Pharmacokinetics of Tramadol and O-Desmethyltramadol Enantiomers Following Administration of Extended-Release Tablets to Elderly and Young Subjects

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Abstract

Background

Tramadol is frequently used in geriatric patients; however, pharmacokinetic (PK) publications on tramadol and O-desmethyltramadol (ODM) in elderly patients are rare.

Objective

Our objective was to characterize the PK of tramadol and ODM, including absorption processes and covariates for tramadol, in elderly and young subjects after singledose administration of 200-mg extended-release tablets.

Methods

We conducted a PK study in 15 elderly (aged ≥75 years) subjects with mild renal insufficiency and 20 young (18–40 years) subjects; blood and urine samples were collected for 48 h post-dose. Non-compartmental analysis (NCA) of each tramadol and ODM enantiomer included area under the concentration-time curve (AUC), terminal elimination rate (kel), total body clearance, volume of distribution (Varea/F), and renal clearance (Clr0–48). A one-compartment population model of total tramadol concentration was parameterized with clearance (CL/F), volume of distribution (V/F), and mixed order absorption (first-order and zero-order absorption rate constants with lag times).

Results

NCA demonstrated comparable maximum plasma concentration (Cmax) and AUC between age groups for tramadol enantiomers, but significant differences in Varea/F (mean 34 % higher) and kel (mean 28 % lower) in the elderly. PK of ODM were significantly different in the elderly for AUC0-inf (mean 35 % higher), Clr0–48 (mean 29 % lower), and kel (mean 33 % lower). The population analysis identified age as a covariate of V/F (young 305 L; elderly 426 L), with a 50 % longer mean elimination halflife in the elderly. No differences in absorption processes were observed.

Conclusions

Tramadol exposure was similar between the age groups; exposure to ODM was higher in elderly subjects.

Key Points

Differences in tramadol pharmacokinetics (PK) between relatively healthy elderly volunteers and young healthy volunteers are not remarkable after a single dose: no differences in PK parameters related to the absorption process were observed; elderly subjects have a slower elimination rate constant and age-dependent increase in volume of distribution (V/F); and food effect associated with higher peak plasma concentrations of tramadol is more frequent in young subjects.

Key Points

Exposure to O-desmethyltramadol (ODM) is higher in relatively healthy elderly subjects versus young healthy subjects: elderly subjects have a slower elimination rate constant that is mostly explained by a reduction in renal clearance. This is important, since ODM+ is postulated to be primarily responsible for the opioid analgesic effect and opioid side effects associated with tramadol administration.

Key Points

Tramadol should only be used in elderly populations, particularly the more frail elderly, after careful consideration of the patient's renal and hepatic function and the increased potential for opioidrelated side effects.

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