A comparison of sexual desire in opiate-dependent men receiving methadone and buprenorphine maintenance treatment

Sexual desire (SD) is commonly acknowledged as an individual’s complex motivational state and an interest in sexual objects or activities [1]. It consists of 3 components namely sexual drive, sexual motivation, and sexual wish [2]. Although sexual desire is considered a subjective feeling state which is often influenced by various sociocultural contexts, some experts had broadly defined this aspect of a person’s sexuality as “a psychological state subjectively experienced by the individual as an awareness that he or she wants or wishes to attain a (presumably pleasurable) sexual goal that is currently unattainable” [3], or “a psychobiological energy that precedes and accompanies arousal and tends to produce sexual behavior” [2]. In 2015, a consensus statement from the Fourth International Consultation on Sexual Medicine defined male hypoactive sexual desire disorder, based on DSM-5 [4], as “persistently or recurrently deficient (or absent) sexual or erotic thoughts or fantasies and desire for sexual activity” [5].

Since methadone maintenance treatment (MMT) is a well-recognized effective replacement therapy for opiate dependence [6], for many decades, clinicians have been using methadone with significant success in reducing cases of heroin use [7, 8], criminal activity [9‐11], unemployment [10, 12], mortality [13‐16] and the transmission of infectious diseases [11, 17, 18]. However, one of the major side effects caused by methadone among male opiate-dependent patients on replacement therapy is sexual dysfunction, such as reduced sexual desire and erectile failure, as it is believed that methadone exerts stronger inhibition effect on sexual desire than heroin [19]. Management for methadone-induced sexual dysfunction remains a challenge for the physicians. Some of the ex opioid-dependent patients relapsed after stopping or reducing their methadone dose. Furthermore, some of them used other illicit drugs to increase their sexual desire [20]. Hence, the physicians need other strategies to manage sexual dysfunction in this group of patients.

Buprenorphine maintenance therapy (BMT), an alternative to MMT, has also been used to treat opioid dependence due to its effectiveness in reducing opioid use. Unlike methadone, buprenorphine is a partial agonist at the µ and κ opioid receptors, and an antagonist at the δ receptors. In a meta-analysis published in 2014 comparing male patients on methadone and buprenorphine, it was shown to have a statistically significant evidence that those males on buprenorphine treatment arm had lower sexual dysfunction compared to the ones on methadone [21].

Previous studies reported that psychiatric disorder, namely depression, is highly prevalent among the MMT population with the prevalence rates range from 19 to 74.3% [22, 23]. Brown et al., [24] and Quaglio et al., [25] reported a statistically significant association between depression and erectile dysfunction among MMT men. However, there were some studies which found no significant associations between depression and erectile dysfunction [6, 26, 27]. Up to date, there are not many studies done to investigate sexual desire among men and even fewer studies to explore the relationship between sexual desire and depression among MMT or BMT patients. Taylor et al. reported that loss of sexual desire was one of the risk factors for relapse and recurrence in major depressive patients who initially responded to cognitive therapy in that 2-year cohort study [28]. Besides, a prospective, 4-week, non-treatment study was conducted on non-depressed men with and without low sexual desire, reported that men with low sexual desire disorder were distressed by their low sexual desire more frequently when compared to men with normal sexual desire [29]. Although previous studies had clearly shown that depression and sexual dysfunction were associated, the relationship between them remained unclear [24‐26, 30, 31].

Although low sexual desire is not a life-threatening condition, the prevalence of sexual dysfunction was reported to be in the range of between 21 and 52% [21, 25]. This has potential impacts on the quality of life (QoL) and the intimacy of a relationship [32, 33]. With sexual dysfunction presented in a wide spectrum of conditions, ranging from erectile dysfunction, premature ejaculation to abnormal orgasms, our main aim of this cross-sectional study is to focus on the comparison of sexual desire between opioid-dependent men receiving methadone and buprenorphine maintenance treatment (BMT).

In this study, 150 men who had been receiving MMT and 55 men who had been receiving BMT were approached. A total of 126 male patients who fulfilled the inclusion and exclusion criteria consented to take part in the study. Four MMT patients and two BMT patients refused to participate in the study. The MMT arm consisted of 75.4% (n = 95) of the patients (methadone dose = 74.53 mg ± 33.68 mg) while the remaining 24.6% (n = 31) made up the BMT group (buprenorphine/naloxone dose = 2.44 mg ± 1.81 mg). Demographic and clinical details of the study subjects are shown in Table 1. The significant differences between patients in both MMT and BMT groups were education level (p < 0.01); hepatitis C status (p < 0.01); OTI Q scores for tobacco (p < 0.01), social functioning and health (p < 0.01), and total MADRS-BM score (p < 0.01) (Table 1).

Comparison of differences was done by using multivariate analysis of covariance in the SDI-2-BM, Mal-IIEF-15 scores, total testosterone (TT) and prolactin between the MMT and BMT groups. This measure also took into account the control of confounders such as education level, hepatitis C status, total MADRS-BM score, Q scores for tobacco, social functioning health OTI domains with pairwise comparisons using Bonferroni multiple testing corrections. Our study revealed that patients on MMT scored statistically significantly lower in the sexual desire domain (Mal-IIEF-15 scores) (p < 0.01), DSD (p = 0.04) and TT plasma level (p < 0.01) when compared to the BMT group after controlling all the confounders (Table 2).

In our study, the total testosterone level for male patients in the MMT group appeared significantly lower (12.46 ± 7.64) when compared to that of the BMT group (18.45 ± 9.40) (p = 0.005). This could be explained by Smith and Elliot’s study in 2012, where they found human and animal data indicating that opioid acted at different sites in the hypothalamus–pituitary axis, leading to an endocrine dysfunction known as opioid associated androgen deficiency (OPIAD) [44]. All pituitary hormones were decreased, such as luteinizing hormone, follicle stimulating hormone, oxytocin, estradiol, and obviously the reduction of testosterone hormone resulted in hypogonadism. In the same year 2012, Heidari et al. also suggested that lower risk of OPIAD was observed in those who were treated with buprenorphine, compared to methadone due to the offset of hypothalamic–pituitary axis inhibition related to κ-opiate receptor antagonist activity [45], though it was a study conducted on animals. Buprenorphine had minimal influence on testosterone levels [27], as the antagonism of buprenorphine κ-opiate receptor might have possibly counteracted on the μ-opiate receptor-mediated depression of the gonadal axis. In contrast, the pharmacodynamic effects of methadone on sexual behavior are similar to those anti-androgenic effects [46] presenting with symptoms of testosterone deficiency such as fatigue, weakness, mood disturbances, and decrease in libido and sexual function [47].

Chronic exposure to tobacco by long-term smoking can lead to decrease in serum testosterone level, subsequently causing erectile dysfunction in males [48]. In our study, those patients in the MMT group scored statistically significantly lower in the sexual desire domain (Mal-IIEF-15 scores) (p < 0.01), DSD (p = 0.04) and TT plasma level (p < 0.01) when compared to BMT group after controlling all the confounders. This means that if smoking habit continues, there is a higher chance of these male opiate-dependent patients developing even lower testosterone levels, consequently leading to sexual dysfunction. Clinicians should, therefore, play an active role in advising and helping all male patients on methadone therapy to cease smoking, to reduce sexual dysfunction among them.

In a previous study, it was found that sexual desire does not solely depend on its biological component, and its psychological component is influenced by the interpersonal state (presence or absence of sexual partner) and social context [49]. However, in our study, the severity of depression and social functioning were not statistically significant post-linear regression. This implies that the low sexual desire was exclusively caused by methadone in this group of patients.

Our study is not without its limitations. First, this is a cross-sectional study and recall bias might have taken place as we had to rely on self-report data based on patient’s memory. Second, in a relatively conservative society in Malaysia, participants might have concealed their true feelings because they felt uncomfortable to reveal everything to the researchers, hence leading to the possibility of response bias. Third, all male opioid-dependent patients were recruited from a university hospital methadone clinic and the findings may not be generalized to the population with substance misuse. Fourth, the clinical severity of opioid dependence, such as frequency and duration of opioid use, prior to the treatment was not considered in this study. However, it is worth noting that our study carries strengths such as the inclusion of a sample size determined by power calculation, exclusion of mental and physical illness associated with sexual dysfunction, and the use of validated instrument to measure sexual dysfunction.

The present data suggest that the use of methadone is associated with lower sexual desire when compared with the use of buprenorphine in opioid-dependent patients, but larger studies are needed to confirm the present findings. These results highlight the importance of awareness among clinicians who treat sexual desire disorder when making treatment decisions in this population. Reducing this ubiquitous complication arising from replacement therapy will, in the long run, greatly influence the positive prognosis of their treatment compliance and drug dependence.