Authors: Gheshlaghi N et al.
Source: Anesthesia & Analgesia. February 2026. Volume 142(2):280–283.
Summary:
In this translational modeling study, Gheshlaghi and colleagues explore how pediatric pharmacokinetic simulations can inform safer, more individualized opioid dosing—specifically morphine—by accounting for pharmacogenetic variability. Despite morphine’s widespread use in children, a substantial proportion of pediatric patients experience inadequate analgesia or dose-related toxicity, driven in part by genetic variation affecting drug transport and clearance.
The authors focus on polymorphisms in SLC22A1 (OCT1), the hepatic uptake transporter responsible for morphine influx into hepatocytes. Well-characterized loss-of-function alleles (*2–*5) reduce hepatic uptake and clearance, leading to higher systemic morphine exposure. Using an adapted pediatric pharmacokinetic model originally developed for IV morphine, the investigators simulated both IV and oral administration of a standard 0.2 mg/kg dose in a representative 6-year-old child across SLC22A1 genotypes.
Simulations demonstrated genotype-dependent differences that were modest after IV dosing but markedly amplified with oral administration. Children carrying two loss-of-function alleles exhibited approximately 20% higher exposure after IV morphine, but a 52% increase in exposure and a 45% increase in peak concentration after oral dosing. These route-dependent effects reflect morphine’s high hepatic extraction ratio, where impaired transporter function disproportionately increases oral bioavailability in addition to reducing hepatic clearance.
Based on model predictions, the authors estimate that children with two loss-of-function alleles may require a 17% IV dose reduction and a substantially larger 34% oral dose reduction to achieve morphine exposures comparable to those in children without these variants. The study also highlights how concomitant medications that inhibit SLC22A1—such as ondansetron or verapamil—may further compound genetic effects, increasing the risk of toxicity.
What You Should Know:
• Pharmacogenetic variation in SLC22A1 significantly affects morphine exposure in children.
• Route of administration matters: genetic effects are far greater with oral morphine than IV morphine.
• Pediatric pharmacokinetic simulations can guide dose adjustments without exposing children to additional clinical trials.
• Combining pharmacogenetics with modeling may enable safer, more personalized opioid dosing in pediatrics.
Key Points:
• Loss-of-function SLC22A1 alleles increase morphine exposure, especially after oral dosing.
• Oral morphine may require roughly double the dose reduction compared with IV morphine in high-risk genotypes.
• Model-based simulations provide actionable dosing insights while minimizing ethical and logistical burdens in pediatrics.
• Integration of rapid genotyping could facilitate real-world personalized opioid prescribing.
Thank you to Anesthesia & Analgesia for publishing this timely and thoughtful analysis highlighting how pharmacokinetic modeling and pharmacogenetics can advance precision pain management in pediatric patients.