title: Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer.
abstract: BACKGROUND
  Tramadol is a synthetic, centrally acting analgesic for the treatment of moderate to severe pain. The marketed tramadol is a racemic mixture containing 50% (+)tramadol and 50% (-)tramadol and is mainly metabolized to O-desmethyltramadol (M1) by the cytochrome P450 CYP2D6. Tramadol is generally considered to be devoid of any serious adverse effects of traditional opioid receptor agonists, such as respiratory depression and drug dependence.
  
  
  METHODS
  A 22-year-old Caucasian female patient was admitted to our ICU in refractory cardiac arrest requiring extracorporeal membrane oxygenation. This aggressive support allowed resolution of multi-organ dysfunction syndrome. Repeated blood analyses using liquid chromatography-tandem mass spectrometry confirmed high concentrations of both tramadol and its main metabolite O-desmethyltramadol. Genotyping of CYP2D6 revealed the patient to be heterozygous for a duplicated wild-type allele, predictive of a CYP2D6 ultrarapid metabolizer (UM) phenotype, confirmed by calculation of the tramadol/M1 (MR1) metabolic ratio at all time points.
  
  
  CONCLUSIONS
  We here report a case of near-fatal isolated tramadol cardiotoxicity. Because of the inhibition of norepinephrine reuptake, excessive blood epinephrine levels in this CYP2D6R UM patient following excessive tramadol ingestion could explain the observed strong myocardial stunning. This patient admitted intermittent tramadol consumption to gain a "high" sensation. In patients with excessive morphinomimetic effects, levels of tramadol and its main metabolite M1could be measured, ideally combined with CYP2D6 genotyping, to identify individuals at risk of tramadol-related cardiotoxicity. Tramadol treatment could be optimized in these at-risk individuals, consequently improving patient outcome and safety.
authors.affiliation: Service de Réanimation Polyvalente, Hôpital Roger Salengro, CHRU Lille, Rue Emile Laine, 59037, Lille Cedex, France. ahmedelkalioubie@mac.com
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elkalioubie
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.forename: Laurent
authors.initials: L
authors.lastname: Robriquet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Wiart
authors.forename: Anne
authors.initials: A
authors.lastname: Garat
authors.forename: Franck
authors.initials: F
authors.lastname: Broly
authors.forename: François
authors.initials: F
authors.lastname: Fourrier
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics / Q000506:poisoning*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D016903:Drug Monitoring; D062787:Drug Overdose; D004837:Epinephrine / Q000097:blood; D005260:Female; D005838:Genotype; D006323:Heart Arrest / Q000209:etiology; D006801:Humans; D050216:Metabolic Detoxication, Phase I; D017682:Myocardial Stunning / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D009293:Opioid-Related Disorders / Q000523:psychology; D014147:Tramadol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000506:poisoning*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; C080580:O-demethyltramadol; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6; D004837:Epinephrine