Opiate misuse has increased in prevalence

Original Article Sexual Dysfunctions in Male Opiate Users: A Comparative Study of Heroin, Methadone, and Buprenorphine Omar Al-Gommer, MRCPsych,* Sanju George, MRCPsych,w Sayeed Haque, BSc (Hons), MSc, PhD,z Hamdy Moselhy, MD, MSc, DCP, MRCPsych,} and Tharakeshwari Saravanappa, MBBS8 137 Abstract Objective: The aim of this study was to compare sexual dysfunctions in male patients dependent on heroin and those on methadone or buprenorphine treatment for opiate dependence. Methods: Ninety-one patients (30 in the heroin group, 33 in the methadone group, and 28 in the buprenorphine group) were recruited from outpatient attendees at a community drug team in Birmingham, UK. The Loyola University Clinic-special history sheet for men was administered to assess sexual functioning (self-reports), and the Brief Psychiatric Rating Scale was used to assess psychopathology. Results: A wide range of sexual dysfunctions was reported by these patients (n = 90): low sex drive (n = 38; 41.8%), loss of sexual fantasy life (n = 17; 18.7%), loss of morning erection (n = 25; 27.5%), premature ejaculation (n = 54; 59.3%), and ejaculation with soft penis (n = 67; 73.6%). Fewer patients on buprenorphine (as compared with those on heroin and methadone) reported loss of sexual fantasy, loss of sexual desire, loss of erection with movement, premature ejaculation, and loss of angulation of penis (all P<0.05). Conclusions: The results of this study indicate that sexual dysfunctions are common in male opiate misusers and that buprenorphine is significantly less likely than methadone or heroin to induce this side effect. Further research is needed to explore the pathophysiology and treatment implications of these findings. From a clinical perspective, it is imperative that patients misusing opiates and those treated with methadone or buprenorphine are routinely asked about their sexual functioning and appropriate investigations and treatment planned if indicated. Key Words: buprenorphine, males, methadone, opiates, sexual side effects, sexual functioning (Addict Disord Their Treatment 2007;6:137 143) Opiate misuse has increased in prevalence over the last few decades in the western world, and particularly in the United Kingdom. It was estimated that around 200,0000 opiate misusers presented to General Practitioners and drug misuse services for treatment during 2004 to 2005 in the United Kingdom. More than half of them were abusing heroin and around a tenth were using misusing methadone. It is argued that if this is the number presenting to treatment, true figures could be 2.5 to 5 times this estimate. 1 Methadone maintenance treatment has been the mainstay of pharmacologic management of opiate dependence for over 40 years, and more recently buprenorphine has been demonstrated to be effective as well. 2,3 Among a range of potential side effects of heroin misuse and opiate-substitute treatment, sexual dysfunction is common and clinically significant. This is an area often neglected and hence unexplored in routine clinical care of opiate addicts, and is yet highly clinically relevant, as it could lead to nonadherence to treatment. Sexual dysfunctions noted in chronic opiate-addicts include reduced libido and sexual performance in males 4 and females, erectile dysfunction and delayed ejaculation From the *Worcestershire Mental Health NHS Trust, Redditch, Worcestershire, B98 7WG; wqueen Elizabeth Psychiatric Hospital, Birmingham, B15 2QZ; 8The Bridge, Birmingham, B37 7UR, England; zuniversity of Birmingham, Edgbaston, B15 2QZ; and }Sandwell Mental Health NHS Trust, West Midlands, B70 8ET. Declaration of interest: None. Reprints: Dr Sanju George, MRCPsych, Queen Elizabeth Psychiatric Hospital, Birmingham, B15 2QZ, England (e-mail: sanju.george@talk21.com). Copyright r 2007 by Lippincott Williams & Wilkins

138 Al-Gommer et al times in males, 5,6 and amenorrhea 7 and reduced fertility in females. 8 Goldsmith et al 9 found that 85% of male heroin users recruited to methadone maintenance treatment had sexual difficulties including lack of sexual desire, difficulty in achieving orgasm, and reduced satisfaction with sexual relations. Various hypotheses have been postulated to explain the sexual dysfunctions in male opiate misusers. Plasma testosterone levels have been shown to be consistently lower in opiate addicts as compared with controls. 10,11 Cushman 12 demonstrated that patients on lower doses of heroin and methadone had higher testosterone levels. Similar findings of a negative correlation between high dose methadone and low plasma testosterone levels were reported by Cushman and Kreek. 13 Apart from the effect of heroin and methadone on reducing testosterone levels in males, other explanations offered to explain opiate-induced sexual dysfunction include: a-adrenergic blocking activity of opiates which may directly influence the functioning of accessory sex organs, 14 psychologic factors such as sedation, euphoria and a chaotic life style in addicts impairing sexual desire and performance, and these patients preferring drug-procuring behaviors to sexual encounter opportunities. 15 Various studies have identified a range of sexual dysfunctions in male patients addicted to heroin and those treated with methadone. However, as buprenorphine is a relatively recent addition to the therapeutic armamentarium for opiate dependence treatment, its sexual side effect profile has not yet been fully evaluated. We compared the sexual functioning (on the basis of self-reports) of males using heroin, methadone, or buprenorphine. Any significant differences between methadone and buprenorphine in their propensity to induce sexual dysfunctions (as a side effect) would have potential implications for opiate-substitute prescribing in clinical practice. r 2007 Lippincott Williams & Wilkins MATERIALS AND METHODS Patients and Procedure Patients were recruited from outpatient attendees at a community drug treatment service in Birmingham, United Kingdom, between July 2002 and August 2003. Male patients aged between 18 and 55 years, with an ICD-10 16 diagnosis of opiate dependence syndrome, who were dependent on heroin or were being prescribed methadone or buprenorphine were included in the study. Patients who were on buprenorphine or methadone had to have been on it for at least 6 months. A sample size of 30 in each of the 3 groups (heroin users, methadone users, and buprenorphine users) was aimed for, and all consecutive attendees at the clinic were interviewed, until this number was reached. Patients were excluded from the study if they had any of the following conditions: comorbid alcohol dependence, chronic physical disorders such as diabetes mellitus, hypertension, chronic pain, rheumatoid arthritis, endocrine disorders, urologic disorders, or a history of pelvic trauma. All eligible patients (on the basis of self-reports of drug use) were then subjected to a urinalysis for psychoactive substances to confirm their use of heroin, methadone, or buprenorphine, and to exclude concurrent use of other psychoactive substances. Three patients had severe hypertension, 2 had undergone pelvic trauma, 9 gave a history of comorbid alcohol dependence, 8 had urine test results suggestive of cocaine use, and 11 refused to participate in the study. All of these patients were excluded and a final number of 91 patients participated in the study. Of these, 30 were dependent on heroin (as their only drug of misuse), 33 patients were on treatment with methadone (and not using any other psychoactive substance), and 28 patients were on buprenorphine treatment. The interviews were conducted in quiet, comfortable settings and each interview lasted about an hour.

Measures A predesigned data sheet was used to extract socio-demographic information and detailed clinical and drug use histories from patients. The Loyola University Clinic-special history sheet for men questionnaire 17 was employed to assess aspects of sexual functioning. This is a self-report, semistructured instrument that assesses various parameters of sexual functioning in men. It is easy to administer and has good reliability and validity. Patients level of psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS). 18 The nature and scope of the study was discussed with each patient and written informed consent was obtained from all patients. The North Birmingham Local Ethics Committee approved this study. Analyses Descriptive statistics (mean and standard deviation or median and range, as appropriate) were calculated for the study sample on the demographic and clinical variables. The differences in these characteristics were tested by the Kruskall-Wallis test, and the w 2 test was used to compare the frequencies of sexual dysfunctions between the 3 groups. The data are presented as median and range; 2-tailed tests were used and a P value of 0.05 or less was regarded as Sexual Dysfunctions in Male Opiate Users significant. The data were checked for deviations from the Gaussian distribution using the Kormogorov-Smirnov test. The data analysis was performed using SPSS, Version 11.0. RESULTS Study Sample Description Ninety-one patients participated in this study: 30 were dependent on heroin, 33 were on methadone treatment, and 28 were on buprenorphine treatment. The median age of the sample was 28 years (range = 17 to 52 y). Majority of the sample were White British (62%), unemployed (91%) and were living alone (80%). Some of the important demographic and clinical characteristics of the sample are given in Table 1. There were no significant baseline differences between the 3 groups. Use of Concurrent Psychoactive Substances Table 2 presents data on the concurrent use of other psychoactive substances by this group of patients. The use of alcohol and nicotine were specifically explored as they can independently cause sexual dysfunction. Although majority of the patients (n = 76) smoked cigarettes, there were no 139 TABLE 1. Baseline Demographic and Clinical Characteristics by Patient Heroin (n = 30) Methadone (n = 33) Buprenorphine (n = 28) Age (y) (median, range) 26.5 (18-42) 29 (19-52) 25.5 (17-42) Ethnicity White British 20 18 18 Asian 10 15 10 Employment status Unemployed 29 30 24 Employed 1 3 4 Living with partner or not Yes 7 10 1 No 23 23 27 Mean daily dose of drug used 0.8 g 56 mg 6.45 mg Route of drug intake 28 (oral) 28 (oral) 28 (sublingual) 2 (IV) 5 (IV) Mean duration of use (y) 4.2 y 2.6 y 7.4 mo

140 Al-Gommer et al TABLE 2. Concurrent Use of Psychoactive Substances Heroin (n = 30) Methadone (n = 33) Buprenorphine (n = 28) v 2 df Asymp.sig Smoking (cigarettes) 30 (100%) 21 (63.6%) 25 (89.2%) Cigarettes/d (mean rank) 50.22 39.26 49.43 3.542 2 0.170 Duration (y) (mean rank) 51.43 39.88 47.39 3.147 2 0.207 Units of alcohol/wk (mean rank) 44.68 40.21 54.23 6.559 2 0.028 Duration (y) (mean rank) 43.35 40.83 54.93 7.155 2 0.028 Cannabis (n) 4 0 3 Benzodiazepines (n) 1 0 1 Methadone (n) 2 0 0 Cocaine (n) 0 1 0 significant differences between the 3 groups on either the duration of smoking history (P = 0.207) or the number of cigarettes smoked (P = 0.170). The few patients who abused cannabis, cocaine, benzodiazepine, or heroin, used it infrequently and in relatively small amounts. Levels of Psychopathology and Prescribed Psychotropic Medication As evident from the scores on the BPRS, none of the 91 patients suffered syndromal psychopathology and there were no significant differences between the 3 groups. One patient in the heroin-using group was on prescribed zopiclone 7.5 mg daily and another patient in the same group was on venlafaxine 75 mg daily and olanzapine 10 mg daily. None of the other patients were on any prescribed psychotropic medication. Sexual Dysfunctions Across the 3 s Sexual functioning of patients was assessed using the Loyola University Clinicspecial history sheet for men questionnaire. Patients could give yes/no answers to most questions and the numbers (and percentages) of those who reported problems are given in Table 3. It is interesting to note the wide range and high prevalence of sexual dysfunctions reported by this group. As a group (n = 91), nearly a quarter reported TABLE 3. Comparison of Sexual Dysfunctions Across the 3 s Heroin Methadone Buprenorphine v 2 df P Loss of sexual fantasy 10 (33%) 5 (15.1%) 2 (7.14%) 6.964 2 0.031* Loss of sexual desire 17 (56.6%) 19 (57.5%) 2 (7.14%) 19.931 2 0.001* Loss of morning erection 14 (46.6%) 8 (24.2%) 3 (10.7%) 9.666 2 0.008* Loss of dream erection 11 (36.6%) 7 (21%) 7 (25%) 2.008 2 0.366 Loss of erection with movement 10 (33.3%) 8 (24.2%) 0 (0) 10.791 2 0.005* Inability to ejaculate 7 (23.3%) 14 (42.4%) 10 (35.7%) 2.599 2 0.273 Ejaculation with soft penis 9 (30%) 9 (27.3%) 6 (21.4%) 0.570 2 0.752 Premature ejaculation 17 (56.6%) 14 (42.4%) 6 (21.4%) 7.520 2 0.023* Loss of angulation of penis 15 (50%) 23 (69.7%) 6 (21.42%) 14.181 2 0.001* *Statistically significant. r 2007 Lippincott Williams & Wilkins

problems in sexual fantasy life (n = 17, 18.7%), loss of morning erection (n = 25, 27.5%), and loss of dream erection (n = 25, 27.5%); 38 (41.8%) had low sex drive and more than 60% had ejaculatory disturbances [premature ejaculation (n = 54, 59.3%), inability to ejaculate (n = 60, 65.9%), and ejaculation with soft penis (n = 67, 73.6%)]. Buprenorphine was less likely than the other 2 groups to induce sexual dysfunctions such as loss of sexual fantasy (P = 0.031), loss of sexual desire (P = 0.001), loss of erection with movement (P = 0.005), premature ejaculation (P = 0.023), and loss of angulation of penis (P = 0.001). Sexual Dysfunctions in Methadone Versus Buprenorphine-treated Patients Methadone and buprenorphine were superior to heroin in that they induced fewer sexual dysfunctions in areas of sexual fantasy, morning erection, dream erection, and premature ejaculation (Table 3). Buprenorphine was superior to heroin on most aspects of sexual functioning measured and the difference reached statistically significant levels on the following: loss of sexual fantasy (w 2 = 6.054, df =1, P = 0.014), loss of morning erection (w 2 = 9.035, df =1, P = 0.003), loss of erection with movement (w 2 = 11.278, df =1, P<0.001), and loss of sexual desire (w 2 = 16.126, df =1, P<0.001). Methadone-treated patients had fewer sexual dysfunctions as compared with patients using heroin but the differences were not found to be statistically significant. A more striking observation was the difference between patients on methadone treatment and those on buprenorphine treatment. Buprenorphine was found to be superior to methadone on all aspects of sexual functioning assessed in that it caused fewer sexual dysfunctions and the following were noted to be statistically significant: loss of sexual fantasy (P = 0.031), loss of morning erection (P = 0.008), loss of angulation of penis (P<0.001), loss of erection with Sexual Dysfunctions in Male Opiate Users movement (P<0.005), and loss of sexual desire (P<0.001). Overall, sexual dysfunctions (ranging from disturbances in sexual desire and fantasy, erection, and ejaculation) were common in patients misusing heroin and those on opiate-substitute medication. Methadone was superior to heroin in this regard and patients treated with buprenorphine reported significantly fewer sexual dysfunctions than the other 2 groups. DISCUSSION One of the limitations of this study was the lack of a control group. As we only set out to comparatively evaluate the sexual side effect profile of heroin, methadone, and buprenorphine, it was not considered necessary to include a group of normal healthy controls. It seems reasonable to extrapolate findings from other studies demonstrating a rate of 5% to 10% for sexual dysfunctions in a healthy, young population. The limited sample size, inclusion of only outpatients, and exclusion of females are other potential limitations that could limit the validity and generalizability of our findings. Although the 3 groups of patients did not differ statistically on any demographic or clinical characteristic, variations were still evident. Patients on methadone treatment were older (median = 29 y, range = 19 to 52 y) than the heroin using group (median = 26.5 y, range = 18 to 42 y) and the buprenorphine group (median = 25.5 y, range = 17 to 42 y). This could have been because, patients using heroin were often making their first contact with the drug treatment service, whereas patients on methadone had been in treatment for longer. The mean daily dose of drug use was: heroin (0.8 gm), methadone (56 mg), and buprenorphine (6.45 gm), and the mean durations of use for the 3 groups were 4.2 years, 2.6 years, and 7.4 months, respectively. Contrary to findings from previous 141

142 Al-Gommer et al studies which have found an inverse relationship between methadone or heroin dose and plasma testosterone levels (and hence sexual dysfunctions), 11,12 we failed to demonstrate any such relationship between heroin or methadone dose and reported sexual dysfunctions. A wide range of sexual dysfunctions was reported by our sample of patients. They included disturbances in sexual desire (n = 38, 41.8%), erectile disturbances (loss of morning erection, n = 25, 27.5%), and ejaculatory disturbances (premature ejaculation, n = 54, 59.3%; and ejaculation with soft penis, n = 67, 73.6%). Only few patients reported loss of sexual fantasy life (n = 17, 18.7%) and only a quarter (n = 25, 27.5%) complained of loss of dream erection. We also did not demonstrate any significant differences between patients on heroin and methadone, across the following parameters of sexual functioning: sex drive, premature ejaculation, loss of erection with movement, and dream erection. Cushman 12 in a study of heroin addicts and methadone maintained patients, demonstrated impaired sex drive in 22% of methadone maintained patients and 61% of heroin addicts. Our study found the rates to be 57% and 56% respectively. Having not estimated the plasma levels of pituitary or gonadal hormones in our patient sample, it is difficult to comment on the possible etiologic mechanisms for sexual dysfunctions in these patients. However, we did exclude the more common etiologic factors such as chronic physical disease, psychiatric disorders, alcoholism, etc. Some researchers have proposed that a chaotic life style of some heroin addicts could be responsible for sexual dysfunction. However, in our patient sample they all seemed reasonably stable, as they were not using any other psychoactive substance (as confirmed by urine testing) and were well engaged in treatment. As assessed on BPRS, none of the patients suffered from severe mental disorder, and hence that could not have contributed to sexual problems. This r 2007 Lippincott Williams & Wilkins finding is inconsistent with some previous research. Spring et al 19 in a study of sexual functioning of 25 methadone maintained patients, found that coexisting psychiatric disorders were the primary cause of sexual dysfunction rather than opiates themselves. In our study, having excluded the more common causes, it is reasonable to assume that sexual dysfunctions in these patients could have been a direct action of opiates. If indeed, the sexual dysfunctions reported are likely to be a direct effect of opiates (whether mediated by hormonal mechanisms or not), it is striking that patients on buprenorphine had significantly fewer problems compared to patients on heroin or methadone. Buprenorphine induced significantly fewer sexual dysfunctions than methadone in areas of sexual desire (P<0.001), sexual fantasy (P = 0.031), loss of erection with movement (P<0.005), and loss of angulation of penis (P<0.001). Buprenorphine was also superior (although not statistically significant) to heroin and methadone in aspects of loss of morning erection and premature ejaculation. Not having evaluated the endocrine profile of these patients, it is not possible to conclude whether buprenorphine induces relatively less suppression of testosterone and hence causes fewer sexual dysfunctions. However, this is tempting to speculate, as buprenorphine (as opposed to heroin and methadone which are opiate agonists) is only a mixed agonist-antagonist of opiates, and hence is likely to induce less endocrine changes. However, this needs further evaluation before any firm and valid conclusions are drawn. In summary, sexual dysfunctions in male patients on heroin and methadone are relatively common, affecting sex drive, erection, and ejaculation. Buprenorphine seems to be superior to heroin and methadone in this regard. Notwithstanding the lack of endocrinologic evaluation of our patient sample (having controlled for most of the common confounders), it is reasonable to conclude that sexual dysfunctions in

heroin users and those on methadone or buprenorphine treatment are a direct result of opiate use itself. Further research is needed to explore the possible superiority of buprenorphine over methadone in its potential to cause sexual problems, and the underlying biologic correlates and pathophysiologic mechanisms too need detailed evaluation. For the clinician, greater awareness of opiate-induced sexual dysfunction can lead to routine enquiry and thereby appropriate management. This could result in improved treatment adherence and improved quality of life of these patients. ACKNOWLEDGMENTS The authors thank all patients who participated in this study. REFERENCES 1. Hartnoll R, Lewis R, Mitcheson M, et al. Estimating the prevalence of opiod dependence. The Lancet. 1985;1:203 205. 2. Ahmadi J. Methadone versus buprenorphine maintenance for the treatment of heroin-dependent outpatients. J Sub Abuse Treatment. 2003;24: 217 220. 3. Barnett P, Rodgers J, Bloch D. A meta-analysis comparing buprenorphine to methadone for treatment for opiate dependence. Addiction. 2001;96:683 690. 4. Cushman P Jr. Sexual behaviour in heroin addiction and methadone maintenance-correlation with plasma LH. NY State J Med. 1972;72:1261. 5. Wieland WE, Yunger M. Sexual Effects and Side Effects of Heroin and Methadone. Proceedings of Sexual Dysfunctions in Male Opiate Users the Third National Conference on Methadone Treatment. Washington, DC: US Government Printing Office; 1970:50 53. 6. Mirin SM, Meyer RE, Mendelson JH, et al. Opiate use and sexual function. Am J Psychiatr. 1980; 137:909 915. 7. Santen RJ, Bilic N. Evaluation of the pituitarygonadal axis in women with amenorrhoea associated with narcotic addiction, abstract, 55th meeting of the endocrine society, Illinois, June 1972; 22 24. 8. Mathis JL. Sexual aspects of heroin addiction. Med Aspects Hum Sex Sept. 1970;4:98. 9. Goldsmith DS, Hunt DE, Lipton DS, et al. Methadone folklore: beliefs about side effects and their impact on treatment. Hum Organ. 1984;43: 330 340. 10. Martin WR, Jasinski DR, Haertzen CA, et al. Methadone a re-evaluation. Arch Gen Psych. 1973; 28:286. 11. Mendelson JH, Mendelson JE, Patch VD. Plasma testosterone levels in heroin addiction and during methadone maintenance. J Pharmacol Exp Ther. 1975;192:211 2117. 12. Cushman P Jr. Plasma testosterone in narcotic addiction. Am J Med. 1973;55:452 458. 13. Cushman P, Kreek MJ. Methadone-maintained patients: effect of methadone on plasma testosterone, FSH, LH and prolactin. NY State J Med. 1974;74: 1970 1973. 14. Cicero TJ, Bell RD, Wiest WG, et al. Function of the male sex organs in heroin and methadone users. New Engl J Med. 1975;24:882 887. 15. Cooper AJ. Factors in male sexual inadequacy, a review. J Nerv Ment Dis. 1969;149:337. 16. World Health Organisation. The ICD-10 Classification of Mental and Behavioural Disorders. Geneva: WHO; 1992. 17. Renshaw DC. Physicians and frontline sex counselling. CME. 1998;16:824 829. 18. Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep. 1962;10:799 812. 19. Spring WD Jr, Willenbring ML, Maddox TL. Sexual dysfunction and psychological distress in methadone maintenance. Intl J Addict. 1992;27: 1325 1334. 143