Abstract Background: Approximately 30% of patients with multiple sclerosis (MS) have central pain (CP). The anticonvulsant lamotrigine has been shown to be efficacious in some types of CP, but its efficacy in MS-related CP has not been confirmed. Objective: The aim of this pilot trial was to provide preliminary data for a planned larger trial. Methods: A randomized, double-blind, placebo-controlled, 2-period, crossover pilot study was conducted in a sample of patients aged ≥18 years with CP due to MS. The 2 treatment periods began with an 8-week, double-blind titration period, during which the number of pills of study drug was increased until either total pain relief was achieved, 1 or more unmanageable adverse events were reported, or a maximum of 16 pills (400 mg of lamotrigine) were used daily. A 3-week maintenance period at the final prescribed amount was followed by a 2-week tapering period; there was a 2-week washout between the 2 treatment periods, after which patients were administered the alternate drug. Outcomes before, during, and after each study period were assessed using validated measures of pain and quality of life (the Brief Pain Inventory BH, the Neuropathic Pain Scale NPS, and the 54-item MS Quality of Life MSQOL-54 questionnaire). Throughout the trial, patients completed a daily diary consisting of questions from the BPI-Short Form, as well as questions about the use of other analgesic drugs, changes in health, and the occurrence of adverse events. The BPI and NPS were completed weekly during telephone calls with the research coordinator, and the MSQOL-54 was administered during clinic visits (ie, visits at screening, baseline, end of period 1, and termination). The primary outcome measure was the mean pain intensity score during the final maintenance week of each of the 2 study periods. Results: A total of 12 patients were enrolled and completed at least the first period of the study. Ten patients were women. The mean (SD) age was 49.3 (11.7) years, and the mean (SD) weight was 76.5 (19.9) kg. The analysis revealed no significant differences between the lamotrigine and placebo periods in any of the study outcomes related to pain or quality of life. Regarding adverse events, 1 patient developed a moderate rash during the study, but the physician attributed this lesion to herpes zoster; this patient completed the study. While other adverse events were mild, 2 patients were withdrawn from the study after experiencing adverse events during the first study period; 1 had been receiving lamotrigine and the other placebo. Conclusion: The results from this pilot trial did not support either the use of lamotrigine in patients with MS-related CP or the need for a larger trial.