Anesthesiology, V 118 • No 6 1395 June 2013 ABSTRACT Background: e presence of the A118G single nucleo- tide polymorphism in the OPRM1 gene as well as noxious stimulation might aﬀect the requirements of remifentanil for patients undergoing ultrasonographic endoscopy under sedation-analgesia with propofol and remifentanil. Bispec- tral index (BIS) was used as a surrogate measure of eﬀect. Methods: A total of 207 patients were screened for A118G and randomly received diﬀerent combinations of propofol and remifentanil, changed depending on the nausea response to endoscopy tube introduction. Nonlinear mixed eﬀects modelling was used to establish the relation between propofol and remifentanil with respect to BIS and to investigate the inﬂuence of A118G or noxious stimulation. e value of k e0 for propofol and remifentanil was estimated to avoid the hysteresis between predicted eﬀect site concentration (Ce) and BIS. Results: Data from 176 patients were analysed. Eleven were recessive homozygous for A118G (OPRM = 1). A total of 165 patients were either dominant homozygous or hetero- zygous and considered normal (OPRM = 0). e estimated values of k e0 for propofol and remifentanil were 0.122 and 0.148 min −1 . Propofol and remifentanil were synergistic with respect to the BIS (α = 1.85). EC 50 estimate for propofol was 3.86 µg/ml and for remifentanil 19.6 ng/ml in normal patients and 326 ng/ml in OPRM = 1 patients. BIS increases around 4% for the same eﬀect site concentrations with nox- ious stimulation. Conclusions: Predicted eﬀect site concentration of remifen- tanil ranging 1–5 ng/ml synergistically potentiates the eﬀects Modeling the Inﬂuence of the A118G Polymorphism in the OPRM1 Gene and of Noxious Stimulation on the Synergistic Relation between Propofol and Remifentanil Sedation and Analgesia in Endoscopic Procedures Xavier Borrat, M.D.,* Iñaki F. Trocóniz, Ph.D.,† José F. Valencia, M.Sc., Ph.D.,‡ Silvia Rivadulla, C.R.N.A.,§ Oriol Sendino, M.D.,|| Josep Llach, M.D.,# Jenifer Muñoz B.Sc.,** Sergi Castellví-Bel, Ph.D.,†† Mathieu Jospin, M.Sc.,‡‡ Erik W. Jensen, M.Sc., Ph.D.,‡‡ Antoni Castells, M.D.,§§ Pedro L. Gambús, M.D.|||| What We Already Know about This Topic • The common A118G polymorphism (single nucleotide poly- morphism) in the μ1 opioid receptor gene is associated with reduced opioid sensitivity, and could thus contribute to vari- ability in drug responsiveness • Propofol and remifentanil infusions interact synergistically in producing sedation What This Article Tells Us That Is New • Subjects with A118G single nucleotide polymorphism showed no synergy between propofol and remifentanil under sedation for upper endoscopy using bispectral index as a measure of effect • Genetic polymorphisms can affect sensitivity to opioids, which has implications for drug dosing or selection Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins. Anesthesiology 2013; 118:1395-407 * Staff Anesthesiologist, ‡ Research Associate in Bioengineer- ing, Systems Pharmacology Effect Control and Modeling Research Group of the Department of Anesthesia, Hospital CLINIC de Bar- celona, Barcelona, Spain. † Professor, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, Universidad de Navarra, Pamplona, Spain. § Staff CRNA, ‖ Staff Gastroenterologist, # Associate Professor, ** Research Technician, †† Research Associ- ate, §§ Professor and Head, Gastroenterology Department, Hospital CLINIC, CIBERehd, The August Pi i Sunyer Biomedical Research Institute, University of Barcelona, Barcelona, Spain. ‡‡ Research Associate, Centre for Biomedical Engineering Research, Universi- tat Politècnica de Catalunya, CIBER of Bioengineering, Biomaterials and Nanomedicine, Barcelona, Spain. ‖‖ Visiting Associate Profes- sor, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, and Systems Pharmacology Effect Control and Modeling Research Group of the Department of Anesthesia, Hospital CLINIC de Barcelona. Received from the Systems Pharmacology Effect Control and Modeling Research Group of the Department of Anesthesia, Hos- pital CLINIC de Barcelona, Barcelona, Spain. Submitted for publi- cation April 15, 2012. Accepted for publication February 5, 2013. Supported by a Residency Award of Hospital CLINIC de Barce- lona, Spain (Dr. Borrat), FIS (Fondo de Investigaciones Sanitarias, Health Department, Government of Spain) grants nº FIS PI/050072 and FIS PS09/01209 (Dr. Gambús), FIS PI08/0024 (Dr. Castellví- Bel), Ministerio de Economia y Competitividad (2010–19273; Dr. Castells), and Agència de Gestió d’Ajuts Universitaris i de Recerca (2009 849; Dr. Castells). Dr. Castellví-Bel is supported by a Miguel Servet contract from the FIS (CP 03-0070). Dr. Valencia is sup- ported by a FIS contract under grant FIS PS09/01209 (Dr. Gambús). Address correspondence to Dr. Gambús: Anesthesiology Department, Hospital CLINIC de Barcelona, C/Villarroel 170, 08036 Barcelona, Spain. plgambus@hospitalclinic.org. Information on pur- chasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. ANESTHESIOLOGY’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/6/1395/260975/20130600_0-00027.pdf by guest on 23 October 2022