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Genotyping without phenotyping: does it really matter?

January 2013 • Volume 116 • Number 1 Copyright © 2012 International Anesthesia Research Society DOI: 10.1213/ANE.0b013e318275355a In the last decade, clinicians have been somewhat disillusioned after the promise that pharmacogenomics would substantially transform the way anesthesia and perioperative medicine are delivered. Indeed, recommendations based on pharmacogenetic testing to help anesthesiologists and pain doctors tailor opioid regimens for safe and effective analgesia are still awaited. This turbulent journey has been depicted in the journals relevant to anesthesia and pain medicine, with a myriad of publications and more than a dozen editorials describing the quest for a better understanding of the impact of genetic variants on opioid action and ways to improve clinical research in the field of pain genetics and opioid response. In 2002, we had envisioned light at the end of the tunnel and imagined how the Human Genome Project would “infuse new life into human physiology.”1 Soon after, we were invited to embark on an effective “fishing expedition” to explore pain genes,2 and numerous reports examining the μ-opioid receptor gene as a target for postoperative opioids emphasized that “one size does not fit all”3 and that genes associated with analgesic effect are distinct from those associated with side effects and adverse reactions.4 After recognizing the need to educate the audience and inform anesthesiologists,5–7 the current premise is a bittersweet realization that the heritability of opioid responsiveness is probably less straightforward and predictable than previously foreseen.8,9 Therefore, tailoring opioid therapy based on genetic testing may not be that simple, because different effects of opioids seem to be controlled by different genes, and preexisting environmental influences may more significantly contribute to some opioid responses than genes per se, as elegantly identified in a recent twin study.10 In this issue of Anesthesia & Analgesia, readers will find an observational investigation in a pediatric cohort undergoing surgery,11 for which, once again, a variety of genes was examined to shed more light on the genetic basis of postoperative pain and the response to morphine; the novelty, however, resides in the fact that this is the first study performed in an ethnically diverse group of children. The authors selected 6 candidate genes, identified as being relevant to explain the variability in opioid disposition, either because of their involvement as a key target receptor for opioid binding (OPRM1), or their role in opioid metabolism (CYP2D6), endorphins synthesis (POMC), transport across the blood-brain barrier (ABCB1), nociceptors development (NTRK1), or inactivation of dopaminergic neurotransmitters (COMT). Some of these genes would therefore seem more important as modulating pain perception (POMC, NTRK1, and COMT), whereas the remainder are more directly implicated in the pharmacokinetics and pharmacodynamics of opioid action. Compared with previous studies searching for an association between genetic variants of selected genes and postoperative pain as a phenotype, this Swiss study by Mamie et al.11 is undoubtedly sophisticated and elaborate. Clinical outcomes included pain scores and morphine consumption, and genotyping included 6 genes. In addition, to adjust for population admixture in this ethnically diverse population, parental mating type was considered. The study was designed to determine the effect of each genetic variant separately on pain outcomes in a sample of children sufficient to identify an increased risk (adjusted relative risk) for the more prevalent genes (NTRK1, COMT, ABCB1, and OPRM1). One hundred sixty-eight children completed the study, and genotyping for the triad (both parents and child) was available in just over 100 cases. Because of the low prevalence in this cohort for the considered genetic variants of CYP2D6 and POMC, further analysis accounting for these 2 genes was not performed. The total dose of IV morphine consumed over the first 24 hours postoperatively was recorded for each child, and as often required in a pediatric setting, children younger than the age of 6 years were placed on a patient-parent-nurse–controlled analgesia system, and those aged 6 years and older received an IV morphine patient-controlled analgesia system. Pain scores, assessed with the revised faces pain scale (FPS), were recorded up to 11 times over the 24-hour study period, at rest and during mobilization, and it was assumed that a polymorphism would be considered to “boost” the pain Genotyping Without Phenotyping: Does It Really Matter?