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.

Supplementary

The article’s supplementary files as

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.