The legal blood morphine concentration for driving in England and Wales has been set at 80 µg/L, based on consensus. There is little information regarding the doses likely to cause levels above this limit. Knowledge of the dose-concentration relationship would aid doctors’ prescribing ?decisions and individualised advice. The aim of this study was to investigate the in silico relationship of oral morphine dose and plasma concentration in the context of a morphine plasma concentration of 80 µg/L in different patient groups.Methods
A dose-concentration in silico model for different genders, ages and morphine formulations was generated using Simcyp, a population-based pharmacokinetic simulator. This software simulates absorption and metabolism in a physiology based modelling platform, calculating a range of steady state dose-plasma concentrations across a diverse population. The morphine model created was validated against clinical pharmacokinetic data for oral immediate-release and modified-release preparations. This model calculates only morphine ?concentrations not its active metabolites; in line with the ?driving law.Results
Older age, female gender, modified-release formulation and renal dysfunction were associated with higher plasma concentrations at steady state. Except in females over 80 years old or in people with impaired renal function, morphine doses below 120 mg/d were unlikely to result in a morphine plasma concentration above 80 µg/L. In males less than 40 years old with normal renal function, doses up to 250 mg/d were unlikely to result in a morphine plasma concentration above 80 µg/L. An immediate-release morphine dose taken alongside modified-release morphine leads to a higher plasma concentration.Conclusion
These derived morphine dose-concentrations could provide a reference frame for the prescribing clinician. However, the decision and communication to the patient must ?primarily take into account clinical judgment, the individual patient‘s level of impairment and insight for any given dose and plasma concentration.