Modality Choice Before and After Failure for the Treatment of Painful Diabetic Neuropathy

The research team will perform a comparative-effectiveness sequential, multiple assignment, randomized trial in painful diabetic neuropathy (PDN) patients for 8 total months, divided into two 4-month stages. 600 participants 18+ with PDN will be enrolled in this study. The main goal is to compare the utility of three modalities (oral, topical, and behavioral) for initial PDN treatment, and to compare the utility of switching modalities versus continuing with the same modality for non-responders. Pain and discontinuation will be assessed weekly, whereas other outcomes will be assessed monthly for 8 months.

Inclusion Criteria: * Diabetes * Painful Diabetic Neuropathy (confirmed at screening visit) * Willing to accept random treatment assignment to any of the proposed interventions Exclusion Criteria: * Pregnancy or plans to become pregnant during the study * History of neuropathy from causes other than diabetes as determined through medical and family history, physical and neurologic examinations * HbA1c \>10% * Participation in an experimental medication trial within 3 months of starting the study * Undergoing therapy for malignant disease other than basal-cell or squamous-cell skin cancer * Medical or psychiatric reason for not being a study candidate according to the site PI's discretion * Contraindications preventing trialing two interventions within any of the 3 modalities * Cirrhosis of the liver