Neuropathic pain, often associated with diabetic neuropathy or nerve compression injuries, arises from damage or dysfunction in the somatosensory nervous system. Tramadol, frequently prescribed for this pain, has its fraction unbound and that of its active metabolite (M1) significantly altered by diabetes. Yet, dosing adjustments for diabetic neuropathic pain remain underexplored. This study developed a comprehensive population pharmacokinetics/pharmacodynamics (PK/PD) model for tramadol and its major metabolites, focusing on diabetes's impact on PK and PK-PD relationship to identify optimal dosing regimens. Data from patients with chronic neuropathic pain on oral tramadol were used to develop enantiomer-specific population models, considering both total and unbound concentrations. Tramadol's PK was best described by a two-compartment model with Weibull absorption and linear elimination and a one-compartment model with enterohepatic circulation and first-pass metabolism for the active M1. Simulations showed higher unbound fractions of the active M1 in patients with type 1 and type 2 diabetes. Despite a 67% and 14% reduction in the AUC of total (1R,2R)-M1 in patients with type 1 and type 2 diabetes, respectively, the AUC of unbound (1R,2R)-M1 remained consistent. The unbound concentration of the active M1 required to achieve 50% of the maximum pain reduction (IC