Study design and setting
This study was a prospective randomized, single-blind sham-controlled, clinical trial with an allocation ratio of participants 1:1. The study was conducted at the Okasha Institute of Psychiatry, Faculty of Medicine, Ain Shams University, located in Eastern Cairo. The study participants were recruited from the substance use disorder clinic and those admitted to the Institute of Psychiatry, in the addiction ward.
Study subjects
The study targeted males with a diagnosis of SUD, seeking help mainly for opioids. According to the MedCalc computer program (a computer program for medical statistics), the number of subjects was 26 patients diagnosed with substance use disorder (dependence syndrome) as group 1 (active intervention group) and 26 patients diagnosed with substance use disorder (dependence syndrome) as group 2 (sham intervention group). The effect size was used in this exploratory study to estimate the sample size. Group sample sizes of 26 patients in the active intervention group and 26 in the sham intervention group were to achieve 80.75% power to reject the null hypothesis of zero effect size when the population effect size is relatively large (=0.80) and the significance level (alpha) is 0.050 using a two-sided two-sample equal-variance t test. The main methods of recruitment included suggesting rTMS as a potential therapeutic method under trial at the Ain Shams University substance dependence treatment clinic. Patients were then randomly allocated in the study arms using a research randomizer, a computer-based random number generator that uses the “Math random” method within the JavaScript programming language as the core method for generating random numbers. Two sets consisting of 26 participants were generated with a random sequence. The sets were generated and sent to operators conducting the rTMS sessions. Subjects eligible for the trial were randomized according to the generated sequence by the operators.
Inclusion and exclusion criteria
Male patients were included with an age range of 18–65 years old with a diagnosis of opioid use disorder according to the DSM-5 in early abstinence (early abstinence starting 1 week up to 1 month); all participants were approached during this period of time (early abstinence), with exclusion in case of the presence of other serious mental illness (e.g., psychotic disorders, bipolar affective disorder, depression with psychotic features), any other serious medical illness, previous treatment with repetitive, transcranial magnetic stimulation, and patients with contraindications to rTMS as cardiac patients with a pacemaker. All participants were 100 % abstinent throughout the trial period regarding all substances except tobacco, and patients had variable durations of OUD with a variable number of admissions ranging from a year up to 10 years of dependence; this was not considered as an exclusion or inclusion criteria. During the recruitment, in patients reporting intake of substances other than opioids, such as cannabinoids, only those with symptoms not mounting up to a diagnosis of a cannabinoids use disorder were included, and if symptoms mounted up to reach a diagnosis of another comorbid substance use disorder, the participant was excluded.
Procedure and data collection tools
The participants were assessed using a clinical psychiatric semi-structured interview of the Okasha Institute of Psychiatry, Ain Shams University, which examined demographic data, psychiatric history, examination, and medical history, and the Arabic version of SCID-I [9, 10] was used to screen for psychiatric illnesses other than OUD. The diagnosis of dependence was according to the criteria of the DSMV 5 classification. Consent was taken from patients using written informed consent then the following tools were used:
The heroin craving questionnaire (HCQ)
The HCQ was designed according to five theoretically distinct conceptualizations of drug craving: (1) desire to use, (2) intention to use, (3) anticipation of positive outcome, (4) anticipation of relief from withdrawal or dysphoria, and (5) lack of control over use. There is a 14-item version available that contains a subset of items from the 45-item version, and this was the version used in the study. Self-rated responses to each item are recorded on a seven-point Likert scale. A total craving score can be derived from the sum of the 14 individual items. Each item is scored on a scale ranging from 1 for strongly disagree to 7 for strongly agree. Items 1, 5, 8, 9, 10, and 14 are reverse scored. For the total score, the sum of all 14 questions is calculated and divided by 14, for the higher order factor score, the sum of all items except item 1 is calculated and divided by 13 instead, both scores were taken into consideration during the data collection of the study and referred to as HCQ-14 for the 14-item score and HCQ-13 for the higher-order factor score. The higher-order factor score can be used as a uni-dimensional assessment of craving; it correlates with the total score on the 45-item HCQ and with visual analog scales for crave, want, and need [11, 12]. We translated the HCQ into Arabic with translation and back translation by 2 independent translators.
The brief substance craving scale (BSCS)
The BSCS is a 16-item, self-report instrument that assesses craving for cocaine and other substances of abuse over a 24-h period. We used the 8-item version with 4 self-report questions regarding 2 potentially craved drugs, measuring the intensity, frequency, length, and number of times for cravings. Each question has 5 answers scored from 0 to 4, 0 being the least and 4 being the highest. The last question inquires about the number of cravings within the past 24 h. The total score is by summing the totals of all questions [13, 14]. We translated BSCS into Arabic with translation and back translation by 2 independent translators.
Beck’s depression inventory
The Beck Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression (Beck, et al., 1961). The BDI has been developed in different forms, including several computerized forms, a card form, the 13-item short form, and the more recent BDI-II [15]. For subclinical depression, only scores ranging from 0 to 13 are taken into account. The Arabic version of the BDI by Abdel-Khalek will be used [16].
Repetitivetrans cranial magnetic stimulation (rTMS)
The rTMS will be administered using a Magventure R 30 stimulator with a 75-mm Fig. 8 coil. A total of 18 sessions will be administered, day after day for a total duration of 6 weeks. Patients will be stimulated at a frequency of 10 Hz in 100 trains with a number of 20 pulses per train with an inter-train interval of 15s. each session would last about 13 min. Stimulation intensity will be done at 90% of the motor threshold. The F3 location from the EEG 10–20 system will be used to target the left dorsolateral pre-frontal cortex [17]. For placebo stimulation, a sham coil will be used.
Methodological and procedural considerations
Medications prescribed included antidepressants as well as mood stabilizers and opioid antagonists (Naltrexone); not all patients received the same pharmacotherapy, yet there was no statistically significant difference or discrepancy between the cases and the control as regards the patterns of pharmacotherapy, hence the inter-individual variation of medication subtype and compliance was disregarded as a confounding factor.
Patients were receiving standard protocol at the institute which entails tailored pharmacotherapy, individual CBT sessions as well as family education, and there were no group therapies held at the time on account of COVID-19 restrictions.
Statistical analysis
Descriptive statistics were used to express sociodemographic and clinical characteristics. The appropriate statistical tests such as Student’s t test and Mann-Whitney U test were used to express the group difference for clinical variables on the scores of different scales (for comparison of two groups), and two-way repeated measure ANOVA was run to determine the effect of active rTMS treatment against sham procedure over time. Pearson correlation was used to measure the linear correlation between data. Participants who completed the treatment course and were lost in the course of follow-ups were included. By the end of the data, the study was processed and analyzed by Statistical Package for Social Sciences (SPSS) software version 22.0.