Authors (including presenting author) :
Lam WK(1), Law WYF(1), Yip SF(1)
Affiliation :
(1)Department of Clinical Pathology, Tuen Mun Hospital
Introduction :
Drug-induced oxidative haemolysis, though linked to glucose-6-phosphate dehydrogenase (G6PD) deficiency, remains poorly characterised. Zopiclone is typically not considered a causative agent. However, this study reveals zopiclone as a significant and previously under-appreciated cause, highlighting its clinical and public health implications.
Objectives :
To characterize the clinicopathological features of drug-induced oxidative haemolysis at Tuen Mun Hospital.
Methodology :
We retrospectively analysed all Heinz body test requests at Tuen Mun Hospital from 1st January 2012 to 31st December 2022 for suspected oxidative haemolysis. Oxidative haemolysis was defined by morphological evidence (bite/blister cells and polychromasia) plus ≥1 biochemical marker (elevated indirect bilirubin >12 μmol/L, lactate dehydrogenase >220 U/L, or reduced haptoglobin < 0.30 g/L). Patient clinical histories, medication records, and laboratory data were reviewed through 31st December 2023.
Result & Outcome :
Results: Of 27 confirmed oxidative haemolysis cases (from 41 Heinz body tests in 37 patients), 15 (55.6%) had drug exposure. Astonishingly, zopiclone was implicated in 73.3% (n=11) of these, surpassing dapsone (13.3%, n=2), nitrofurantoin (6.7%, n=1), and sulfasalazine (6.7%, n=1). Zopiclone-induced haemolysis predominantly affected females (81.8%), often with comorbid depression/substance use disorders (81.8%). Only one male had G6PD deficiency. We identified two distinct presentations: acute overdose (36.3%, n=4), three of whom with methaemoglobinaemia; and a previously undescribed presentation of chronic overdose (63.7%, n=7), characterised by prolonged use of 3-30 times the recommended daily dose (7.5mg) of zopiclone without typical psychomotor symptoms. All chronic overdose cases had missed or delayed (7-61 months) diagnosis. Missed cases remained clinically unsuspected and were identified solely through positive urine toxicology. Alarmingly, some patients suffered recurrent anaemia requiring multiple transfusions (up to 56 units over 26 admissions). Despite its prescription-only status, 90.9% obtained zopiclone from unknown or illegitimate sources; two reported acquiring hundreds of tablets without prescriptions.
Conclusion: This study is the largest series to date on drug-induced oxidative haemolysis that identifies zopiclone as an important causative agent. We described the distinct presentations of acute and chronic zopiclone overdoses which are hitherto not emphasized, and the diagnosis of atypical chronic overdose presentations requires a high index of suspicion. Furthermore, our findings expose a critical public health concern regarding illicit zopiclone access, demanding intervention to prevent morbidity and ensure patient safety. Multidisciplinary collaborations and updates in medical educational materials (e.g. UpToDate) are ongoing to address this issue.
