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In silico (computed) modelling of doses and dosing regimens associated with morphine levels above international legal driving limits

Boland, Jason W.; Johnson, Miriam; Ferreira, Diana; Berry, David J.


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Dr Jason Boland
Senior Clinical Lecturer and Honorary Consultant in Palliative Medicine

Diana Ferreira

David J. Berry


Morphine can cause central nervous system side effects which impair driving skills. The legal blood morphine concentration limit for driving is 20 µg/L in France/Poland/Netherlands and 80 µg/L in England/Wales. There is no guidance as to the morphine dose leading to this concentration.

The in silico (computed) relationship of oral morphine dose and plasma concentration was modelled to provide dose estimates for a morphine plasma concentration above 20 and 80 µg/L in different patient groups.

A dose–concentration model for different genders, ages and oral morphine formulations, validated against clinical pharmacokinetic data, was generated using Simcyp®, a population-based pharmacokinetic simulator.

Healthy Northern European population parameters were used with age, gender and renal function being varied in the different simulation groups. In total, 36,000 simulated human subjects (100 per modelled group of different ages and gender) received repeated simulated morphine dosing with modified-release or immediate-release formulations.

Older age, women, modified-release formulation and worse renal function were associated with higher plasma concentrations. Across all groups, morphine doses below 20 mg/day were unlikely to result in a morphine plasma concentration above 20 µg/L; this was 80 mg/day with the 80 µg/L limit.

This novel study provides predictions of the in silico (computed) dose–concentration relationship for international application. Individualised morphine prescribing decisions by clinicians must be informed by clinical judgement considering the individual patient’s level of impairment and insight irrespective of the blood morphine concentration as people who have impaired driving will be breaking the law. Taking into account expected morphine concentrations enables improved individualised decision making.


Boland, J. W., Johnson, M., Ferreira, D., & Berry, D. J. (2018). In silico (computed) modelling of doses and dosing regimens associated with morphine levels above international legal driving limits. Palliative medicine, 32(7), 1222-1232.

Journal Article Type Article
Acceptance Date Apr 10, 2018
Online Publication Date May 4, 2018
Publication Date Jul 1, 2018
Deposit Date Aug 29, 2018
Publicly Available Date Aug 29, 2018
Journal Palliative Medicine
Print ISSN 0269-2163
Electronic ISSN 1477-030X
Publisher SAGE Publications
Peer Reviewed Peer Reviewed
Volume 32
Issue 7
Pages 1222-1232
Keywords Anesthesiology and Pain Medicine; General Medicine
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