Gabapentin as an add-on analgesic to morphine in paediatric patients with chronic pain

Off-label use of gabapentin for the treatment of chronic pain in children has increased over the last decade, with multiple clinical trials evaluating its role pain management and potential opioid-sparing effects. To date, however, these studies appear to rely on empirical evidence without further consideration of pharmacokinetic-pharmacodynamic principles. Here, we use clinical trial simulations and apply extrapolation concepts to identify dosing regimens of morphine and gabapentin in children that correlate with effective analgesia.

Simulation scenarios were based on a clinical study (NCT03275012) aimed at the evaluation of the efficacy of gabapentin-morphine combination vs. morphine alone in a paediatric cohort (n = 66, aged 3 months to 18 years). Concentration vs. time profiles of morphine and gabapentin in the target paediatric population were derived using established population pharmacokinetic models. AUC, Cmax and Css were used as metrics of exposure across the titration and maintenance phases of therapy.

Morphine doses titrated from 0.6 to 1.2 mg/kg/day resulted in concentrations within established analgesic ranges (Cmax: 36.3-82.0 ng/mL; Css: 8.5-19.5 ng/mL). Add-on gabapentin can be titrated in a stepwise manner from 5 up to a maximum of 63 mg/kg. At the maximum dose, median exposure (AUC_0-8) corresponded to approximately 35 mg/L·h (i.e., 1200 mg/day adult dose equivalent).

A weight-banded dosing regimen results in consistent exposure to gabapentin and morphine across different age groups while ensuring acceptable safety margins. In addition, these results offer a rational basis for future clinical trials aiming to reduce opioid burden and optimize pain control in children.