RESUMEN
BACKGROUND: Age-related changes in the concentration-effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly. OBJECTIVE: The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets. METHODS: A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18-40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/fm), volume of distribution (V/fm) and a sigmoid maximum effect (Emax) model incorporating baseline (E0) and placebo effect was used. RESULTS: Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/fm was 76% larger and CL/fm 16% slower. Baseline (E0) and sensitivity (C50) for pain tolerance were similar between young and elderly subjects. However, the Emax parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135-221) in the young and 194 (149-252) in the elderly; that is, 15% higher in the elderly. CONCLUSIONS: This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.