Two cases of methemoglobinemia following zopiclone ingestion

Abstract

Introduction. Most cases of methemoglobinemia result from exposure to certain medications and chemicals such as nitrates, nitrites, aniline, dapsone, phenazopyridine, benzocaine, and chlorates which oxidize the iron from the ferrous state. Intoxication with zopiclone is expected to produce drowsiness, confusion and coma but not methemoglobinemia. We report two cases of zopiclone overdose with methemoglobinemia. Case Reports. Case one: A 43-year-old woman presented to the emergency department two hours after ingesting 100 tablets of 7.5 mg zopiclone. Her initial vital signs, physical examination, chest x-ray, and electrocardiogram were normal. Two hours post-ingestion her methemoglobin level was 9.8%; 14 hours post-arrival she showed cyanosis of the lips and extremities and dyspnea after walking. The blood sample 16 hours post-ingestion was dark brown in color and the methemoglobin was 23.8%. Shortly after the second of two doses of methylene blue (1 mg/kg each) her methemoglobin was 3.6%. Case two: A 30-year-old woman came to the emergency department 50 hours after ingesting 150 to 200 tablets of 7.5 mg zopiclone. Her vital signs and physical examination were normal. Her methemoglobin level was 5.2% at 52 hours post-ingestion and it peaked at 10.4% one hour later. She recovered following symptomatic care. Discussion and Conclusions. Methemoglobinemia has not previously been reported following acute zopiclone overdose. In our patients, there were no identifiable alternative causes explaining the methemoglobinemia and zopiclone was confirmed in both patients by laboratory analysis. These two cases suggest that zopiclone overdose is capable of producing delayed methemoglobinemia, which may be related to formation of a sufficient quantity of the N-oxide metabolite.

N,N-Dimethyl-p-toluidine, a Component in Dental Materials, Causes Hematologic Toxic and Carcinogenic Responses in Rodent Model Systems

“…Dimethylaniline N -oxide has been shown to autocatalyze oxidization of hemoglobin (Kiese 1967). Further, methemoglobinemia has been attributed to formation of an N -oxide metabolite in humans ingesting toxic doses of the drug, zopiclone (Fung et al 2008). …”

Dapsone‐Associated Methemoglobinemia in a Patient With Slow NAT2*5B Haplotype and Impaired Cytochrome b5 Reductase Activity

“…Clinical risk factors associated with dapsone methemoglobinemia include renal failure, 25 administration of other drugs known to contribute to methemoglobinemia (lidocaine, benzocaine, prilocaine, acetaminophen, nitroprusside, phenazopyridine, and possibly zopiclone), 26 , 27 slow N ‐acetyltransferase 2 activity, 9 , 10 and decreased G6PD activity 28 . G6PD is necessary to generate NADPH, which otherwise maintains adequate glutathione concentrations within erythrocytes; this counteracts oxidation of hemoglobin.…”

The Clinical and Forensic Toxicology of Z-drugs

“…Since then, reports of agitation, hallucinations, psychosis, and coma from Z-drug overdose have been published [70][71][72][73]. Other unusual reports include hemolytic anemia and methemoglobinemia from zopiclone, suggesting oxidative stress from either the parent drug or its metabolites, one of which is an N-oxide derivative [74][75][76].…”