Opioid use disorder (OUD) is prevalent and causes substantial health and social burdens. Although evidence have showed the effectiveness of opioid agonist maintenance therapy in OUD, high drop-out rate and the requirement of continuing use of opioid agonists are the major problems. Therefore, to develop novel treatment for OUD is important.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method of brain stimulation used to treat a variety of neuropsychiatric disorders. Recent studies showed that there may be potential therapeutic effects in rTMS for addictive disorder, including reducing craving and substance use severity. The underlying mechanisms of rTMS in treating addictions may involve increased dopamine function in corticomesolimbic brain circuits and modulation of neural activity in brain circuits that relevant to addiction. However, the treatment results of rTMS in OUD were lacked, and the analysis in functional brain imaging study, neuropsychological tests and other potential biomarkers under rTMS treatment were limited, too.

Thus, the investigators will conduct the add-on double-blinded, sham-controlled study rTMS treatment in 40-60 patients with OUD under methadone maintenance therapy. Patients will be allocated to active and sham rTMS in a 1 : 1 ratio, and participants will receive rTMS on the left dorsolateral prefrontal cortex (DLPFC) (15 Hz frequency, 4 seconds per train, inter-train interval of 26 seconds, 40 trains per session, total 11 sessions in 4 weeks). The treatment response, urine drug tests, craving scales and side effects to evaluate the therapeutic effects of rTMS will be examined. Neuropsychological assessments, functional magnetic resonance imaging (fMRI) and tests for potential biomarkers of immune parameters will also be measured during 12-weeks follow up. The study results will provide the important data in whether rTMS add-on methadone maintenance therapy is able to 1) reduce heroin use; 2) reduce craving for heroin; 3) be an effective treatment for OUD, and 4) be associated with improvement in fMRI, biological markers and psychological tests.

Inclusion Criteria:

1. Signed informed consent by patient or legal representative.
2. Male or female patient aged ≧20 and ≦65 years.
3. A diagnosis of OUD according to DSM criteria made by a specialist in psychiatry.
4. Patient or a reliable caregiver can be expected to ensure acceptable compliance and visit attendance for the duration of the study.

Exclusion Criteria:

1. Women of childbearing potential, not using adequate contraception as per investigator judgment or not willing to comply with contraception for the duration of the study.
2. Females who are pregnant or lactation.
3. Current evidence of an uncontrolled and/or clinically significant medical condition, e.g.,cardiac, hepatic and renal failure that would compromise patient safety or preclude study participation.
4. History of seizure or epilepsy.
5. History of neurological diseases or traumatic brain injury.
6. Suicidal attempts or risks during screen or study period.
7. Presence of devices, e.g. pace-makers, cochlear prosthesis, neuro-stimulators, magnetic cochlear prosthesis, intraocular metallic fragments.
8. Patient has received electroconvulsive therapy (ECT) within 4 weeks prior to the first intervention of the double-blinded treatment.