title: Trends in Tramadol: Pharmacology, Metabolism, and Misuse.
abstract: Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects. The importance of the CYP metabolism has led to the adoption of computer clinical decision support with pharmacogenomics tools guiding tramadol treatment in major medical centers. Tramadol's simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions that must be considered. Abrupt cessation of tramadol increases the risk for both opioid and serotonin-norepinephrine reuptake inhibitor withdrawal syndromes. This review provides updated important information on the pharmacology, pharmacokinetics, CYP genetic polymorphisms, drug interactions, toxicity, withdrawal, and illicit use of tramadol.
authors.affiliation: From the *Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California; †Molecular & Medical Pharmacology/Environmental Health Sciences, UCLA, Los Angeles, California; ‡Psychiatry & Addiction, Kasr Al Ainy School of Medicine, Cairo University, Cairo, El Manial, Egypt; §Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California; ‖Department of Anesthesiology and Pain Management, Division of Critical Care Medicine, UT Southwestern Medical Center, Dallas, Texas; and ¶Vermont Center for Behavior and Health, Department of Psychiatry, University of Vermont, Burlington, Vermont.
authors.forename: Karen
authors.initials: K
authors.lastname: Miotto
authors.forename: Arthur K
authors.initials: AK
authors.lastname: Cho
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Khalil
authors.forename: Kirsten
authors.initials: K
authors.lastname: Blanco
authors.forename: Jun D
authors.initials: JD
authors.lastname: Sasaki
authors.forename: Richard
authors.initials: R
authors.lastname: Rawson
mesh_terms: D059787:Acute Pain / Q000188:drug therapy*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004339:Drug Compounding; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D009293:Opioid-Related Disorders / Q000453:epidemiology*; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D011110:Polymorphism, Genetic; D063487:Prescription Drug Misuse; D012307:Risk Factors; D014147:Tramadol / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol; D003577:Cytochrome P-450 Enzyme System; C509164:CYP2D7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human