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

Abstract

Background: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.Aim: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.Design: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.Setting/participants: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.Results: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.Conclusion: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.

Computational Approaches in Preclinical Studies on Drug Discovery and Development

“…The results showed that the 90% confidence intervals for geometric mean ratios were within standard bioequivalence boundaries for all other pharmacokinetic parameters, indicating that both tablet formulations were located in the accepted bioequivalence criteria compared with the oral solution (Ye et al, 2018 ). Boland et al ( 2018 ) used SIMCYP to generate a dose-concentration model by using data from different genders, ages, and oral morphine formulations. The model was then validated against clinical pharmacokinetics data and used to calculate the association of the morphine dose with the plasma concentration.…”

“…The model was then validated against clinical pharmacokinetics data and used to calculate the association of the morphine dose with the plasma concentration. Finally, the analysis showed that older age, female sex, modified-release formulation, and inferior renal function were related to higher plasma concentrations (Boland et al, 2018 ). This result can help clinicians provide personalized prescription decisions.…”

Patients’ and caregivers’ experiences of driving with chronic breathlessness before and after regular low-dose sustained-release morphine: A qualitative study

“…[46] The relation between breathlessness and driving performance whist on opioids must also be explored as current legal morphine limits for driving (where imposed) are far higher than the doses used in this study. [13]…”

“…Regular, low-dose (≤30mg/day), [13] sustained-release morphine safely reduces chronic breathlessness in people with COPD. [14,15] Recently, low-dose, sustained-release morphine has been approved by regulatory bodies in Australia for the treatment of chronic breathlessness.…”

Simultaneous determination of methadone and morphine at a modified electrode with 3D β-MnO2nanoflowers: application for pharmaceutical sample analysis

“…The Royal College of Anaesthetists states that doses of about 200 mg day À1 could be as dangerous as having borderline illegal driving blood alcohol levels. 2 In fact, the clear desensitization of opioid receptors may cause methadone to intervene in impacts started by morphine, and in its continual presence, may even interrupt the cascade of cellular episodes and avoid lengthy neuro-chemical modications due to the chronic exposure to morphine. 3 One of the studies reported methadone as a synthetic analgesic drug with widespread utilization for treating opioid dependence since the mid-1960s.…”