Effects of Melatonin and Zolpidem on Sleep Quality and General Health Status in Patients Undergoing Methadone Maintenance Treatment: A Comparative Study

Effects of Melatonin and Zolpidem on Sleep Quality and General Health Status in Patients Undergoing Methadone Maintenance Treatment: A Comparative Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Melatonin and Zolpidem on Sleep Quality and General Health Status in Patients Undergoing Methadone Maintenance Treatment: A Comparative Study Zahra Amini, Negin Etminani, Mina Moeini, Ebrahim Heidari-Farsani This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6683560/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and Aim: Substance use disorder (SUD) and the subsequent symptoms of withdrawal are likely to impact all life aspects, including poor sleep quality and low general health status. In view of that, poor sleep quality is simultaneously considered as a side effect and a risk factor. Against this background, the present study was to compare the effects of melatonin (MEL) and zolpidem (ZPD) on sleep quality and general health status in patients undergoing methadone maintenance treatment (MMT). Methods In total, 105 male patients on MMT, referred to outpatient addiction treatment centers, were divided into three groups, viz., MEL, ZPD, and placebo (PBO), using a randomized clinical trial (RCT) design with a control group (CG) (N = 35 in each group). The intervention groups were then given MEL (9 mg) 30 min before bedtime and ZPD (10 mg) right before it. At the pre- and post-intervention stages, all participants also completed the Pittsburgh Sleep Quality Index (PSQI) and the General Health Questionnaire-28 (GHQ-28). Results As compared to ZPD and PBO, MEL reduced sleep onset latency (p = 0.003) and daytime dysfunction (p = 0.043). Both MEL (p = 0.001) and ZPD (p = 0.022) further improved sleep quality, wherein the MEL group obtained a higher score. Moreover, MEL was shown to be more effective than ZPD and PBO in terms of lowering anxiety (p = 0.013) and depression (p < 0.001), as well as promoting general health status (p < 0.001). Conclusion The study results revealed that MEL could successfully enhance sleep quality and general health status in patients on MMT in comparison to ZPD and PBO. Trial Registration The research protocol has been also listed on the Iranian Registry of Clinical Trials (IRCT) with the code no. IR20201214049718N1(date: 25/01/2021) Methadone Melatonin Zolpidem Sleep General Health Figures Figure 1 Highlights • Substance use disorder causes poor sleep quality, as a risk factor for relapse after treatment, along with low general health status. • Long-term use of sleeping pills gives rise to tolerance and dependence, so it is not advised during withdrawal. • Melatonin, as compared to zolpidem and placebos, may improve sleep quality and mental health status in patients on methadone maintenance treatment. 1. Introduction Sleep disorders, defined as “a group of conditions that disturb normal sleep patterns”, are common in the modern world, and they among the most frequent mental health issues facing the human being. As reported, 30–40% of the adult population in the United States are experiencing insomnia ( 1 ). In the Netherlands, 32% of the population have general sleep disturbances and 43% of the cases are suffering from sleep deprivation ( 2 ). This has been even higher, up to 60%, among students in Norway ( 3 ). No surprise that sleep epidemiology is now a rapidly growing field ( 4 ). Of note, one more typical way that sleep disturbances might present themselves is insomnia, which has been so far associated with numerous psychological disorders. Studies have accordingly demonstrated that insomnia can be both a symptom of depression ( 5 ) and one of its risk factors ( 6 ). It is also likely to redouble the risk of depression in patients ( 7 ) and just easily increase anxiety disorders ( 8 , 9 ). Such conditions are thus assumed as risk factors for substance use disorders (SUD) development or relapse. Sleep disorders are now prevalent in patients with SUD or those suffering from withdrawal. Such disorders are seen in 75–84% of the cases ( 10 ). Withdrawal is also correlated with increased sleep onset latency and lower attentiveness during the day ( 11 ). Patients with SUD and those on methadone maintenance treatment (MMT) thus tend to sleep in the daytime, which results in a reduction in nighttime sleep quality ( 12 , 13 ). In the course of withdrawal, sleep disturbances further cause depression, stress, anxiety, low cognitive ability, and decreased pain tolerance, which lead to erosion in mental health status, treatment failure, and many relapses ( 14 ). Long-term MMT, while helping with some symptoms of withdrawal, does not alleviate the aforementioned sleep disorders. Patients undergoing MMT accordingly have poor sleep efficiency, shorter sleep total time, more awakenings, reduced rapid eye movement (REM) sleep, and shorter duration of slow wave sleep ( 14 , 15 ). All through MMT, patients are thus under personal and social pressure and at a high risk of developing or suffering from mental disorders, even without the added risk of sleep disturbances ( 16 ). A wide variety of treatments are currently available, including multidimensional behavioral and cognitive interventions to enhance sleep quality and general health status ( 17 ). One such medical intervention practiced is zolpidem (ZPD) use, which improves sleep onset latency and duration in individuals with insomnia, although it has some side effects, such as headache, dizziness, sleepiness, nausea, disorientation, and vomiting ( 18 ). ZPD has been historically utilized to treat insomnia in patients with SUD ( 16 ); however, the complications and the tendency for its use cause dependence, as a very real concern in patients undergoing treatment. Accordingly, it is less than ideal in such populations ( 19 ). Another medication utilized for this purpose is melatonin (MEL) that can lower sleep onset latency and help improve sleep hygiene, thereby reducing the risk of relapses ( 20 ). It can also be safely used in younger populations, promote their general health status, and decrease the risk of anxiety disorders in their cohorts suffering from insomnia ( 21 ). As well, MEL is well tolerated by patients and has no long- or short-term negative effects. Its administration has been additionally found to be successful and simple in children, adolescents, adults, and women with sleep problems, such as sleep onset latency, short sleep duration, and poor sleep quality ( 22 ). Even though there are studies on the role of either MEL or ZPD as sleep aids in patients with SUD, undergoing withdrawal or being treated with MMT, ZPD has thus far had good results in patients on MMT ( 23 ) as compared to MEL ( 24 ). Aim Considering the high withdrawal rate in MMT programs alongside sleep and general health problems in patients with SUD, not many studies have to date compared the effects of MEL and ZPD. Accordingly, the present study aimed to compare the both medications in patients with SUD undergoing MMT. 2. Methods 2.1. Study Design This study was conducted on 105 patients on MMT, referred to outpatient addiction treatment centers in Isfahan, Iran, from 2020 to 2021, using a randomized clinical trial (RCT) design with a control group (CG) (Code no. IR20201214049718N1). The study approval (Code no. IR.MUI.MED.REC.1399.813) was granted by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran 2.2. Participants The statistical population included adult patients with SUD undergoing MMT. The sample size was thus estimated as 32 individuals in each group, with reference to a similar study with 80% test power and 95% confidence interval (CI). Considering the 20% sample loss, the final sample size in each group was determined to be 40 patients. The researcher then referred to the selected centers for sampling of the convenience type. For this purpose, first, the patients with SUD on MMT were examined in terms of meeting the inclusion criteria. Next, the study objectives and procedure, data confidentiality, and the voluntary basis of participation and withdrawal from the study were presented during face-to-face meetings with the eligible individuals. Afterward, those who agreed to participate in the study signed an informed consent form. Finally, out of 123 patients with SUD, referred to the addiction treatment centers concerned, 118 individuals with a history of at least three months of receiving methadone (MTD) met the inclusion criteria, of which 105 cases agreed to participate in the study. The convenience sampling technique was further applied to select 105 patients, which were subsequently divided into three groups, namely, MEL, ZPD, and placebo (PBO) (N = 35 in each group), using the Random Allocation software. The inclusion criteria were the male patients showing consent to participate in the study, being at least 18, and having the ability to read and write, whose SUD had been confirmed via a positive urine test. They also had obtained the > 5 score in the Pittsburgh Sleep Quality Index (PSQI) and had no contraindications for ZPD, such as respiratory compromise, depression, or suicidal thoughts as well as allergy to this medication or its active metabolites or taking any other medications with known adverse interactions ( 25 ). The participants had also been treated with MMT for at least three months. In contrast, the exclusion criteria were some modifications in the treatment regimen for any reason prior to the intervention, as well as a history of severe allergy to MEL or ZPD. Those in charge of data collection and statistical analysis were also blinded to the study groups and participant assignment. The CONSORT flow diagram of the study is illustrated in Fig. 1 . 2.3. Data Collection The demographic characteristics information of the participants, such as age, educational attainment, employment type, and marital status were initially collected. Additionally, all participants completed the PSQI and the General Health Questionnaire-28 (GHQ-28) at the pre- and post-intervention stages. 2.3.1. PSQI The PSQI was developed by Buysee et al. (1989) to evaluate sleep quality in patients over the previous month ( 26 ). It included 18 elements, divided into seven categories of subjective sleep quality, sleep onset latency, sleep duration, sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. Each item was also scored on a scale of zero to three, in the range of extremely good (zero), moderately good ( 1 ), comparatively terrible ( 2 ), and very awful ( 3 ). The PSQI global score could further vary from 0 to 21, so the score of five or above showed inadequate sleep quality. Of note, there was a negative relationship between sleep quality and overall PSQI score. As well, Fathi-Ashtiani and Dastani (2009) had already assessed the validity and reliability of the Persian version of this questionnaire (α = 0.89) ( 27 ). 2.3.2. GHQ-28 The GHQ-28, created by Goldenberg (1978), was a screening tool for different mental disorders ( 28 ). This questionnaire was available in four versions, viz., 12, 28, 30, and 60, but the 28-item form was administered in this study. Items no. 1–7 were thus about physical symptoms and general health status, items no.14–18 were associated with anxiety, and items no.15–21 and 22–28 were on the subjects of social dysfunction and depression, respectively. Each item was also scored on a Likert-type scale from zero to three, with the maximum score of 84. Notably, there was a positive relationship between the GHQ-28 score and mental health status. As well, Taghavi (2002) (α = 0.90) had by this time established the validity and reliability of the Persian version of this questionnaire ( 29 ). 2.4. Intervention The participants assigned to the intervention groups were visited by a physician every two weeks. Then, the first group was given MEL and received MMT according to the treatment plan, and the second group took ZPD and was on MMT in the same way. All patients took MTD syrup once in the morning and once four hours before bedtime. The individuals in the first group also used three MEL (3 mg) pills (9 mg in total) half an hour before bedtime, and those in the second group received ZPD (10 mg) pills just before bedtime. In the CG, MTD and PBO were also given to the participants in line with the treatment plan, and their referrals were arranged every two weeks to receive MTD and PBO and have visits by a physician or a nurse. The patients in the PBO group additionally took starch-filled capsules half an hour before bedtime. Notably, all the study participants were asked not to change their diet and medications at the end of the study. 2.5. Statistical Analysis The IBM SPSS Statistics (ver.21) software was run to analyze the data. The quantitative data were thus reported as mean ± standard deviation (SD) and the qualitative ones were presented as frequency and percentage. Moreover, the qualitative data were analyzed using Kruskal-Wallis test, Chi-square test, or one-way analysis of covariance (ANCOVA). On the other hand, Wilcoxon signed-rank test and paired-samples t-test were recruited to analyze the quantitative data. Besides, p-value < 0.05 was expressed as the statistical significance. 3. Results In total, 123 patients with SUD were evaluated in this study, of whom five individuals did not meet the inclusion criteria, three cases refused to sign the consent from, and 10 individuals failed to show up for the intervention. In the end, 105 male participants were recruited and assigned to the study groups. Some patients did not also adhere to the intervention protocol or come in for the follow-up, so they were excluded. Out of 105 patients, 98 ended the trial with 34, 32, and 32 cases in the MEL and ZPD groups and CG, respectively (Fig. 1 ). No statistically significant difference was further observed in the study groups in terms of age, employment type, marital status, smoking status, and educational attainment. All groups were also similar in terms of their PSQI and GHQ-28 scores (Table 1 ). Moreover, both intervention groups showed significant improvement in sleep onset latency (P < 0.05), as compared to the CG. The patients in the ZPD group also experienced a significant reduction in their sleep disturbance score (p = 0.019). Besides, the MEL group had a significant drop in their daytime dysfunction (p = 0.045). Although both intervention groups showed a significant fall in their total PSQI scores, a more significant reduction was seen in the MEL group (Table 2 ). As for the GHQ-28, there was a significant difference between the study groups with regard to anxiety (p = 0.013), depression (p < 0.001), and total score (p < 0.001), so MEL improved the anxiety (P = 0.008), depression (P < 0.001), and general health status (p < 0.001) scores. Of note, the MEL group was the only one with a significant decrease in their total score (Table 3 ). Table 1 Comparison of demographic factors and pre intervention scores among study groups P value Zolpidem = 32 Melatonin = 34 Control = 32 Studied variable 0.79* 35.9± 9.3 35.8± 9.6 37.2± 7.8 Age (year) Mean ± SD 0.28** 12 (35.3%) 22 (64.7%) 18 (57.9%) 16 (47.1%) 12 (37.5%) 20 (62.5%) Employed Unemployed Occupation, N (%) 0.54** 12 (35.3%) 22 (64.7%) 14 (41.2%) 20 (58.8%) 9 (28.1%) 23 (71.9%) Married Single Marriage status, N (%) 0.93** 30 (88.2%) 4 (11.8%) 29 (85.3%) 5 (14.7%) 28 (87.5%) 4 (12.5%) Yes No Smoking, N (%) 0.72*** 11 (32.4%) 17 (50%) 5 (14.7%) 1 (2.9%) 0 (0%) 14 (41.2%) 14 (41.2%) 2 (5.9%) 2 (5.9%) 2 (5.9%) 8 (25%) 19 (54.9%) 4 (12.5%) 1 (3.1%) 0 (0%) Illiterate Less than Diploma Diploma Bachelorette Master Education Level, N (%) 0.66* 8.87± 3.26 8.26± 2.79 8.29± 3.22 Pittsburgh sleep quality index score, mean ± SD 0.59* 34.51± 11.42 43.14± 11.54 32.50±10.53 General health questionnaire score, mean ± SD *** Kruskal-Wallis; ** Chi-Square; *one-way variance analysis Table 2 Mean of Pittsburgh sleep quality index score and its dimensions in patients under MMT Studied variable Before the intervention Mean ± Std After the intervention Mean ± Std P 1 P 2 subjective sleep quality Placebo Melatonin Zolpidem 1.59 ± 0.798 2.21 ± 0.845 1.53 ± 0.896 1.47 ± 0.897 1.56 ± 0.960 1.26 ± 0.836 0.402 0.005 0.222 0.466 sleep latency Placebo Melatonin Zolpidem 2.97 ± 1.555 3.09 ± 1.422 3.68 ± 1.408 3.09 ± 1.573 2.35 ± 1.667 2.73 ± 1.582 0.705 0.001 0.005 0.003 sleep duration Placebo Melatonin Zolpidem 1.25 ± 1.295 1.35 ± 1.178 1.21 ± 1.175 1.29 ± 1.06 1.12 ± 1.06 1.14 ± 1.03 0.280 0.106 0.245 0.992 habitual sleep efficiency Placebo Melatonin Zolpidem 0.87 ± 0.43 0.67 ± 0.29 0.93 ± 0.65 0.69 ± 0.31 0.40 ± 0.11 0.67 ± 0.29 0.431 0.244 0.114 0.299 sleep disturbances Placebo Melatonin Zolpidem 1.78 ± 0.55 1.64 ± 0.69 1.82 ± 0.71 1.62 ± 0.65 1.44 ± 0.56 1.47 ± 0.56 0.335 0.175 0.019 0.413 use of sleeping medications Placebo Melatonin Zolpidem 1.22 ± 1.09 1.41 ± 1.18 1.15 ± 1.05 1.38 ± 1.15 1.09 ± 0.79 1.12 ± 1.02 0.476 0.056 0.718 0.089 daytime dysfunction Placebo Melatonin Zolpidem 1.71 ± 0.95 1.55 ± 0.92 1.64 ± 0.91 1.78 ± 1.00 1.17 ± 0.86 1.55 ± 1.07 0.804 0.045 0.583 0.043 Total score Placebo Melatonin Zolpidem 8.29 ± 3.22 8.26 ± 2.79 8.87 ± 3.26 7.64 ± 3.14 5.82 ± 2.88 7.00 ± 3.42 0.133 0.001 0.022 0.080 P1: Wilcoxon Signed Ranks Test P2: Kruskal-Wallis Test Table 3 Mean of general health score and its dimensions in patients under MMT Studied variable Before the intervention Mean ± SD After the intervention Mean ± SD P 1 P 2 Partial Eta Squared Observed Power Physical domain Placebo Melatonin Zolpidem 8.25 ± 4.19 9.61 ± 4.86 9.00 ± 4.31 7.96 ± 3.89 8.38 ± 4.24 7.66 ± 3.85 0.670 0.085 0.051 0.462 0.016 0.179 Anxiety Placebo Melatonin Zolpidem 7.40 ± 3.24 9.97 ± 3.88 8.73 ± 3.20 6.90 ± 3.04 7.82 ± 3.75 7.55 ± 3.67 0.030 0.008 0.035 0.013 0.085 0.759 Social function Placebo Melatonin Zolpidem 9.03 ± 5.16 9.76 ± 5.22 9.20 ± 5.60 8.96 ± 5.26 9.44 ± 4.40 9.61 ± 4.60 0.956 0.730 0.685 0.842 0.004 0.076 Depression Placebo Melatonin Zolpidem 7.81 ± 2.92 13.79 ± 4.22 7.70 ± 4.46 8.43 ± 3.51 9.35 ± 3.70 7..32 ± 3.27 0.446 ˂0.001 0.692 ˂0.001 0.351 1 General health Placebo Melatonin Zolpidem 32.50 ± 10.53 43.14 ± 11.54 34.51 ± 11.42 32.28 ± 10.81 35.00 ± 9.09 32.33 ± 10.91 0.910 ˂0.001 0.309 ˂0.001 0.118 0.898 P1: Paired T-Test at 0.05 significance P2: At the 0.05 level of ANCOVA test by moderating the effect of pre-test Partial Eta Square interpret: 0.01 ∼ small, 0.06 ∼ medium, > 0.14 ∼ large 4. Discussion The study results demonstrated that MEL could have a more profound effect on sleep onset latency and daytime dysfunction, as compared to ZPD and PBO. However, no significant difference was spotted between all groups in terms of subjective sleep quality, sleep duration, sleep efficiency, and use of sleeping medications. MEL and ZPD were further given for four weeks and decreased the PSQI overall score significantly, with a greater reduction in the MEL group. In this line, Ghaderi et al. (2019) had reported that MEL could enhance sleep quality, sadness, and anxiety in patients undergoing MMT, as compared to PBO ( 30 ). Low, Choo, and Tan (2020) had similarly found that MEL could significantly improve sleep onset latency and sleep total time in a review study on the impact of MEL and its agonists on primary insomnia disorder and the like; however, they had raised some methodological issues that were likely to affect the quality of evidence ( 31 ). In a study on adults and children with primary sleep problems, Ferracioli-Oda, Qawasmi, and Bloch (2013) had further discovered that MEL might boost up sleep quality and duration, as compared to PBOs ( 32 ). Somewhere else, Kakhaki et al. (2020) had learned that MEL could expand sleep quality in patients with Parkinson’s disease ( 33 ). Moreover, Morera-Fumero, Fernandez-Lopez, and Abreu-Gonzalez (2020) had found that MEL had a good effect on people suffering from insomnia, so these patients could either discontinue or lower the dosage of benzodiazepines taken for primary insomnia ( 34 ). In a meta-analysis, Cuomo et al. (2017) had additionally shown that no intervention could adequately address all sleep difficulties in children with autism spectrum disorder (ASD). Nevertheless, the combined use of MEL, behavioral therapies, and parental education could successfully help deal with various sleep problems, as compared to other interventions ( 35 ). Of note, MEL could do more than regulating sleep and circadian rhythm. It was inextricably linked to entertainment, metabolism, immunity, and other functions of a healthy body ( 36 ). In a review by Onaolapo and Onaolapo (2018), MEL had been accordingly reported to affect drug-seeking behaviors, so neuroplasticity could assist patients during their withdrawal with more than just sleep regulation ( 37 ). Overall, it has been established that MEL could be an effective medication for improving sleep quality in different people with regard to their disabilities and age groups. These findings were in agreement with the results in the present study, indicating that sleep onset latency and daytime dysfunction could upgrade with high efficacy upon taking MEL. Considering the role of MEL in enhancing general health status, it could effectively reduce anxiety and depression and then increase the general health status scores, as compared to ZPD and PBO. In spite of this, there was no statistically significant difference between all study groups in terms of the physical and social functioning categories. Ghaderi et al. (2019) had also established that MEL could beneficially influence the general mood in individuals undergoing MMT ( 30 ). However, they had compared the patients using the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI), which was different from the GHQ-28 practiced in the present study, although the results were consistent. As a whole, the effects of MEL on mental health status in patients on MMT had been poorly investigated, so more research was needed to reach a clearer understanding of their relationship. Some studies, then again, had looked at the positive effects of agomelatine (AGO) as MEL agonists in treating and avoiding the recurrence of a generalized anxiety disorder (GAD) ( 38 ), but it was a MEL agonist and a serotonin receptor blocker whose impact might not be the same as MEL in isolation. Obviously, there were contradictory results in this respect, e.g., Bondi et al. (2018) had in a randomized, double-blind, PBO-controlled trial had found that MEL (5 mg) had been ineffective against anxiety, depression, and stress, as compared to PBO, in the male patients undergoing a residential treatment program ( 39 ). The discrepancy in their results could be further explained by lower MEL dosage and acute general health status in the patients compared to those in the present study. Furthermore, McCleery and Sharpley (2020) and Gendy (2020) had not reported the beneficial effects of MEL on sleep quality in patients with Alzheimer’s disease and unhealthy alcohol use, which might have been related to a low dosage of the medication ( 40 , 41 ). Of note, MEL had not improved mood disorders in the study by De Crescenzo et al. (2017), although there had been a much smaller sample size with a methodologically imperfect research design ( 42 ). In spite of this, some studies like the review and meta-analysis by Das, Prithviraj, and Mohanraj (2022) had concluded that MEL had brought no significant effects to sleep quality or benzodiazepine cessation in individuals with SUD, prompting more research in this regard ( 43 ). Thus far, the investigations on the effects of MEL on sleep quality and general health status in patients with SUD or those undergoing MMT have been contradictory and confusing. The results of the present study accordingly could add to the body of literature arguing for the role of MEL in improving sleep quality and mental health status in such patients. Therefore, more research is hoped to shed some light on this problem and paint a clearer picture. The study results additionally revealed that ZPD reduced sleep onset latency and daytime dysfunction just like MEL, if not quite as effective. While this medication did decrease the mean anxiety score in the patients according to the GHQ-28, it did not significantly impact their overall score. There were also some studies with similar results, e.g., Shen and Lin (2016) had reported that ZPD could significantly diminish the PSQI score in patients on MMT ( 23 ), while Stein et al. (2017) had indicated that ZPD could decrease sleep onset latency and generally enhance sleeping conditions in patients with a non-significant difference ( 44 ). Of note, ZPD was not free of risk as it could cause dependence and addiction. This had been well documented in many studies, such as Monti et al. (2017) who had concluded that the individuals with SUD taking ZPD had exhibited addiction and dependence with or without some mental health problems ( 45 ). Thus, extreme caution needed to be taken while prescribing this medication in patients in recovery. In other studies, ZPD plus MEL administration had shown a substantial influence on sleep quality in individuals with colorectal cancer; however, no significant change had been seen in sleep onset latency or quality, and neither MEL nor ZPD had significantly affected anxiety or sadness ( 10 ). 5. Limitations To interpret the study results, some limitations were taken into account. First, this RCT was conducted in only one addiction treatment center, located in an urban area in ​​Isfahan, Iran, which could reduce the generalizability of the results to all patients with SUD undergoing MMT. Second, sleep quality and general health status here were assessed using self-report scales; however, the implementation of some objective methods could be more useful in assessing the impact of the intervention programs in a better manner. Third, the effect of MEL and ZPD in the present study on sleep quality and general health status was not measured within long intervals after the completion of the one-month intervention program. Fourth, one of the major limitations was the mere inclusion of the male patients, partly due to the low number of female cases undergoing MMT who were willing to enter such studies and the social situations in Iran, making medical interventions for female patients much difficult. It was thus suggested to do more research, recruiting both genders as the study groups or laying focus on female patients to complement the body of literature. Of note, the nature of the intervention practiced in this study made it challenging to blind the participants. 6. Implications for Clinical Practice This study had some implications for clinical practice. In view of that, the study results highlighted the effectiveness of MEL in reducing anxiety and depression and boosting up general health status in patients with SUD on MMT. Therefore, healthcare providers could introduce MEL into treatment plans for such individuals to help diminish their anxiety and depression and then enhance their general health status and poor sleep quality. However, further research was needed to replicate such outcomes. In addition, it was recommended to conduct more studies to reflect on the challenges facing MEL administration in clinical practice from the perspective of healthcare providers and patients with SUD undergoing MMT, which could then aid in making decisions for the inclusion of MEL into the treatment plan of such populations. 7. Conclusion MEL could efficiently reduce sleep onset latency and daytime dysfunction in comparison to ZPD and PBO, as evidenced in the study results. Moreover, it could successfully decrease anxiety and depression and potentially improve general health status. Abbreviations Substance use disorder (SUD) Melatonin (MEL) Zolpidem (ZPD) Methadone maintenance treatment (MMT) Placebo (PBO) Pittsburgh Sleep Quality Index (PSQI) General Health Questionnaire-28 (GHQ-28). Declarations Acknowledgements The authors hereby would like to extend their gratitude to all participants and the staff in the addiction treatment centers concerned, who cooperated to fulfill this study. Appreciations also go to the Vice-Chancellor’s Office for Research affiliated to Isfahan University of Medical Sciences, Isfahan, Iran, for their financial support. Funding Not applicable. Author Contribution All authors contributed to the study procedures, data collection, and analysis. The authors prepared the first draft and read and approved the final version. Author details 1,2,4 Department of Community Medicine Isfahan University of Medical Sciences, Isfahan, Iran. 3 Isfahan University of Medical Sciences. Competing Interests The authors did not declare any conflict of interest. Consent to Publish Not applicable. Availability of data and material The data used in this study will be made available from the corresponding author upon reasonable request. Ethics Approval and Consent to Participate A written informed consent form was obtained from all participants once the study objectives and methods were explained. The Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran, correspondingly approved this study with the ethics code no. IR.MUI.MED.REC. 1399.813. Moreover, the principles of the Declaration of Helsinki (DoH) were met. References Dopheide JA. 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Sleep Disturbances and Substance Use Disorders: A Bi-Directional Relationship. Psychiatric Annals. 2016;46(7):408-12. Barati N, Amini Z. The effect of multicomponent sleep hygiene education on sleep quality and mental health in patients suffering from substance abuse. Current Psychology. 2020:1-7. Schroeck JL, Ford J, Conway EL, Kurtzhalts KE, Gee ME, Vollmer KA, et al. Review of safety and efficacy of sleep medicines in older adults. Clinical therapeutics. 2016;38(11):2340-72. Victorri-Vigneau C, Gérardin M, Rousselet M, Guerlais M, Grall-Bronnec M, Jolliet P. An update on zolpidem abuse and dependence. Journal of addictive diseases. 2014;33(1):15-23. Takahashi TT, Vengeliene V, Spanagel R. Melatonin reduces motivation for cocaine self-administration and prevents relapse-like behavior in rats. Psychopharmacology. 2017;234(11):1741-8. Castaño MY, Garrido M, Rodríguez AB, Gómez MÁ. Melatonin improves mood status and quality of life and decreases cortisol levels in fibromyalgia. Biological research for nursing. 2019;21(1):22-9. Xie Z, Chen F, Li WA, Geng X, Li C, Meng X, et al. A review of sleep disorders and melatonin. Neurological research. 2017;39(6):559-65. Shen J, Lin Y. Efficacy observation of zolpidem in improvement of sleep quality of patients received methadone maintenance treatment. Chinese Journal of Primary Medicine and Pharmacy. 2016:2052-4. Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen M, Mehrzad F, Bahmani F, et al. The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment. Addiction Biology. 2019;24(4):754-64. Bouchette D, Akhondi H, Quick J. Zolpidem. StatPearls. Treasure Island (FL)2022. Mollayeva T, Thurairajah P, Burton K, Mollayeva S, Shapiro CM, Colantonio A. The Pittsburgh sleep quality index as a screening tool for sleep dysfunction in clinical and non-clinical samples: A systematic review and meta-analysis. Sleep Medicine Reviews. 2016;25:52-73. Fathi-Ashtiani A, Dastani M. Psychological tests: Personality and mental health. Tehran: besat. 2009;46. Sterling M. General health questionnaire–28 (GHQ-28). Journal of physiotherapy. 2011;57(4):259. Taghavi S. Validity and reliability of the general health questionnaire (ghq-28) in college students of shiraz university. Journal of psychology. 2002;5(4):381-98. Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen M, Mehrzad F, Bahmani F, et al. The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment. Addiction biology. 2019;24(4):754-64. Low TL, Choo FN, Tan SM. The efficacy of melatonin and melatonin agonists in insomnia–An umbrella review. Journal of Psychiatric Research. 2020;121:10-23. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PloS one. 2013;8(5):e63773. Kakhaki RD, Ostadmohammadi V, Kouchaki E, Aghadavod E, Bahmani F, Tamtaji OR, et al. Melatonin supplementation and the effects on clinical and metabolic status in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. Clinical Neurology and Neurosurgery. 2020;195:105878. Morera-Fumero AL, Fernandez-Lopez L, Abreu-Gonzalez P. Melatonin and melatonin agonists as treatments for benzodiazepines and hypnotics withdrawal in patients with primary insomnia. A systematic review. Drug and Alcohol Dependence. 2020;212:107994. Cuomo BM, Vaz S, Lee EAL, Thompson C, Rogerson JM, Falkmer T. Effectiveness of sleep‐based interventions for children with autism spectrum disorder: a meta‐synthesis. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2017;37(5):555-78. Tonon AC, Pilz LK, Markus RP, Hidalgo MP, Elisabetsky E. Melatonin and Depression: A Translational Perspective From Animal Models to Clinical Studies. Frontiers in Psychiatry. 2021;12. Onaolapo OJ, Onaolapo AY. Melatonin in drug addiction and addiction management: Exploring an evolving multidimensional relationship. World J Psychiatry. 2018;8(2):64-74. Stein DJ, Ahokas A, Jarema M, Avedisova AS, Vavrusova L, Chaban O, et al. Efficacy and safety of agomelatine (10 or 25 mg/day) in non-depressed out-patients with generalized anxiety disorder: a 12-week, double-blind, placebo-controlled study. European Neuropsychopharmacology. 2017;27(5):526-37. Bondi CD, Kamal KM, Johnson DA, Witt-Enderby PA, Giannetti VJ. The Effect of Melatonin Upon Postacute Withdrawal Among Males in a Residential Treatment Program (M-PAWS): A Randomized, Double-blind, Placebo-controlled Trial. Journal of Addiction Medicine. 2018;12(3):201-6. McCleery J, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database of Systematic Reviews. 2020(11). Gendy MN, Lagzdins D, Schaman J, Le Foll B. Melatonin for treatment-seeking alcohol use disorder patients with sleeping problems: a randomized clinical pilot trial. Scientific Reports. 2020;10(1):1-10. De Crescenzo F, Lennox A, Gibson J, Cordey J, Stockton S, Cowen P, et al. Melatonin as a treatment for mood disorders: a systematic review. Acta Psychiatrica Scandinavica. 2017;136(6):549-58. Das A, Prithviraj M, Mohanraj PS. Role of Melatonin in the Management of Substance Addiction: A Systematic Review. Cureus. 2022;14(7):e26764. Stein MD, Kurth ME, Anderson BJ, Blevins CE. A Pilot Crossover Trial of Sleep Medications for Sleep-disturbed Methadone Maintenance Patients. J Addict Med. 2020;14(2):126-31. Monti JM, Spence DW, Buttoo K, Pandi-Perumal SR. Zolpidem’s use for insomnia. Asian journal of psychiatry. 2017;25:79-90. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6683560","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":462882416,"identity":"1b157f1f-139d-4809-90cb-d5efb15e2e6f","order_by":0,"name":"Zahra Amini","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIie3QPQuCQBjA8ccObDlovUm/ghKIH0eXXBScpEkOAv00gS3SqBzkcjTrFBFtLS1BW6dC42lbw/3hOHjgx70AqFT/mgfEEJslFhkG1Ryy/pGIfDqSGZkU3Yvr0Q32+a5YdJkLq7zS2FZCNKo7rc9JVPJTjKKMAOEe1FxCEIAgmSBtaA0EWoCaSogOy1dPAufyGIk5RTDg4RTPafFIrClCEE56Ypd8E7PwTLDNfSolZp6X3TtLTadhh1uYpIbRMPaUkf7936rhpuIXZUClUqlUM/oA/S5KAX44EcsAAAAASUVORK5CYII=","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Zahra","middleName":"","lastName":"Amini","suffix":""},{"id":462882417,"identity":"bfd804e6-a24b-4cc0-a140-1d9a89e6206b","order_by":1,"name":"Negin Etminani","email":"","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Negin","middleName":"","lastName":"Etminani","suffix":""},{"id":462882418,"identity":"42588395-88a5-4583-9949-aca34a896dbb","order_by":2,"name":"Mina Moeini","email":"","orcid":"","institution":"Isfahan University of Medical Sciences, Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mina","middleName":"","lastName":"Moeini","suffix":""},{"id":462882419,"identity":"7a1a7a21-613d-4664-bf68-da7abc959541","order_by":3,"name":"Ebrahim Heidari-Farsani","email":"","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Ebrahim","middleName":"","lastName":"Heidari-Farsani","suffix":""}],"badges":[],"createdAt":"2025-05-16 21:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6683560/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6683560/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83681396,"identity":"27993456-5f78-454b-a823-ef5255951c97","added_by":"auto","created_at":"2025-05-30 16:13:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":309890,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of patient participants\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6683560/v1/9fbed102dbee87937cc78d78.png"},{"id":85551006,"identity":"032cac33-dc55-4c4e-8348-97d55688ff4b","added_by":"auto","created_at":"2025-06-27 09:47:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1029454,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6683560/v1/2e0681a9-e0b0-42e7-913f-d97a658c619f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Melatonin and Zolpidem on Sleep Quality and General Health Status in Patients Undergoing Methadone Maintenance Treatment: A Comparative Study","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; Substance use disorder causes poor sleep quality, as a risk factor for relapse after treatment, along with low general health status.\u003c/p\u003e\u003cp\u003e\u0026bull; Long-term use of sleeping pills gives rise to tolerance and dependence, so it is not advised during withdrawal.\u003c/p\u003e\u003cp\u003e\u0026bull; Melatonin, as compared to zolpidem and placebos, may improve sleep quality and mental health status in patients on methadone maintenance treatment.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eSleep disorders, defined as \u0026ldquo;a group of conditions that disturb normal sleep patterns\u0026rdquo;, are common in the modern world, and they among the most frequent mental health issues facing the human being. As reported, 30\u0026ndash;40% of the adult population in the United States are experiencing insomnia (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In the Netherlands, 32% of the population have general sleep disturbances and 43% of the cases are suffering from sleep deprivation (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). This has been even higher, up to 60%, among students in Norway (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). No surprise that sleep epidemiology is now a rapidly growing field (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Of note, one more typical way that sleep disturbances might present themselves is insomnia, which has been so far associated with numerous psychological disorders. Studies have accordingly demonstrated that insomnia can be both a symptom of depression (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and one of its risk factors (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). It is also likely to redouble the risk of depression in patients (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and just easily increase anxiety disorders (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Such conditions are thus assumed as risk factors for substance use disorders (SUD) development or relapse.\u003c/p\u003e \u003cp\u003eSleep disorders are now prevalent in patients with SUD or those suffering from withdrawal. Such disorders are seen in 75\u0026ndash;84% of the cases (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Withdrawal is also correlated with increased sleep onset latency and lower attentiveness during the day (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Patients with SUD and those on methadone maintenance treatment (MMT) thus tend to sleep in the daytime, which results in a reduction in nighttime sleep quality (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In the course of withdrawal, sleep disturbances further cause depression, stress, anxiety, low cognitive ability, and decreased pain tolerance, which lead to erosion in mental health status, treatment failure, and many relapses (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Long-term MMT, while helping with some symptoms of withdrawal, does not alleviate the aforementioned sleep disorders. Patients undergoing MMT accordingly have poor sleep efficiency, shorter sleep total time, more awakenings, reduced rapid eye movement (REM) sleep, and shorter duration of slow wave sleep (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). All through MMT, patients are thus under personal and social pressure and at a high risk of developing or suffering from mental disorders, even without the added risk of sleep disturbances (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eA wide variety of treatments are currently available, including multidimensional behavioral and cognitive interventions to enhance sleep quality and general health status (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). One such medical intervention practiced is zolpidem (ZPD) use, which improves sleep onset latency and duration in individuals with insomnia, although it has some side effects, such as headache, dizziness, sleepiness, nausea, disorientation, and vomiting (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). ZPD has been historically utilized to treat insomnia in patients with SUD (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e); however, the complications and the tendency for its use cause dependence, as a very real concern in patients undergoing treatment. Accordingly, it is less than ideal in such populations (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Another medication utilized for this purpose is melatonin (MEL) that can lower sleep onset latency and help improve sleep hygiene, thereby reducing the risk of relapses (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). It can also be safely used in younger populations, promote their general health status, and decrease the risk of anxiety disorders in their cohorts suffering from insomnia (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). As well, MEL is well tolerated by patients and has no long- or short-term negative effects. Its administration has been additionally found to be successful and simple in children, adolescents, adults, and women with sleep problems, such as sleep onset latency, short sleep duration, and poor sleep quality (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEven though there are studies on the role of either MEL or ZPD as sleep aids in patients with SUD, undergoing withdrawal or being treated with MMT, ZPD has thus far had good results in patients on MMT (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) as compared to MEL (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003eAim\u003c/b\u003e \u003c/p\u003e \u003cp\u003eConsidering the high withdrawal rate in MMT programs alongside sleep and general health problems in patients with SUD, not many studies have to date compared the effects of MEL and ZPD. Accordingly, the present study aimed to compare the both medications in patients with SUD undergoing MMT.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study Design\u003c/h2\u003e \u003cp\u003eThis study was conducted on 105 patients on MMT, referred to outpatient addiction treatment centers in Isfahan, Iran, from 2020 to 2021, using a randomized clinical trial (RCT) design with a control group (CG) (Code no. IR20201214049718N1). The study approval (Code no. IR.MUI.MED.REC.1399.813) was granted by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Participants\u003c/h2\u003e \u003cp\u003eThe statistical population included adult patients with SUD undergoing MMT. The sample size was thus estimated as 32 individuals in each group, with reference to a similar study with 80% test power and 95% confidence interval (CI). Considering the 20% sample loss, the final sample size in each group was determined to be 40 patients. The researcher then referred to the selected centers for sampling of the convenience type. For this purpose, first, the patients with SUD on MMT were examined in terms of meeting the inclusion criteria. Next, the study objectives and procedure, data confidentiality, and the voluntary basis of participation and withdrawal from the study were presented during face-to-face meetings with the eligible individuals. Afterward, those who agreed to participate in the study signed an informed consent form. Finally, out of 123 patients with SUD, referred to the addiction treatment centers concerned, 118 individuals with a history of at least three months of receiving methadone (MTD) met the inclusion criteria, of which 105 cases agreed to participate in the study. The convenience sampling technique was further applied to select 105 patients, which were subsequently divided into three groups, namely, MEL, ZPD, and placebo (PBO) (N\u0026thinsp;=\u0026thinsp;35 in each group), using the Random Allocation software. The inclusion criteria were the male patients showing consent to participate in the study, being at least 18, and having the ability to read and write, whose SUD had been confirmed via a positive urine test. They also had obtained the \u0026gt;\u0026thinsp;5 score in the Pittsburgh Sleep Quality Index (PSQI) and had no contraindications for ZPD, such as respiratory compromise, depression, or suicidal thoughts as well as allergy to this medication or its active metabolites or taking any other medications with known adverse interactions (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The participants had also been treated with MMT for at least three months. In contrast, the exclusion criteria were some modifications in the treatment regimen for any reason prior to the intervention, as well as a history of severe allergy to MEL or ZPD. Those in charge of data collection and statistical analysis were also blinded to the study groups and participant assignment. The CONSORT flow diagram of the study is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Data Collection\u003c/h2\u003e \u003cp\u003eThe demographic characteristics information of the participants, such as age, educational attainment, employment type, and marital status were initially collected. Additionally, all participants completed the PSQI and the General Health Questionnaire-28 (GHQ-28) at the pre- and post-intervention stages.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1. PSQI\u003c/h2\u003e \u003cp\u003eThe PSQI was developed by Buysee et al. (1989) to evaluate sleep quality in patients over the previous month (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). It included 18 elements, divided into seven categories of subjective sleep quality, sleep onset latency, sleep duration, sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction. Each item was also scored on a scale of zero to three, in the range of extremely good (zero), moderately good (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e), comparatively terrible (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), and very awful (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The PSQI global score could further vary from 0 to 21, so the score of five or above showed inadequate sleep quality. Of note, there was a negative relationship between sleep quality and overall PSQI score. As well, Fathi-Ashtiani and Dastani (2009) had already assessed the validity and reliability of the Persian version of this questionnaire (α\u0026thinsp;=\u0026thinsp;0.89) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2. GHQ-28\u003c/h2\u003e \u003cp\u003eThe GHQ-28, created by Goldenberg (1978), was a screening tool for different mental disorders (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). This questionnaire was available in four versions, viz., 12, 28, 30, and 60, but the 28-item form was administered in this study. Items no. 1\u0026ndash;7 were thus about physical symptoms and general health status, items no.14\u0026ndash;18 were associated with anxiety, and items no.15\u0026ndash;21 and 22\u0026ndash;28 were on the subjects of social dysfunction and depression, respectively. Each item was also scored on a Likert-type scale from zero to three, with the maximum score of 84. Notably, there was a positive relationship between the GHQ-28 score and mental health status. As well, Taghavi (2002) (α\u0026thinsp;=\u0026thinsp;0.90) had by this time established the validity and reliability of the Persian version of this questionnaire (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Intervention\u003c/h2\u003e \u003cp\u003eThe participants assigned to the intervention groups were visited by a physician every two weeks. Then, the first group was given MEL and received MMT according to the treatment plan, and the second group took ZPD and was on MMT in the same way. All patients took MTD syrup once in the morning and once four hours before bedtime. The individuals in the first group also used three MEL (3 mg) pills (9 mg in total) half an hour before bedtime, and those in the second group received ZPD (10 mg) pills just before bedtime. In the CG, MTD and PBO were also given to the participants in line with the treatment plan, and their referrals were arranged every two weeks to receive MTD and PBO and have visits by a physician or a nurse. The patients in the PBO group additionally took starch-filled capsules half an hour before bedtime. Notably, all the study participants were asked not to change their diet and medications at the end of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Statistical Analysis\u003c/h2\u003e \u003cp\u003eThe IBM SPSS Statistics (ver.21) software was run to analyze the data. The quantitative data were thus reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and the qualitative ones were presented as frequency and percentage. Moreover, the qualitative data were analyzed using Kruskal-Wallis test, Chi-square test, or one-way analysis of covariance (ANCOVA). On the other hand, Wilcoxon signed-rank test and paired-samples t-test were recruited to analyze the quantitative data. Besides, p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was expressed as the statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eIn total, 123 patients with SUD were evaluated in this study, of whom five individuals did not meet the inclusion criteria, three cases refused to sign the consent from, and 10 individuals failed to show up for the intervention. In the end, 105 male participants were recruited and assigned to the study groups. Some patients did not also adhere to the intervention protocol or come in for the follow-up, so they were excluded. Out of 105 patients, 98 ended the trial with 34, 32, and 32 cases in the MEL and ZPD groups and CG, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). No statistically significant difference was further observed in the study groups in terms of age, employment type, marital status, smoking status, and educational attainment. All groups were also similar in terms of their PSQI and GHQ-28 scores (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Moreover, both intervention groups showed significant improvement in sleep onset latency (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), as compared to the CG. The patients in the ZPD group also experienced a significant reduction in their sleep disturbance score (p\u0026thinsp;=\u0026thinsp;0.019). Besides, the MEL group had a significant drop in their daytime dysfunction (p\u0026thinsp;=\u0026thinsp;0.045). Although both intervention groups showed a significant fall in their total PSQI scores, a more significant reduction was seen in the MEL group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). As for the GHQ-28, there was a significant difference between the study groups with regard to anxiety (p\u0026thinsp;=\u0026thinsp;0.013), depression (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and total score (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), so MEL improved the anxiety (P\u0026thinsp;=\u0026thinsp;0.008), depression (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and general health status (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) scores. Of note, the MEL group was the only one with a significant decrease in their total score (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Table 1\u003c/strong\u003e Comparison of demographic factors and pre intervention scores among study groups\u003c/p\u003e\n\u003cdiv align=\"right\"\u003e\n \u003ctable dir=\"rtl\" border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eZolpidem = 32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eMelatonin = 34\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eControl = 32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003eStudied variable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.79*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e35.9\u0026plusmn; 9.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e35.8\u0026plusmn; 9.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e37.2\u0026plusmn; 7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003eAge (year)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.28**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e12 (35.3%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e22 (64.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e18 (57.9%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e16 (47.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e12 (37.5%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e20 (62.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003eEmployed\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eUnemployed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003eOccupation,\u0026nbsp;\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eN (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.54**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e12 (35.3%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e22 (64.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e14 (41.2%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e20 (58.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e9 (28.1%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e23 (71.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003eMarried\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eSingle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003eMarriage status, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.93**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e30 (88.2%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e4 (11.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e29 (85.3%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e5 (14.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e28 (87.5%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e4 (12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003eYes\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003eSmoking,\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.72***\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e11 (32.4%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e17 (50%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e5 (14.7%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e1 (2.9%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e14 (41.2%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e14 (41.2%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e2 (5.9%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e2 (5.9%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e2 (5.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e8 (25%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e19 (54.9%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e4 (12.5%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e1 (3.1%)\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003eIlliterate\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eLess than Diploma\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eDiploma\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eBachelorette\u003c/p\u003e\n \u003cp dir=\"LTR\"\u003eMaster\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003eEducation Level, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.66*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e8.87\u0026plusmn; 3.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e8.26\u0026plusmn; 2.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e8.29\u0026plusmn; 3.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003ePittsburgh sleep quality index score, mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.2769%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u003cstrong\u003e0.59*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.9204%;\"\u003e\n \u003cp dir=\"LTR\"\u003e34.51\u0026plusmn; 11.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16.9154%;\"\u003e\n \u003cp dir=\"LTR\"\u003e43.14\u0026plusmn; 11.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.9254%;\"\u003e\n \u003cp dir=\"LTR\"\u003e32.50\u0026plusmn;10.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 23.7148%;\"\u003e\n \u003cp dir=\"LTR\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.2471%;\"\u003e\n \u003cp dir=\"LTR\"\u003eGeneral health questionnaire score, mean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;*** Kruskal-Wallis; ** Chi-Square;\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e*one-way variance analysis\u003c/p\u003e\n\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003c/table\u003e\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMean of Pittsburgh sleep quality index score and its dimensions in patients under MMT\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudied variable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore the intervention\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;Std\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter the intervention\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;Std\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esubjective sleep quality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.59\u0026thinsp;\u0026plusmn;\u0026thinsp;0.798\u003c/p\u003e\n \u003cp\u003e2.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.845\u003c/p\u003e\n \u003cp\u003e1.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.896\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.897\u003c/p\u003e\n \u003cp\u003e1.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.960\u003c/p\u003e\n \u003cp\u003e1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.836\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.402\u003c/p\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003cp\u003e0.222\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.466\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esleep latency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.97\u0026thinsp;\u0026plusmn;\u0026thinsp;1.555\u003c/p\u003e\n \u003cp\u003e3.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.422\u003c/p\u003e\n \u003cp\u003e3.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.408\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.573\u003c/p\u003e\n \u003cp\u003e2.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.667\u003c/p\u003e\n \u003cp\u003e2.73\u0026thinsp;\u0026plusmn;\u0026thinsp;1.582\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.705\u003c/p\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esleep duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;1.295\u003c/p\u003e\n \u003cp\u003e1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1.178\u003c/p\u003e\n \u003cp\u003e1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;1.175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.29\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e\n \u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.06\u003c/p\u003e\n \u003cp\u003e1.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.280\u003c/p\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003cp\u003e0.245\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.992\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehabitual sleep efficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e\n \u003cp\u003e0.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\n \u003cp\u003e0.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e\n \u003cp\u003e0.40\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11\u003c/p\u003e\n \u003cp\u003e0.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.431\u003c/p\u003e\n \u003cp\u003e0.244\u003c/p\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esleep disturbances\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\n \u003cp\u003e1.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e\n \u003cp\u003e1.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.62\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e\n \u003cp\u003e1.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\n \u003cp\u003e1.47\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.335\u003c/p\u003e\n \u003cp\u003e0.175\u003c/p\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.413\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003euse of sleeping medications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.22\u0026thinsp;\u0026plusmn;\u0026thinsp;1.09\u003c/p\u003e\n \u003cp\u003e1.41\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18\u003c/p\u003e\n \u003cp\u003e1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.38\u0026thinsp;\u0026plusmn;\u0026thinsp;1.15\u003c/p\u003e\n \u003cp\u003e1.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79\u003c/p\u003e\n \u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.476\u003c/p\u003e\n \u003cp\u003e0.056\u003c/p\u003e\n \u003cp\u003e0.718\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.089\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edaytime dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003c/p\u003e\n \u003cp\u003e1.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\n \u003cp\u003e1.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00\u003c/p\u003e\n \u003cp\u003e1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.86\u003c/p\u003e\n \u003cp\u003e1.55\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.804\u003c/p\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003cp\u003e0.583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.22\u003c/p\u003e\n \u003cp\u003e8.26\u0026thinsp;\u0026plusmn;\u0026thinsp;2.79\u003c/p\u003e\n \u003cp\u003e8.87\u0026thinsp;\u0026plusmn;\u0026thinsp;3.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.14\u003c/p\u003e\n \u003cp\u003e5.82\u0026thinsp;\u0026plusmn;\u0026thinsp;2.88\u003c/p\u003e\n \u003cp\u003e7.00\u0026thinsp;\u0026plusmn;\u0026thinsp;3.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eP1: Wilcoxon Signed Ranks Test\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003eP2: Kruskal-Wallis Test\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMean of general health score and its dimensions in patients under MMT\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudied variable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBefore the intervention\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAfter the intervention\u003c/p\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePartial Eta Squared\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eObserved Power\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhysical domain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.25\u0026thinsp;\u0026plusmn;\u0026thinsp;4.19\u003c/p\u003e\n \u003cp\u003e9.61\u0026thinsp;\u0026plusmn;\u0026thinsp;4.86\u003c/p\u003e\n \u003cp\u003e9.00\u0026thinsp;\u0026plusmn;\u0026thinsp;4.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.96\u0026thinsp;\u0026plusmn;\u0026thinsp;3.89\u003c/p\u003e\n \u003cp\u003e8.38\u0026thinsp;\u0026plusmn;\u0026thinsp;4.24\u003c/p\u003e\n \u003cp\u003e7.66\u0026thinsp;\u0026plusmn;\u0026thinsp;3.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.670\u003c/p\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.462\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.179\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnxiety\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.40\u0026thinsp;\u0026plusmn;\u0026thinsp;3.24\u003c/p\u003e\n \u003cp\u003e9.97\u0026thinsp;\u0026plusmn;\u0026thinsp;3.88\u003c/p\u003e\n \u003cp\u003e8.73\u0026thinsp;\u0026plusmn;\u0026thinsp;3.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.90\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003c/p\u003e\n \u003cp\u003e7.82\u0026thinsp;\u0026plusmn;\u0026thinsp;3.75\u003c/p\u003e\n \u003cp\u003e7.55\u0026thinsp;\u0026plusmn;\u0026thinsp;3.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.030\u003c/p\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.759\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSocial function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.03\u0026thinsp;\u0026plusmn;\u0026thinsp;5.16\u003c/p\u003e\n \u003cp\u003e9.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.22\u003c/p\u003e\n \u003cp\u003e9.20\u0026thinsp;\u0026plusmn;\u0026thinsp;5.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.96\u0026thinsp;\u0026plusmn;\u0026thinsp;5.26\u003c/p\u003e\n \u003cp\u003e9.44\u0026thinsp;\u0026plusmn;\u0026thinsp;4.40\u003c/p\u003e\n \u003cp\u003e9.61\u0026thinsp;\u0026plusmn;\u0026thinsp;4.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.956\u003c/p\u003e\n \u003cp\u003e0.730\u003c/p\u003e\n \u003cp\u003e0.685\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.842\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDepression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.81\u0026thinsp;\u0026plusmn;\u0026thinsp;2.92\u003c/p\u003e\n \u003cp\u003e13.79\u0026thinsp;\u0026plusmn;\u0026thinsp;4.22\u003c/p\u003e\n \u003cp\u003e7.70\u0026thinsp;\u0026plusmn;\u0026thinsp;4.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.43\u0026thinsp;\u0026plusmn;\u0026thinsp;3.51\u003c/p\u003e\n \u003cp\u003e9.35\u0026thinsp;\u0026plusmn;\u0026thinsp;3.70\u003c/p\u003e\n \u003cp\u003e7..32\u0026thinsp;\u0026plusmn;\u0026thinsp;3.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.446\u003c/p\u003e\n \u003cp\u003e˂0.001\u003c/p\u003e\n \u003cp\u003e0.692\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e˂0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.351\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGeneral health\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlacebo\u003c/p\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003cp\u003eZolpidem\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.50\u0026thinsp;\u0026plusmn;\u0026thinsp;10.53\u003c/p\u003e\n \u003cp\u003e43.14\u0026thinsp;\u0026plusmn;\u0026thinsp;11.54\u003c/p\u003e\n \u003cp\u003e34.51\u0026thinsp;\u0026plusmn;\u0026thinsp;11.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.28\u0026thinsp;\u0026plusmn;\u0026thinsp;10.81\u003c/p\u003e\n \u003cp\u003e35.00\u0026thinsp;\u0026plusmn;\u0026thinsp;9.09\u003c/p\u003e\n \u003cp\u003e32.33\u0026thinsp;\u0026plusmn;\u0026thinsp;10.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.910\u003c/p\u003e\n \u003cp\u003e˂0.001\u003c/p\u003e\n \u003cp\u003e0.309\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e˂0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.898\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003eP1: Paired T-Test at 0.05 significance\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003eP2: At the 0.05 level of ANCOVA test by moderating the effect of pre-test\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003ePartial Eta Square interpret: 0.01 \u0026sim; small, 0.06 \u0026sim; medium, \u0026gt;\u0026thinsp;0.14 \u0026sim; large\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n\u003c/table\u003e\n"},{"header":"4. Discussion","content":"\u003cp\u003eThe study results demonstrated that MEL could have a more profound effect on sleep onset latency and daytime dysfunction, as compared to ZPD and PBO. However, no significant difference was spotted between all groups in terms of subjective sleep quality, sleep duration, sleep efficiency, and use of sleeping medications. MEL and ZPD were further given for four weeks and decreased the PSQI overall score significantly, with a greater reduction in the MEL group.\u003c/p\u003e \u003cp\u003eIn this line, Ghaderi et al. (2019) had reported that MEL could enhance sleep quality, sadness, and anxiety in patients undergoing MMT, as compared to PBO (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Low, Choo, and Tan (2020) had similarly found that MEL could significantly improve sleep onset latency and sleep total time in a review study on the impact of MEL and its agonists on primary insomnia disorder and the like; however, they had raised some methodological issues that were likely to affect the quality of evidence (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). In a study on adults and children with primary sleep problems, Ferracioli-Oda, Qawasmi, and Bloch (2013) had further discovered that MEL might boost up sleep quality and duration, as compared to PBOs (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Somewhere else, Kakhaki et al. (2020) had learned that MEL could expand sleep quality in patients with Parkinson\u0026rsquo;s disease (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Moreover, Morera-Fumero, Fernandez-Lopez, and Abreu-Gonzalez (2020) had found that MEL had a good effect on people suffering from insomnia, so these patients could either discontinue or lower the dosage of benzodiazepines taken for primary insomnia (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In a meta-analysis, Cuomo et al. (2017) had additionally shown that no intervention could adequately address all sleep difficulties in children with autism spectrum disorder (ASD). Nevertheless, the combined use of MEL, behavioral therapies, and parental education could successfully help deal with various sleep problems, as compared to other interventions (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Of note, MEL could do more than regulating sleep and circadian rhythm. It was inextricably linked to entertainment, metabolism, immunity, and other functions of a healthy body (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). In a review by Onaolapo and Onaolapo (2018), MEL had been accordingly reported to affect drug-seeking behaviors, so neuroplasticity could assist patients during their withdrawal with more than just sleep regulation (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Overall, it has been established that MEL could be an effective medication for improving sleep quality in different people with regard to their disabilities and age groups. These findings were in agreement with the results in the present study, indicating that sleep onset latency and daytime dysfunction could upgrade with high efficacy upon taking MEL.\u003c/p\u003e \u003cp\u003eConsidering the role of MEL in enhancing general health status, it could effectively reduce anxiety and depression and then increase the general health status scores, as compared to ZPD and PBO. In spite of this, there was no statistically significant difference between all study groups in terms of the physical and social functioning categories. Ghaderi et al. (2019) had also established that MEL could beneficially influence the general mood in individuals undergoing MMT (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). However, they had compared the patients using the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory (BAI), which was different from the GHQ-28 practiced in the present study, although the results were consistent. As a whole, the effects of MEL on mental health status in patients on MMT had been poorly investigated, so more research was needed to reach a clearer understanding of their relationship. Some studies, then again, had looked at the positive effects of agomelatine (AGO) as MEL agonists in treating and avoiding the recurrence of a generalized anxiety disorder (GAD) (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e), but it was a MEL agonist and a serotonin receptor blocker whose impact might not be the same as MEL in isolation.\u003c/p\u003e \u003cp\u003eObviously, there were contradictory results in this respect, e.g., Bondi et al. (2018) had in a randomized, double-blind, PBO-controlled trial had found that MEL (5 mg) had been ineffective against anxiety, depression, and stress, as compared to PBO, in the male patients undergoing a residential treatment program (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). The discrepancy in their results could be further explained by lower MEL dosage and acute general health status in the patients compared to those in the present study. Furthermore, McCleery and Sharpley (2020) and Gendy (2020) had not reported the beneficial effects of MEL on sleep quality in patients with Alzheimer\u0026rsquo;s disease and unhealthy alcohol use, which might have been related to a low dosage of the medication (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Of note, MEL had not improved mood disorders in the study by De Crescenzo et al. (2017), although there had been a much smaller sample size with a methodologically imperfect research design (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). In spite of this, some studies like the review and meta-analysis by Das, Prithviraj, and Mohanraj (2022) had concluded that MEL had brought no significant effects to sleep quality or benzodiazepine cessation in individuals with SUD, prompting more research in this regard (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). Thus far, the investigations on the effects of MEL on sleep quality and general health status in patients with SUD or those undergoing MMT have been contradictory and confusing. The results of the present study accordingly could add to the body of literature arguing for the role of MEL in improving sleep quality and mental health status in such patients. Therefore, more research is hoped to shed some light on this problem and paint a clearer picture.\u003c/p\u003e \u003cp\u003eThe study results additionally revealed that ZPD reduced sleep onset latency and daytime dysfunction just like MEL, if not quite as effective. While this medication did decrease the mean anxiety score in the patients according to the GHQ-28, it did not significantly impact their overall score. There were also some studies with similar results, e.g., Shen and Lin (2016) had reported that ZPD could significantly diminish the PSQI score in patients on MMT (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), while Stein et al. (2017) had indicated that ZPD could decrease sleep onset latency and generally enhance sleeping conditions in patients with a non-significant difference (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Of note, ZPD was not free of risk as it could cause dependence and addiction. This had been well documented in many studies, such as Monti et al. (2017) who had concluded that the individuals with SUD taking ZPD had exhibited addiction and dependence with or without some mental health problems (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Thus, extreme caution needed to be taken while prescribing this medication in patients in recovery. In other studies, ZPD plus MEL administration had shown a substantial influence on sleep quality in individuals with colorectal cancer; however, no significant change had been seen in sleep onset latency or quality, and neither MEL nor ZPD had significantly affected anxiety or sadness (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eTo interpret the study results, some limitations were taken into account. First, this RCT was conducted in only one addiction treatment center, located in an urban area in ​​Isfahan, Iran, which could reduce the generalizability of the results to all patients with SUD undergoing MMT. Second, sleep quality and general health status here were assessed using self-report scales; however, the implementation of some objective methods could be more useful in assessing the impact of the intervention programs in a better manner. Third, the effect of MEL and ZPD in the present study on sleep quality and general health status was not measured within long intervals after the completion of the one-month intervention program. Fourth, one of the major limitations was the mere inclusion of the male patients, partly due to the low number of female cases undergoing MMT who were willing to enter such studies and the social situations in Iran, making medical interventions for female patients much difficult. It was thus suggested to do more research, recruiting both genders as the study groups or laying focus on female patients to complement the body of literature. Of note, the nature of the intervention practiced in this study made it challenging to blind the participants.\u003c/p\u003e"},{"header":"6. Implications for Clinical Practice","content":"\u003cp\u003eThis study had some implications for clinical practice. In view of that, the study results highlighted the effectiveness of MEL in reducing anxiety and depression and boosting up general health status in patients with SUD on MMT. Therefore, healthcare providers could introduce MEL into treatment plans for such individuals to help diminish their anxiety and depression and then enhance their general health status and poor sleep quality. However, further research was needed to replicate such outcomes. In addition, it was recommended to conduct more studies to reflect on the challenges facing MEL administration in clinical practice from the perspective of healthcare providers and patients with SUD undergoing MMT, which could then aid in making decisions for the inclusion of MEL into the treatment plan of such populations.\u003c/p\u003e"},{"header":"7. Conclusion","content":"\u003cp\u003eMEL could efficiently reduce sleep onset latency and daytime dysfunction in comparison to ZPD and PBO, as evidenced in the study results. Moreover, it could successfully decrease anxiety and depression and potentially improve general health status.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSubstance use disorder (SUD)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMelatonin (MEL)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZolpidem (ZPD)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethadone maintenance treatment (MMT)\u003c/p\u003e\n\u003cp\u003ePlacebo (PBO)\u003c/p\u003e\n\u003cp\u003ePittsburgh Sleep Quality Index (PSQI)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGeneral Health Questionnaire-28 (GHQ-28).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors hereby would like to extend their gratitude to all participants and the staff in the addiction treatment centers concerned, who cooperated to fulfill this study. Appreciations also go to the Vice-Chancellor\u0026rsquo;s Office for Research affiliated to Isfahan University of Medical Sciences, Isfahan, Iran, for their financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study procedures, data collection, and analysis. The authors prepared the first draft and read and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1,2,4\u003c/sup\u003eDepartment of Community Medicine Isfahan University of Medical Sciences, Isfahan, Iran.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003csup\u003e3\u003c/sup\u003eIsfahan University of Medical Sciences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e \u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003eCompeting Interests \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The authors did not declare any conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; The data used in this study will be made available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA written informed consent form was obtained from all participants once the study objectives and methods were explained.\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eThe Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran, correspondingly approved this study with the ethics code no. IR.MUI.MED.REC. 1399.813. Moreover, the principles of the Declaration of Helsinki (DoH) were met.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDopheide JA. Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy. The American journal of managed care. 2020;26(4 Suppl):S76-S84.\u003c/li\u003e\n\u003cli\u003eKerkhof GA. Epidemiology of sleep and sleep disorders in The Netherlands. Sleep Med. 2017;30:229-39.\u003c/li\u003e\n\u003cli\u003eSivertsen B, Hysing M, Harvey AG, Petrie KJ. The Epidemiology of Insomnia and Sleep Duration Across Mental and Physical Health: The SHoT Study. Frontiers in Psychology. 2021;12.\u003c/li\u003e\n\u003cli\u003eFerrie JE, Kumari M, Salo P, Singh-Manoux A, Kivim\u0026auml;ki M. Sleep epidemiology\u0026mdash;a rapidly growing field. International Journal of Epidemiology. 2011;40(6):1431-7.\u003c/li\u003e\n\u003cli\u003eNutt D, Wilson S, Paterson L. 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Scientific Reports. 2020;10(1):1-10.\u003c/li\u003e\n\u003cli\u003eDe Crescenzo F, Lennox A, Gibson J, Cordey J, Stockton S, Cowen P, et al. Melatonin as a treatment for mood disorders: a systematic review. Acta Psychiatrica Scandinavica. 2017;136(6):549-58.\u003c/li\u003e\n\u003cli\u003eDas A, Prithviraj M, Mohanraj PS. Role of Melatonin in the Management of Substance Addiction: A Systematic Review. Cureus. 2022;14(7):e26764.\u003c/li\u003e\n\u003cli\u003eStein MD, Kurth ME, Anderson BJ, Blevins CE. A Pilot Crossover Trial of Sleep Medications for Sleep-disturbed Methadone Maintenance Patients. J Addict Med. 2020;14(2):126-31.\u003c/li\u003e\n\u003cli\u003eMonti JM, Spence DW, Buttoo K, Pandi-Perumal SR. Zolpidem\u0026rsquo;s use for insomnia. Asian journal of psychiatry. 2017;25:79-90.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Methadone, Melatonin, Zolpidem, Sleep, General Health","lastPublishedDoi":"10.21203/rs.3.rs-6683560/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6683560/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground and Aim:\u003c/p\u003e\n\u003cp\u003eSubstance use disorder (SUD) and the subsequent symptoms of withdrawal are likely to impact all life aspects, including poor sleep quality and low general health status. In view of that, poor sleep quality is simultaneously considered as a side effect and a risk factor. Against this background, the present study was to compare the effects of melatonin (MEL) and zolpidem (ZPD) on sleep quality and general health status in patients undergoing methadone maintenance treatment (MMT).\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eIn total, 105 male patients on MMT, referred to outpatient addiction treatment centers, were divided into three groups, viz., MEL, ZPD, and placebo (PBO), using a randomized clinical trial (RCT) design with a control group (CG) (N = 35 in each group). The intervention groups were then given MEL (9 mg) 30 min before bedtime and ZPD (10 mg) right before it. At the pre- and post-intervention stages, all participants also completed the Pittsburgh Sleep Quality Index (PSQI) and the General Health Questionnaire-28 (GHQ-28).\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eAs compared to ZPD and PBO, MEL reduced sleep onset latency (p = 0.003) and daytime dysfunction (p = 0.043). Both MEL (p = 0.001) and ZPD (p = 0.022) further improved sleep quality, wherein the MEL group obtained a higher score. Moreover, MEL was shown to be more effective than ZPD and PBO in terms of lowering anxiety (p = 0.013) and depression (p \u0026lt; 0.001), as well as promoting general health status (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eThe study results revealed that MEL could successfully enhance sleep quality and general health status in patients on MMT in comparison to ZPD and PBO.\u003c/p\u003e\n\u003cp\u003eTrial Registration\u003c/p\u003e\n\u003cp\u003eThe research protocol has been also listed on the Iranian Registry of Clinical Trials (IRCT) with the code no. IR20201214049718N1(date: 25/01/2021)\u003c/p\u003e","manuscriptTitle":"Effects of Melatonin and Zolpidem on Sleep Quality and General Health Status in Patients Undergoing Methadone Maintenance Treatment: A Comparative Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-30 16:13:39","doi":"10.21203/rs.3.rs-6683560/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fde3436a-b8b1-4481-9414-b234d07c86d4","owner":[],"postedDate":"May 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-27T09:38:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-30 16:13:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6683560","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6683560","identity":"rs-6683560","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}