Zopiclone-associated methemoglobinemia and renal impairment

To the Editor:

Zolpidem, zaleplon, and eszopiclone are commonly prescribed sedative-hypnotic drugs in the United States (1). Zopiclone has safety profile similar to that of benzodiazepines (2). Following acute zopiclone overdose, the main feature is central nervous system depression, but cases of two patients who developed methemoglobinemia were reported recently (3). We report a case of zopiclone overdose associated with methemoglobinemia and renal impairment.

Case report

A 53-year-old woman presented to the emergency department 60 h after she took 2,250 mg of zopiclone in a suicide attempt. She slept at home for 1 day after the overdose. When she awoke, she had a headache and felt dizzy. She had no fever, rash, or joint pain. She had been previously healthy (except for a flare-up of psoriasis), was taking no medications, and had normal renal function tests 2 months before. Her blood pressure was 117/53 mmHg and pulse rate was 77 beats/minute. She was alert and cyanotic. Bedside pulse oximeter showed an oxygen saturation of 86% (not corrected with supplementary oxygen). Physical examination was otherwise unremarkable. She had satisfactory urine output of more than 150 mL/h. Her blood methemoglobin level was 19.4%. Methylene blue 50 mg was given intravenously. Important investigation results are listed in Table 1. High-pressure liquid chromatography (HPLC) of the urine identified only zopiclone and its metabolites. Serum zopiclone concentrations were measured by HPLC–fluorescence detection. New onset significant renal impairment was noticed. The highest blood creatinine concentration was 5.4 mg/dL at 80 h after the ingestion. Blood hemoglobin level dropped over 9 h, which was probably due to dilutional effect of intravenous fluid. Renal ultrasound showed normal kidney size of 12 cm length with no hydronephrosis. Urine β₂-microglobulin was elevated significantly. The investigation results were compatible with acute tubular necrosis. As she had good urine output, normal potassium, normal acid base status, and improving renal function, renal biopsy was not performed. She was discharged on day 4. Her blood creatinine level returned to normal on follow up on day 9.

Table 1.  Detailed blood and urine investigation results of the patient

Investigations		Day 0 (admission)	Day 1	Day 2	Day 3	Day 4 (discharge)	Day 6 (follow up)	Normal values
Complete blood count	White blood cell	11.5^a	9.5	10.0	9.2	9.9	–	3.9–10.7 × 10^9/L
	Hemoglobin	12.4	10.2	10.5	10.8	11.1	–	11.6–15.5 g/dL
	Platelet	293	268	324	355	414	–	152–358 × 10^9/L
Renal function test	Blood urea nitrogen (BUN)	36	43	30	30	26	23	8–22 mg/dL
	Creatinine	4.2^b	5.3	5.1	3.3	2.0	1.3	0.6–0.9 mg/dL
	Sodium	138	134	142	142	138	141	136–148 mmol/L
	Potassium	4.2	4.5	4.0	3.6	3.9	3.4	3.6–5.0 mmol/L
	BUN/creatinine	8.6	8.4	5.9	9.1	13.0	17.7	>20 in pre-renal failure
Liver function test	Bilirubin	12	13	–	18	19	–	4–23 μmol/L
Other blood test	Haptoglobin	–	1.29	–	–	–	–	0.16–1.97 g/L
Urine tests	Microscopy	Inconclusive^c	–	–	–	–	–
	Sodium	–	46	–	–	–	–	<20 mmol/L in pre-renal failure
	Creatinine	–	30.8	–	–	–	–	0.6–0.9 mg/dL
	Fractional sodium excretion	–	5.9%	–	–	–	–	<1% in pre-renal failure
Toxicology tests	Blood methemoglobin	19.4	6	4.4	1.6	1.6	–	<1.5%
	Serum zopiclone concentration	1,690	215	–	32	<10	–	40–70 ng/mL in peak therapeutic level, >600 ng/mL in lethal dose
	β2-Microglobulin	–	6.2	–	–	–	–	<0.2 μg/mL

^aNeutrophil 8.54, lymphocyte 2.09, monocyte 0.55, eosinophil 0.14, and basophil 0.04.

^bThe patient had normal renal function (blood creatinine of 0.6 mg/dL) 2 months before the overdose.

^cProtein 100 mg/dL; red cells <30/μL; white cells 10–50/μL; and no cast, epithelial cells, and bacteria present. Urine culture had insignificant bacterial growth.

Discussion

Two cases of zopiclone-induced methemoglobinemia have been reported recently (3), but zopiclone-overdose-associated renal impairment has not been reported. In this case report, zopiclone was likely associated with the methemoglobinemia and renal impairment because urine drug screenings by HPLC did not detect other agents known to cause these complications.

Zopiclone abuse is a rising trend in Hong Kong Special Administrative Region (HKSAR) because it is not under strict restriction as benzodiazepines (4). The escalating dose in abuse or poisoning may contribute to the two reported complications. In addition, genetic susceptibility may be a contributing factor because so far the two complications have only been reported among Chinese people in HKSAR.

We postulate that either zopiclone or its metabolites causes an oxidizing stress on red blood cells and renal tubules. Alternative explanations for the renal toxicity include pigment nephropathy from methemoglobinemia or acute interstitial nephritis. There was a report of acute interstitial nephritis with therapeutic use of zopiclone (5). Renal biopsy will be useful in elucidating the exact renal pathology.

Although oral N-acetylcysteine and intravenous l-carnitine were used in a patient with phenazopyridine-associated methemoglobinemia and acute renal failure (6), the efficacy of either agent in zopiclone-induced renal impairment is unknown.

Eszopiclone, the S-isomer of racemic zopiclone (R-, S-isomer), is marketed in the United States but zopiclone is not. As zopiclone and eszopiclone have similar structures, eszopiclone may also be associated with methemoglobinemia and renal impairment.

Further studies are needed to determine the dose of zopiclone causing methemoglobinemia and renal impairment, the incidence and relation of methemoglobinemia with renal impairment, the role of zopiclone and its metabolites, the pathophysiology of the renal impairment, the role of genetic polymorphism, and the optimal treatment.

Conclusions

We presented a case report of methemoglobinemia and renal impairment associated with zopiclone overdose. Supportive measures are the mainstay of treatment and methylene blue was administrated. The patient recovered with normal renal function tests. In patients with massive zopiclone overdose, methemoglobinemia and renal impairment may occur.