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Editorial: Editorials

Anesthesia and Pharmacogenomics: Not Ready for Prime Time

Candiotti, Keith MD

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doi: 10.1213/ANE.0b013e3181b9857a

The age of interindividualized medicine has been upon us for several years. Pharmacogenomics has made significant contributions to several areas of medicine, including psychiatry, where it may be useful for drug selection,1 and oncology, where it may play a significant role in predicting drug efficacy and preventing potentially fatal adverse drug reactions.2 Despite its gains in other areas of medicine, pharmacogenomics has had limited impact on the clinical practice of anesthesiology. The impetus for genotyping a patient in clinical practice is that it needs to make a significant impact on the outcome, or the drug being evaluated has to be costly and/or difficult to predict clinically. Although a negative anesthetic outcome, such as postoperative vomiting (POV), is relatively costly, it does not currently compare to the cost, time, and effort required to genotype a patient to possibly lower the incidence of such an event. This relative “cost” of time and money is 1 reason why pharmacogenomics has been of limited utility in routine clinical anesthesiology practice. Many of our negative outcomes, which may be genetically predisposed, although certainly significant to our patients, cannot be compared on a relative cost basis to the recurrence of cancer or the need for a prolonged psychiatric admission, areas whereby genetic analysis may in fact be cost and outcome effective.

In this issue of Anesthesia & Analgesia, an article by Rueffert et al.3 deals with the subject of POV and how variations in the 5-HT3A and 5-HT3B subunits for the serotonin receptor genes (coding regions, the 5′flanking regions, and exon/intron boundaries) influence outcomes.4 It has been proposed that the serotonin receptor is a 5-unit heteromeric structure composed of A and B subunits.5,6 Variations in the gene coding for these subunits have been investigated in patients undergoing chemotherapy and were noted to have an effect on the incidence of chemotherapy-induced nausea and vomiting.7,8 Rueffert et al. have attempted to evaluate whether some of the same genetic variables found to be significant in chemotherapy-induced nausea and vomiting, as well as other genetic variants, also play a significant role in the clinical course of POV. In the end, in addition to the well-described clinical postoperative nausea and vomiting risk factors, several genetic variables were found to be potentially associated with a risk of developing POV as well as other variations that may in fact eventually be determined to be protective.

Unfortunately, the results from this trial cannot be considered definitive because of the relatively small size of the study population, which the authors clearly discuss in the article. Insufficient power is a problem with many genetic association studies, probably because of the expense and the difficulty running these types of trials. That being said, studies such as this are necessary to help develop the framework for larger trials by both determining the genetic variations to be investigated as well as calculating the required patient number to achieve an adequately powered trial.

Although it is highly unlikely in the foreseeable future that anesthesiologists will know the actual genetic sequence of their patient’s DNA, the concepts gained from this type of study are quite useful in explaining already well-observed phenomena such as familial patterns for postoperative nausea and vomiting.9 Additionally, it has been reported on numerous occasions that patients who failed 5-HT3 antagonists in the postoperative period could not be rescued by repeating those same drugs10 or even by using other drugs in the same class of drug.11 Although reasons involving genetic variations in metabolism may explain some drug failures,12 they would not account for the resistance of different drugs in the same class that are metabolized via different specific pathways (e.g., ondansetron versus granisetron). If in fact 5-HT3 antagonists are sometimes failing to work because of individual genetic receptor variations, this could then partially explain the above-mentioned observations. This concept of “genetic drug resistance” may be potentially carried 1 step further by suggesting that if a patient failed a prophylactic dose of a 5-HT3 antagonist then that class of drug may not be an optimal drug when the patient has future need of antiemetic drugs. Although there are certainly many reasons why a drug fails, the possibility of a genetic resistance is a concept that is not often considered.

When translating genetic studies, such as the work of Rueffert et al., to the clinical practice of anesthesiology, the exact location of a particular variant is essentially irrelevant to the clinician at this time. What is relevant, as was mentioned, is that genetic studies help to potentially clarify observed clinical phenomena. By understanding the mechanisms of medication and treatment failures, alternative practices can be recommended, put into practice, and reinforced. I would suggest that although many practitioners have been informed of the published data supporting the inability to rescue a 5-HT3 antagonist failure with another dose of a 5-HT3 antagonist, many clinicians still attempt it. Although this practice may persist for several reasons, studies that help demonstrate the mechanisms of why this practice is potentially ineffective may help change persistent ineffective behaviors.

The human genome has now been fully decoded; the extrapolation of those basic data to clinical practice will take many years. Some of the initial steps in learning how to use those data effectively in our current practice involve performing gene association trials, even limited ones, to help clarify mechanisms and direct future research. As genetic research in our field progresses, I believe many other observed behaviors and outcomes will be found to have strong genetic links.

REFERENCES

1. de Leon J. Pharmacogenomics: the promise of personalized medicine for CNS disorders. Neuropsychopharmacology 2009; 34:159–72
2. Dawood S, Leyland-Jones B. Pharmacology and pharmacogenetics of chemotherapeutic agents. Cancer Invest 2009;27:482–8
3. Rueffert H, Thieme V, Wallenborn J, Lemnitz N, Bergmann A, Rudlof K, Wehner M, Olthoff D, Kaisers UX. Do variations in the 5-HT3A and 5HT3B serotonin receptor genes (HTR3A, HTR3B) influence the occurrence of postoperative nausea and vomiting (PONV)? Anesth Analg 2009;109:1442–7
4. Bruss M, Eucker T, Gothert M, Bonisch H. Exon-intron organization of the human 5-HT3A receptor gene. Neuropharmacology 2000;39:308–15
5. Dubin AE, Huvar R, D’Andrea MR, Pyati J, Zhu JY, Joy KC, Wilson SJ, Galindo JE, Glass CA, Luo L, Jackson MR, Lovenberg TW, Erlander MG. The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit. J Biol Chem 1999;274:30799–810
6. Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF. The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 1999;397:359–63
7. Kaiser R, Tremblay PB, Sezer O, Possinger K, Roots I, Brockmoller J. Investigation of the association between 5-HT3A receptor gene polymorphisms and efficiency of antiemetic treatment with 5-HT3 receptor antagonists. Pharmacogenetics 2004;12:271–8
8. Tremblay PB, Kaiser R, Sezer O, Rosler N, Schelenz C, Possinger K, Roots I, Brookmoller J. Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients. J Clin Oncol 2003;21:2147–55
9. Apfel CC, Roewer N. Risk factors for nausea and vomiting after general anesthesia: fictions and facts. Anaesthesist 2000;49: 629–42
10. Kovac A, O’Connoer TA, Pearman MH, Kekoler LJ, Edmondson D, Baughman VL, Angel JJ, Campbell C, Jense HG, Mingus M, Shahvari MB, Creed MR. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial. J Clin Anesth 1999;11:453–9
11. Candiotti KA, Nhuch F, Kamat A, Deepika K, Arheart KL, Birnbach DJ, Lubarsky DA. Granisetron versus ondansetron treatment for breakthrough postoperative nausea and vomiting after prophylactic ondansetron failure: a pilot study. Anesth Analg 2007;104:1370–3
12. Candiotti KA, Birnbach DJ, Lubarsky DA, Nhuch F, Kamat A, Koch WH, Nikoloff M, Wu L, Andrews D. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 2005;102:543–9
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