AIM:Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles. METHOD:To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced. RESULTS:Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity. CONCLUSION:Hence, CYP2D6 genotype contributes to treatment outcome and may be useful for guiding drug therapy. Future investigations in a larger patient population are planned to support these preliminary findings.