The Effect of Zinc Supplementation on Dosage and Sleep in People Suffering from Opioids Dependence Under Methadone-Maintenance Therapy

The Effect of Zinc Supplementation on Dosage and Sleep in People Suffering from Opioids Dependence Under Methadone-Maintenance Therapy | 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 The Effect of Zinc Supplementation on Dosage and Sleep in People Suffering from Opioids Dependence Under Methadone-Maintenance Therapy Zahra Amini, Ebrahim HeidariFarsani This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4525716/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 Objectives Zinc deficiency has been shown to affect the central nervous system, according to animal and human studies. In people under methadone-maintenance therapy (MMT), zinc deficiency is accompanied by various consequences. This study intended to evaluate the impact of zinc supplementation on dosage and sleep in people suffering from opioid dependence under MMT. Methods Following a clinical trial design, a total of 68 cases referring to outpatient MMT centers in Isfahan province in 2021 were recruited using the convenience sampling technique. Data were collected using the Pittsburgh Sleep Quality Index, a demographic questionnaire form, and a methadone dose form, which was performed before providing the intervention, and one and three months later. Data analysis was administered using SPSS version 23. Results some sleep quality subcomponents, including the score of sleep efficiency (p = 0.001), sleep disturbances (p < 0.001), and use of sleep medication (p < 0.001) were decreased for those in the intervention group, which was statistically significant. However, there was no statistically significant difference in the control group. Regarding components of subjective sleep quality (p = 0.04) and daily functional impairment (p = 0.01), the overall mean difference (before and after the intervention) between the intervention and control groups was statistically significant. However, There was a significant difference between the intervention and control groups concerning total sleep quality (p = 0.002); however, such difference was not found for methadone consumption (p = 0.73). Conclusion Zinc supplementation showed a positive effect on some subcomponents of sleep quality in people under MMT. However, it did not affect the dose of methadone. Zinc supplementation Sleep Quality Methadone Dose Abuse Figures Figure 1 Introduction Zinc (Zn) is an important mineral for various biological activities ( 1 ). Behind iron, Zn is the second most common trace mineral in the body, which mainly has a catalytic and structural role. In addition, Zn is a cofactor and regulator of copper-zinc superoxide dismutase, which is the key defense antioxidant of the human body ( 2 , 3 ). Zn imbalance causes several central nervous system diseases ( 4 ). The contribution of Zn in functions of CNS is well-established, including memory and sleep ( 5 ). Zn ions have a major effect on several neurotransmitters, such as dopaminergic, glutamatergic, and serotonergic systems, which all play a particular role in addiction and its related phenomena ( 6 , 7 ). Nowadays, the phenomenon of opioid dependence and abuse is one of the major problems worldwide, which is categorized as the fourth major global concern, behind the nuclear crisis, population growth, and environmental pollution ( 8 ). Treating addiction and breaking its vicious cycle is costly and difficult ( 9 ). Methadone is an opioid agonist that is effective in addressing addiction and treatment of opioid use disorder. Methadone is taken orally so that it reaches the brain slowly, dampening the "high" that occurs with other routes of administration while preventing withdrawal symptoms ( 10 ). Methadone is effective in treating opioid dependence and chronic pain management. Economic studies indicated the affordability of methadone. Methadone maintenance therapy (MMT) improves physical and mental health, social functioning, and, ultimately, quality of life ( 11 ). On the other hand, there are evidence indicating an association between receiving MMT and immune system suppression, metabolic disorders, increased inflammatory response, stress, and sleep disorders ( 12 ), leading to irregularities in the sleep cycle and decreased overall sleep efficiency ( 13 , 14 ). Noushin Parvaresh showed that MMT had a significant effect on sexual function, sleep disorders, and weight gain, causing sleep pattern disturbances ( 15 ). Various studies mentioned the high prevalence of sleep problems among those receiving MMT, with a prevalence of 70–99%. Duration of drug abuse, psychological problems, methadone dosage and duration, and substance abuse are among the factors that predispose sleep disorder ( 16 , 17 ). Sleep disorders occur six months to three years after methadone use, which is associated with an increased likelihood of recurrence, as evidenced for alcohol ( 15 , 18 , 19 ). Micronutrients also contribute to sleep duration. In addition, it is positively associated with iron, zinc, and magnesium levels ( 20 ). The nutritional importance of Zn has been known for a long time, and studies have shown the positive effect of Zn on mental disorders ( 5 , 21 ). Various studies noted a significant increase in Zn deficiency during MMT ( 22 ). Sadlik et al. reported lower levels of Zn in heroin-addicted patients who were hospitalized in comparison to healthy people, which was statistically significant ( 23 ). Regarding the increased consumption of methadone and its side effects (e.g., decreased serum levels of zinc and subsequently decreased sleep quality), this study intended to evaluate the impact of zinc supplementation on dosage and sleep in people suffering from opioid addiction under MMT. Methods Following a randomized, single-blind, two-arm, parallel-group trial, this study was performed on those under MMT in an urban center in Iran (Isfahan/Isfahan/Iran) from April-July 2021. The study protocol is registered at the Iranian Registry of Clinical Trials (code: IRCT2020050904736N1). Participants After determining the appropriate sample size, of 140 patients referring to the addiction treatment center, 100 subjects with at least three months of receiving MMT were found as eligible. Finally, 80 declared their willingness to participate after a comprehensive introduction to the study protocol. Participants were recruited using a convenience sampling technique. The Inclusion criteria were being older than 18 years, ability to read and write, drug abuse confirmed by a urine test, at least three months of receiving MMT (as prescribed by a physician), no acute mental disorder (e.g., psychosis, bipolar disorder, and schizophrenia), and PSQI score higher than five. The exclusion criteria were changes in methadone treatment protocol, use of Zn-containing compounds before receiving the intervention, and history of sensitivity to zinc. Initially, a comprehensive introduction to the study protocol was provided to all those referring to the addiction treatment center, including the pros and cons of the intervention as well as its dosage and duration, and their informed written consent was obtained. Participants were divided into two groups of control and intervention using a random block framework (20 blocks with four subjects) by random allocation software. Details of the allocated group were given on hidden cards marked as A (for intervention) and B (for control) in sequentially numbered, sealed envelopes. The cards were read by a blinded person. In this study, only the data analyst was blinded to the allocation of participants to the study groups to ensure the validity of all analytical decisions. The CONSORT chart is provided in Fig. 1 . Noteworthy, the study groups were matched based on gender and living conditions. The participants were asked not to change their diet and prescribed drugs. Data were collected using the Pittsburgh Sleep Quality Index and a demographic questionnaire form before providing the intervention and one and three months later. A nurse working in the clinic distributed all questionnaires. Also, the nurse filled out the methadone dose form. The intervention was provided from April-July 2021 (i.e., about three months). Those in the intervention group were examined by a physician twice a week, and they had access to Zn supplementation for two weeks. In addition, they were called three times a week to ensure compliance with the study protocol and to answer any questions. Those in the control group only received methadone tablets, and they were asked to referee to the center to receive methadone and examination by a physician and a nurse every two weeks. No placebo was used in this study. For those in the intervention group, the assumed average maintenance dose per day was 12 mg. The administered drug was Suzin (zinc sulfate) produced by Al-Hawi Company (each capsule contained 110 mg zinc sulfate equivalent to 25 mg zinc). The data collector, analyzer, and researcher were blinded to the allocation of participants. Data were collected using the Pittsburgh Sleep Quality Index, a demographic questionnaire form, and a methadone dose form, which was performed before providing the intervention, and one and three months later. Demographic information form It contained information on age, gender, education level, marital status, living condition (alone or with family), and smoking status (cigarettes or hookahs). Pittsburgh Sleep Quality Index (PSQI) : It is a self-rated questionnaire that intends to assess sleep quality over the past month. The PSQI contains 18 items categorized into seven groups: Subjective sleep quality; Sleep latency; Sleep duration; Habitual sleep efficiency; Sleep disturbances; Use of sleep medication; and Daytime dysfunction. The PSQI questions are rated from zero (strongly appropriate), one (relatively appropriate), two (relatively inappropriate), and three (strongly inappropriate), and the maximum score of each component is three. The scores of all seven components are summed to yield a total score ranging from zero to 21, with the higher the total score, the lower the sleep quality, which applies to all components. A score > 5 indicates a significant sleep disturbance, while a score ranging from zero to five shows appropriate sleep quality( 24 ). Farahi et al. conducted a study to assess the psychometric properties of the Persian version of the PSQI and reported a sensitivity of 100% and Cronbach's alpha of 0.89. Methadone dose form Data of this form were collected by the researcher while asking for the help of physicians and nurses working at the clinic. Data were converted to mg (some patients were treated with methadone syrup and others with methadone tablets). Statistical Analysis Data analysis was administered using SPSS version 23 using descriptive statistics (i.e., frequency tables and central tendency indicators) and repeated measure ANOVA, Kolmogorov–Smirnov test, chi-2, and independent t-test. Statistical significance was considered when the p-value < 0.0.5. Findings A total of 80 participants were recruited in this study, with 40 subjects in each group. One month after the intervention, four patients from the intervention group and three from the control group were excluded due to unwillingness to continue the study. Also, after two months, two other subjects from the intervention group and three from the control group were excluded due to not referring to the addiction treatment center. Hence, data of 68 subjects, 34 in each group, were analyzed (Fig. 1 ). The mean age of those in the intervention and control groups was 40.85 ± 8.3 and 38.21 ± 9.1 years, respectively, and there was no significant difference between the study group (P = 0.21). Overall, there was no significant difference between the study groups concerning demographic characteristics (Table 1 ). For those in the intervention group, the total score of sleep quality was improved during the intervention, one month after the intervention, and at the end of the intervention (p < .001). However, there was no significant difference in total sleep quality score during the intervention, one month after the intervention, and at the end of the intervention for those in the control group (p = 0.26). At the end of the intervention, there was significant difference between the two groups concerning mean total sleep quality score before the intervention and three months after providing the intervention (P = 0.002). Table 1. Demographic variables by study groups Variables Subgroups Intervention group Frequency (percentage) Control group Frequency (percentage) P-value Marital status Married 24 (70.6%) 22 (64.7%) 0.60* Single 10 (29.4%) 12 (35.3%) Tobacco use Cigarette smoking 18 52.9%) 17 (50.0%) 0.96* Hookah 10 (29.4) 11 (32.4%) None 6 (17.6%) 6 (17.6%) Occupation Unemployed 6 (17.6%) 6 (17.6%) 0.16** Self-employed 2 (5.9%) 8 (23.5%) Employee 6 (17.6%) 2 (5.9%) Worker 9 (26.5%) 4 (11.8%) Homekeeper 3 (8.8%) 4 (11.8%) Retired 8 (23.5%) 10 (29.4%) Education Level Less than diploma 24(70/6%) 22(64/7%) .004** Diploma 4/(11.8%) 12/(35.3%) University degree 6/(17.6%) 0/(0.0%) * Chi-square test, ** Fisher's exact test Concerning subcomponents of sleep quality, the score of sleep efficiency (p = 0.001), sleep disturbances (p < 0.001), use of sleep medication (p < 0.001) and total sleep quality(p < 0.001) were decreased for those in the intervention group, which was statistically significant. However, there was no statistically significant difference in the control group. Regarding components of subjective sleep quality (p = 0.04) and daily functional impairment (p = 0.01), the overall mean difference (before and after the intervention) between the intervention and control groups was statistically significant (Table 1 ). Table 2. PSQI score of various subcomponents and methadone dose, separated by the study group Studied variable Groups Before the intervention Mean±Sd One month after the intervention Mean±Sd Three months after the intervention Mean±Sd P 1 P 3 Partial eta square $ P 2 Subjective sleep quality Control 1.70±.80 1.65±.81 1.79±.84 .37 .04 .07 Intervention 1.32±.53 1.26±.71 1.00±.95 .06 Sleep latency Control 1.38±.92 1.65±.81 1.56±.93 .08 .06 .06 Intervention 1.82±.97 1.70±.83 1.53±.86 .07 Sleep duration Control 1.50±.82 1.44±.82 1.35±.88 .26 .1 .04 Intervention 1.29±.67 1.06±.69 1.09±.75 .08 Habitual sleep efficiency Control 1.18±.76 1.23±.70 1.26±.83 .57 .85 .001 Intervention 1.20±.88 1.44±.50 .94±.65 .001 Sleep disturbances Control 1.18±.87 1.29±.80 1.32±.88 .2 .49 .007 Intervention 1.35±.64 1.23±.65 .85±.61 <.001 Use of sleep medications Control 1.32±.77 1.38±.78 1.41±.86 .45 .13 .03 Intervention 1.47±.71 1.12±.64 .79±.64 <.001 daily functional impairment Control 1.50±.99 1.47±.89 1.47±.93 .89 .01 .09 Intervention 1.15±.50 1.00±.55 .91±.83 .07 Total sleep quality Control 9.76±2.51 10.12±2.47 10.18±2.50 .26 .002 .135 Intervention 9.62±1.61 8.82±1.47 7.12±2.03 <.001 Methadone dose Control 43.68±20.31 43.53±20.36 43.23±20.48 .43 .73 .002 Intervention 45.44±19.24 45.15±19.71 44.85±19.71 .42 Table 2. PSQI score of various subcomponents and methadone dose, separated by the study group P1= it was significant for means trend in the control group (repeated ANOVA measures) . P2= it was significant for means trend in the intervention group (repeated ANOVA measures) . P3= it was significant for overall difference of means (before and after the intervention) between intervention and control groups (repeated ANOVA measures). $: Partial Eta Square interpret: 0.01 ∼ small, 0.06 ∼ medium, >0.14 ∼ large Concerning the effect of the intervention on methadone dose and the trend of changes in mean total score, there was no significant change for both groups and the overall mean difference in the dose of the drug before and three months after the intervention was not significantly different between the study groups (p = 0.73). Discussion According to the authors' best knowledge, this study is the first of its kind that investigated the effect of zinc supplementation on sleep quality and methadone dose in patients under MMT. Overall, the findings indicated the positive effect of Zn on sleep quality of those under MMT. In other words, it not only could improve subcomponents of habitual sleep efficiency, sleep disturbances, subjective sleep quality and daytime dysfunction but also decreased the need for receiving sleeping pills. However, there was no considerable effect for subcomponents of sleep latency, Sleep duration and methadone dose. Few studies investigate the effect of various interventions on sleep disturbances in patients suffering from drug abuse. For instance, Khalatbari et al. investigated the effect of Crocin on psychological parameters in patients under MMT and reported improved total sleep quality scores( 25 ). Molavi's study showed the positive effect of probiotic supplementation on opiate-related disorders in patients under MMT on total sleep quality score ( 26 ). Also, Qaderi et al. reported the significant effect of melatonin supplementation on mental health and metabolic and genetic status in patients under MMT ( 12 ). A study conducted by Javedan also showed that those under MMT experienced improved mental health and cognitive responses to Quetiapine ( 27 ). Qaderi also mentioned the positive effect of Vitamin D supplementation on psychological symptoms and metabolic properties of patients under MMT on overall sleep quality score ( 28 ). D. Stein et al. also showed that in patients under MMT, methadone consumption was effective on all components of sleep quality (i.e., sleep duration, wakefulness minutes, sleep efficiency, sleep latency, and sleep disturbances). However, zolpidem and combined mirtazapine/zolpidem showed no effect on sleep quality subscales, which may be due to different effects on sleep mechanisms ( 29 ). Jundi et al. showed that melatonin supplementation did not affect sleep quality in people with alcohol abuse. Noteworthy, they followed participants only for four weeks, which seems not to be sufficient to control damages caused by alcohol on the sleep cycle ( 30 ). Various studies investigated the effect of Zn supplementation on the sleep quality of different individuals. Kordas et al. provided evidence on the association between Zn and sleep duration in various populations ( 31 ). Also, Kim Sung and Liu mentioned an association between declined level of Zn and short sleep duration. Researchers found that short sleep duration or increased likelihood of sleep disturbances were associated with decreased serum levels of Zn in women and youngsters ( 32 , 33 ). Rondanelli et al. showed that receiving melatonin, magnesium, and Zn at night could improve sleep quality and quality of life in residents of long-term care centers with primary insomnia. In addition, all four areas of LSEQ (getting to sleep, quality of sleep, ease of awakening from sleep, and alertness) were improved ( 34 ). Hajianfar et al. also reported an association between Zn-containing diet and sleep quality and mental health in Iranian female students. So declined Zn intake is associated with disturbed sleep quality and poor mental health, particularly there is a significant association between Zn intake and sleep disturbance, sleep duration, and disturbed daytime function ( 35 ). In a systematic review on the effectiveness of supplementation in improving sleep quality, Chan et al. concluded that amino acids, vitamin D, and melatonin supplements were significantly beneficial for improving sleep quality. However, further studies are needed to extend our knowledge about the effect of magnesium, Zn, resveratrol, and nitrate supplementation on improving sleep quality ( 36 ). Despite extensive evidence regarding the association between sleep and Zn in adults, such association is not proved in children aged six to eight years old, which can be attributed to the power of predicting the level of Zn in children, adolescents, and adults ( 32 ). Also, this study demonstrated that Zn supplementation has no effect on methadone dose, which is consistent with Kim et al.'s study that reported vitamin D supplementation had no effect on the methadone dose of those under MMT ( 37 ). In contrast to the present study's findings, Qaderi et al. showed that vitamin supplementation was effective on withdrawal symptoms, mainly due to seducing deprivation symptoms( 38 ). Kendall's study also mentioned the importance of nutrition in addressing health disorders and the dosage of drug abuse because Zn improves withdrawal symptoms ( 39 ). Also, Ciubotariu et al. reported that prescribing Zn, as a dietary supplement, for cancer patients under treatment with opiates could seduce chronic pain ( 23 ). However, few studies investigated the received dose. There are limited studies regarding the effect of Zn on methadone doses. Concerning sleep regulation, future research should include focusing on interactions between micronutrients and/or macronutrients that may be effective in optimizing sleep quality. Zn deficiency is considered a consequence of reduced consumption or disruption of absorption. Deficiency is not just a dietary imbalance, as it results in metabolic consequences. This study intended to evaluate the impact of Zn supplementation on dosage and sleep in people suffering from opioid addiction under MMT( 40 ). Evaluation of mineral status in drug abusers is often neglected. Limitations Herein, some limitations and challenges must be considered before application of the findings, including small sample size, and not controlling food habits and diet of participants. However, all participants were asked to follow their usual diet and food habit. Hence, further studies are needed to extend our knowledge. Conclusion This study demonstrated the positive effect of zinc supplementation on sleep quality in people under MMT. However, it did not affect the dose of methadone. Abbreviations MMT : methadone maintenance treatment SD: standard deviation, ANOVA: repeated measures analysis of variance, PSQI: Pittsburgh Sleep Quality Index Declarations Human Ethics approval and consent to participate A written informed consent form was obtained from all the participants once the research objectives and methodology were explained. The Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran, approved this study with the ethics code no. (IR.MUI.MED.REC. 1399.385). Moreover, the principles of the Declaration of Helsinki were met. Consent for publication Not applicable. Availability of data and material The data used in this study will be made available from the corresponding author upon reasonable request. Competing interests The authors did not declare any conflict of interest. Funding Not applicable. Authors' contributions Both authors contributed to the study procedures, data collection, and analysis. The authors prepared the first draft and read and approved the final version. Acknowledgments The authors hereby would like to extend their gratitude to all the participants and the staff of the addiction treatment clinic concerned, who cooperated to fulfill this study. 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The effects of Vitamin D supplementation on withdrawal symptoms and the expression of inflammatory cytokines and insulin in patients under methadone maintenance treatment: A randomized, double-blind, placebo-controlled trial. Iranian Journal of Psychiatry and Behavioral Sciences. 2020;14(1). Jeynes KD, Gibson EL. The importance of nutrition in aiding recovery from substance use disorders: A review. Drug and alcohol dependence. 2017;179:229-39. Sato-Mito N, Sasaki S, Murakami K, Okubo H, Takahashi Y, Shibata S, et al. The midpoint of sleep is associated with dietary intake and dietary behavior among young Japanese women. Sleep medicine. 2011;12(3):289-94. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-4525716","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":314322167,"identity":"abd4b534-8912-4cca-863b-cc52cf36b7b1","order_by":0,"name":"Zahra Amini","email":"","orcid":"","institution":"University of Medical Sciences, Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Zahra","middleName":"","lastName":"Amini","suffix":""},{"id":314322171,"identity":"32c2e817-d4f1-41d6-9796-e130dea3e174","order_by":1,"name":"Ebrahim HeidariFarsani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIiWNgGAWjYDACCQYGZgYDhgQwmfjvnxxI8MADorUksB0wBmtJIKiFgQGkxoCBge1AYgMDlIsL8Ev3PvxcULAtj5+deduHBzx30ueHHX4ItMVOTrcBuxbJOceNpWcY3C6WbGYrnpEg8Sx34+00A6CWZGOzA9i1GNxIY5DmMbiduOEwjzFDggFz7sbZCSAtBxK34dBifyON+TdIy36wlgTmdMPZ6R/wajGQSGOD2MIM0nLgcIK8dA5+WyTuHGOzBmmZcZitmCGxIc1wg3ROwYEEA9x+4Z/dxnyb58/txP7+w5sZfzbYyMvPTt/84UOFnRwuLVicClZpQKxyEJBvIEX1KBgFo2AUjAQAAMhZYalROrn5AAAAAElFTkSuQmCC","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Ebrahim","middleName":"","lastName":"HeidariFarsani","suffix":""}],"badges":[],"createdAt":"2024-06-04 06:41:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4525716/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4525716/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59054932,"identity":"6d62887e-e34c-4079-af14-19d88336cfbe","added_by":"auto","created_at":"2024-06-25 20:42:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137836,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4525716/v1/eeb0033d600976a61dfec15b.png"},{"id":62398403,"identity":"1ce68bb2-67b4-4bbb-8389-0db4ee31bdb8","added_by":"auto","created_at":"2024-08-13 17:59:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":660779,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4525716/v1/12f51500-c921-44c7-8ae8-8498013ae25c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of Zinc Supplementation on Dosage and Sleep in People Suffering from Opioids Dependence Under Methadone-Maintenance Therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eZinc (Zn) is an important mineral for various biological activities (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Behind iron, Zn is the second most common trace mineral in the body, which mainly has a catalytic and structural role. In addition, Zn is a cofactor and regulator of copper-zinc superoxide dismutase, which is the key defense antioxidant of the human body (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Zn imbalance causes several central nervous system diseases (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The contribution of Zn in functions of CNS is well-established, including memory and sleep (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Zn ions have a major effect on several neurotransmitters, such as dopaminergic, glutamatergic, and serotonergic systems, which all play a particular role in addiction and its related phenomena (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNowadays, the phenomenon of opioid dependence and abuse is one of the major problems worldwide, which is categorized as the fourth major global concern, behind the nuclear crisis, population growth, and environmental pollution (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Treating addiction and breaking its vicious cycle is costly and difficult (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Methadone is an opioid agonist that is effective in addressing addiction and treatment of opioid use disorder. Methadone is taken orally so that it reaches the brain slowly, dampening the \"high\" that occurs with other routes of administration while preventing withdrawal symptoms (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMethadone is effective in treating opioid dependence and chronic pain management. Economic studies indicated the affordability of methadone. Methadone maintenance therapy (MMT) improves physical and mental health, social functioning, and, ultimately, quality of life (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn the other hand, there are evidence indicating an association between receiving MMT and immune system suppression, metabolic disorders, increased inflammatory response, stress, and sleep disorders (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), leading to irregularities in the sleep cycle and decreased overall sleep efficiency (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Noushin Parvaresh showed that MMT had a significant effect on sexual function, sleep disorders, and weight gain, causing sleep pattern disturbances (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Various studies mentioned the high prevalence of sleep problems among those receiving MMT, with a prevalence of 70\u0026ndash;99%. Duration of drug abuse, psychological problems, methadone dosage and duration, and substance abuse are among the factors that predispose sleep disorder (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Sleep disorders occur six months to three years after methadone use, which is associated with an increased likelihood of recurrence, as evidenced for alcohol (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Micronutrients also contribute to sleep duration. In addition, it is positively associated with iron, zinc, and magnesium levels (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The nutritional importance of Zn has been known for a long time, and studies have shown the positive effect of Zn on mental disorders (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Various studies noted a significant increase in Zn deficiency during MMT (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Sadlik et al. reported lower levels of Zn in heroin-addicted patients who were hospitalized in comparison to healthy people, which was statistically significant (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Regarding the increased consumption of methadone and its side effects (e.g., decreased serum levels of zinc and subsequently decreased sleep quality), this study intended to evaluate the impact of zinc supplementation on dosage and sleep in people suffering from opioid addiction under MMT.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eFollowing a randomized, single-blind, two-arm, parallel-group trial, this study was performed on those under MMT in an urban center in Iran (Isfahan/Isfahan/Iran) from April-July 2021. The study protocol is registered at the Iranian Registry of Clinical Trials (code: IRCT2020050904736N1).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eAfter determining the appropriate sample size, of 140 patients referring to the addiction treatment center, 100 subjects with at least three months of receiving MMT were found as eligible. Finally, 80 declared their willingness to participate after a comprehensive introduction to the study protocol. Participants were recruited using a convenience sampling technique. The Inclusion criteria were being older than 18 years, ability to read and write, drug abuse confirmed by a urine test, at least three months of receiving MMT (as prescribed by a physician), no acute mental disorder (e.g., psychosis, bipolar disorder, and schizophrenia), and PSQI score higher than five. The exclusion criteria were changes in methadone treatment protocol, use of Zn-containing compounds before receiving the intervention, and history of sensitivity to zinc.\u003c/p\u003e \u003cp\u003eInitially, a comprehensive introduction to the study protocol was provided to all those referring to the addiction treatment center, including the pros and cons of the intervention as well as its dosage and duration, and their informed written consent was obtained. Participants were divided into two groups of control and intervention using a random block framework (20 blocks with four subjects) by random allocation software. Details of the allocated group were given on hidden cards marked as A (for intervention) and B (for control) in sequentially numbered, sealed envelopes. The cards were read by a blinded person. In this study, only the data analyst was blinded to the allocation of participants to the study groups to ensure the validity of all analytical decisions. The CONSORT chart is provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Noteworthy, the study groups were matched based on gender and living conditions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe participants were asked not to change their diet and prescribed drugs. Data were collected using the Pittsburgh Sleep Quality Index and a demographic questionnaire form before providing the intervention and one and three months later. A nurse working in the clinic distributed all questionnaires. Also, the nurse filled out the methadone dose form. The intervention was provided from April-July 2021 (i.e., about three months). Those in the intervention group were examined by a physician twice a week, and they had access to Zn supplementation for two weeks. In addition, they were called three times a week to ensure compliance with the study protocol and to answer any questions. Those in the control group only received methadone tablets, and they were asked to referee to the center to receive methadone and examination by a physician and a nurse every two weeks. No placebo was used in this study. For those in the intervention group, the assumed average maintenance dose per day was 12 mg. The administered drug was Suzin (zinc sulfate) produced by Al-Hawi Company (each capsule contained 110 mg zinc sulfate equivalent to 25 mg zinc). The data collector, analyzer, and researcher were blinded to the allocation of participants. Data were collected using the Pittsburgh Sleep Quality Index, a demographic questionnaire form, and a methadone dose form, which was performed before providing the intervention, and one and three months later.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDemographic information form\u003c/h2\u003e \u003cp\u003eIt contained information on age, gender, education level, marital status, living condition (alone or with family), and smoking status (cigarettes or hookahs).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e\u003cb\u003ePittsburgh Sleep Quality Index (PSQI)\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eIt is a self-rated questionnaire that intends to assess sleep quality over the past month. The PSQI contains 18 items categorized into seven groups:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSubjective sleep quality;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSleep latency;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSleep duration;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eHabitual sleep efficiency;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSleep disturbances;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eUse of sleep medication; and\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDaytime dysfunction.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eThe PSQI questions are rated from zero (strongly appropriate), one (relatively appropriate), two (relatively inappropriate), and three (strongly inappropriate), and the maximum score of each component is three. The scores of all seven components are summed to yield a total score ranging from zero to 21, with the higher the total score, the lower the sleep quality, which applies to all components. A score\u0026thinsp;\u0026gt;\u0026thinsp;5 indicates a significant sleep disturbance, while a score ranging from zero to five shows appropriate sleep quality(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Farahi et al. conducted a study to assess the psychometric properties of the Persian version of the PSQI and reported a sensitivity of 100% and Cronbach's alpha of 0.89.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eMethadone dose form\u003c/h2\u003e \u003cp\u003eData of this form were collected by the researcher while asking for the help of physicians and nurses working at the clinic. Data were converted to mg (some patients were treated with methadone syrup and others with methadone tablets).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData analysis was administered using SPSS version 23 using descriptive statistics (i.e., frequency tables and central tendency indicators) and repeated measure ANOVA, Kolmogorov\u0026ndash;Smirnov test, chi-2, and independent t-test. Statistical significance was considered when the p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.0.5.\u003c/p\u003e \u003c/div\u003e"},{"header":"Findings","content":"\u003cp\u003eA total of 80 participants were recruited in this study, with 40 subjects in each group. One month after the intervention, four patients from the intervention group and three from the control group were excluded due to unwillingness to continue the study. Also, after two months, two other subjects from the intervention group and three from the control group were excluded due to not referring to the addiction treatment center. Hence, data of 68 subjects, 34 in each group, were analyzed (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean age of those in the intervention and control groups was 40.85\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3 and 38.21\u0026thinsp;\u0026plusmn;\u0026thinsp;9.1 years, respectively, and there was no significant difference between the study group (P\u0026thinsp;=\u0026thinsp;0.21). Overall, there was no significant difference between the study groups concerning demographic characteristics (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). For those in the intervention group, the total score of sleep quality was improved during the intervention, one month after the intervention, and at the end of the intervention (p\u0026thinsp;\u0026lt;\u0026thinsp;.001). However, there was no significant difference in total sleep quality score during the intervention, one month after the intervention, and at the end of the intervention for those in the control group (p\u0026thinsp;=\u0026thinsp;0.26). At the end of the intervention, there was significant difference between the two groups concerning mean total sleep quality score before the intervention and three months after providing the intervention (P\u0026thinsp;=\u0026thinsp;0.002).\u003c/p\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eTable 1. Demographic variables by study groups\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"width:447.95pt;margin-left:5.4pt;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:79.4pt;border-top:solid windowtext 1.0pt;border-left:solid windowtext 1.0pt;border-bottom:double windowtext 1.5pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:39.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eVariables\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:double windowtext 1.5pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:39.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eSubgroups\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:double windowtext 1.5pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:39.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eIntervention group\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eFrequency (percentage)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:double windowtext 1.5pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:39.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eControl group\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eFrequency (percentage)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:double windowtext 1.5pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:39.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eP-value\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:79.4pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMarital status\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eMarried\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan dir=\"RTL\" style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e24\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e(70.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e22\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e(64.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:49.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.60*\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eSingle\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e10\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e(29.4%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e12\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e(35.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width:79.4pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding: 0in 5.4pt 0in 5.4pt;height:23.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New 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52.9%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e17 (50.0%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width:49.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:23.2pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New 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0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e10 (29.4)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e11 (32.4%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eNone\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e6 (17.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e6 (17.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width:79.4pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding: 0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eOccupation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eUnemployed\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan dir=\"RTL\" style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e6 (17.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e6 (17.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"6\" style=\"width:49.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0.16**\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:26.15pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eSelf-employed\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:26.15pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e2 (5.9%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:26.15pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e8 (23.5%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eEmployee\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan dir=\"RTL\" style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e6 (17.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:17.6pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e2 (5.9%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eWorker\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan dir=\"RTL\" style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e9 (26.5%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e4 (11.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eHomekeeper\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan dir=\"RTL\" style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e3 (8.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e4 (11.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eRetired\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e8 (23.5%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e10 (29.4%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width:79.4pt;border-top:none;border-left:solid windowtext 1.0pt;border-bottom:solid windowtext 1.0pt;border-right:none;padding: 0in 5.4pt 0in 5.4pt;height:21.75pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003eEducation Level\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:21.75pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:normal;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;'\u003eLess than diploma\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:21.75pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e24(70/6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:21.75pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e22(64/7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width:49.6pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:21.75pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e.004**\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:22.55pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:normal;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;'\u003eDiploma\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:22.55pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:normal;'\u003e\u003cspan style='font-size:13px;font-family:\"Times New Roman\",serif;'\u003e4/(11.8%)\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan dir=\"RTL\" style='font-size:13px;line-height:115%;font-family:\"Times New Roman\",serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:22.55pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e12/(35.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:92.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:28.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height: 115%;font-family:\"Times New Roman\",serif;'\u003eUniversity degree\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:28.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e6/(17.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:113.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:28.0pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;text-align:center;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height:115%;font-family: \"Times New Roman\",serif;'\u003e0/(0.0%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width:447.95pt;border:solid windowtext 1.0pt;border-top:none;padding:0in 5.4pt 0in 5.4pt;height:18.05pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;line-height:115%;'\u003e\u003cspan style='font-size:13px;line-height: 115%;font-family:\"Times New Roman\",serif;'\u003e* Chi-square test, ** Fisher\u0026apos;s exact test\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;'\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003eConcerning subcomponents of sleep quality, the score of sleep efficiency (p\u0026thinsp;=\u0026thinsp;0.001), sleep disturbances (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), use of sleep medication (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and total sleep quality(p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were decreased for those in the intervention group, which was statistically significant. However, there was no statistically significant difference in the control group. Regarding components of subjective sleep quality (p\u0026thinsp;=\u0026thinsp;0.04) and daily functional impairment (p\u0026thinsp;=\u0026thinsp;0.01), the overall mean difference (before and after the intervention) between the intervention and control groups was statistically significant (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/div\u003e\n\u003cp\u003eTable 2. \u0026nbsp;PSQI score of various subcomponents and methadone dose, separated by the study group\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudied variable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore the intervention\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026plusmn;Sd\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOne month after the intervention\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026plusmn;Sd\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eThree months after the intervention\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026plusmn;Sd\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003csup\u003e3\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePartial eta\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;square\u003c/strong\u003e\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eSubjective sleep quality\u003c/p\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e1.70\u0026plusmn;.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e1.65\u0026plusmn;.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e1.79\u0026plusmn;.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e1.32\u0026plusmn;.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e1.26\u0026plusmn;.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e1.00\u0026plusmn;.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eSleep latency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e1.38\u0026plusmn;.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e1.65\u0026plusmn;.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e1.56\u0026plusmn;.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e1.82\u0026plusmn;.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e1.70\u0026plusmn;.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e1.53\u0026plusmn;.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eSleep duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e1.50\u0026plusmn;.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e1.44\u0026plusmn;.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e1.35\u0026plusmn;.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e1.29\u0026plusmn;.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e1.06\u0026plusmn;.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e1.09\u0026plusmn;.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eHabitual sleep efficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e1.18\u0026plusmn;.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e1.23\u0026plusmn;.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e1.26\u0026plusmn;.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e1.20\u0026plusmn;.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e1.44\u0026plusmn;.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e.94\u0026plusmn;.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eSleep disturbances\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e1.18\u0026plusmn;.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e1.29\u0026plusmn;.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e1.32\u0026plusmn;.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e1.35\u0026plusmn;.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e1.23\u0026plusmn;.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e.85\u0026plusmn;.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eUse of sleep medications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e1.32\u0026plusmn;.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e1.38\u0026plusmn;.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e1.41\u0026plusmn;.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e1.47\u0026plusmn;.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e1.12\u0026plusmn;.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e.79\u0026plusmn;.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003edaily functional impairment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e1.50\u0026plusmn;.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e1.47\u0026plusmn;.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e1.47\u0026plusmn;.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e1.15\u0026plusmn;.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e1.00\u0026plusmn;.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e.91\u0026plusmn;.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eTotal sleep quality\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e9.76\u0026plusmn;2.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e10.12\u0026plusmn;2.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e10.18\u0026plusmn;2.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e9.62\u0026plusmn;1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e8.82\u0026plusmn;1.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e7.12\u0026plusmn;2.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.331316187594553%\" rowspan=\"2\"\u003e\n \u003cp\u003eMethadone dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.254160363086234%\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.069591527987898%\"\u003e\n \u003cp\u003e43.68\u0026plusmn;20.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.733736762481088%\"\u003e\n \u003cp\u003e43.53\u0026plusmn;20.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.22087745839637%\"\u003e\n \u003cp\u003e43.23\u0026plusmn;20.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.169440242057489%\"\u003e\n \u003cp\u003e.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.80786686838124%\" rowspan=\"2\"\u003e\n \u003cp\u003e.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.413010590015128%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.014084507042252%\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.830985915492956%\"\u003e\n \u003cp\u003e45.44\u0026plusmn;19.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.413145539906104%\"\u003e\n \u003cp\u003e45.15\u0026plusmn;19.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.065727699530516%\"\u003e\n \u003cp\u003e44.85\u0026plusmn;19.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.67605633802817%\"\u003e\n \u003cp\u003e.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2. \u0026nbsp;PSQI score of various subcomponents and methadone dose, separated by the study group\u003c/p\u003e\n\u003cp\u003eP1= it was significant for means trend in the control group (repeated ANOVA measures)\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eP2= it was significant for means trend in the intervention group (repeated ANOVA measures)\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eP3= it was significant for overall difference of means (before and after the intervention) between intervention and control groups (repeated ANOVA measures).\u003c/p\u003e\n\u003cp\u003e$: Partial Eta Square interpret: 0.01\u0026nbsp;\u0026sim;\u0026nbsp;small, 0.06\u0026nbsp;\u0026sim;\u0026nbsp;medium, \u0026gt;0.14\u0026nbsp;\u0026sim;\u0026nbsp;large\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Concerning the effect of the intervention on methadone dose and the trend of changes in mean total score, there was no significant change for both groups and the overall mean difference in the dose of the drug before and three months after the intervention was not significantly different between the study groups (p\u0026thinsp;=\u0026thinsp;0.73).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAccording to the authors' best knowledge, this study is the first of its kind that investigated the effect of zinc supplementation on sleep quality and methadone dose in patients under MMT. Overall, the findings indicated the positive effect of Zn on sleep quality of those under MMT. In other words, it not only could improve subcomponents of habitual sleep efficiency, sleep disturbances, subjective sleep quality and daytime dysfunction but also decreased the need for receiving sleeping pills. However, there was no considerable effect for subcomponents of sleep latency, Sleep duration and methadone dose.\u003c/p\u003e \u003cp\u003eFew studies investigate the effect of various interventions on sleep disturbances in patients suffering from drug abuse. For instance, Khalatbari et al. investigated the effect of Crocin on psychological parameters in patients under MMT and reported improved total sleep quality scores(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Molavi's study showed the positive effect of probiotic supplementation on opiate-related disorders in patients under MMT on total sleep quality score (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Also, Qaderi et al. reported the significant effect of melatonin supplementation on mental health and metabolic and genetic status in patients under MMT (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). A study conducted by Javedan also showed that those under MMT experienced improved mental health and cognitive responses to Quetiapine (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Qaderi also mentioned the positive effect of Vitamin D supplementation on psychological symptoms and metabolic properties of patients under MMT on overall sleep quality score (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). D. Stein et al. also showed that in patients under MMT, methadone consumption was effective on all components of sleep quality (i.e., sleep duration, wakefulness minutes, sleep efficiency, sleep latency, and sleep disturbances). However, zolpidem and combined mirtazapine/zolpidem showed no effect on sleep quality subscales, which may be due to different effects on sleep mechanisms (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Jundi et al. showed that melatonin supplementation did not affect sleep quality in people with alcohol abuse. Noteworthy, they followed participants only for four weeks, which seems not to be sufficient to control damages caused by alcohol on the sleep cycle (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Various studies investigated the effect of Zn supplementation on the sleep quality of different individuals. Kordas et al. provided evidence on the association between Zn and sleep duration in various populations (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlso, Kim Sung and Liu mentioned an association between declined level of Zn and short sleep duration. Researchers found that short sleep duration or increased likelihood of sleep disturbances were associated with decreased serum levels of Zn in women and youngsters (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRondanelli et al. showed that receiving melatonin, magnesium, and Zn at night could improve sleep quality and quality of life in residents of long-term care centers with primary insomnia. In addition, all four areas of LSEQ (getting to sleep, quality of sleep, ease of awakening from sleep, and alertness) were improved (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Hajianfar et al. also reported an association between Zn-containing diet and sleep quality and mental health in Iranian female students. So declined Zn intake is associated with disturbed sleep quality and poor mental health, particularly there is a significant association between Zn intake and sleep disturbance, sleep duration, and disturbed daytime function (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn a systematic review on the effectiveness of supplementation in improving sleep quality, Chan et al. concluded that amino acids, vitamin D, and melatonin supplements were significantly beneficial for improving sleep quality. However, further studies are needed to extend our knowledge about the effect of magnesium, Zn, resveratrol, and nitrate supplementation on improving sleep quality (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite extensive evidence regarding the association between sleep and Zn in adults, such association is not proved in children aged six to eight years old, which can be attributed to the power of predicting the level of Zn in children, adolescents, and adults (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlso, this study demonstrated that Zn supplementation has no effect on methadone dose, which is consistent with Kim et al.'s study that reported vitamin D supplementation had no effect on the methadone dose of those under MMT (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). In contrast to the present study's findings, Qaderi et al. showed that vitamin supplementation was effective on withdrawal symptoms, mainly due to seducing deprivation symptoms(\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Kendall's study also mentioned the importance of nutrition in addressing health disorders and the dosage of drug abuse because Zn improves withdrawal symptoms (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Also, Ciubotariu et al. reported that prescribing Zn, as a dietary supplement, for cancer patients under treatment with opiates could seduce chronic pain (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, few studies investigated the received dose.\u003c/p\u003e \u003cp\u003eThere are limited studies regarding the effect of Zn on methadone doses. Concerning sleep regulation, future research should include focusing on interactions between micronutrients and/or macronutrients that may be effective in optimizing sleep quality. Zn deficiency is considered a consequence of reduced consumption or disruption of absorption. Deficiency is not just a dietary imbalance, as it results in metabolic consequences. This study intended to evaluate the impact of Zn supplementation on dosage and sleep in people suffering from opioid addiction under MMT(\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Evaluation of mineral status in drug abusers is often neglected.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003e Herein, some limitations and challenges must be considered before application of the findings, including small sample size, and not controlling food habits and diet of participants. However, all participants were asked to follow their usual diet and food habit. Hence, further studies are needed to extend our knowledge.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study demonstrated the positive effect of zinc supplementation on sleep quality in people under MMT. However, it did not affect the dose of methadone.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eMMT\u003cspan dir=\"RTL\"\u003e:\u003c/span\u003e methadone maintenance treatment SD: standard deviation, ANOVA: repeated measures analysis of variance, PSQI:\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePittsburgh Sleep Quality Index\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eHuman Ethics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA written informed consent form was obtained from all the participants once the research objectives and methodology were explained.\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003eThe Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran, approved this study with the ethics code no. (IR.MUI.MED.REC. 1399.385). Moreover, the principles of the Declaration of Helsinki were met.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this study will be made available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not declare any conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth 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\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors hereby would like to extend their gratitude to all the participants and the staff of the addiction treatment clinic concerned, who cooperated to fulfill this study. They also appreciate the Vice-Chancellor\u0026apos;s Office for Research, affiliated with Isfahan University of Medical Sciences, Isfahan, Iran, for the financial support of this research.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1,2\u003c/sup\u003eDepartment of Community Medicine Isfahan University of Medical Sciences, Isfahan, Iran.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMwangi S, Timmons J, Ao T, Paul M, Macalintal L, Pescatore A, et al. 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Alcohol research \u0026amp; health. 2001;25(2):110.\u003c/li\u003e\n\u003cli\u003eJi X, Grandner MA, Liu J. The relationship between micronutrient status and sleep patterns: a systematic review. Public health nutrition. 2017;20(4):687-701.\u003c/li\u003e\n\u003cli\u003eJafari F, Tarrahi MJ, Farhang A, Amani R. Effect of zinc supplementation on quality of life and sleep quality in young women with premenstrual syndrome: a randomized, double-blind, placebo-controlled trial. Archives of Gynecology and Obstetrics. 2020;302(3):657-64.\u003c/li\u003e\n\u003cli\u003eIyengar V, Chou P, Costantino A, Cook C. Excessive urinary excretion of zinc in drug addicts: a preliminary study during methadone detoxification. Journal of trace elements and electrolytes in health and disease. 1994;8(3-4):213-5.\u003c/li\u003e\n\u003cli\u003eCiubotariu D, Ghiciuc CM, Lupușoru CE. Zinc involvement in opioid addiction and analgesia\u0026ndash;should zinc supplementation be recommended for opioid-treated persons? Substance abuse treatment, prevention, and policy. 2015;10(1):1-14.\u003c/li\u003e\n\u003cli\u003eFathi-Ashtiani A, Dastani M. Psychological tests: Personality and mental health. Tehran: besat. 2009;46.\u003c/li\u003e\n\u003cli\u003eKhalatbari-Mohseni A, Banafshe HR, Mirhosseini N, Asemi Z, Ghaderi A, Omidi A. The effects of crocin on psychological parameters in patients under methadone maintenance treatment: a randomized clinical trial. Substance Abuse Treatment, Prevention, and Policy. 2019;14(1):1-8.\u003c/li\u003e\n\u003cli\u003eMolavi N, Rasouli-Azad M, Mirzaei H, Matini AH, Banafshe HR, Valiollahzadeh M, et al. The Effects of Probiotic Supplementation on Opioid-Related Disorder in Patients under Methadone Maintenance Treatment Programs. International Journal of Clinical Practice. 2022;2022.\u003c/li\u003e\n\u003cli\u003eJavdan NS, Ghoreishi FS, Sehat M, Ghaderi A, Banafshe HR. Mental health and cognitive function responses to quetiapine in patients with methamphetamine abuse under methadone maintenance treatment. Journal of affective disorders. 2019;251:235-41.\u003c/li\u003e\n\u003cli\u003eGhaderi A, Banafshe HR, Motmaen M, Rasouli-Azad M, Bahmani F, Asemi Z. Clinical trial of the effects of vitamin D supplementation on psychological symptoms and metabolic profiles in maintenance methadone treatment patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2017;79:84-9.\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. Journal of addiction medicine. 2020.\u003c/li\u003e\n\u003cli\u003eAmini Z, Etminani N, Moeini M. Comparative Study of the Effect of Melatonin and Zolpidem on Sleep Quality and General Health of Patients on Methadone Maintenance Treatment. Available at SSRN 4051105.\u003c/li\u003e\n\u003cli\u003eKordas K, Siegel EH, Olney DK, Katz J, Tielsch JM, Kariger PK, et al. The effects of iron and/or zinc supplementation on maternal reports of sleep in infants from Nepal and Zanzibar. Journal of developmental and behavioral pediatrics: JDBP. 2009;30(2):131.\u003c/li\u003e\n\u003cli\u003eJi X, Liu J. Associations between blood zinc concentrations and sleep quality in childhood: a cohort study. Nutrients. 2015;7(7):5684-96.\u003c/li\u003e\n\u003cli\u003eSong C-H, Kim Y-H, Jung K-I. Associations of zinc and copper levels in serum and hair with sleep duration in adult women. Biological trace element research. 2012;149(1):16-21.\u003c/li\u003e\n\u003cli\u003eRondanelli M, Opizzi A, Monteferrario F, Antoniello N, Manni R, Klersy C. The effect of melatonin, magnesium, and zinc on primary insomnia in long‐term care facility residents in Italy: a double‐blind, placebo‐controlled clinical trial. Journal of the American Geriatrics Society. 2011;59(1):82-90.\u003c/li\u003e\n\u003cli\u003eHajianfar H, Mollaghasemi N, Tavakoly R, Campbell MS, Mohtashamrad M, Arab A. The association between dietary zinc intake and health status, including mental health and sleep quality, among Iranian female students. Biological Trace Element Research. 2021;199(5):1754-61.\u003c/li\u003e\n\u003cli\u003eChan V, Lo K. Efficacy of dietary supplements on improving sleep quality: a systematic review and meta-analysis. Postgraduate Medical Journal. 2022;98(1158):285-93.\u003c/li\u003e\n\u003cli\u003eKim TW, Alford DP, Holick MF, Malabanan AO, Samet JH. Low vitamin d status of patients in methadone maintenance treatment. Journal of addiction medicine. 2009;3(3):134.\u003c/li\u003e\n\u003cli\u003eGhaderi A, Banafshe H, Aghadavod E, Gholami M, Asemi Z, Mesdaghinia A. The effects of Vitamin D supplementation on withdrawal symptoms and the expression of inflammatory cytokines and insulin in patients under methadone maintenance treatment: A randomized, double-blind, placebo-controlled trial. Iranian Journal of Psychiatry and Behavioral Sciences. 2020;14(1).\u003c/li\u003e\n\u003cli\u003eJeynes KD, Gibson EL. The importance of nutrition in aiding recovery from substance use disorders: A review. Drug and alcohol dependence. 2017;179:229-39.\u003c/li\u003e\n\u003cli\u003eSato-Mito N, Sasaki S, Murakami K, Okubo H, Takahashi Y, Shibata S, et al. The midpoint of sleep is associated with dietary intake and dietary behavior among young Japanese women. Sleep medicine. 2011;12(3):289-94.\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":"Zinc supplementation, Sleep Quality, Methadone Dose, Abuse","lastPublishedDoi":"10.21203/rs.3.rs-4525716/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4525716/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eZinc deficiency has been shown to affect the central nervous system, according to animal and human studies. In people under methadone-maintenance therapy (MMT), zinc deficiency is accompanied by various consequences. This study intended to evaluate the impact of zinc supplementation on dosage and sleep in people suffering from opioid dependence under MMT.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFollowing a clinical trial design, a total of 68 cases referring to outpatient MMT centers in Isfahan province in 2021 were recruited using the convenience sampling technique. Data were collected using the Pittsburgh Sleep Quality Index, a demographic questionnaire form, and a methadone dose form, which was performed before providing the intervention, and one and three months later. Data analysis was administered using SPSS version 23.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003esome sleep quality subcomponents, including the score of sleep efficiency (p\u0026thinsp;=\u0026thinsp;0.001), sleep disturbances (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and use of sleep medication (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were decreased for those in the intervention group, which was statistically significant. However, there was no statistically significant difference in the control group. Regarding components of subjective sleep quality (p\u0026thinsp;=\u0026thinsp;0.04) and daily functional impairment (p\u0026thinsp;=\u0026thinsp;0.01), the overall mean difference (before and after the intervention) between the intervention and control groups was statistically significant. However, There was a significant difference between the intervention and control groups concerning total sleep quality (p\u0026thinsp;=\u0026thinsp;0.002); however, such difference was not found for methadone consumption (p\u0026thinsp;=\u0026thinsp;0.73).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eZinc supplementation showed a positive effect on some subcomponents of sleep quality in people under MMT. However, it did not affect the dose of methadone.\u003c/p\u003e","manuscriptTitle":"The Effect of Zinc Supplementation on Dosage and Sleep in People Suffering from Opioids Dependence Under Methadone-Maintenance Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-25 20:42:09","doi":"10.21203/rs.3.rs-4525716/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":"604b618c-f342-4407-8ed9-be3c0b9e4091","owner":[],"postedDate":"June 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-13T17:51:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-25 20:42:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4525716","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4525716","identity":"rs-4525716","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}