Following confirmation of eligibility, acquisition of written informed consent, and completion of baseline assessments, participants will be allocated in a 1:1 ratio to receive either memantine or placebo. Individual-level stratified permuted-block randomization will be used. The stratification variables will include participant age, categorized as 18–39 years and 40–60 years, and duration of regular opioid use, categorized as less than 10 years and 10 years or longer. Accordingly, four strata will be formed. Within each stratum, an independent randomization sequence will be generated using randomly varying permuted block sizes of 4 and 6, with a 1:1 allocation ratio.
The random allocation sequence will be generated before participant recruitment by an independent statistician using computer-based randomization software. Information regarding block sizes and sequence order will not be disclosed to members of the research team involved in participant recruitment, treatment administration, or outcome assessment. Memantine and placebo will be prepared and packaged in an identical manner by an independent pharmacist and labeled only with sequential numerical codes. Participants, treating physicians, outcome assessors, and investigators will remain blinded to treatment allocation until completion of the initial data analysis.
Participants will be informed, before enrollment, about the nature of the trial, the possibility of receiving either memantine or placebo, and the 1:1 allocation ratio, and will provide written informed consent. However, they will remain unaware of their assigned intervention until completion of the initial data analysis.
Memantine and placebo will be prepared, packaged, and coded by an independent pharmacist who will have no role in participant recruitment, clinical care, data collection, outcome assessment, or data analysis. The active medication and placebo will be made as similar as possible with respect to appearance, color, size, odor, packaging, and administration schedule. Participants in the placebo group will follow the same dose-escalation schedule as those in the memantine group, with corresponding stages matching the 7-, 14-, and 21-mg doses, to prevent the capsule-administration pattern from revealing treatment allocation. Medication packages will be labeled only with sequential numerical codes and will contain no information indicating the assigned intervention.
The following individuals will remain blinded to participants’ treatment allocation:
Participants;
The principal investigator and other academic investigators involved in conducting the study;
Outcome assessors, including personnel responsible for administering the Desire for Drug Questionnaire (DDQ), the delay-discounting task, the cue-induced craving task, and recording urine drug-screening results.
The random allocation sequence will be generated by an independent statistician. For operational reasons, the statistician responsible for generating the sequence and the pharmacist responsible for coding the study medications will be aware of the correspondence between allocation codes and treatment assignments. However, neither individual will be involved in participant recruitment, treatment delivery, outcome assessment, or the primary data analysis.
The code-identification list linking medication codes to treatment allocation will be stored in an encrypted electronic file or in sealed envelopes and will be accessible only to the independent pharmacist or another designated code custodian. During statistical analysis, the dataset will be provided to the analyst using neutral labels, such as “Group A” and “Group B.” The treatment codes will be revealed only after the database has been locked and the initial analysis of the prespecified outcomes has been finalized. Whenever feasible, the initial draft of the study results will also be prepared using these neutral group labels.