Continuing Education Activity

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. It improves measures of sleep latency and 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. This activity reviews the indications of zolpidem, including pharmacology, adverse events, dosing, contraindications, and the role of the interprofessional team in the management of patients with insomnia.

Objectives:

• Describe the indications for zolpidem.
• Summarize the mechanism of action of zolpidem.
• Review the adverse effects of zolpidem.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients with insomnia.

Indications

Zolpidem tartrate 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] It belongs to the control substance class C IV medicines and is regulated by Drug Enforcement Agency. It improves measures of sleep latency and sleep duration and reduces the number of awakenings in patients with transient insomnia.[2] It also improves sleep quality in patients with chronic insomnia and can act as a minor muscle relaxant.[3] 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 gamma-aminobutyric acid (GABA), a receptor chloride channel modulator/agonist that increases GABA inhibitory effects leading to sedation. The GABAa receptor, also called 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]

Differing from benzodiazepines, which non-selectively bind to and activate all benzodiazepine (BZ) receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high-affinity ratio of the alpha1/alpha5 subunits.[5] 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 a first-line treatment because of its high potential for abuse. Drugs like controlled-release melatonin and doxepin may be used as the first-line therapy in addition to proper sleep hygiene and cognitive behavioral therapy for patients with insomnia.

Administration

Zolpidem is rapidly absorbed by the gastrointestinal tract and has a short half-life in healthy patients. Zolpidem oral formulation is available as a tablet and an extended-release tablet. Zolpidem is also available as an oral spray, which is sprayed into the mouth over the tongue, and a sublingual tablet to place under the tongue. It is administered in 5 mg or 10 mg tablets orally, depending on the patient's sleep quality. 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. 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 to 8 hours remaining before the planned time of awakening. Zolpidem clearance is lower in women.[6]

Hepatic Impairment

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 in patients with normal health. 

Renal Impairment

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

Pediatric Patients

Pediatric patients should not be given zolpidem as its effectiveness has not been found yet. In addition, the research found that hallucinations might occur in a small percentage of pediatric patients who received zolpidem.[7]

Pregnant Women

As zolpidem can cross the placenta, maternal use of zolpidem in the third trimester of pregnancy or during labor could lead to respiratory depression and sedation in neonates upon birth. Therefore, it is recommended to monitor and manage neonates exposed to maternal zolpidem or during labor for signs of hypotonia, excessive sedation, and respiratory depression. However, published data from post-marketing surveillance, observational studies, case reports, and birth registries on the maternal use of zolpidem during pregnancy has not concluded a clear association between zolpidem use and major congenital disabilities. There are limited moderate to severe cases of respiratory depression reported after birth in neonates who required intratracheal intubation or artificial ventilation. However, most of these neonates recovered within hours to a few weeks after birth once treated.[8]

Breastfeeding Consideration

Limited published literature reported that zolpidem is excreted in human milk and lacks information on its effects on milk production. There are reports of excessive sedation in infants exposed to zolpidem through breast milk. The health and developmental benefits of breastfeeding should be considered along with the mother's clinical requirement for zolpidem and any potential adverse reactions on the breastfed infant from zolpidem or the underlying maternal condition. Infants exposed to zolpidem through breastmilk should be monitored for hypotonia, excess sedation, and/or­­ respiratory depression. To minimize exposure to a breastfed infant, a lactating woman may consider temporarily interrupting breastfeeding and discarding breast milk during treatment and for 23 hours (approximately five elimination half-lives) after zolpidem intake.[9]

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 the patient with the drug. Patients who experience closure in the throat, glottis, or larynx should be sent to the emergency department.[10]

Changes in behavior and abnormal thinking have been reported as well. In addition, patients have shown aggressiveness and extroversion, which is abnormal for the person's usual behavior. Patients with alcohol or drug toxicities 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 and suicidal ideations and actions.[11]

Contraindications

Zolpidem 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 deprivation must be evaluated, for example, any presenting physical or psychiatric histories.

Caution should be used in patients taking drugs that affect drug metabolism via cytochrome P450. Consider giving a lower zolpidem dosage as patients have shown to enhance sedative effects. In addition, patients taking imipramine and chlorpromazine should avoid using zolpidem. When combined, these medications cause decreased alertness and psychomotor performance.[12]

Worsening of depression and/or suicidal ideation may occur with zolpidem therapy. Therefore, clinicians should prescribe the least amount of tablets possible to avoid intentional zolpidem overdose. Consider this risk of respiratory depression before prescribing zolpidem in patients with compromised respiratory function. Withdrawal symptoms may occur if the zolpidem dose is tapered off rapidly or discontinued. Therefore it is recommended to taper off slowly to avoid unnecessary withdrawal and adverse reactions in chronic zolpidem users.[13]

Monitoring

The drug elimination half-life for 5 mg of zolpidem was found to be 2.6 hours. Respectively, the elimination for patients given 10 mg of zolpidem is 2.5 hours, ranging between 1.4 to 3.8 hours. Zolpidem undergoes a linear kinetics pattern when the dose range is between 5 mg and 20 mg. The drug was also found to be mostly bound to protein and remained unchanged in concentration subsequently extracted through the renal system.[14]

This drug has a high potential for overuse and daily dependence. Patients with a few weeks of 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. Patients experience anterograde amnesia after drug administration if plasma concentrations are high at the time of the stimulus. This is attributed to either inattention or consolidation of the memory process.[15]

Toxicity

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

If a patient shows any symptoms, gastric lavage should only be attempted 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, it 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.[16]

Enhancing Healthcare Team Outcomes

Managing insomnia and zolpidem use requires an interprofessional team approach of healthcare professionals, including pharmacists, therapists, nurses, and clinicians (MD, DO, NP, PA). [Level 5] Prescribers should consider the possibility of addiction and withdrawal symptoms when starting patients on zolpidem. Without proper management, significant drug-drug interactions may occur. For example, 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, and the team should coordinate monitoring for dependency concerns. In addition, the patient should be counseled by nurses and pharmacists to avoid alcohol and other CNS depressants when taking zolpidem. Nurses can verify dose and therapy duration before zolpidem administration, and pharmacists can perform medication reconciliation to optimize the treatment with zolpidem and enhance patient outcomes.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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. Clin Mol Hepatol. 2019 Jun;25(2):199-209. [PMC free article: PMC6589852] [PubMed: 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. J Clin Psychiatry. 2019 Feb 05;80(2) [PubMed: 30840786]

3.

Bjurström MF, Irwin MR. Perioperative Pharmacological Sleep-Promotion and Pain Control: A Systematic Review. Pain Pract. 2019 Jun;19(5):552-569. [PubMed: 30762974]

4.

Neumann E, Rudolph U, Knutson DE, Li G, Cook JM, Hentschke H, Antkowiak B, Drexler B. Zolpidem Activation of Alpha 1-Containing GABA_A Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons. Front Pharmacol. 2018;9:1523. [PMC free article: PMC6333667] [PubMed: 30687091]

5.

Nigam G, Camacho M, Riaz M. The effect of nonbenzodiazepines sedative hypnotics on apnea-hypopnea index: A meta-analysis. Ann Thorac Med. 2019 Jan-Mar;14(1):49-55. [PMC free article: PMC6341859] [PubMed: 30745935]

6.

Expanded table: Some oral hypnotics for chronic insomnia. Med Lett Drugs Ther. 2018 May 07;60(1546):e209-e213. [PubMed: 30625124]

7.

McDonagh MS, Holmes R, Hsu F. Pharmacologic Treatments for Sleep Disorders in Children: A Systematic Review. J Child Neurol. 2019 Apr;34(5):237-247. [PubMed: 30674203]

8.

Juric S, Newport DJ, Ritchie JC, Galanti M, Stowe ZN. Zolpidem (Ambien) in pregnancy: placental passage and outcome. Arch Womens Ment Health. 2009 Dec;12(6):441-6. [PubMed: 19657707]

9.

Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Feb 15, 2023. Zolpidem. [PubMed: 30000324]

10.

Zammit G. Comparative tolerability of newer agents for insomnia. Drug Saf. 2009;32(9):735-48. [PubMed: 19670914]

11.

Drugs for chronic insomnia. Med Lett Drugs Ther. 2018 Dec 17;60(1562):201-205. [PubMed: 30625122]

12.

Hesse LM, von Moltke LL, Greenblatt DJ. Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs. 2003;17(7):513-32. [PubMed: 12751920]

13.

Edinoff AN, Wu N, Ghaffar YT, Prejean R, Gremillion R, Cogburn M, Chami AA, Kaye AM, Kaye AD. Zolpidem: Efficacy and Side Effects for Insomnia. Health Psychol Res. 2021;9(1):24927. [PMC free article: PMC8567759] [PubMed: 34746488]

14.

Salvà P, Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications. Clin Pharmacokinet. 1995 Sep;29(3):142-53. [PubMed: 8521677]

15.

Tsai MJ, Tsai YH, Huang YB. Compulsive activity and anterograde amnesia after zolpidem use. Clin Toxicol (Phila). 2007;45(2):179-81. [PubMed: 17364638]

16.

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. J Psychopharmacol. 2018 Jun;32(6):654-662. [PubMed: 29442611]

Disclosure: Daniel Bouchette declares no relevant financial relationships with ineligible companies.

Disclosure: Hossein Akhondi declares no relevant financial relationships with ineligible companies.

Disclosure: Judy Quick declares no relevant financial relationships with ineligible companies.