Shafer, S.L.

Struys, Michel

English

Ghent University Academic Bibliography

Mixed Effect Modeling inAnalgesia TrialsSteven L. Shafer, MD*Michel M. R. F. Struys, MD†Two articles in this month’s issue of Anesthesia & Analgesia present novelanalgesic concepts. The paper by Aasvang et al.1 explores the effect ofinstilling capsaicin into the wound during surgery. In the absence of someform of anesthesia, the capsaicin would be intensely painful. However,since the wound is also anesthetized using local, regional, or generalanesthesia, the patient does not experience the immediate pain fromC-fiber activation. Instead, C fibers innervating the wound are renderedinactive from the calcium influx, providing long lasting postoperativeanalgesia. Also in this issue, the paper by Zeidan et al.2 demonstrates theanalgesic utility of instilling a combination of tramadol and bupivacaineinto the knee following arthroscopic knee surgery. The combinationprovides superior analgesia to either drug given alone.What is unique about these papers is that the analgesic response wasanalyzed using a program unfamiliar to most analgesic investigators:NONMEM.3 NONMEM is a software program for nonlinear mixed effectsmodeling developed by Lewis Sheiner and Stuart Beal at the University ofCalifornia. NONMEM was primarily developed to analyze pharmacoki-netic data, and grew out of the recognition that pharmacokinetic datatypically have two sources of variability: interpatient variability (how eachpatient’s volumes and clearances were different from a “typical” patient)and residual intrasubject variability (assay noise, model misspecification,and other sources of noise). The bifurcation of variability into truebiological variability, how we all differ from each other, and residual noiseushered in an era of individualized pharmacokinetics and therapeutic drugmonitoring.The authors of these two papers did not independently decide toanalyze their data using NONMEM. Instead, their initial submissionsreflected more traditional analyses that did not take full advantage of therepeated measures in their study design. For example, in the originalsubmission on the effect of capsaicin, the analgesic effect was reported asa trend that did not reach statistical significance. Visual examination of thedata during peer review clearly demonstrated that the groups weredifferent at every point in time. The inability to distinguish this in theanalysis was an artifact of the statistical approach.Mixed effects analysis with NONMEM brought two unique aspects tothe data analysis of these trials. Since pain is highly subjective, subjectsdiffer enormously in their sensitivity to pain and their response toanalgesics. A statistical approach must be able to isolate and characterizeintersubject variability. Second, the analgesic response is not constant, butfollows its own unique time course. Does the analgesia last for one day?Two days? Three days? Four days? Is the effect the same each day, or doesit change over time?These characteristics play to NONMEM’s strengths. NONMEM cananalyze intersubject variability (i.e., the unique sensitivity of subjects topain and pain relief), and permits the analyst to precisely characterize thetime course of the analgesic response. The model need not look like apharmacokinetic model. Indeed, the model for both analgesics was asimple decrement in visual analog scale score that persisted over severaldays.From the *Department of Anesthesiol-ogy, Columbia University, New York City,New York; and †Department of Anesthesi-ology, University of Ghent, Ghent, Belgium.Accepted for publication March 3, 2008.Dr. Shafer regularly teaches the “Fisher/Shafer NONMEM Workshop,” and receivesrevenue from the course tuition.Address correspondence to Steven L.Shafer, MD, 630 West 168th St., P&S Box 46,New York City, NY 10032. Address e-mail tosshafer@columbia. edu.Copyright © 2008 International Anesthe-sia Research SocietyDOI: 10.1213/ane.0b013e3181753288Vol. 107, No. 1, July 2008 9EditorialThe net result was that the data were allowed toforcefully speak to the underlying hypothesis. In thecase of wound instillation of capsaicin, the result wentfrom not being statistically significant, to being a largeeffect (about 50% reduction in visual analog scalescore) that was significant at P  0.0001! The “tradi-tional” analysis was essentially blind to an effect thatwas visually obvious and enormously statisticallysignificant once interindividual variability was prop-erly factored into the model.The lesson to be learned is that mixed effect modelsshould become the standard approach for analysis ofanalgesic trials. Mixed effect models can be imple-mented with many programs, including SAS, R, and Splus. However, NONMEM is optimized for suchapproaches, has been vetted by over two decades oftesting, and has thousands of active users able to helpinvestigators implement these approaches.REFERENCES1. Aasvang EK, Hansen JB, Malmstrøm J, Asmussen T, GennevoisD, Struys MMRF, Kehlet H. The effect of wound instillation of anovel purified capsaicin formulation on postherniotomy pain: adouble-blind, randomized, placebo controlled study. AnesthAnalg 2008;107:282–912. Zeidan A, Kassem R, Nahleh N, Maaliki H, El-khatib M, StruysMMRF, Baraka A. Intraarticular tramadol - bupivacaine combi-nation prolongs the duration of postoperative analgesia afteroutpatient arthroscopic knee surgery. Anesth Analg 2008;107:292–93. Beal SL, Sheiner LB, NONMEM User Guides. NONMEM ProjectGroup, UCSF, San Francisco, 199210 Editorial ANESTHESIA & ANALGESIA

Mixed effect modeling in analgesia trials

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Mixed effect modeling in analgesia trials

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