Morphine versus hydromorphone pharmacokinetic vs. pharmacodynamic variabilities

De Aquino et al. (1) provide a thoughtful and insightful recapitulation of our articles on the comparative pharmacokinetic and pharmacodynamic variabilities of morphine and hydromorphone (2-4), which highlights the principle findings and clinical implications, and crystalizes the major messages. In addition, their commentary expands upon elements in the Discussion section of our articles and points out additional considerations that we could not discuss in detail due to journal word length restrictions. Their essay also emphasizes the importance of appropriate study design (superiority of within-subjects crossover vs. between-subject comparison of different cohorts) and illuminates unanswered questions regarding special populations and other opioids. Their theses, synthesis, propositions, and arguments are entirely in concert with our own (2-4).

We agree that differences in the interindividual pharmacokinetic variability between morphine vs hydromorphone are negligible, and “unlikely to be the differentiator” influencing drug selection between the two opioids. We also agree that differences in the interindividual pharmacodynamic variability between morphine vs. hydromorphone are also negligible. Nevertheless, nestled within this consideration are the findings that pharmacodynamic variability greatly exceeds that of pharmacokinetic variability, for both opioids, and, that even within an opioid (i.e., morphine) there are meaningful differences in the pharmacology (pharmacokinetics and pharmacodynamics) of the various clinical effects, a finding not heretofore appreciated (3,4). We agree that once excepting pharmacokinetic variability as a major determinant in decision-making regarding opioid choice, the more actionable aspect is opioid pharmacodynamics (exposure-to-effect translation, per these authors), or, even more comprehensively, clinical effects as we initially identified (2). But even more important is the necessity for practitioners to possess the fundamental and comprehensive pharmacologic knowledge that enables them to devise and implement anesthetic regimens and opioid selection that maximizes analgesia and minimizes untoward side effects (5).

De Aquino et al. (1) suggest that our comprehensive clinical protocol and pharmacokinetic-pharmacodynamic analysis could serve as a blueprint for further evaluation of other opioids and other patient populations, and that such model-informed drug development may offer the type of “high-signal comparative evidence that is often conspicuously absent from clinical decision-making”. We agree.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0145/coif). A.D. receives consulting fees from ZMI Pharma and Enalare Therapeutics, all paid to MediD Consultancy BV, Amsterdam. E.D.K. serves on an Independent Data Monitoring Committee for Vertex Pharmaceutical, unrelated to this letter. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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4. Olofsen E, Meissner K, Dahan A, et al. Morphine and hydromorphone pharmacodynamics in human volunteers: population-based modelling of interindividual response variability and utility. Br J Anaesth 2026;136:1459-71. [Crossref] [PubMed]
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