Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer

• Published in: European journal of clinical pharmacology 2011-08, Vol.67 (8), p.855-858
• Main Authors: Elkalioubie, Ahmed, Allorge, Delphine, Robriquet, Laurent, Wiart, Jean-François, Garat, Anne, Broly, Franck, Fourrier, François
• Format: Article
• Language: English
• Subjects: Adult; Analgesics; Analgesics, Opioid - blood; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - poisoning; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cardiovascular system; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Drug Monitoring; Drug Overdose; Drug toxicity and drugs side effects treatment; Epinephrine - blood; Female; Genotype; Heart Arrest - etiology; Humans; Life Sciences; Medical sciences; Metabolic Detoxication, Phase I; Metabolism; Myocardial Stunning - blood; Myocardial Stunning - chemically induced; Myocardial Stunning - physiopathology; Narcotics; Opioid-Related Disorders - psychology; Pharmaceutical sciences; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Short Communication; Side effects; Toxicity; Toxicity: cardiovascular system; Tramadol - analogs & derivatives; Tramadol - blood; Tramadol - pharmacokinetics; Tramadol - poisoning; Young Adult
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-011-1080-x

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. Case report 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. Discussion 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.