Comprehensive toxicological analysis in a case of unexpected fatal codeine intoxication

Margalho, Cláudia; Emanuel Santos Pinheiro, João; Dinis, Pedro; Mendonça, Ricardo; Castanheira, Alice; Franco, João

http://hdl.handle.net/10400.26/53928

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Authors

Margalho, Cláudia

Emanuel Santos Pinheiro, João

Abstract(s)

Background and Aims: Codeine, a commonly prescribed opioid analgesic and antitussive, is widely used either alone or in combination with other medications. This substance is typically administered orally and is well absorbed from the gastrointestinal tract. After being absorbed, it is distributed throughout the body and crosses the blood-brain barrier to reach the central nervous system, where it exerts its pharmacological effects. Metabolized extensively by the liver enzyme CYP2D6, codeine is converted to its active metabolite, morphine, along with other metabolites such as norcodeine, codeine-6-glucuronide, and morphine-3-glucuronide. Despite its therapeutic benefits, codeine can induce adverse effects such as drowsiness, constipation, nausea, and respiratory depression, particularly at higher doses or in susceptible individuals. We present an unusual case concerning a 60-year-old woman that was found dead at home by his husband, when he came back home for lunch. In that morning, he left her sleeping in the bed. She had diarrhoea in the previous 48h, was obese, and suffer of asthma and psychiatric illness. Her usual prescribed medications included the antidepressants escitalopram and triticum, the anticonvulsant oxcarbazepine (used primarily to treat epilepsy and bipolar disorder), the anxiolytic lorazepam, the antipsychotic quetiapine, the asthma control montelukast and the atorvastatin used to treat hypercholesterolemia. There was no history of ingestion of any formulation containing codeine. Autopsy showed no evidence of trauma. A slight cardiac hypertrophy related with a hypertensive cardiopathy was observed macro and microscopically. Fragments of white pills were found in stomach and a dark liquid content until the jejune. Methods: Validated analytical procedures, routinely used in our casework, were applied to analyze peripheral and cardiac blood, urine, gastric content, and liver specimens. Initially, drugs of abuse and benzodiazepines were screened using immunoassay methodology, while ethanol screening was conducted by gas chromatography-flame ionization detector with headspace injection (GC-FID-HS). Subsequently, systematic toxicological analyses were performed using gas chromatography-mass spectrometry (GC-MS) for drugs of abuse and unknown substances, and ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS-MS) for prescription substances. Results and Discussion: No ethanol or drugs of abuse were detected in blood samples. However, codeine was confirmed, in all analyzed specimens, in significantly high concentrations: peripheral (5309 ng/mL) and cardiac (7545 ng/mL) blood, suggesting recent consumption; liver (9935 ng/mL), confirming extensive metabolism; urine (205918 ng/mL), indicating substantial drug excretion before death; and gastric content (197428 ng/mL), confirming ingestion prior to death. Additionally, morphine, a codeine metabolite, was present in peripheral and cardiac blood at concentrations of 190 and 616 ng/mL, respectively. Furthermore, therapeutic levels of various prescription medications were detected in peripheral blood, including atorvastatin, citalopram, oxcarbazepine, paracetamol, quetiapine, norquetiapine, trazodone and its metabolite mCPP, lorazepam and its metabolite desalkylflurazepam. Conclusion: The autopsy was negative except for a hypertensive cardiopathy, that was not severe enough to justify the death. On the other hand, toxicological results showed unexpectedly codeine in the blood, stomach, liver, and urine, in high concentrations. The pills fragments found in the gastric content reinforce its ingestion before death. Taking into account all these facts, the cause of death was attributed to codeine ingestion, although in an unknown formulation. The manner of death remains unascertained, as suicide could be a possibility according to her psychiatric antecedents, as well as an accident, if codeine had been taken to treat the diarrhoea she had.