is summarized in Table 2. With sample sizes of 18-816 covering men, women, or both, the rates of SD have ranged 40-95.2%, with rates being consistently much higher in alcohol-dependent population than in the healthy controls or social drinkers. The common SDs reported have been ED followed by premature ejaculation, retarded ejaculation and decreased sexual desire among men, and dyspareunia and vaginal dryness among women. Association between long-term and high amount of alcohol consumption and SD has been widely reported[60,61] and men with SD are frequently noted to be chronic alcohol dependent.[78] A review of clinical and experimental studies concluded that in male alcoholics, the greater quantity, frequency, and duration of drinking are associated with ED, inhibited libido, and retarded ejaculation.[79] A major limitation of these data has been the lack of standard instruments to assess SD; only four recent studies using International Index of Erectile Function (IIEF), of which two used full form of IIEF to assess SD.

Table 2.

Prevalence of SD in patients with alcohol dependence

One consistent correlate that emerges in these studies is advancing age; other correlates include age of onset for alcohol use, duration of chronic alcoholism, presence of liver disease, cigarette use, education level, and unemployment.

However, some of the recent studies refute the link between SD and alcohol. One study which evaluated the effect of alcohol abuse, panic disorder, and depression on ED did not report any increase in the risk of ED with alcohol abuse.[80] Another study with HIV-positive men reported IIEF assessed ED to be related to nonalcohol drinking status.[81] A more recent population-based cross-sectional postal survey of men's health which assessed the association between usual alcohol consumption and IIEF assessed ED reported that compared to never-drinkers, the age-adjusted odds of having ED were lower among current, weekend, and binge drinkers and higher among ex-drinkers. Among current drinkers, the odds were the lowest for consumption of 1-20 standard drinks a week. After adjustment for cardiovascular disease or cigarette smoking, age-adjusted odds of ED were reduced by 25-30%.[82] A meta-analysis of population-based cross-sectional studies to assess association of alcohol consumption and ED yielded a protective association of alcohol on ED.[83] Studies on patients presenting with SD have reported a variable percentage of alcohol use. Fagan et al.[84] reported 29% of 145 consecutive patients with sexual problems to score on the probable alcoholism range on the Michigan Alcohol Screening Test, of which only six were diagnosed with alcoholism. Masters and Johnson[85] reported that in 35 out of 213 men with secondary impotence, the ED occurred as a direct result of acute alcohol intake; they did not detail out the chronicity of alcohol intake. One study from China reported alcohol as one of the important risk factors for low sexual function among urban women; the odds ratio of 2.67 was more than that for age, depression, low education level, chronic medical disease, and living apart from the partner.[86] Snyder and Karacan[87] measured nocturnal penile tumescence in 26 alcoholic men going through detoxification and found that their nocturnal erections were fewer, slower, and less rigid than in a nonalcoholic comparison group; they speculated peripheral neuropathology as the explanatory factor. Another double-blind study[88] reported significantly decreased frequency and duration of full erections in abstinent alcoholics on disulfiram. This finding is of particular importance due to the possible confounding effect of disulfiram on the reported frequency of sexual disorders.

Correlates of sexual dysfunction

Other studies have correlated ED with older age[4,9,13] and lower total testosterone.[4,20] Studies which have tried to establish a correlation between altered hormonal levels (testosterone, prolactin, and LH) and SD have in general come up with negative findings.[6,9,18,20] Some studies suggest that there is no correlation between methadone dose and SD[10,21,22] whereas others suggest that ED is higher in those taking higher doses of methadone.[5,18,23] Studies have also reported that higher methadone dose correlates negatively with ejaculation frequency[22] and positively with orgasmic dysfunction in men on MMT.[11] Other studies suggest that the rates of SD are affected by co-morbid depression[15] and number of psychological symptoms[23] whereas some studies suggest no correlation between SD and depression.[12,13,18]

A study in patients on MMT reported that those with altered sexual function while on street heroin represented a high-risk group for developing inadequate sexual function upon initiation of MMT.[35] Other studies have correlated ED with older age[42,46,55] and lower total testosterone.[42,48] Some others failed to establish a correlation between altered hormonal levels (testosterone, prolactin, LH) and SD.[46,48,50,52] While some studies suggest no correlation between methadone dose and SD[35,37,89] others suggest that ED is higher in those taking higher doses of methadone.[36,49,50] In contrast, some studies have also reported that higher methadone dose correlates negatively with ejaculation frequency[89] and positively with orgasmic dysfunction in men on MMT.[39] Other studies suggest that the rates of SD are affected by co-morbid depression[43] and number of psychological symptoms[36] whereas some studies suggest no correlation between SD and depression in patients with opioid dependence.[50,51,55]

A longitudinal study evaluated the effect of short-term and long-term abstinence from alcohol, opioids, speedball, cocaine, and cocaine plus alcohol on SD; the authors recorded the SD to persist after 3 weeks as also 1-year despite continued abstinence from substance abuse.[54]

DISCUSSION

In substance dependence, SD is of high clinical relevance as it often leads to treatment nonadherence and sexual or marital disharmony. Yet, it is often neglected and unexplored in routine clinical care. This is also reflected by the limited research in this area. This review suggests that long-term use of alcohol and opioids are associated with SD in almost all domains of sexual functioning. Studies in patients with either heroin addiction or on MMT or BMT have demonstrated higher rates of SD than in the general population, the rates ranging 34-85% for heroin addicts, 14-81% for MMT, 36-83% for BMT, and 90% for naltrexone maintenance. In contrast, in case of alcohol dependence, the SD rates have varied from 51% to 58% for low sexual desire, 16-59% for erectile impotence, 4-15.9% for premature ejaculation, and 17.8-25.4% for retarded ejaculation. There is evidence to suggest that endogenous opioids play a role in alcohol-related SD too.

However, the available studies suffer from many limitations. Some assessed SD by either spontaneous self-reporting (which might give lower rates) or by open questions (which may be interpreted differently by different patients). Some used inconsistent and nonvalidated measures of SD. Others took mixed groups of subjects (i.e., single and married subjects) or did not evaluate for contextual factors which could contribute to SD. Still others lacked consecutive or random samples and matched controls, or did not evaluate the impact of other opioids like dextropropoxyphene, codeine, etc. Furthermore, some studies did not try to distinguish the SD due to harmful effects of alcohol/opioid per se and SD due to other co-morbidities like use of other substances, effects of co-administered medications, the presence of a primary sexual disorder, presence of a medical condition affecting sexual function, psychosocial factors such as relationship conflict, presence of co-morbid psychiatric disorder, hepatocellular dysfunction, etc. Many co-morbid disorders are known to influence the prevalence of SD. Among the major predictors of ED observed in the Massachusetts Male Aging Study, diabetes mellitus, heart disease, hypertension, and decreased high-density lipoprotein levels were all associated with increased risk for ED. Medications for diabetes, hypertension, and cardiovascular disease also increase the risk of ED.[90] A prospective study[91] showed obesity and smoking to be additional risk factors for ED. In addition, there is a higher prevalence of ED among men who have undergone radiation or surgery for prostate cancer, or who have a lower spinal cord injury. Delayed or absent ejaculation may be associated with a variety of medical or surgical conditions (e.g., multiple sclerosis, spinal cord injury, surgical prostatectomy), or the use of anti-adrenergic or neuroleptic medications. A recent study that assessed the bio-psychosocial determinants of sexual desire in men concluded that cognitive factors (sexual beliefs and automatic thoughts during sexual activity) were the best predictors of sexual desire in men.[92] Various beliefs related to restrictive attitudes toward sexuality, erection concerns, and lack of erotic thoughts in a sexual context had a significant direct effect on reduced sexual desire. This set of cognitive-emotional factors also mediated the relationship between medical problems, age, and sexual desire. Another similar study[93] also highlighted the impact of early maladaptive schemas, helpless, and incompetence schemas impacting sexual function in men. A major limitation of existing research is that most of the studies have focused only on men, and the data for women are very limited.

Sexual side effects are not spontaneously reported by patients due to associated feelings of inadequacy; hence, direct inquiry is required. A careful enquiry can establish the patient's baseline levels of desire, arousal, and orgasmic function and determine whether a plausible chronological relationship exists between the onset of substance dependence and the beginning of SD. The most valuable asset is the patient's own history and description. SD is most obviously a side effect when it is reported as a new symptom after onset of substance dependence. In such a situation, clinicians should take measures to keep the patient abstinent and evaluate the SD longitudinally and treat it with appropriate measures.

There is thus, a need to study the multiple dimensions of association of substance abuse and SD. Future research should attempt to overcome the limitations of the existing literature. There is a need for studies with larger sample size using standardized instruments. These studies should attempt to evaluate the SDs in various phases of drug dependence, especially during the stable abstinence phase. Although studies have evaluated efficacy of various pharmacological agents in patients with SD, there is a need to evaluate these agents in patients with drug dependence using double-blind randomized control trials.