Two Case Reports of Zolpidem Abuse and a Contemporary Review

Abstract

Zolpidem is a short-acting nonbenzodiazepine hypnotic agent. It was commonly considered a preferable treatment for insomnia because it was associated with low risks of abuse and dependency. However, those risks were underestimated, and the withdrawal symptoms associated with zolpidem can be life-threatening. Moreover, besides the gradual discontinuation of the long-term (≥4 wk) prescription of zolpidem, other effective strategies for zolpidem detoxification are being explored. We report 2 cases of zolpidem abuse with daily doses of 800 and 240 mg, respectively. The patients were successfully detoxified with clonazepam, trazodone, quetiapine, and simplified cognitive behavioral therapy for insomnia (CBT-I) without experiencing any significant withdrawal symptoms. Shifting from zolpidem to benzodiazepines with longer half-lives and gradual dose tapering may be useful in patients with zolpidem abuse. In addition to pharmacotherapy, simplified CBT-I can be helpful.

Zolpidem is a short-acting nonbenzodiazepine hypnotic with an imidazopyridine structure. Zolpidem is an agonist of the gamma-aminobutyric acid (GABA) A-type receptor and acts selectively on alpha subunit-containing GABA benzodiazepine receptors.¹ As zolpidem has low or no affinity for other subtypes of GABA receptors, it has relatively few side effects and is associated with lower risks of abuse and dependence than benzodiazepines; this has led to its being one of the most commonly prescribed hypnotics.² However, this selectivity is lost at higher-than-standard hypnotic dosages; in such cases, zolpidem acts like a benzodiazepine.³ Case reports involving zolpidem dependence and a variety of harmful withdrawal symptoms have been published. These withdrawal symptoms mainly included anxiety, hand tremors, sweating, palpitations, distractibility, impaired memory, and generalized tonic-clonic seizures. The seizures, in particular, can be life-threatening.⁴ Currently, there is no consensus concerning the most effective therapy for detoxification from zolpidem.

Here we report 2 cases of zolpidem abuse with daily doses of 800 and 240 mg, respectively. The patients were successfully detoxified with clonazepam, trazodone, quetiapine, and cognitive behavioral therapy for insomnia (CBT-I) without any significant withdrawal symptoms.

CASE PRESENTATION

Consent for Publication

The patients in these cases gave written informed consent for publication of their clinical details.

Case 1

Two years before her presentation to our hospital, patient 1, a 38-year-old woman, received a prescription for zolpidem at a dosage of 10 mg/d as a treatment for insomnia, even though the highest recommended daily dose for women is 5 mg. She reported an improvement in her sleep and a reduction in her anxiety. Gradually, she increased the number of tablets and began to take zolpidem even during the day whenever there was work-related or relationship-related tension. Over a 1-year period, her use escalated to 100 to 200 mg/d. When she had to skip or delay intake, she would become irritable with minimal provocation, express a lack of enthusiasm or interest in work, and become restless and anxious. During the 3 months before her presentation, the patient’s use had escalated to a maximum of 80 tablets/day (800 mg of zolpidem), with an average daily intake of 60 tablets (600 mg of zolpidem). She had to spend much time searching for the medicine and could not focus on her work and daily life. Her family found out about her craving for more tablets and referred her to this hospital. To summarize, patient 1 gradually increased the dosage of zolpidem to 800 mg/d, and her social functioning was severely compromised by this uncontrolled use. The patient’s history of somatic disease and her family history were negative.

After admission, the patient was assessed for associated physical problems, and the results were within the normal range. Given her presentation of uncontrolled use of zolpidem and her withdrawal symptoms, the patient was diagnosed with “sedative-hypnotic-anxiolytic use disorder, severe” (per DSM-5 criteria). Given the severe withdrawal symptoms, we decided not to discontinue all of the zolpidem immediately, but to retain 25% of the original dose. The patient was maintained on 200 mg of zolpidem at night and was started on clonazepam 58 mg/d (12 mg at 8:00 am, 12 mg at 11:00 am, 4 mg at 5:00 pm, and 30 mg at 10:00 pm) for replacement. Because clonazepam is also addictive, we used it for transition and also treated her with quetiapine 25 mg and trazodone 25 mg at night. The patient tolerated this therapy, and we were able to increase the nightly dose of clonazepam to gradually replace the zolpidem. Based on the patient’s sleep status and other reactions, the nighttime dosage of clonazepam was increased by 2 to 8 mg every 2 to 3 days until it reached 48 mg. At the same time, we titrated the dosage of quetiapine to 150 mg at night and trazodone to 100 mg at night (Fig. 1). At this point, the patient showed no withdrawal symptoms except difficulty maintaining sleep after midnight and intermittent anxiety.

FIGURE 1.

Medication dosage adjustment in case 1.

The patient also received CBT-I. As a result, she reported adequate sleep, and the dose of clonazepam was gradually reduced to 10 mg at night. Her anxiety subsided after treatment with escitalopram 7.5 mg/d. After discharge, she was followed as an outpatient for 1 month with no further zolpidem use, and the clonazepam was reduced to 7 mg/d. No further follow-up information was available after that.

Case 2

Patient 2 was a 25-year-old woman who had received a prescription for zolpidem 10 mg/d to treat insomnia, even though the highest recommended daily dose for women is 5 mg. She progressively increased the dose as she started experiencing euphoria. Over a 6-month period, her use escalated to a maximum of 240 mg/d. She tried to stop taking zolpidem, but she would have withdrawal symptoms within 4 to 6 hours of the last dose, which manifested as marked irritability, anxiety, palpitations, and sweating.

Patient 2 was admitted to our ward. Her history of somatic disease and family history were negative, and her physical assessment was normal. This patient was also diagnosed with “sedative-hypnotic-anxiolytic use disorder, severe” (per DSM-5 criteria). We stopped all of the zolpidem on the first day of her admission and treated her with 28 mg clonazepam to reduce withdrawal symptoms, with quetiapine and trazodone also started with the goal of later replacing clonazepam. The doses of quetiapine and trazodone were titrated to 75 and 100 mg, respectively, based on the patient’s sleep situation, while the clonazepam was reduced (Fig. 2). Apart from anxiety, the patient did not exhibit any other obvious withdrawal symptoms. Escitalopram (10 mg) was used to alleviate anxiety. She also received CBT-I to improve sleep quality. At discharge, patient 2 had a regular and healthy sleep-wake cycle and a stable mood state on a regimen of quetiapine 75 mg at night, trazodone 100 mg at night, clonazepam 3.5 mg at night, and escitalopram 10 mg/d. At 1-year follow-up, she continued to take 25 mg quetiapine and 1.5 mg clonazepam.

FIGURE 2.

Medication dosage adjustment in case 2.

DISCUSSION

Zolpidem is considered to be a preferable treatment for insomnia because of its low risks for abuse and dependency.² However, the risk of zolpidem abuse has been underestimated.^{5,6 5,6} We searched for the key words zolpidem abuse and zolpidem dependence on PUBMED and located a number of case reports published since 2000, which are summarized in Table 1.^2,4,6–19 The maximum abused dose of zolpidem reached 2400 mg in the case reports we identified.¹⁶ The findings of this case review revealed a remarkable phenomenon. The patients’ presentations differed considerably, yet they developed a similar pattern of abuse due to the ability of zolpidem to alleviate anxiety or produce euphoria.

TABLE 1.

Summary of Cases of Zolpidem Abuse and Dependency

Report	Age, y	Gender	Zolpidem max dose (mg)	Other substance abuse	Underlying disease	Therapy	Withdrawal symptoms during hospitalization	Prognosis/outcome
Kim et al2	69	F	50-60	Analgesics	None	Clonazepam 1 mg, chlordiazepoxide 2.0 mg, quetiapine 100 mg, duloxetine 30 mg	None	Several subsequent episodes of analgesic and zolpidem use
Jana et al7	33	M	150	Nicotine	None	Clonazepam 4 mg as alternative treatment, bupropion 300 mg	Depressed feelings and lethargic	No further problems during hospitalization
Keuroghlian et al8	34	M	200	Alcohol and prescription opioids	Bipolar disorder	Chlordiazepoxide taper	None	Substance-free at 8-month follow-up
Mariani and Levin9	52	M	250	Alcohol, cannabis, and cocaine		Quetiapine 800 mg	None	Maintained abstinence from zolpidem at 6-mo follow-up
Fernandes et al10	72	F	300	None	None	Clonazepam 6 mg as alternative treatment, gabapentin 1200 mg	None	Asymptomatic after 2 wk
Bhatia and Kohli11	48	F	500	None	Bipolar disorder	Mirtazapine 30 mg	None	Zolpidem intake decreased in 8 weeks
Krueger et al12	39	F	600		Severe facial pain	Oxazepam 20 mg, carbamazepine 200 mg	Epileptic seizure	Facial pain reappeared and did not respond to any further treatment
Ohshima et al13	29	M	400	None	None	Chlorpromazine 125 mg plus clonazepam 6 mg as alternative treatment	Excessive tension and irritability	Difficulty falling asleep
Kar and Dwivedi14	56	M	100	None	Bipolar disorder, epilepsy	Quetiapine 100 mg	None	Well maintained at 6 mo
Dong et al15	33	F	1080	None	Bipolar disorder	Escitalopram plus flupentixol plus melitracen, quetiapine plus lamotrigine (dose unknown)	None	Left the hospital against medical advice on 10 mg/d zolpidem
Heydari and Isfeedvajani6	32	M	2000	Heroin	None	Not mentioned	Not mentioned	Zolpidem was discontinued for 1 mo but then zolpidem 400-1000 mg/d was prescribed again
Bajaj et al16	45	M	2400	Alcohol	None	Clonazepam 80 mg as alternative treatment plus propranolol 40 mg for sleep hygiene	Severe insomnia, tremors, and marked irritability	Withdrawal symptoms resolved within 10 d of admission
Liappas et al17	30	M	300	Cocaine	None	Fluoxetine 40 mg plus cognitive behavioral therapy	Hypersomnia, hyperphagia and depression (induced by cocaine discontinuation)	Total abstinence from the substances at 8 mo follow-up.
Liappas et al17	35	F	150	None	None	Fluoxetine 40 mg plus cognitive behavioral therapy	None	After 6 mo, patient is still abstinent from zolpidem.
Liappas et al17	42	M	600	None	None	Fluoxetine 60 mg	None	Patient is completely asymptomatic after 1 mo of therapy.
Lyu et al18	22	F	800	None	None	Diazepam as alternative treatment,bupropion 300 mg plus mirtazapine 30 mg	Obvious depressive symptoms, suicidal ideation, and insomnia	Patient relapsed twice in the ensuing year but was managed well in outpatient treatment.
Mao et al4	25	M	80	Alcohol, nicotine, occasional marijuana and nitrous oxide use	Bipolar disorder	Clonazepam 2 mg, lithium carbonate 750 mg, quetiapine 100 mg replaced by olanzapine 5 mg, propranolol 30 mg	Obvious insomnia, influenza-like symptoms, anxiety symptoms, strong craving, tonic-clonic-type seizures	Patient’s life and work normal (clonazepam was reduced to 0.25 mg after 12 mo).
He et al19	59	M	40			Trazodone 100 mg plus quetiapine 100 mg	Muscle pain, mild dizziness for a day	Patient still abstinent from zolpidem after 1 mo.

In the past, it has been suggested that zolpidem exhibits selective activity on GABA A receptors with alpha 1 subunits, which have hypnotic action.¹ However, alpha 2 subunit receptors can strongly contribute to the anxiolytic action of benzodiazepines, and it has been suggested that a high dose of zolpidem might lose its selectivity for the GABA-A receptor and exert the same pharmacological effects as classical benzodiazepines.⁶ This could also explain why our patients were successfully detoxified with clonazepam. In addition, the 2022 case report by Lyu et al¹⁸ demonstrated that cerebellar electrical signal activation increased after the onset of zolpidem-induced euphoria. Although the study involved only 1 patient, it suggests that the cerebellum may play a role in the euphoric effect of zolpidem.

Reports have noted a wide variety of zolpidem detoxification therapies, including antidepressant agents (duloxetine, bupropion, escitalopram, fluoxetine, mirtazapine, and trazodone), antipsychotic drugs (quetiapine, olanzapine, and chlorpromazine), benzodiac (clonazepam, diazepam, and chlordiazepoxide), and other drugs (gabapentin, carbamazepine, and propranolol), which have been combined in different ways depending on the specific conditions of the patients (Table 1).^2,4,6–19 A coincidence seen in a number of cases was that benzodiazepines, as represented by clonazepam, were used as an alternative therapy early in treatment, and no serious withdrawal symptoms occurred in these cases. As summarized by Soyka,²⁰ no medication is approved for the treatment of benzodiazepine use disorders. Whether switching to a long-acting agent has fundamental advantages is unclear, but withdrawal from short-acting benzodiazepines is associated with higher dropout rates than withdrawal from longer-acting agents.²⁰ Similarly, in our 2 cases presented here, clonazepam was used to replace zolpidem.

Benzodiazepines should not be used in the long term, but a reduction plan was not mentioned in the published articles we reviewed. Therefore, we describe here the process we use to reduce benzodiazepines. First, we replace part or all of the short half-life benzodiazepines with long half-life benzodiazepines. Second, we gradually reduce the remaining short half-life benzodiazepines. Third, we reduce the dosage of long half-life benzodiazepines by 20% each time a change is made and extend the reduction interval gradually from ~3 days to 2 weeks. Finally and most importantly, we observe the withdrawal symptoms during the whole course of treatment. If the patients cannot tolerate the withdrawal symptoms, we add the decreased dosage back.

It is easy to understand that effective sedative antidepressant and antipsychotic drugs have been widely used in the reported cases of zolpidem detoxification to improve patients’ sleep quality. Selective serotonin reuptake inhibitors have also been commonly used. Liappas et al¹⁷ reported on 3 patients treated with fluoxetine who remained abstinent from zolpidem. He posited a hypothesis involving an interaction of the serotonergic and GABAergic systems: zolpidem reduces serotonin synthesis, and activation of presynaptic serotonin receptors has been found to inhibit synaptic GABA release. The serotonergic system lacks functional specialization and can interact with GABAergic systems.¹⁷ This theory may explain the positive response of patients to selective serotonin reuptake inhibitors, such as our 2 patients’ excellent response to escitalopram. In another case, Fernandes et al¹⁰ used gabapentin in the successful treatment of zolpidem dependence and pointed out its GABAergic activity. Given that gabapentin has been used efficiently to assist or treat alcohol withdrawal and to manage cocaine and benzodiazepine dependence and detoxification, it appears that gabapentin may be a promising alternative for nonbenzodiazepine detoxification.

Apart from pharmacotherapy, it is widely recognized that CBT-I is the first-line treatment for insomnia and an effective treatment for patients with insomnia and a comorbid mental disorder.²¹ Bajaj et al¹⁶ and Liappas et al¹⁷ mentioned sleep hygiene and CBT, and their patients showed a satisfactory outcome. In our cases, CBT-I played an important role in the treatment, and we summarize the key points of the therapy in 5 words: the first word, “go,” refers to going to bed on time. The second word, “out,” refers to getting out of bed on time. It should be noted that for younger people, the appropriate time in bed is 7 to 8 hours, while for elderly people, the appropriate time in bed is 6 to 7 hours. The third word, “no,” refers to not taking a nap and not doing things unrelated to sleep (with the exception of sex) in bed. The fourth word, “exercise,” refers to 1 hour of aerobic exercise per day. The fifth word, “calmness,” refers to practicing meditation for 1 hour every day, such as body scans and mindfulness breathing. Our patients report that the therapy is easy to understand and take back home for long-term benefits.

Limitations

This report had several limitations. First, we only describe the management of 2 cases of abuse of high doses of zolpidem, and we did not provide continuous systemic support for the patients after they left the hospital. However, we plan to provide more comprehensive therapy for this type of patient in the future to achieve better outcomes. Secondly, because of ward management policies and other reasons, it was not possible to individualize our sleep behavior therapy. Patients needed to follow the ward schedule and get in and out of bed at fixed times under the supervision of nurses, without individualized sleep prescriptions. We will further refine and standardize the treatment in future work.

In addition, because we did not follow a formalized process in our literature search, we missed a number of reports and guidelines with information on the abuse potential of zolpidem and recommendations for the use of Z-drugs. We undertook an additional literature review to locate such sources, some of which are discussed below. Publications as early as 2007²² and 2014²³ reported on data from the French Center for Evaluation and Information on Pharmacodependence-Addictovigilance, which highlighted a significant dependence and abuse potential for zolpidem based on numerous case reports. This finding led the authors to propose stronger rules concerning the use of zolpidem to mitigate its abuse potential. In 2019, Schifano et al²⁴ analyzed the adverse drug reaction databases provided by the European Medicines Agency for the Z-drugs zaleplon, zolpidem, and zopiclone. They found that, in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues, while zopiclone was most involved in overdose adverse drug reactions. The authors concluded that caution should be exercised when prescribing these agents, especially for patients with psychiatric illnesses and/or histories of drug abuse.²⁴ Although there have been warnings in the literature for nearly 20 years, patients still present with severe zolpidem abuse, as did the 2 patients in our cases. From a preventive perspective, based on a 2023 systematic review and meta-analysis from Europe, Soni et al²⁵ concluded that discontinuing long-term (≥4 wk) prescription of benzodiazepines and Z-drugs is recommended to reduce the risk of abuse and dependence. They also found that such deprescribing was more successful when supported by nonpharmacological methods versus routine care.²⁵ Based on a case report and literature review published in 2024, Xie et al²⁶ concluded that a comprehensive approach, involving both pharmacological agents and psychological interventions (eg, mindfulness-based cognitive therapy), is essential for an effective detoxification strategy for zolpidem addiction.

CONCLUSIONS

In conclusion, based on the cases presented here, we suggest that shifting from zolpidem to treatment with long half-life benzodiazepines and subsequent gradual dose tapering may be useful in patients with zolpidem abuse. In addition to pharmacotherapy, simplified CBT-I can be helpful. Further studies should address a standardized therapy for zolpidem abuse.