Z-Drug and benzodiazepine misuse and withdrawal – a case report

Sio-pan Chan 陳少斌

HK Pract 2025;47:105-107

Summary

A 69-year-old female patient presented with a one-week history of altered mental state that deteriorated into a semi-conscious condition. She later developed a generalised seizure. She was found to be suffering from chronic insomnia and had developed dependence on Z-drugs. Sudden withdrawal of Z-drugs can result in unpredictable and potentially life-threatening complications, as illustrated in this case.

摘要

一名69歲女性患者出現為期一週的精神狀態不穩定，後續惡化至半昏迷狀態，並發展為全身性癲癇發作。經診斷發現，患者長期受慢性失眠症困擾，且已對Z- 類藥物(非苯二氮平類安眠藥)產生依賴性。如本案例所示，突然停用此類藥物可能引發罕見且危險的併發症。

Introduction

Z-drugs are non-benzodiazepine hypnotics and are among the most frequently prescribed hypnotics worldwide. In Hong Kong, Z-drugs are not included in the Dangerous Drug Ordinance (DDO) First Schedule¹ , and therefore are not as strictly controlled as benzodiazepines, which are regulated under the DDO. Although Z-drugs are often perceived as safer alternatives, their safety profile in real-world practice is increasingly disputed. This article reports a case of Z-drug misuse and withdrawal with bizarre and potentially serious consequences.

Case Presentation

The patient was a 69-year-old retired business executive with a history of intracerebral aneurysm and haemorrhage, treated by coiling more than 10 years ago. Postoperative recovery was uneventful. Her long-term medicines included amlodipine 5 mg, atorvastatin 5 mg, and losartan 50 mg. In recent months, potassium chloride (600 mg twice daily) and sodium chloride (900 mg three times daily) were added due to recurrent hyponatraemia and hypokalaemia of unclear aetiology.

Furthermore, she was under long-term psychiatric follow-up for chronic insomnia. Her medication included:

• Psychiatric medicines: alprazolam 0.25 mg four times daily, pregabalin 25 mg daytime and 150 mg at night, trazodone 50 mg, mirtazapine 30 mg, and zolpidem 10 mg nightly.


• Non-psychiatric medicines: as listed above.

In addition, she was consuming an unknown quantities of non-prescription zolpidem to overcome her stage fright in giving public presentations.

A few days before presentation, her husband noted behavioural changes with alternating agitation and drowsiness. She became anorexic, with markedly reduced oral intake, and was unable to take meals or medicines for 2–3 days, leading to abrupt withdrawal. She was admitted to a private hospital.

On admission, she was semi-conscious and dehydrated. Blood tests showed hyponatraemia (125 mmol/L), hypokalaemia (2.9 mmol/L), and mildly abnormal liver function. A CT brain scan revealed no acute changes, only old post-operative findings.

Soon after receiving contrast during the CT scan, she developed a generalised tonic–clonic seizure with transient loss of consciousness, during which she sustained a lip laceration and fractured a canine tooth. A neurologist was consulted, and intravenous levetiracetam was initiated together with fluid and electrolyte replacement therapy.

Treatment and Progress

Over subsequent days, her mental state fluctuated between delirium and excessive drowsiness. She was unable to communicate verbally and exhibited depersonalisation, delusions, and paranoid ideation. A psychiatrist attributed these symptoms to Z-drug withdrawal, possibly compounded by withdrawal from other psychotropics. Olanzapine 5 mg daily was prescribed, and all medicines except levetiracetam were discontinued.

Her vital signs remained stable. Serum potassium transiently dropped to 3.2 mmol/L, requiring resumption of oral potassium supplementation. By day 8, her mental state improved dramatically, and she regained normal cognition, though she had no recollection of events.

On discharge, she was prescribed olanzapine 5 mg daily and clonazepam 3 mg nightly, with strict avoidance of Z-drugs. At follow-up, her regimen was adjusted to mirtazapine 30 mg and clonazepam 2 mg nightly. She reported improved sleep quality and overall well-being.

Discussion

This patient was prescribed multiple psychotropic medicines for insomnia, yet she continued to consume large amounts of illicit zolpidem. This suggests that her underlying insomnia remained unresolved and that her dependence on zolpidem was not disclosed to clinicians. The concurrent prescription of benzodiazepines, Z-drugs, and other sedatives without adequate risk–benefit review was inconsistent with established guidelines.²

Zolpidem’s pharmacological profile may explain her escalating use. Unlike benzodiazepines, which act on multiple GABA-A receptor subunits, Z-drugs selectively target the α1 subunit.³ This provides hypnotic but limited anxiolytic effects, potentially driving dose escalation in attempts to manage anxiety. Chronic high-dose use increases the risks of tolerance, dependence, and severe withdrawal, which in this case were compounded by concurrent alprazolam use. Although marketed as safer alternatives, Z-drugs such as zolpidem are associated with adverse effects including retrograde amnesia, falls, “sleep driving,” and complex behaviours.^4,5 These can occur even at therapeutic doses, but extreme misuse magnifies harm beyond reported data.

Her recurrent hyponatraemia resolved after discontinuing zolpidem, consistent with a published case linking high-dose zolpidem to SIADH.⁶ Although causation was not proven, this temporal association highlights the importance of considering rare drugrelated adverse effects in unexplained electrolyte disturbances. Of the two Z-drugs available in Hong Kong, zopiclone appears safer than zolpidem in terms of dependence and adverse effects.⁷ Nevertheless, all Z-drugs share comparable risks of tolerance, dependence, and misuse with benzodiazepines, and clinicians should exercise the same level of caution when prescribing them.

Conclusion

This case highlights the complex and potentially dangerous consequences of Z-drug dependence and abrupt withdrawal, particularly in elderly patients with polypharmacy. Despite their widespread use and perceived safety, Z-drugs can lead to unpredictable neuropsychiatric and medical complications, including seizures, delirium, and electrolyte disturbances. Clinicians should remain vigilant when prescribing hypnotics, carefully review risk–benefit profiles, and avoid unnecessary polypharmacy. Greater awareness of illicit Z-drug use and its potential harm is essential to improve patient safety and treatment outcomes.

References

1. Laws of Hong Kong, Chapter 134 Dangerous Drug Ordinance First Schedule.
2. Benzodiazepines and Z-Drugs: Professional Standards Regarding Benzodiazepines and Z-Drugs, College of Surgeons & Physicians of Nova Scotia.
3. Sanger DJ. The pharmacology and mechanisms of action of new-generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004;18 Suppl 1:9-15.
4. Edinoff AN. Zolpidem: Efficacy and Side Effects for Insomnia. Health Psychol Res. 2021;9(1):24927.
5. Full Prescribing Information – Stilnox package insert.
6. Shanmuga Priya S, et al. Zolpidem-induced hyponatraemia. J Clin Diagn Res. 2014;8(9):HD03-HD04.
7. Yen CF, Yen CN, Ko CH, et al. Correlates of dependence and beliefs about the use of hypnotics among zolpidem and zopiclone users. Subst Use Misuse. 2014;49(13):1828-1832. PMID: 25458710. DOI: 10.3109/10826084.2014.980955.