Research Design
This study was a randomized, single-blind, parallel, two-arm clinical trial on patients with substance abuse disorder receiving MMT in an addiction treatment clinic, located in an urban area of Iran, from April 2021, lasting three months. The research protocol was also listed on the Iranian Registry of Clinical Trials (IRCT) with the code no. IRCT2020050904736N1.
Participants
The statistical population included adult patients with substance abuse disorder undergoing MMT. The inclusion criteria in this study were the willingness to participate, age over 18, literacy, drug abuse confirmed by positive urine tests, taking methadone as supervised by a physician for at least three months, and no chronic mental illnesses, such as psychosis, bipolar disorder, and schizophrenia. As well, the exclusion criteria were the participants' decline to continue the study for any reasons, changes to the treatment plan, and the use of zinc-containing compounds prior to the intervention program.
The sample size was thus estimated at 32 individuals in each group, with reference to a similar study with 80% test power and 95% confidence interval. Considering the 20% sample loss, the final sample size in each group was determined to be 40. The researcher then referred to the selected addiction treatment clinic for sampling of the convenience type. For this purpose, first, the patients with substance abuse disorder undergoing MMT were examined in terms of meeting the inclusion criteria. Next, the study objectives and phases, data confidentiality, and the voluntary basis of entering into and withdrawing from the research process were presented by holding face-to-face meetings with the eligible individuals. Afterward, the cases who agreed to participate in the study signed an informed consent form. Finally, out of 140 patients with substance abuse disorder referred to the addiction treatment clinic concerned, 100 individuals with a history of at least three months of receiving methadone met the inclusion criteria, of which 80 cases declined to participate in the study. A randomized block design was further utilized to allocate the samples to the intervention and control groups. The random allocation sequence (with 20 blocks of four) was accordingly established, using the Random Allocation Software. For the act of concealment, some closed envelopes containing cards with the letters A (for the intervention group) and B (for the control group) were prepared, according to an encoded allocation sequence. An envelope was then opened by an outsider, who had no role in the study and did not know about the card inside for each individual. Based on the card inside, the patients with substance abuse disorder were allocated to one of the intervention or control groups. Of note, only the data analyst was blinded to the allocation of the participants to the groups in this study, to ensure that all the analytical decisions were made without bias. The CONSORT flow diagram of the study is illustrated in Figure 1. the study groups were matched based on gender and living conditions
Data Collection
The study data were collected, using the Demographic Survey Form (DSF), the Relapse Prediction Scale (RPS), and the Depression, Anxiety, and Stress Scale 21 (DASS-21) before, one month after, and three months after the intervention (i.e., the completion of the intervention program).
DSF
The DSF consisted of items, focused on the participants' age, gender, marital status, living conditions(alone or with family), and smoking status (cigarettes or hookahs), education level, and occupation.
RPS
The 45-item RPS was administered to assess the PoR. Each item included a situation in which the respondent could rate the PoR and drug craving (25), on a five-point Likert-type scale (including 0=none, 1=weak, 2=moderate, 3=strong, 4=very strong), with the minimum and maximum scores of zero and 180, respectively. Thus, the score between 0 and 60 indicated a low relapse rate, the values from 60 to 90 predicted a moderate relapse rate, and the score above 90 implied a strong relapse rate. Previous studies had further shown that the internal consistency of the Persian version of this scale was between 0.74 and 0.91 (26-28).
DASS-21
The DASS-21 was implemented to measure the MH status of the study participants. This 42-item scale was initially developed by Lovibond and Lovibond (29), and its short form contained 21 items to assess depression, anxiety, and stress (viz. seven items in each case), using a four-point Likert-type scale (including 0=never, 1=sometimes, 2=often, 3=always). The overall score for each construct was calculated by the sum of the scores of the seven relevant items, and then multiplied by two (30). The psychometric properties of this scale had been examined in previous studies, and its internal consistency had been reported, using the Cronbach's alpha coefficient of 0.74-0.90 and the two-week test-retest reliability of 0.74 (31). For the Persian version of this scale, the mean Cronbach's alpha coefficient has been 0.96 for the subscales, and the two-week test-retest reliability of 0.85 has been presented based on the Pearson correlation coefficient (32).
Intervention Program
The participants allocated to the intervention group were visited by a physician every two weeks, and then received a two-week supplement of zinc combined with methadone as planned. The daily dosage of the zinc supplement was about 12 mg. The supplement used in this study was Suzin Zinc Sulfate, made by Alhawi Pharmaceutical Co., Iran (of note, each capsule of 110 mg of zinc sulfate was equivalent to 25 mg of zinc). To check the participants' cooperation in the intervention group as well as their regular zinc supplement intake, their families were contacted three times a week. The researcher also welcomed their questions and ambiguities.
On the other hand, the participants in the control group only received methadone, according to the treatment plan, and their visits were fixed every two weeks to check their methadone use by a physician or a nurse. Of note, no placebo was given to this group. All the study participants were also asked not to change their diet and type of medication at the end of the study. The methadone dose was registered in both intervention and control groups.
Data Analysis
The SPSS Statistics software package (ver. 23) was used for the data analysis. To this end, the data from the intervention and control groups were summarized in a descriptive manner, using frequency and percentage for the categorical variables and mean and standard deviation (SD) for the continuous ones. The Kolmogorov-Smirnov test was further implemented to examine the normal distribution of data. To evaluate the homogeneity of the study groups, independent-samples t-test, Chi-square test, and Fisher's exact test were utilized. Moreover, repeated measures analysis of variance (ANOVA) was performed to compare the predictive scores of the PoR and MH in the study groups. All the inferential tests were completed at the significance level of 0.05.