Introduction
Opioid dependence syndrome is a growing social problem. Opioid dependence syndrome usually requires long-term treatment and care to reduce personal risks, prevent criminal behavior, and improve the long-term physical and mental health of the individual. Several medications are used to treat opioid dependence syndrome. The buprenorphine-naloxone combination is one of the most effective drugs used to treat opioid dependence syndrome. It contains a 4:1 ratio of buprenorphine and naloxone. Buprenorphine-naloxone is effective in treating patients with opioid dependence syndrome; however, it has certain adverse effects which can affect treatment outcome [1]. Many patients discontinue maintenance therapy because of its side effects, with sexual dysfunction being one of the most common [2].
Regarding the effects of Opioid Substitution Therapy (OST) on sexual functioning, most of the existing research has focused on methadone [3]. Sexual dysfunctions due to opioids is thought to result from their effects on the gonadal–hypothalamic-pituitary axis [4]. Buprenorphine-naloxone combination has lower rates of sexual dysfunction when compared with methadone [5]. The bioavailability of naloxone and buprenorphine when given sublingually is 25% and more than 50% respectively. This systemic exposure to the mu receptor antagonist, naloxone, might influence sexual function [6].
In Outpatient Opioid Assisted Treatment (OOAT) clinics in Punjab, the buprenorphine-naloxone combination is the mainstay of treatment for patients diagnosed with opioid dependence syndrome. Though buprenorphine-naloxone is well tolerated by most patients, it has certain adverse effects. The patients on buprenorphine naloxone maintenance therapy frequently complain of sexual dysfunction and sleep disturbances. According to the literature, sexual dysfunctions and sleep disturbances are common in patients on buprenorphine-naloxone maintenance treatment [1]. There is also a paucity of literature on this subject in the Indian setting. Hence there was a need to study the effect of buprenorphine-naloxone maintenance treatment on sexual dysfunction.
Material and Methods
This cross-sectional study was conducted at the OOAT (Outpatient Opioid Assisted Treatment) clinic at a tertiary care centre of Punjab. Patients aged 18-60 years diagnosed with opioid dependence syndrome according to ICD 10 criteria and on buprenorphine-naloxone maintenance treatment for at least 6 months who consented to participate, were included in the study. Patients with comorbid medical illness. (HIV, HBsAg, and HCV screening was done), those reciving treatment for other psychiatric illness were excluded from the study. Patients who were taking substances other than opioids like alcohol, benzodiazepines, barbiturates, cannabis, and stimulants within the 6 months preceding enrolment (except caffeine and nicotine) were also excluded from the study. Patients taking other illicit opioids like heroin, morphine, tramadol, and oxycodone (confirmed by urine screening tests and caregiver reports) those who were non-compliant with buprenorphine-naloxone treatment (confirmed by urine screening tests and caregiver reports) and having active opioid withdrawal symptoms (assessed clinically) were also excluded from the study.
A total sample size of 150 participants was included in the present study. Sample size was estimated using the following formula for a cross-sectional study with qualitative data [7]. Sample size = 4pq/L2
Where:
4: constant corresponding to a 95% confidence level
p: proportion of sexual dysfunction in patients treated with buprenorphine naloxone,
which is 40% [5]
q: 100-p = 60%
L: allowable error = 8%
After substituting these values in the above formula, the sample size estimated was 150. Thus, in the present study 150 participants were enrolled using a simple random sampling method.
Institutional Ethical clearance and written informed consent from all participants were obtained.
Almost 320 patients were screened in the OOAT clinic, of which 260 fulfilled inclusion and exclusion criteria. Fifty of them refused to give consent. Of the remaining 210 patients, 60 did not follow up and finally, 150 were included in the analysis Participants were verbally interviewed, during which the investigator obtained a brief sociodemographic details of the participants followed by a history of medical comorbidities like hypertension, diabetes mellitus, cardiac disorder, any ongoing long-term chronic illness, or current medication use. Participants included in the study were then evaluated for sexual dysfunction and the type of sexual dysfunction by using Arizona Sexual Experience Scale (ASEX) [8].
Statistical analysis
Data were collected and compiled using Microsoft Excel 2016 and then analyzed using SPSS 20.0 version. The means and standard deviations (SD) were calculated for the continuous variables. Descriptive statistics like frequency and percentage were used to summarize the data. A p-value of <0.05 was considered statistically significant.
Results
Table 1 describes the demographic profile of the study population. The mean age of the sample population was around 41 years and about 30% of them were educated up to mid-school. Sikhs formed the major religious group in the study sample (85%) and only 4 % of them were unemployed. The majority of them belonged to the upper lower and middle socio-economic class with 84% of them currently working.
| Parameter (N = 150) | Mean ± S.D. (Min.- Max.)/ Frequency (%) | |
| Age in years | 40.63 ± 11.29 (19-60) | |
| Education in years | 6.48 ± 4.46 (0-16) | |
| Religion | Sikh | 127 (84.7%) |
| Hindu | 21 (14%) | |
| Muslim | 1 (0.7%) | |
| Christian | 1 (0.7%) | |
| Marital Status | Married | 128 (85.3%) |
| Unmarried | 16 (10.7%) | |
| Separated | 3 (2.0%) | |
| Widowed | 3 (2.0%) | |
| Occupation | Farmer | 56 (37.3%) |
| Labourer | 50 (33.3%) | |
| Employed | 38 (25.3%) | |
| Unemployed | 6 (4.0%) |
Among the 150 participants, the most frequently prescribed buprenorphine–naloxone dose was 4 mg + 1 mg, used by 48 patients (32.0%), followed by 2 mg + 0.5 mg in 41 patients (27.3%). Together, these two dose regimens accounted for nearly 60% of the sample. Higher-dose regimens of 6 mg + 1.5 mg and 8 mg + 2 mg were used by 10.0% and 8.0% of patients, respectively, while the remaining lower-dose regimens were prescribed to smaller proportions of participants [Table 2].
| Dose in mg (N=150) | No. of Patients (%) |
| 4 + 1 | 48 (32%) |
| 2 + 0.5 | 41 (27.3%) |
| 6 + 1.5 | 15 (10%) |
| 8 + 2 | 12 (8%) |
| 1.6 + 0.4 | 11 (7.3%) |
| 0.8 + 0.2 | 11 (7.3%) |
| 3.2 + 0.8 | 6 (4%) |
| 1.2 + 0.3 | 6 (4%) |
Among the 150 participants, the mean total Arizona Sexual Experience Scale (ASEX) score was 11.53 ± 4.97. Of the individual ASEX domains, the highest mean score was observed for erection (2.71 ± 1.18), followed by satisfaction with orgasm (2.61 ± 1.17). The lowest mean score was recorded for arousal (2.00 ± 1.02) [Table 3].
| Sr. No. | ASEX Score (N = 150) | Mean (S.D.) |
| 1. | Desire/ Drive | 2.06 (1.04) |
| 2. | Arousal | 2.00 (1.02) |
| 3. | Erection | 2.71 (1.18) |
| 4. | Ability to reach Orgasm | 2.25 (1.08) |
| 5. | Satisfaction with Orgasm | 2.61 (1.17) |
| 6. | Total Score | 11.53 (4.97) |
Table 4 shows that 17.33% of patients had sexual dysfunction as per ASEX Score with erectile dysfunction being the most common domain of dysfunction.
| ASEX Domain (N =150) | Frequency (%) |
| Desire/ Drive | 2 (1.3%) |
| Arousal | 1 (0.66%) |
| Erection | 11 (7.33%) |
| Ability to reach Orgasm | 2 (1.3%) |
| Satisfaction with Orgasm | 9 (6%) |
| Any 3 items >4 | 26 (17.33%) |
| Total Score >19 | 16 (10.67%) |
Participants with sexual dysfunction had significantly higher scores in all ASEX domains and on the total ASEX score than those without sexual dysfunction ( p<0.01 ), indicating greater impairment in desire, arousal, erection, orgasm, and orgasmic satisfaction [Table 5].
| ASEX Domain (N=150) | Sexual Dysfunction Present (N=26) | Sexual Dysfunction Absent (N =124) | t value, p value |
| Desire/ Drive | 3.65 ± 0.85 | 1.73 ± 0.71 | 12.11, <0.01* |
| Arousal | 3.62 ± 0.80 | 1.66 ± 0.69 | 12.81, <0.01* |
| Erection | 4.42 ± 0.50 | 2.35 ± 0.95 | 10.79, <0.01* |
| Ability to reach Orgasm | 3.92 ± 0.48 | 1.90 ± 0.81 | 12.23, <0.01* |
| Satisfaction with Orgasm | 4.38 ± 0.57 | 2.23 ± 0.88 | 11.87, <0.01* |
| Total Score | 19.42 ± 2.61 | 9.88 ± 3.56 | 12.92, <0.01* |
Table 6 compares age and daily buprenorphine–naloxone doses between participants with and without sexual dysfunction. The sexual-dysfunction group was significantly older (53.23 ± 7.15 vs. 37.99 ± 10.17 years) and received significantly higher doses of buprenorphine (5.80 ± 1.97 vs. 2.92 ± 1.60 mg) and naloxone (1.45 ± 0.49 vs. 0.73 ± 0.40 mg) than the group without sexual dysfunction ( p<0.01 ).
| Parameter | Sexual Dysfunction Present (N=26) | Sexual Dysfunction Absent (N =124) | t value, p value |
| Age | 53.23 ± 7.15 | 37.99 ± 10.17 | 7.26, <0.01* |
| Dose of Buprenorphine | 5.80 ± 1.97 | 2.92 ± 1.60 | 7.98, <0.01* |
| Dose of Naloxone | 1.45 ± 0.49 | 0.73 ± 0.40 | 7.98, <0.01* |
Discussion
In our study, 17.33% of the patients were found to have sexual dysfunction using the Arizona Sexual Experience Scale (ASEX) scale with a mean ASEX Score of 11.53 ± 4.97 and a mean dose of buprenorphine 3.41 ± 1.99 mg per day and naloxone of 0.85 ± 0.49 mg per day. The data available on prevalence studies on sexual dysfunction during OST are quite variable. The study conducted by Mattoo SK et al [5] found a 40% prevalence of sexual dysfunction on mean BNX dose of 4.5 (±1.6) mg per day and Tripathi R et al. [9] reported findings at a mean dose of 10.2 (SD 3.8) mg per day. A meta-analysis by Yee A et al. [2] found the aggregate prevalence as 24%. However, a study from India by Ramdurg S et al. reported sexual dysfunction among 83% of men on buprenorphine [10]. The high variability in the reported prevalence may be attributed to differences in study designs and sample populations.
In our study, patients suffered from dysfunction in all stages of sexual cycle with erection issues being commonest. Mattoo SK et al. found a higher prevalence of sexual dysfunction in their study with hypoactive sexual desire in 92.5%, hypo-arousal, and ED in 77.5%, orgasmic dissatisfaction in 52.5%, and intercourse dissatisfaction in 95% [5]. The possible causes of sexual dysfunction in patients taking opioids are still under speculation. Evidence from most of the studies suggests that opioids cause testosterone levels to decrease; the underlying mechanism may involve inhibition of the pulsatile release of gonadotropin-releasing hormone, followed by inhibition of the secretion of follicle-stimulating hormone and luteinizing hormone, and finally inhibition of testosterone production [4].
The study found sexual dysfunction to have a significant correlation with higher age (p<0.01), buprenorphine dose (p<0.01), and naloxone dose (p<0.01). In a meta-analysis by Yee A et al., there was a significant association between younger age (<50 years) and opioid use duration (>3 years) with erectile dysfunction [2]. This study showed that opioid-dependent men on buprenorphine-naloxone maintenance treatment had poor sexual functioning. The significant correlation of buprenorphine-naloxone treatment and sexual dysfunction might impact treatment adherence. The suspected aphrodisiac effect of illicit opioids might result in non-compliance to treatment and relapse. This study highlights that the clinicians who prescribe buprenorphine-naloxone treatment should be aware of this correlation and should routinely assess patients for complaints of sexual dysfunction.
Limitations
This study had certain limitations. The study was carried out in a small sample of a single OOAT clinic-based population, and hence the findings could not be generalized to other population groups. In this study, hormonal assays were not performed and no instrument was used to assess the opioid withdrawal symptoms. In addition, information regarding sexual dysfunction before the initiation of the buprenorphine-naloxone treatment was not available. All participants being men and the majority being young and chronic opioid users, which further limits the generalizability of this study.
Conclusion
This study showed that patients on buprenorphine-naloxone maintenance treatment of opioid dependence may experience sexual dysfunction particularly erectile dysfunction and reduced satisfaction after intercourse. Though this study shows a positive correlation between the dose of buprenorphine and naloxone and sexual dysfunction, other factors like age could also contribute to the sexual side effects.
Future Directions
Future research should employ longitudinal designs with repeated assessments of sexual functioning to establish the temporal sequence and clarify the potential causal relationship between buprenorphine–naloxone treatment variables, particularly dose, and sexual dysfunction. Studies involving larger, more diverse, and adequately powered samples are required to improve the precision and generalizability of the findings. In addition, well-designed interventional studies are warranted to evaluate whether dose optimization, modification of pharmacotherapy, or targeted interventions for sexual dysfunction improve sexual outcomes and overall treatment adherence among individuals receiving buprenorphine–naloxone maintenance therapy.
Declarations
Acknowledgements
NIL
Conflict of interests
NIL
Sources of Funding
None
Ethical Clearance
The study was approved by the Institutional Ethics Committee of Institute of Mental Health, Amritsar.