Zolpidem withdrawal delirium.

The Z-category hypnotics are promoted for their relative safety. However, this view is challenged by the emerging clinical evidence in the form of zolpidem related intoxication delirium and seizures, and dependence and complicated withdrawal. We report the case of a zolpidem-naive alcohol-dependent inpatient that, while undergoing alcohol de-addiction, was prescribed zolpidem for insomnia and developed delirium during taper-off. He was successfully detoxified for alcohol, treated for delirium and put on disulfiram prophylaxis. The case highlights the need for being cautious while using zolpidem for insomnia in alcohol dependent subjects.

Introduction

The hypnotic drug zolpidem, acts at the α1-subunit of gamma aminobutyric acid (GABA)-benzodiazepine receptor complex. Efficacy and a better safety profile make it a popular alternative to benzodiazepines.[1] However, its use in and by psychiatric patients has led to abuse, dependence, and complications like delirium.[1-3] We report here a case of zolpidem withdrawal delirium in a patient with alcohol dependence syndrome unusual in its presentation in that the delirium was not a part of zolpidem intoxication or dependence syndrome and occurred at only slightly higher than recommended dose.

Case Report

AM, a 45-year-old was admitted for alcohol de-addiction. He had a history of alcohol dependence for 12 years and dysthymia for 7 years. Off and on, he was on escitalopram 10-20 mg for past one year. At admission (day 1), all his physical parameters were within normal limits except for bilateral fine tremors of hands (post-detoxification diagnosed by neurologist as essential tremors) and a mild hepatomegaly (with fatty change on ultrasound). Alcohol detoxification was done using lorazepam 8 mg/day, tapered off between days 4 and 22. Escitalopram (20 mg/day) was continued and for tremors long-acting propranolol (40 mg/day) was added on day 1, increased to 80 mg on day 24, and 120 mg on day 29. For persisting sleep initiation disturbance, he was prescribed zolpidem (10 mg) on day 13, increased to 15 mg and 20 mg on days 17 and 18, respectively. Persistence of sleep problems led to addition of mirtazapine 7.5 mg at bed time from day 21. His sleep normalized, and on day 24, prescription instructions were revised to initiate taper-off of zolpidem from 20 mg/day at the rate of 5 mg every fourth day. On day 36, about 20 hours after the last dose of zolpidem, he was observed to be pacing in the ward and misrecognizing the treating staff. He became agitated, refused medication, and soiled his clothes. He was disorientated to time and place, and refused to change soiled clothes. His delirium rating scale score was 29.[4] All medications were stopped and his vitals were monitored. He was afebrile with normal respiratory rate. Blood pressure varied from 130/90 to 160/110 mmHg, and pulse from 84 to 100 beats per minute. Neurological and fundus examination were normal. Arterial blood gas analysis, ECG, full blood count, blood sugar, serum electrolytes, liver function test, blood urea, serum creatinine, and urine analysis were within normal limits. Over next 24 hours, his condition persisted despite haloperidol being increased from 0.5 mg to 2 mg daily.

A review of medication over past 72 hours revealed an inconsistency between the prescription order and the actual administration of zolpidem. On day 24, zolpidem prescription was written in two brand names and either one was to be administered depending on availability. The nurse, however, administered both the brands concurrently resulting in doses of 25 mg and 20 mg instead of 10 mg and 5 mg on days 28 to 32, respectively. On day 35, when zolpidem was to be omitted (from 5 mg/day), the nurse realized her mistake and reduced the ‘additional’ zolpidem from 15 mg to 7.5 mg, making the actual dose reduction from 20 mg to 7.5 mg [Figure 1]. After this discovery, lorazepam 1 mg twice daily (b.i.d.) was initiated. Over next two days, delirium subsided completely. After proper relapse prevention counseling, AM was started on disulfiram and later discharged.

Figure 1

Zolpidem doses as prescribed and administered

Discussion

The causation of delirium in the index case could be considered from various angles. One, the possibility as an adverse drug reaction of escitalopram, propranolol, zolpidem, and mirtazapine is unlikely as the patient was on these medications for 2-4 weeks without any abrupt dose change except for zolpidem. Two, pharmacodynamic interaction between escitalopram and mirtazapine causing delirium is easily ruled out as there were no concurrent symptoms suggestive of serotonin syndrome. Three, zolpidem is highly plasma-protein bound (92.5%) and other such drugs (propranolol – 90%; mirtazapine – 85%) can displace it resulting in toxicity. Four, medications (escitalopram and mirtazapine) that are substrates for or inhibitors of zolpidem-metabolizing hepatic cytochrome P450 3A4 isozyme may raise plasma zolpidem levels. Both these possibilities are unlikely as the delirium occurred during weaning-off and not with peak dose of zolpidem.

Due to wrong prescription implementation, the index case was maintained on zolpidem at a higher (15-25 mg/day) than usually recommended dose (5-10 mg/day; range=5-20 mg)[5] for 18 days. Within 24 hours of dose reduction (20 mg/day to 7.5 mg/day), the patient became delirious [Figure 1]. His symptom profile resembled DSM-IV-TR criteria for sedative-hypnotic withdrawal.[6] The Naranjo's adverse drug reaction score[7] of five identifies zolpidem as a ‘probable’ cause of delirium.

The withdrawal symptoms of zolpidem reported in less than 1% of the subjects appear within 48 hours of discontinuation.[1] Zolpidem withdrawal is hypothesized to be due to long-term supratherapeutic doses saturating the lower-affinity α2, α3 and α5 subunits on GABAA receptors along with α1 subunits.[8] Abrupt cessation then leads to a withdrawal syndrome that mimics benzodiazepine withdrawal syndrome. The index case was on slightly higher than recommended dosages (15-25 mg vs 5-10 mg daily) for 18 days, and had shown no evidence of developing dependence on zolpidem.

Long-term alcohol use had possibly caused structural or receptor level neuronal changes rendering the index case susceptible to even smaller alterations in zolpidem dose and resulting in delirium.[9] These changes may further interact with other novel properties of zolpidem such as electrochemistry and electrostatics.[10]

While most cases of delirium reported in literature were either during withdrawal from very high-doses (up to 180 mg/day) zolpidem dependence, or were single dose (5-200 mg) intoxication,[1-38] the index case differed in that it developed delirium on abrupt dose reduction from 20 mg to 7.5 mg. Also, the index case had none of the predisposing factors such as acute hospitalization, older age, female gender, and hepatorenal dysfunction, that could lead to higher than optimal drug plasma levels even at recommended dose-range; thus, increasing the risk of an adverse event. Instead, the temporal relation between symptom onset after abrupt dose reduction, failure of the trial of low dose haloperidol, and an almost dramatic response to lorazepam strongly implicate zolpidem as the cause of delirium.

This case highlights the risk of prescription of zolpidem in dual diagnosis patients on multiple medications. It re-emphasizes the merits of strict adherence to recommended doses and to the time-tested practice of gradual taper-off. Lastly, it reinforces the sanctity of medical charting and prescription writing so as to minimize the prescription errors.