Objective: To characterize the risk of methemoglobinemia and hemolytic anemia following large overdoses of zopiclone, a cyclopyrrolone hypnotic-sedative and a racemic mixture of R-zopiclone and S-zopiclone (eszopiclone).
Methods: This review included all reports of zopiclone induced methemoglobinemia, hemolytic anemia, and oxidative stress that had been published in medical journals or discussed in continuous medical education (CME) programs. These reports were identified by searching the Medline (1980 - December 9, 2013), China Journal Net (1994 - December 2013), and Google Scholar, using zopiclone, eszopiclone, methemoglobinemia, hemolytic anemia, and oxidative stress as the search terms.
Results: Six cases of methemoglobinemia, one case of methemoglobinemia, with concomitant hemolytic anemia, and one case of hemolytic anemia were identified. These complications occurred after large zopiclone overdoses (450 - 3,750, 1,125 - 1,500, and 375 - 750 mg, respectively, i.e., 60 - 500, 150 - 200, and 50 - 100 times the daily dose of 7.5 mg). The resulting methemoglobinemia could be severe (19.4 - 24.5%), while the hemolytic anemia was mild (Hb 9.0 - 9.6 g/dL). Molecular modelling analyses indicate that eszopiclone and its two metabolites will be kinetically labile. Their molecular surfaces have significant amounts of electron-deficient regions. All three compounds are expected to react with cellular nucleophiles, such as glutathione, causing its depletion and oxidative stress.
Conclusions: After large overdoses, zopiclone, alone or together with its metabolites, most probably causes oxidative stress in erythrocytes to account for the methemoglobinemia and hemolytic anemia. Further studies are required to determine their incidence and the dose-related capacity of zopiclone and its metabolites in producing erythrocyte oxidative stress.