Introduction
Opioid addiction is a global public health concern, with high relapse rate and difficulties in maintaining abstinence among detoxified patients. Neurocognitive disorders and working memory deficits are major contributors to the poor treatment outcomes in people with substance abuse. Working memory, involved by essential skills in cognitive rehabilitation tasks, plays a crucial role in addiction recovery. Impaired working memory is related to reduced impulse control, decreased resistance to drug craving, and high risk of relapse. Individuals with low working memory tend to show high levels of impulsivity, which is the predictor of craving in both drug abusers and those abstinent from drug use. Furthermore, inadequate performance in computerized working memory training (WMT)  is associated with suboptimal responses to psychotherapy, higher rates of relapse, and shorter durations of abstinence after drug cessation. Recent studies using WMT have shown promising results in improving cognitive function. This study sought to assess the effect of WMT combined with attention control training (ACT) using a mobile application on craving, impulsivity, and working memory of opioid users under methadone therapy.

Methods
In this randomized controlled clinical trial, 50 male opioid addicts were selected from four addiction treatment clinics in Mashhad, Iran, using a purposive sampling method. Inclusion criteria were age 18-49 years, reading and writing literacy, having an Android phone, maintaining a stable methadone dose for a least four weeks prior to the study, and continuing to keep this dosage stable during the study period. Participants were examined by a psychiatrist, and those with a psychotic episode in the last month, severe brain damage and/or a neurodegenerative disease, unwillingness to continue participation, failure to use the designated application for at least one week during the study were excluded. After obtaining informed consent from the participants, they were randomly assigned to intervention group (n=25) and control group (n=25).
The intervention group played a neuro-rehab game weekly for four consecutive weeks. This mobile application is a cognitive-based game for brain training that consists of both ACT and WMT [10]. The control group did not play any game during this period and received treatment as usual which was methadone therapy at the steady dose. At the end of the 4-week intervention period, a post-test assessment was administered to both groups. The collected data were analyzed in SPSS software, version 25.

Results
According to the information in Table 1, the mean age variable of participants was 36.64±7.94 years in the intervention group and 35.24±7.21 years in the control group.


Participants were 9 single people (18%) and 41 married people (82%). In terms of education in overall, 9 participants had middle school education, 15 had a high school diploma, 9 had an associate degree, 13 had a bachelor's degree, and 4 had a master’s degree. The mean duration of addiction was 11.24±5.28 years in the intervention group and 11.44±5.67 years in the control group. The results of chi-square test showed that the two groups were similar in terms of age, duration of addiction, gender, and education level and there were no significant differences between them (Table 1). The mean training duration for the intervention group was 28.22±22.26 minutes. Table 2 presents the mean pre-test and post-test scores of the study participants.


As presented in Table 3, the difference between the two groups in craving (F=67.90, P<0.001, partial eta=0.59) and impulsivity (F=14.37, P<0.001, partial eta=0.23) was significant, but the differences in forward digit span (P=0.59), backward digit span (P=0.12), and total score of digit span test (P=0.12) were not significant.


The mean value for the ratio of the number of wrong answers to the total answers in the pre-test and post-test phases was 54.36±13.80 and 46.40±13.92, respectively.

Conclusion
The results of this study showed that the combination of WMT and ACT delivered on a mobile application could significantly reduce craving and impulsivity in male opioid addicts under methadone therapy. These findings suggest the potential of this combined intervention in reducing the risk of relapse in these people. However, we found no significant increase in working memory after combined intervention.

Ethical Considerations
Compliance with ethical guidelines
This study has ethical approval from the Ethics Committee of Mashhad University of Medical Sciences (Code: IR.MUMS.MEDICAL.REC.1401.018). The study was registered by the Iranian Registry of Clinical Trials (IRCT ) (ID: IRCT20171031037145N3).

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors contributions
Conceptualization: Reza Emran; Methodology: Shokoufe Aalayi, Farshad Sheybani and Ali Talaei; Investigation: Reza Emran; Funding acquisition: Farshad Sheybani and Reza Emran; Writing, resources and supervision: All authors.

Conflicts of interest
The authors declared no conflict of interest.


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