Authors: Henthorn PK et al.
Source: Anesthesia & Analgesia, 142(2):274–275, February 2026.
Summary
This editorial examines whether pharmacogenomic information—specifically loss-of-function variants in the drug transporter SLC22A1 (formerly OCT1)—should meaningfully alter how clinicians dose oral morphine. The authors note that anesthesiology has largely avoided drugs requiring genetic dose adjustment by favoring agents with flow-limited metabolism, organ-independent elimination, or reliable reversal strategies. As a result, clinically relevant pharmacogenomic variability in anesthetic drug dosing is uncommon, and clinicians more often contend with physiologic variability rather than genetic differences.
The editorial highlights work by Gheshlaghi et al suggesting that oral, but not intravenous, morphine may represent a clinically relevant exception. Prior studies show that SLC22A1 loss-of-function variants reduce hepatic morphine uptake, decreasing clearance by about 17%. While this degree of variability would not typically justify changing intravenous morphine dosing—given the much larger inherent pharmacokinetic and pharmacodynamic variability of morphine—the situation differs with oral administration.
Oral morphine undergoes substantial first-pass metabolism, resulting in only about 30% bioavailability under normal circumstances. Using pharmacokinetic modeling in a pediatric population, Gheshlaghi et al simulated the effects of impaired intestinal and hepatic uptake during first-pass metabolism. Their model predicted a 45% higher peak morphine concentration and a 52% increase in total exposure in children with SLC22A1 loss-of-function genotypes. These predicted differences are large enough to rival or exceed known variability in morphine clearance and approach variability in morphine concentration–effect relationships, particularly for respiratory depression.
Supporting evidence comes from prior clinical studies of oral codeine, in which subjects with SLC22A1 loss-of-function alleles exhibited markedly higher morphine exposure after metabolism. Based on these findings, the authors argue that while only a modest dose reduction would be justified for intravenous morphine, oral morphine doses may need to be reduced by roughly one-third in patients known to have two loss-of-function SLC22A1 alleles.
The editorial also emphasizes important limitations of simulation-based conclusions. The modeling did not incorporate the full extent of known interindividual pharmacokinetic and pharmacodynamic variability, which could influence real-world risk–benefit tradeoffs. Nevertheless, the authors argue that these findings warrant prospective clinical studies in genotyped patients, particularly in pediatrics, where inadequate analgesia remains common and dosing precision is especially important.
Key Points
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Pharmacogenomic dose adjustment is uncommon in anesthetic practice due to drug selection strategies
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SLC22A1 loss-of-function variants modestly reduce intravenous morphine clearance
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Oral morphine is more affected due to first-pass metabolism
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Simulations suggest substantially higher morphine exposure with oral dosing in affected genotypes
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Oral dose reduction may be clinically relevant in patients with known SLC22A1 loss-of-function
What You Should Know
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Genetic variability may matter more for oral than intravenous opioid dosing
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First-pass metabolism can amplify pharmacogenomic effects
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Predicted increases in oral morphine exposure approach clinically meaningful thresholds
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Pediatric patients may be particularly affected
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Prospective clinical studies are needed before routine genotype-guided dosing is adopted
Thank you for allowing us to highlight and summarize this provocative editorial from Anesthesia & Analgesia, which challenges long-held assumptions about pharmacogenomics and opioid dosing in perioperative care.