Anesthesiology, V 120 • No 5 1126 May 2014 L IPOPHILIC opioids are commonly coadministered with local anesthetics for spinal and epidural analgesia in obstetrics and other subspecialties. 1–3 Combining drugs has the advantage of reducing the dose that would be necessary if either drug were used alone, thus potentially decreasing the incidence and severity of associated side efects such as hypo- tension and motor block. 1 However, the nature of the phar- macologic interaction between opioids and local anesthetics given neuraxially has not been clearly elucidated in a clinical context. Several studies in animals have reported a synergistic interaction. 4,5 However, few experimental data examining the interaction of neuraxial drugs in humans are available. Te aim of this randomized, double-blinded study was to describe the pharmacologic interaction between fentanyl and bupivacaine when administered intrathecally in combina- tion for labor analgesia. We hypothesized that combinations of fentanyl and bupivacaine would produce greater analgesia than that predicted by simple additivity between drugs. Materials and Methods Te study was approved by the Joint Chinese University of Hong Kong – New Territories East Cluster Clinical Research Ethics Committee, Shatin, Hong Kong, China, and the pro- tocol was registered in the Centre of Clinical Trials Clinical Registry of the Chinese University of Hong Kong (reference no. CUHK_CCT00124). We recruited 300 women with American Society of Anes- thesiologists physical status 1 to 2 who matched the follow- ing criteria: nulliparous, singleton pregnancy, gestation of 36 weeks or greater, in active labor with cervical dilatation What We Already Know about This Topic • Quantitative analysis of drug interactions is commonplace for general anesthetics and sedatives, but has been little applied to intrathecal drugs in clinical practice • Addition of fentanyl enhances the analgesic effect of intrathe- cal bupivacaine for labor, but quantitative analysis of this inter - action has not been adequately described What This Article Tells Us That Is New • In a study of 300 parturients receiving intrathecal fentanyl and bupivacaine for labor analgesia, these drugs interacted in a clearly synergistic fashion Copyright © 2014, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2014; 120:1126-36 ABSTRACT Background: Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. How- ever, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. Methods: Tree hundred nulliparous women randomly received 1 of 30 diferent combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the frst stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defned by percentage decrease in pain score from baseline at 15 and 30 min. Dose–response curves for individual drugs were ftted to a hyperbolic dose–response model using nonlinear regression. Te nature of the drug interaction was determined using dose equivalence methodology to compare observed efects of drug com- binations with efects predicted by additivity. Results: Te derived dose–response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater efects than those predicted by additivity at 15 min (P < 0.001) and 30 min (P = 0.015) (mean diferences, 9.1 [95% CI, 4.1–14.1] and 6.4 [95% CI, 1.2–11.5] units of the normalized response, respectively), indicating a synergistic interaction. Conclusions: Te pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantifcation of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics. (ANESTHESIOLOGY 2014; 120:1126-36) Presented in part as a free article at Obstetric Anaesthesia 2013, Bournemouth, United Kingdom, May 23, 2013. Submitted for publication August 26, 2013. Accepted for publication November 27, 2013. From the Department of Anaesthesia and Inten- sive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China (W.D.N.K., K.S.K., F.F.N., K.K.L.N., R.S., and A.L.). Synergistic Interaction between Fentanyl and Bupivacaine Given Intrathecally for Labor Analgesia Warwick D. Ngan Kee, M.B., Ch.B., M.D., F.A.N.Z.C.A., F.H.K.A.M., Kim S. Khaw, M.B.B.S., M.D., F.R.C.A., F.H.K.A.M., Floria F. Ng, R.N., B.A.Sc., Karman K. L. Ng, M.B., Ch.B., F.A.N.Z.C.A., F.H.K.A.M., Rita So, M.B., Ch.B., F.A.N.Z.C.A., F.H.K.A.M., Anna Lee, M.P.H., Ph.D. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/120/5/1126/265157/20140500_0-00021.pdf by guest on 05 June 2022