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Keywords:

  • Buprenorphine;
  • Male;
  • Methadone;
  • Meta-Analysis;
  • Opioid-Related Disorders;
  • Sexual Dysfunction

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References

Introduction

For many years, methadone has been recognized as an effective maintenance treatment for opioid dependence. However, of the many adverse events reported, sexual dysfunction is one of the most common side effects.

Aim

We conducted a meta-analysis to evaluate the prevalence of sexual dysfunction among male patients on methadone and buprenorphine treatments.

Methods

Relevant studies published from inception until December 2012 were identified by searching PubMed, OVID, and Embase. Studies were selected using prior defined criteria. Heterogeneity, publication bias, and odds ratio were assessed thoroughly.

Main Outcome Measures

To examine the prevalence and odds ratio of sexual dysfunctions among the methadone and buprenorphine groups.

Results

A total of 1,570 participants from 16 eligible studies were identified in this meta-analysis. The studies provided prevalence estimates for sexual dysfunction among methadone users with a meta-analytical pooled prevalence of 52% (95% confidence interval [CI], 0.39–0.65). Only four studies compared sexual dysfunction between the two groups, with a significantly higher combined odds ratio in the methadone group (OR = 4.01, 95% CI, 1.52–10.55, P = 0.0049).

Conclusions

Evidence showed that the prevalence of sexual dysfunction was higher among the users of methadone compared with buprenorphine. Patients with sexual difficulty while on methadone treatment were advised to switch to buprenorphine. Yee A, Loh HS, Hisham Hashim HM, and Ng CG. The prevalence of sexual dysfunction among male patients on methadone and buprenorphine treatments: A meta-analysis study. J Sex Med 2014;11:22–32.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References

Methadone maintenance treatment is recognized as an effective substitution therapy for opioid dependence [1]. Since its introduction, there were significant reductions in cases of heroin use [2–4], criminal activity [5,6], unemployment [2], mortality [2,3,7,8], and the transmission of infectious diseases namely HIV/AIDS and hepatitis [9,10]. However, there were reports on several adverse events from the use of methadone [1]. One of the most common side effects of methadone use is sexual dysfunction [11].

Sexual dysfunctions such as erectile dysfunction (ED), ejaculatory disturbances, and lack of desire for sexual relations are often reported in a considerable number of male patients on methadone maintenance [11–16]. The exact prevalence of sexual dysfunction among this population is yet to be determined as they vary from study to study. Brown et al. [17] reported an overall sexual dysfunction prevalence range of 30–100%, whereas most studies have reported a subtype of sexual dysfunction namely ED, with prevalence ranging from 16% to 83.6% [11,18,19].

One of the main reasons, aside from the variations among the multiple ethnic populations, that might have accounted for the differences in the prevalence of sexual dysfunctions among this population was the methodological differences between studies. First, it was the use of various questionnaires. Some of the studies used self-administered questionnaires such as International Index of Erectile Function (IIEF) whereas other studies used person-administered questionnaires, such as face-to-face interviews. It was essential to ascertain whether the self-administered questionnaires would have yielded higher prevalence of sexual dysfunction when compared with the person-administered interviews. Second, the validity of the separate studies was uncertain. And third, the definitions of sexual dysfunction were inconsistent among all the studies.

In conjunction with methadone maintenance treatment, there were studies that showed that buprenorphine maintenance treatment was an alternative effective treatment for opioid addiction [20,21] and was not associated with increased risk of sexual dysfunction [22]. A study by Bliesener and colleagues [22] found that patients who were treated with buprenorphine had improved erectile function when compared with those treated with methadone. However, studies by Hallinan et al. [23] and Quaglio et al. [24] found no difference in ED among patients in both the methadone and buprenorphine maintenance treatment arms. Nevertheless, the influence of buprenorphine on sexual dysfunctions among patients is yet to be determined [23,24].

In view of the vast variation of the reported risks of sexual dysfunction in patients treated with methadone and buprenorphine, we aimed to examine the prevalence of sexual dysfunction among these two groups of subjects in the current meta-analysis. In methadone group, particular attention was paid to the methodological quality and value of the individual studies. Our secondary aim was to examine the odds ratio of sexual dysfunction comparing methadone- and buprenorphine-treated patients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References

Search Strategy and Selection Criteria

A.Y. and N.C.G. designed the review protocol and extraction forms in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [25]. A.Y. and H.M.H. conducted a search of the published English-language literature in the PubMed, OVID, and Embase databases from inception until December 2012, using the search terms shown in Box 1. We included all cohort, case-control, and cross-sectional studies that presented original data on any aspect of sexual dysfunction in patients older than 18 years at diagnosis. We allowed all methods of diagnosing sexual dysfunction among methadone and buprenorphine male patients. We excluded case reports, systemic review, case series, and duplicate publications (i.e., two or more studies investigating the same sample). To keep this review as specific as possible, we excluded any study that included patients who used methadone or buprenorphine for nonmalignant or malignant pain.

Box 1. Search strategies (conducted September 5, 2012)

PubMed: (sexual dysfunction [sh] OR sexual disorder [sh] OR sexual performance [sh] OR erectile dysfunction [sh] OR premature ejaculation [sh] OR delayed ejaculation [sh] OR desire disorder [sh] OR orgasm disorder [sh] OR impotence [sh] OR hypoactive disorder [sh] OR decreased libido [sh]) AND (methadone [sh] OR buprenorphine [sh] OR suboxone) AND (male [sh] OR man [sh] OR men [sh] OR man heroin [sh] OR men heroin [sh] OR man opioid [sh] OR men opioid [sh])

OVID: (sexual dysfunction [sh] OR sexual disorder [sh] OR sexual performance [sh] OR erectile dysfunction [sh] OR premature ejaculation [sh] OR delayed ejaculation [sh] OR desire disorder [sh] OR orgasm disorder [sh] OR impotence [sh] OR hypoactive disorder [sh] OR decreased libido [sh]) AND (methadone [sh] OR buprenorphine [sh] OR suboxone) AND (male [sh] OR man [sh] OR men [sh] OR man heroin [sh] OR men heroin [sh] OR man opioid [sh] OR men opioid [sh])

Embase: (Ejaculation disorder [sh] OR impotence [sh] OR potency disorder [sh] OR premature ejaculation [sh] OR sexual arousal disorder [sh] OR hypoactive sexual desire disorder [sh] AND (methadone [sh] OR buprenorphine [sh] OR suboxone) AND (men [sh] OR man [sh] OR male [sh])

Data Extraction and Classification

L.H.S. and H.M.H. extracted the primary data independently, which were reviewed systemically. First, the sampling method was assessed for each study. Second, a methodological quality assessment that was designed by Prins et al. [26], shown in Table 1, was applied to each study. In this methodological quality assessment, external and internal validity were assessed by six questions, respectively. Third, a five-point bias-rating score was applied to each study. Bias-rating score was used to assess any possible bias in the assessment of age, clinical setting, and outcomes with the following scores: 0 = no appreciable bias risk; 1 = low bias risk; 2 = low-to-medium bias risk; 3 = medium-to-high bias risk; and 4 = high bias risk [27]. All areas of disagreement were resolved by A.Y. and N.C.G.

Table 1. Criteria for the methodological quality assessment of prevalence studies
  1. a

    Two or more of: (i) age distribution; (ii) relevant comorbidity; (iii) lifestyle factors (e.g., smoking and alcohol consumption); and (iv) socioeconomic data (e.g., income, educational level, marital status).

  2. b

    Disease is defined as any form of sexual dysfunction in this review.

External validity
Source population
(a) Does the method to select and invite participants result in a study population that covers the complete population or a random sample?
Description of eligibility criteria
(b) Is the age range specified?
(c) Are inclusion and exclusion criteria specified?
Participants and nonresponders
(d) Is the response rate >70%, or is the information on nonresponders sufficient to make inference on the representativeness of the study population? Description of study period
(e) Is the study period specified?
Description of study population
Internal validity
(f) Are important population characteristicsa specified?
Internal validity data collection
(g) Are the data prospectively collected?
Measurement instrument (questionnaire, interview, additional)
(h) Is the measurement instrument validated?
(i) Is the period covered by the measurement instrument specified?
Definition of diseasesb
(j) Is a definition of the disease stated?
Reported prevalences
(k) Are age-specific and gender-specific prevalences reported?
(l) Are possible correlates of disease reported?

Statistical Analysis

We gathered individual study data with DerSimonian–Laird proportion meta-analysis. A random effects meta-analysis was carried out using StatsDirect (version 2.7.9, StatsDirect Ltd, Cheshire, UK), as the heterogeneity was moderate to high. We used the I2 test to assess heterogeneity (threshold were ≥80% = moderate and ≥90% = high), and assessed publication bias with Begg–Mazumdar and Egger tests. For comparative and sub-analyses, we needed a minimum of three independent studies to justify analysis according to convention. Odds ratios (ORs) were calculated only for studies that had methadone and buprenorphine groups.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References

Selection of Studies

The initial search strategy identified 191 titles—61 from PubMed, 57 from OVID, and 73 from Embase (Figure 1). After title screening and elimination of duplicate publications were carried out, 74 publications remained—30 from PubMed, 20 from OVID, and 24 from EMBASE. We then excluded 26 publications after reviewing the abstract. The full text of the remaining 48 (not including the duplicates) studies were reviewed, of which 16 eligible studies were included in this review (Figure 1). Data extraction is shown in Figure 1 in accordance with Quality of Reporting of Meta-analyses guidelines.

figure

Figure 1. Search strategy for eligible journals.

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Description of Selected Study Populations

The designs and aims of all eligible studies were listed in Table 2. Most studies were cross-sectional and focused on sexual dysfunction as the outcome. All the studies were conducted in outpatient clinics or methadone maintainence therapy clinics. Four studies were also conducted in an inpatient setting. Majority of them had no control group. Seven studies measured the hormonal assay. Five of the studies were conducted in the United States while another five studies involved patients from the European continents (i.e., United Kingdom, Italy, Switzerland, Sweden, and France). China contributed to two studies while Australia and Iran contributed to one study each.

Table 2. The methodology and sexual dysfunction-related research question in the eligible studies
First authorSettingCriteria for definition of SDMethadone durationControl groupCountry
  1. BMT = Buprenorphine/Buprenorphine Maintenance Treatment; BMSFI = Brief Male Sexual Function Inventory; DATC = Drug Abstention and Treatment Center; DSFI = Derogatis Sexual Functioning Inventory; DIS = Diagnostic Interview Schedule; DSM-III = Diagnostic and Statistical Manual of Mental Disorders, third edition; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, revised third edition; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth edition; ED = Erectile Dysfunction; EQ-5D = EuroQol; EF = erectile function; FSH = follicle-stimulating hormone; GAQ = Global Assessment Questionnaire; GRP = Group; GRISS = Golombok Rust Inventory of Sexual Satisfaction; ICD-10 = International Classification of Disease 10; IIEF = International Index of Erectile Function Questionnaire; IIEF-5 = International Index of Erectile Function Questionnaire; LH = lutenizing hormone; LUC = Loyola University Clinic; NIH = National Institute of Health; PE = premature ejaculation; PQTS = Partner Quality Test System; SD = sexual dysfunction; RAA = Royal Australian Airforces; RGRP = reference group; SFQ = Sexual Function Questionnaire; SHF = Sexual History Form; TEDIS = Tabibi Erectile Dysfunction Intensity Scale; MMT = Methadone/Methadone Maintenance Treatment; NMT = Naltrexone Maintenance Treatment; NR = not reported; TT = total testosterone

Bliesener [22]NRSFQ, hormone assaysAt least 3 monthsN = 51NR
Brown [17]MMTSHF, hormone assaysGRP 1 = At least 60 days; GRP 2 = 60 days or longerNoUnited States
Chekuri [28]MMTICD-10, IIEF, clinical interview, hormone assaysAt least 30 daysNoScotland
Chen [1]MMT, outpatientsICD-10, IIEF-5, hormone assaysAt least 3 monthsNoChina
Cicero [29]MixedClinical interview, hormone assaysMMT = 1.9 ± 0.3 yearsNarcotic- free control, n = 43United States
Dürsteler-MacFarland [30]MMT, outpatientsSelf-completion questionnaire, Clinical interviewMMT = 85.2 ± 6.4 monthsNoSwitzerland
Giacomuzzi [31]Mixed, MMT or BMTPQTS, EQ-5DNRNoNR
Grönbladh [32]MMT, inpatientsSelf-reported Side EffectsAt least 3 monthsNoSweden
Hallinan [23]Mixed, MMT or BMTIIEF, EF domain of the IIEF, hormone assaysMMT = 67 (±58) months, BMT = 26 (±27) monthsRAA bases, Amberley (N = 415) and Richmond (N = 530)Australia
Hanbury [11]Mixed, MMTClinical interviewPatients with SD = 24.06 months, patients without SD = 29.91 monthsNoUnited States
Novick [33]MMT, inpatientsClinical interviewLong-term MMT intake group = 14.5 ± 0.1 yearsNoUnited States
Patricia [34]BMT, outpatientsNIH, 1 question from the IIEF regarding ED, hormone assaysAt least 6 monthsNoUnited States
Quaglio [24]MMT or BMT, outpatientsIIEF, clinical interviewMMT = 14.5 months, BMT = 11.5 monthsNoItaly
Spring [35]MMTDSFIAt least 2 monthsNoNR
Tatari [36]MMT, mixedNIH, TEDIC, clinical interviewAt least 30 daysNoIran
Zhang [37]MMT, inpatientsICD-10, IIEF-5At least 3 monthsNoChina

Quality Assessment

Table 3 shows the results of the sampling method, methodological quality, and bias assessment. On average, only four studies used convenience sampling; 3.3 items (range 1–6) on external validity and 3.7 items (range 2–6) on internal validity were scored positive, respectively. Not a single study achieved a full score for all the 12 validity criteria. However, two studies obtained full points for the internal validity test scores [1,23].

Table 3. Year published and quality assessment of selected studies
First authorYear*Sample MethodBias riskExternal validityInternal validityDisagreement§
abcdefSumghijklSum
  1. *Year published. sample method 1 = convenience sample, 0 = consecutive or random Bias risk: 0 = no appreciable bias risk, 1 = low bias risk, 2 = low-to-medium bias risk, 3 = medium-to-high bias risk, and 4 = high bias risk. §Items on which the two reviewers disagreed; consensus reported

Cicero [29]197502+++3+++3 
Hanbury [11]197702++2++2f,j
Spring [35]199213++2+++3 
Novick [33]199303+++++5+1b,i
Bliesener [22]200513++++4+++3c,f
Brown [17]200512++2++++4d
Hallinan [23]200802++++4++++++6 
Quaglio [24]200801++++4++++++6 
Giacomuzzi [31]200913+1+++3 
Dürsteler-MacFarland [30]201003++2+1a,i,j,k
Patricia [34]201003++++4++++++6 
Tatari [36]201003+++++5+++3 
Grönbladh [32]201102++2++2j
Zhang [37]201101++++4+++++5l
Chekuri [28]201202+++3+++++5 
Chen [1]201202+++++5++++++6K,l

Data Collection in Selected Studies

Table 4 lists the methods used to obtain data and the definitions used for sexual dysfunction, and the period of time on methadone therapy. Eight studies used self-administered questionnaires, three used interview sessions, and the other five studies applied both methods. Most of the studies did not have distinctive definition of sexual dysfunction; however, they had clearly defined the subtypes of sexual dysfunction in particular ED [34,36]. Various questionnaires were used to assess sexual dysfunction in the population. These questionnaires contained either a single question [11,29–33] or a series of questions on sexual dysfunction from which a sum score was derived [15,17,23,24,35,37]. The minimal time period for each of the subjects in this study was 3 months.

Table 4. Method used to obtain information on erectile dysfunction, definition and time period on Methadone
First author (year)SAQ/ Interview*Definition of male sexual dysfunction and severity when applicableTime period on Methadone
  1. SAQ*: self-administered questionnaire. 1Results published included both males and females; only results published for impotency were used for this study. BMT = Buprenorphine Maintenance Treatment; ED = erectile dysfunction; EF = erectile function; ExD = excitation disturbances; GRP = group; GSD = global sexual dysfunction; ICD-10 = International Classification of Diseases-10; IHT = injectable heroin; IIEF = International Index of Erectile Function Questionnaire; IIEF-5 = International Index of Erectile Function Questionnaire-5; LD = libido dysfunction; LBD = Libido; MMT = Methadone Maintenance Treatment; OD = orgasm disorder; PE = premature ejaculation; SC = sexual climax; SD = sexual dysfunction; NR = not reported

Cicero [29] (1975)InterviewImpaired sexual function of male sex organs1.9 ± 0.3 years
Hanbury [11] (1977)InterviewSexual dysfunction (SD) is determined by the modified version of the questionnaire previously utilized by Espejo and colleagues. Patients were also asked to indicate their degree of concern by classifying their sexual difficulty as minimal, moderate, or severe. Minimal was defined as being a lack of concern; moderate as being associated with anxiety but not of sufficient degree to consider dose reduction.Patients with SD = 24.06 months; patients without SD = 29.91 months
Spring [35] (1992)SAQSexual dysfunction (SD) refers to less sexual drive and satisfaction.2 months
Novick [33] (1993)InterviewSexual dysfunction (SD) is categorized as having abnormal libido, abnormal erections, abnormal ejaculations and/ or abnormal orgasms.Long-term MMT intake group = 14.5 ± 0.1 years
Bliesener [22] (2005)SAQThe sexual parameters assessed included changes in libido and potency. The impairment of libido (LBD) and potency were quantified using a rating scale from 0 (not at all) to 6 (extremely). Suggested cutoff values of the sexual function questionnaire were: 0 = no impairment of LBD or potency; 1–2 = mild impairment; 3–4 = moderate impairment; and 5–6 = severe impairment of LBD or potency.3 months
Brown [17] (2005)SAQDesire or libido dysfunction (LD), arousal or erectile dysfunction (ED), and orgasm dysfunction, were assessed using the Nowinski-Lopicollo Sexual History Form. Patients who scored above 50 on a 0–100 scale were considered to have sexual dysfunction according to the subscales.60 days or more
Hallinan [23] (2008)SAQSexual function is determined by the International Index of Erectile Function Questionnaire (IIEF). For the purpose of this study. As the IIEF contains a number of questions that are intercourse and partner dependent, data for men with current sexual partners (defined as having a sexual partner(s) in the previous four weeks) were analyzed separately whereby only the total score of the IIEF and erectile function (EF) domain were analyzed. The sexual desire domain and erection confidence score, which are independent of recent sexual activity, were also examined for the entire patient group including men without current sexual partners. Results for the EF domain were classified according the method of Cappelleri et al. which distinguishes between men with and without erectile dysfunction (ED), and provides classification of levels of ED severity.MMT = 67 (±58) months; BMT = 26 (±27) months
Quaglio [24] (2008)SAQErectile dysfunction (ED) was defined by the International Index of Erectile Function Questionnaire (IIEF). The questions asked in the IIEF to assess ED were numbers 1, 2, 3, 4, 5 and 15. This IIEF-1 scale is scored as no ED (score 26–30), mild (22–25), mild to moderate (17–21), moderate (11–16), or severe (0–10). The higher the score the lower the ED.MMT = 14.5 months, BMT = 11.5 months
Giacomuzzi [31] (2009)1SAQSexual behavior and dysfunction were described as sexual excitation disturbances (ExD) and problems reaching orgasm.NR
Dürsteler-MacFarland [30] (2010)SAQSexual- specific symptoms were categorized as increased/decreased sex drive, problems with orgasm, and problems with erection.85.2 ± 6.4 months
Patricia [34] (2010)SAQ & InterviewErectile dysfunction (ED) is defined as the inability to achieve or maintain an erection satisfactory for the completion of sexual activity.6 months
Tatari [36] (2010)SAQ & InterviewErectile dysfunction (ED) is defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance.30 days
Grönbladh [32] (2011)SAQSexual-specific side effects were categorized as impotency, difficulties reaching sexual climax (SC), decreased libido (LBD), and trouble with erection.3 months
Zhang [37] (2011)SAQ & InterviewSexual status is defined by the International Classification of Diseases-10 (ICD-10). There are 5 diagnoses: increased libido, reduced libido, inhibited ejaculation, premature ejaculation (PE), erectile dysfunction (ED) and normal sexual function. Erectile function is determined by the International Index of Sexual Function-5 (IIEF-5) which only involves 5 questions that can categorize erectile function as normal (22 and over), minor ED (17–21), Moderate to minor ED (12–16), moderate ED (8–11) and severe ED (7 or less).3 months
Chekuri [28] (2012)SAQ & InterviewPremature ejaculation (PE) was defined as ejaculation which occurs within one minute of vaginal penetration or within 15 thrusts (Waldinger, Hengeveld, Zwinderman, & Olivier, 1998 [38]) pertaining to “lifelong” and “current” situation (4 week period prior to the survey) were recorded. Other form of sexual dysfunction was assessed by the International Index of Erectile Function Questionnaire (IIEF) (Rosen et al., 1997 [39]) such as erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction. Each of the domains was rated as no, mild, mild-moderate, moderate and severe dysfunction.30 days
Chen [1] (2012)SAQ & InterviewErectile dysfunction (ED) is defined by the National Institutes of Health (NIH; 1993 [40]) Consensus Development as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance.3 months

Prevalence of Sexual Dysfunction

In the methadone group, prevalence of sexual dysfunction ranged from 14% to 97% in individual studies. There were 1,570 subjects. Meta-analytical pooled prevalence of sexual dysfunction in patients who took methadone was 52% (95% CI, 0.39–0.65) (Figure 2). Ten studies identified sexual dysfunction cases by self-administrated questionnaires (e.g., IIEF, ED-5D, Golombok Rust Inventory of Sexual Satisfaction), in which the prevalence was 42% (95% CI, 0.26–0.60). Seven studies used person-administered interviews (e.g., International Classification of Disease 10, Diagnostic and Statistical Manual of Mental Disorders, third and fourth editions) to diagnose the sexual dysfunction with prevalence of 66% (95% CI, 0.49–0.82). The mean difference of the reported prevalence between the self-administrated questionnaires and person-administered interview was 24% (95% CI, 39.5–12.7, P = 0.29) but statistically not significant. Only four studies used buprenorphine as controlled group to diagnose the sexual dysfunction, of which the prevalence was 54% (95% CI, 0.37–0.71). The remaining studies had no controlled group, and the prevalence was 68% (95% CI, 0.57–0.79). The mean difference of the prevalence between self-administered questionnaires and person-administered interviews was 13% (95% CI, 0.40–0.14)—however, statistically not significant. Twelve studies identified ED/potency in which the meta-analytical pooled prevalence was 46% (95% CI, 0.34–0.59). Only four studies specifically examined the hypoactive sexual desire or low libido, in which the meta-analytical pooled prevalence was 51% (95% CI, 0.27–0.74).

figure

Figure 2. Prevalence of sexual dysfunction in methadone group. Pooled prevalence of sexual dysfunction in methadone group by random effects (DerSimonian-Laird) meta-analysis.

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In the buprenorphine group, there were 182 subjects, with its prevalence of sexual dysfunction ranged from 10% to 36% in individual studies. Meta-analytical pooled prevalence of sexual dysfunction in patients who took buprenorphine was 24% (95% CI, 0.12–0.38). All the studies in buprenorphine group used self-report questionnaires to identify sexual dysfunction.

There were only four studies that compared the sexual dysfunction between the methadone group and the buprenorphine group. The combined odds ratio of sexual dysfunction by random effects (DerSimonian–Laird) were significantly higher in the methadone group than in the buprenorphine group (OR = 4.01, 95% CI, 1.52–10.55, P = 0.0049).

A funnel plot for all studies included in the analysis was plotted to assess the degree of publication bias. This plot (Figure 3) was asymmetrical, indicating that publication bias was likely to have an influence on the overall analysis.

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Figure 3. Funnel plots for the publication bias.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References

Although there were several informative systematic reviews, no previous studies had quantitatively analyzed a large data set of sexual dysfunction among methadone and buprenorphine users. Our study incorporated and updated these results extensively, and estimated the prevalence and OR of sexual dysfunction in methadone and buprenorphine male patients from 16 studies, with a combined total of 1,570 subjects. In our study, the meta-analytical pooled prevalence of sexual dysfunction in patients who took methadone (52%) was nearly doubled that of patients who took buprenorphine (24%). The combined odds of sexual dysfunction were four times higher in the methadone group compared with the buprenorphine group. Furthermore, in our current study, an overview of the available literature is given and a quality assessment of individual studies is presented, according to the proposed guidelines for reporting of systematic reviews [26].

Methodological Quality Assessment

Although the distinctions were determined to be either valid or invalid based on the overall scores, and the use of cutoff points was arbitrary [26], it should be recognized that some of the selected studies had in fact a high number of negative scores (Table 3). For those studies that had high negative scores in the methodological quality assessment, the comparability with other studies and its use in a systematic review would therefore be restricted. Hence, we had to take this into consideration when we interpreted the prevalence rate of these studies.

Definitions of Sexual Dysfunction and Questionnaires

Most of the authors had vague definitions of sexual dysfunction, but many authors used consensus definition for ED, i.e., “inability to attain and maintain an erection sufficient for satisfactory sexual activity” in their reports (Table 4). Five studies [15,23,24,28,37] used IIEF solely to define erectile function, orgasmic function, sexual desire, and intercourse satisfaction. The design of a questionnaire might have influenced the prevalence rate obtained from it; for example, the IIEF-5 could only be used to evaluate patients who were sexually active. In this scoring scale, nonsexually active patients would be categorized as having severe ED, which was not entirely true, and this might have caused a significant overestimation of the prevalence of ED. In other studies, a single question was used to obtain information on erectile function; however, none of these questions was formally validated. In the study conducted by Albersen et al. [41], it was found that the single-item assessment score produced more optimistic results when compared with the IIEF-5. In that study, they discovered that people who were reported as having erection sufficient for intromission on the single-item assessment score, achieved an average score of 20.4 in IIEF-5 which would have been classified as having mild ED.

Comparison of Prevalence Rates

The current review showed that the reported prevalences of sexual dysfunction varied considerably and that there were major methodological differences among the studies. Therefore, it was unclear whether these varying prevalences reflected true differences among countries or merely due to methodological differences. In our opinion, the large methodological variations, especially the different definitions used, hampered the direct comparison of prevalence rates reported in most studies. Only a few studies could be meaningfully compared. For instance, the two studies [1,37] from China applied the same definition and questionnaire (IIEF-5) in the Chinese ethnic group when making comparisons. We derived the prevalences from the combined report of both studies and noticed 76% (513 out of 686) of these men were reported to have ED. Although this prevalence was higher than that of previous studies conducted in the Western countries, it was difficult to draw any conclusion. In all the review articles, only these two articles used IIEF-5 to diagnose ED. Therefore, it was difficult to ascertain the differences of the prevalence arised were due to ethnic and cultural differences, or purely just the methodological differences. Further studies would be warranted to explain these differences.

Nevertheless, in the current meta-analysis, we demonstrated that the prevalence and odds of sexual dysfunction among patients on buprenorphine were both lower than the methadone group. The difference was because buprenophine acted as a partial μ-agonist and a pure κ-antagonist at the opioid receptors. The antagonism of buprenorphine κ-opioid receptor might have possibly counteracted on the μ-opioid receptor-mediated depression of the gonadal axis. Hence, buprenorphine had little influence on testosterone levels [22]. In contrast, methadone had a significant reduction in the influence of baseline testoterone levels. Due to this, higher risk of sexual dysfunctions were often reported among the male methodone patients.

In the sub-analysis of the subtypes of the sexual dysfunction, hypoactive sexual desire and low libido were the most prevalent sexual dysfunctions among the study subjects, accounting for 51%, respectively (95% CI, 0.27–0.74). The hypoactive sexual desire could have been caused by the methadone-induced suppression of testosterone levels that was mediated by the inhibition of hypothalamic Gonadotropin-releasing hormone production, which also had a direct effect in the reduction of testicular testosterone secretion [24]. Although it had been demonstrated in animal studies that testosterone had direct effects on erectile tissue, it was less clear in humans. Therefore, the causes of ED remained unclear. In addition, only four studies had specifically examined other subtypes of sexual dysfunction apart from ED, which increased issues of biases.

We noted several limitations to this meta-analysis. As we mentioned earlier, the primary studies that were reviewed varied in terms of the patients, interventions, outcomes and methods. Numbers of factors such as methadone dosage, methadone duration, age group of the patients, time of assessment, depression, and definition of sexual dysfunction were different across the studies. Such factors could have been the confounding factors that affected the prevalence rate [42–44]. Furthermore, studies that were reviewed were of variable quality, and seven of them were rated as having medium-to-high risk of bias (Table 3). Besides, the selection of only English language and published studies could have been another source of susceptibility to publication bias, which might have affected the prevalence rates. This likelihood of bias is illustrated in the funnel plot (Figure 3).

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References

Several conclusions could be drawn from this systematic review of the literature on the prevalence of sexual dysfunction in this specific population. First, the information in many of the reports was insufficient to provide valid data on prevalence rates and therefore could not be generalized or used to draw conclusions from comparisons with other studies. Second, the methods used to obtain information on sexual function varied considerably. Differences in definitions (derived from various questionnaires) were the main hindrance when comparing those reported prevalences. Third, we demonstrated that the prevalence and odds of sexual dysfunction were higher among the group of patients on methadone than the buprenorphine group. Therefore, one therapeutic option was to change patients from consuming methadone to buprenorphine if the patients had sexual difficulty while on methadone treatment. Nevertheless, we concluded that it was crucial to further investigate the influence of buprenorphine on sexual dysfunction in the near future.

Conflict of Interest: The author(s) report no conflicts of interest.

Statement of Authorship

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References

Category 1

  • (a)
    Conception and Design
    Anne Yee; Chong Guan Ng; Huai Seng Loh
  • (b)
    Acquisition of Data
    Anne Yee; Helenna Maria bt Hisham Hashim; Huai Seng Loh; Chong Guan Ng
  • (c)
    Analysis and Interpretation of Data
    Anne Yee; Helenna Maria bt Hisham Hashim

Category 2

  • (a)
    Drafting the Article
    Anne Yee; Helenna Maria bt Hisham Hashim
  • (b)
    Revising It for Intellectual Content
    Huai Seng Loh

Category 3

  • (a)
    Final Approval of the Completed Article
    Chong Guan Ng

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Statement of Authorship
  9. References
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