American Society of Regional Anesthesia and Pain Medicine May 2015 - (Page 8)

Pharmacogenetics in Monitoring of Chronic Pain Patients: Are We There Yet? P atients with chronic pain display large variation in analgesic response and side effect profiles to opioid medications, despite their widespread use for moderate and severe pain based on recommendations from the World Health Organization, medical societies, and numerous clinical practice guidelines. A multitude of factors, including age, gender, drug-drug interactions, drug- environment interactions, and genetic variations, can all affect the clinical outcome of these medications. Genetic factors can influence the pharmacokinetics (absorption, distribution, metabolism, and elimination) of the opioids, as well as the pharmacodynamics (receptors and signal transduction elements). Table 1 lists some of the common polymorphic genes and how they can affect various pain medications.1-3 Paul Jannetto, PhD Department of Laboratory Medicine and Pathology Codirector, Toxicology and Drug Monitoring Laboratory Codirector, Metal Laboratory Mayo Clinic, Rochester, Minnesota Polymorphisms in drug transporters can affect the absorption and distribution of drugs. The P-glycoprotein (P-gp) transporter, which is encoded by ABCB1 (MDR1), is a member of the ATP-binding cassette (ABC) family and acts as a transmembrane efflux pump involved in energy-dependent export of drugs from inside the cell.4,5 It is expressed throughout the body (kidney, liver, small intestine, colon, and blood-brain barrier). Several opioids including morphine, methadone, and fentanyl are substrates of P-gp.6,7 As a result, mutations in P-gp may alter the ability of drugs to reach their target receptors and thus affect the efficacy of these pain medications. Loralie Langman, PhD Department of Laboratory Medicine and Pathology Codirector, Toxicology and Drug Monitoring Laboratory Consultant, Personalized Genomics Laboratory Mayo Clinic, Rochester, Minnesota Robin J. Hamill-Ruth, MD Department of Anesthesiology University of Virginia Health System, Charlottesville, Virginia Section Editor: Andrea Nicol, MD Drug-metabolizing enzymes are another polymorphic target that can affect the efficacy or toxicity of analgesics. After absorption, most opioids undergo extensive first-pass metabolism in the liver by phase I metabolism, involving enzymes such as the cytochrome P450 (CYP) enzymes, and phase II metabolism involving enzymes such as uridine diphosphate glucuronosyltransferase. An additional pharmacogenomics target involves the µ-opioid receptor gene (OPRM1), which is the primary binding site target Table 1: Clinically relevant pharmacogenomics targets of commonly prescribed pain medications. Gene Variant Analgesics affected Consequence of genetic variation ABCB1 3435C>T Morphine Homozygous variants cause increased efficacy. CYP2D6 1846G>A, 2549A>del Codeine, oxycodone, tramadol Poor metabolizers (variants) have more adverse drug reactions and less efficacy. Ultrarapid metabolizers also experience more adverse drug reactions. UGT2B7 -840G>A, 802C>T; *2 Morphine Homozygous variants require lower doses of morphine for efficacy; UGT2B7*2 variants have less side effects (nausea) with morphine. COMT 1947G>A, (Rs4680) Morphine Homozygous variants have a threefold to fourfold decrease in COMT activity; wild-type patients require higher doses of morphine for efficacy than variant patients. OPRM1 118A>G Morphine, M6G; fentanyl; methadone Homozygous variants cause decreased effectiveness and increased dose requirements. COMT = catechol-O-methyltransferase; M6G = Morphine-6-glucuronide 8 2 American Society of Regional Anesthesia and Pain Medicine 2015

Table of Contents for the Digital Edition of American Society of Regional Anesthesia and Pain Medicine May 2015

President’s Message
Editorial
Pharmacogenetics in Monitoring of Chronic Pain Patients: Are We There Yet?
Phrenic Nerve Injury and Interscalene Nerve Block: Have We Learned Anything From the Surgical Treatment of Over 150 Cases of Diaphragmatic Paralysis From Multiple Etiologies?
An Exercise in Negotiation: The Success of the Pain Medicine Fellowship Match
Regional Analgesia for Patients with Acute Rib Fractures
Application of Regional Anesthetic Techniques for Cancer Pain

American Society of Regional Anesthesia and Pain Medicine May 2015