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Article Author:
Daniel Bouchette
Article Author:
Hossein Akhondi
Article Editor:
Judy Quick
7/7/2020 12:08:32 AM
For CME on this topic:
Zolpidem CME
PubMed Link:


Zolpidem is a non-benzodiazepine receptor modulator primarily used in the FDA approved short-term treatment of insomnia aimed at patients with difficulty starting sleep. [1][2][3] It improves measures of sleep latency, sleep duration, and reduces the number of awakenings in patients with transient insomnia. It also improves sleep quality in patients with chronic insomnia as well and can act as a minor muscle relaxant. Research also shows it is rapid and effective in restoring brain function in patients who are in a vegetative state after brain injury as the drug has the potential to completely or partially reverse the abnormal metabolism of damaged brain cells. Usually, patients recover if the injury is in non-brain stem areas.

Mechanism of Action

Zolpidem, a non-benzodiazepine hypnotic agent, works as a GABAa receptor chloride channel modulator/agonist that increases GABA inhibitory effects leading to sedation. It also has anticonvulsant, anxiolytic, and minor myorelaxant properties. The GABAa receptor also called also GABA-BZ is found in the sensorimotor cortical regions, globus pallidus, inferior colliculus, pons, ventral thalamic complex, olfactory bulb, cerebellum, and substantial in the brain. The drug upregulates these receptors allowing for the sedative effects leading to the preservation of deep sleep.  [4][5]Differing from benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the alpha1/alpha5 subunits. The selective binding of zolpidem on the BZ1 receptor may explain the relative absence of myorelaxant and anticonvulsant effects. Overall, zolpidem is not recommended for the general population as first-line treatment because of its high potential for abuse. Drugs like controlled release melatonin and doxepin may be used as first line in addition to proper sleep hygiene and cognitive behavioral therapy.


Zolpidem is rapidly absorbed by the gastrointestinal tract and has a short half-life in healthy patients. It is administered in 5 mg and 10 mg tablets orally depending on the quality of sleep in which the patient is receiving. Zolpidem is then converted to an inactive metabolite and excreted by the kidneys. Tablets are not scored. Ingestion with or immediately after food intake may slow the effects of this drug.

Elderly patients must receive a 5 mg dosage as their concentrations were found to be higher than young adults during clinical trials. Dosage should be changed in patients with hepatic impairment as the half-life of zolpidem was found to be a multitude of times larger than patient with normal health.  The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening.  Zolpidem clearance is lower in women. [6][7][8]

Patients with end-stage renal failure undergoing dialysis do not need dosage adjustments, as they were not significantly different from patients with renal impairments. Their concentrations, however, should be closely watched on a daily basis.

Pediatric patients should not be given zolpidem as their effectiveness has not been found yet. The research found that hallucinations might occur in a small percentage of pediatric patients who received zolpidem.

Adverse Effects

Some adverse effects include anaphylaxis, changes in behavior, withdrawal, and central nervous system (CNS) depression.

In rare situations, patients have reported tongue, larynx, or glottis swelling in the form of angioedema. Also, patients have reported shortness of breath, airway closure, nausea, and vomiting. If patients report these, do not re-administer patient with the drug. Patients who do experience closure in throat, glottis, or larynx should be sent to the emergency department.

Changes in behavior and abnormal thinking have been reported as well. Patients have been found to show aggressiveness and extroversion that is abnormal for the person's usual behavior.

Similar to patients who have alcohol or drug toxicities, patients have experienced auditory and visual hallucinations associated with strange behavior and agitation.

The patient was also found to experience a behavior called sleep driving, in which the patient drives while not fully awake after intake of sedative-hypnotic with no recollection of the event. Consumption of alcohol or any other CNS depressant was found to increase these events as they enhance sedation when combined. In these cases, the drug needs to be discontinued.

Patients who are depressed should also not take zolpidem as it worsens depression along with suicidal ideations and actions.


It is only contraindicated in patients with a known allergy to the drug or inactive ingredients in the formula. Also before administering zolpidem, other causes of sleep deprivations must be evaluated, for example, any presenting physical or psychiatric histories.

Caution should be used in patients who are also taking drugs that affect drug metabolism via cytochrome P450. Consider giving a lower dosage of zolpidem as patients have shown to enhance sedative effects.

Patients taking imipramine and chlorpromazine should avoid using zolpidem. When combined, these medications cause decreased alertness and psychomotor performance.


The drug elimination half-life for 5 mg of zolpidem was found to be 2.6 hours. Respectively, the elimination for patients who are given 10 mg of zolpidem is 2.5 hours with ranges between 1.4 to 3.8 hours. Zolpidem undergoes a linear pattern of kinetics when the drug dose range is between 5 mg to 20 mg. The drug was also found to be mostly bound to protein and remained unchanged in concentration subsequently extracted through the renal system.

Patients experience anterograde amnesia after drug administration if plasma concentrations are high at the time of stimulus. This is attributed to either inattention or consolidations to memory process.

This drug has a high potential for overuse and daily dependence. Patients with a few weeks drug use have a low behavioral dependency on zolpidem. Patients who used zolpidem in higher single doses or had a history of drug abuse should be monitored carefully when using zolpidem or any other hypnotic.


Drug overdose with zolpidem involves CNS depression, cognitive impairments leading to somnolence or coma, cardiovascular and respiratory depression, and other fatalities. The acute toxicity for zolpidem is less in severity in comparison to other short-acting benzodiazepines like triazolam and midazolam. However, in combined intoxication with other CNS depressant drugs, zolpidem even with a low concentration can induce coma in patients. Single-drug poisoning is benign and should not require therapeutic intervention. 

If a patient shows any symptoms, gastric lavage should only be attempted if within one hour of ingestion, benefits outweigh risks and if the patient is conscious with a gag reflex or intubated. Patients can also benefit from administration with flumazenil and intravenous fluids as well. Flumazenil is a known reversal agent to benzodiazepine toxicity; however, can contribute to the exacerbations of other neurological symptoms such as convulsive activity.

In the event of drug toxicity, the patient's respiratory function, oxygen saturation, blood pressure, pulse, and other vitals should be monitored.[9]

Enhancing Healthcare Team Outcomes

Managing insomnia and zolpidem use requires an interprofessional team of healthcare professionals that includes a pharmacist, a therapist, a nurse, and a physician. Without proper management, significant drug-drug interactions may occur. CNS depression is increased with the combination of opiates, benzodiazepines, antidepressants or alcohol. Because the drug has the potential to cause dependence, it should not be prescribed for long periods. In addition, the patient should be told to avoid alcohol and other CNS depressants when taking zolpidem.


[1] Sharma MK,Kainth S,Kumar S,Bhardwaj A,Agarwal HK,Maiwall R,Jamwal KD,Shasthry SM,Jindal A,Choudhary A,Anand L,Dhamija RM,Kumar G,Sharma BC,Sarin SK, Effects of zolpidem on sleep parameters in patients with cirrhosis and sleep disturbances: A randomized, placebo-controlled trial. Clinical and molecular hepatology. 2019 Mar 11;     [PubMed PMID: 30856689]
[2] Kim HM,Gerlach LB,Van T,Yosef M,Conroy DA,Zivin K, Predictors of Long-Term and High-Dose Use of Zolpidem in Veterans. The Journal of clinical psychiatry. 2019 Feb 5;     [PubMed PMID: 30840786]
[3] Bjurström MF,Irwin MR, Perioperative Pharmacological Sleep-Promotion and Pain Control: A Systematic Review. Pain practice : the official journal of World Institute of Pain. 2019 Feb 14;     [PubMed PMID: 30762974]
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[5] Neumann E,Rudolph U,Knutson DE,Li G,Cook JM,Hentschke H,Antkowiak B,Drexler B, Zolpidem Activation of Alpha 1-Containing GABA{sub}A{/sub} Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons. Frontiers in pharmacology. 2018;     [PubMed PMID: 30687091]
[6] McDonagh MS,Holmes R,Hsu F, Pharmacologic Treatments for Sleep Disorders in Children: A Systematic Review. Journal of child neurology. 2019 Jan 23;     [PubMed PMID: 30674203]
[7] Expanded table: Some oral hypnotics for chronic insomnia. The Medical letter on drugs and therapeutics. 2018 May 7;     [PubMed PMID: 30625124]
[8] Drugs for chronic insomnia. The Medical letter on drugs and therapeutics. 2018 Dec 17;     [PubMed PMID: 30625122]
[9] Geulayov G,Ferrey A,Casey D,Wells C,Fuller A,Bankhead C,Gunnell D,Clements C,Kapur N,Ness J,Waters K,Hawton K, Relative toxicity of benzodiazepines and hypnotics commonly used for self-poisoning: An epidemiological study of fatal toxicity and case fatality. Journal of psychopharmacology (Oxford, England). 2018 Jun;     [PubMed PMID: 29442611]