To evaluate the effect of tiagabine hydrochloride in painful neuropathy in a pilot, open-label study. Painful neuropathy is characterized by preferential involvement of small sensory and autonomic fibers. Tiagabine increases gamma-aminobutyric acid and might enhance the central pain-control mechanisms. Seventeen patients (10 men, 7 women; mean age 51.4 +/- 7.7 y) with chronic painful neuropathy (>6 months) were enrolled in this study. Week 0: All pain medications were discontinued. Weeks 1-4: Dose of tiagabine was increased weekly by 4 mg orally up to 16 mg in week 4. Quantitative sensory testing for vibration, cooling, and heat-pain, and quantitative sudomotor axon reflex test (QSART) were done at week 0 and week 4. The McGill Pain Questionnaire was administered weekly. Nine patients completed the study; 8 patients discontinued the treatment. Baseline pain intensity was 6.2 +/- 3.1 on the McGill Pain Questionnaire scale (0-10 range). Low doses (4-8 mg) of tiagabine reduced pain symptoms by 16-38%, improving surface pain (37.5%), skin sensitivity (32.8%), burning (38.6%), cold (25.4%) and pain sharpness (29%; p <0.03). Dull and deep pain did not improve. Quantitative sensory testing abnormalities diminished with treatment (p <0.02). Autonomic test results did not change. This pilot study evaluated the potential of tiagabine hydrochloride (Gabitril) in treatment of painful sensory neuropathy. Pain symptoms and quantitative sensory test results improved with treatment, especially at low doses of tiagabine (4-8 mg). Higher doses (12-16 mg) were associated with increased number of adverse events. Tiagabine may have potential benefits for treatment of painful neuropathy; however, assessment of its efficacy in a larger study is needed.