Case report: Tramadol-associated respiratory depression in CYP2D6 ultrarapid metabolizer
Tramadol is metabolized through numerous pathways, including oxidation by the CYP2D6 enzyme to O-desmethyltramadol, which is primarily responsible for its analgesic effects. Although it has been documented that CYP2D6 genetic polymorphisms are associated with variable tramadol exposure, data are limited.
In the March 2015 edition of Pediatrics, Orliaguet and colleagues report the case of a 5.5-year-old boy who experienced severe respiratory depression with use of tramadol after a day-case tonsillectomy. The child underwent adenotonsillectomy for obstructive sleep apnea and was discharged after a 6-hour postoperative hospital stay. He received 20 mg of tramadol orally administered at home approximately 8 hours later that same evening. He was subsequently found to be lethargic the next morning by his parents and was comatose on arrival at the emergency department. He received noninvasive ventilation therapy and intravenous naloxone and fully recovered for discharge the next day. Genotyping revealed 3 functional CYP2D6 alleles (CYP2D6*2 x 2/CYP2D6*2), which authors stated was consistent with ultrarapid CYP2D6 metabolism.
According to the authors, this is the first such report of severe tramadol-associated respiratory depression after tonsillectomy. The patient’s history of obstructive sleep apnea was also proposed as increasing his sensitivity to adverse effects of tramadol. “This case supports the clinical utility of determining CYP2D6 genotype or phenotype in preventing serious drug adverse effects and developing more individualized analgesic therapy based on therapeutic recommendations according to CYP2D6 genotype,” study authors concluded.
Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2D6 genotype and codeine therapy include a summary of current knowledge regarding the effects of CYP2D6 variability on tramadol. Regarding ultrarapid CYP2D6 metabolizers, guideline authors note, “Pharmacokinetic studies in ultrarapid metabolizers showed higher peak plasma concentrations of (+)-O-desmethyltramadol after a dose of tramadol, in addition to greater analgesia, stronger miosis, and higher incidence of nausea as compared with extensive metabolizers.” More information on CYP2D6 genotype and tramadol is available in the Pharmacogenomics KnowledgeBase.
Orliaguet G et al. A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics. 2015;135:e753-5.