Zolpidem

Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available as conventional tablets, extended-release tablets, or sublingual tablets.
Common side effects include daytime sleepiness, headache, nausea, and diarrhea. More severe side effects include memory problems and hallucinations. While flumazenil, a GABA_A receptor antagonist, can reverse zolpidem's effects, usually supportive care is all that is recommended in overdose.
Zolpidem is a nonbenzodiazepine, or Z-drug, which acts as a sedative and hypnotic as a positive allosteric modulator at the GABA_A receptor. It is an imidazopyridine and increases GABA effects in the central nervous system by binding to GABA_A receptors at the same location as benzodiazepines. It generally has a half-life of two to three hours. This, however, is increased in those with liver problems.
Zolpidem was approved for medical use in the United States in 1992. It became available as a generic medication in 2007. Zolpidem is a schedule IV controlled substance in the US under the Controlled Substances Act of 1970. In 2023, it was the 54th most commonly prescribed medication in the United States, with more than 11million prescriptions.

Medical uses

Zolpidem is labeled for short-term treatment of insomnia at the lowest possible dose. It may be used for both improving sleep onset, sleep onset latency, and staying asleep.
Guidelines from NICE, the European Sleep Research Society, and the American College of Physicians recommend medication for insomnia only as a second-line treatment after non-pharmacological treatment options have been tried. This is based in part on a 2012 review which found that zolpidem's effectiveness is nearly as much due to psychological effects as to the medication itself.

Contraindications

Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers. The U.S. Food and Drug Administration recommends lower doses of zolpidem due to impaired function the day after taking it.
Zolpidem should not be prescribed to older people, who are more sensitive to the effects of hypnotics including zolpidem, and are at an increased risk of falls and adverse cognitive effects, such as delirium and neurocognitive disorder.
Animal studies have revealed evidence of incomplete ossification and increased intrauterine fetal death at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data on human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is recommended for use during pregnancy only when the benefits outweigh the risks.

Adverse effects

The most common adverse effects of short-term use include headache, drowsiness, dizziness, and diarrhea ; the most common side effects of long-term use included
drowsiness,
dizziness,
allergy,
sinusitis,
back pain,
diarrhea,
drugged feeling,
dry mouth,
lethargy,
sore throat,
abdominal pain,
constipation,
heart palpitations,
lightheadedness,
rash,
abnormal dreams,
amnesia,
chest pain,
depression,
flu-like symptoms,
and sleep disorder.
Zolpidem increases the risk of depression, falls and bone fracture, poor driving, suppressed respiration and has been associated with an increased risk of death. Upper and lower respiratory infections are also common.
Residual 'hangover' effects, such as sleepiness and impaired psychomotor and cognitive function, may persist into the day following nighttime administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures. In January 2013, the FDA issued a safety communication addressing next-morning cognitive impairment associated with the drug. In May 2013, the FDA recommended avoiding activities requiring alertness the day after using extended-release formulations.

Sleepwalking and complex sleep behaviors

Zolpidem is associated with complex sleep behaviors, defined as activities performed during sleep followed by amnesia. These activities may include walking, driving, eating, having sex, having conversations, and performing other daily activities while asleep. Research by Australia's National Prescribing Service found these activities typically occur after the first dose or within a few days of starting therapy, although they may occur at any time during treatment.
Concerns regarding zolpidem-related CSBs have prompted actions by regulatory authorities, including Australia's Therapeutic Goods Administration and the U.S. Food and Drug Administration. In February 2008, the TGA implemented a boxed warning for the drug. In April 2019, the FDA strengthened the drug's warning labeling by adding a black box warning highlighting the risk of serious injuries and fatalities related to CSBs, even at recommended doses and after single use, and added a contraindication advising against zolpidem use in patients with a history of CSBs.

Tolerance, dependence and withdrawal

As zolpidem is associated with drug tolerance and substance dependence, its prescription guidelines are only for severe insomnia and short periods of use at the lowest effective dose. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other adverse effects, especially if used for prolonged periods and at high doses. When drug tolerance and physical dependence to zolpidem develop, treatment usually entails a gradual dose reduction over a period of months to minimize withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal.
Failing that, an alternative method may be necessary for some people, such as a switch to a benzodiazepine equivalent dose of a longer-acting benzodiazepine drug, as for diazepam or chlordiazepoxide, followed by a gradual reduction in dose of the long-acting benzodiazepine. In people who are difficult to treat, an inpatient flumazenil administration allows for rapid competitive binding of flumazenil to GABA_A–receptor as an antagonist, thus stopping zolpidem from being able to bind as an agonist on GABA_A–receptor; slowly drug dependence or addiction to zolpidem will wane.
Alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem. It is not typically prescribed to people with a history of alcoholism, recreational drug use, physical dependency, or psychological dependency on sedative-hypnotic drugs. A 2014 review found evidence of drug-seeking behavior, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.
Rodent studies of the tolerance-inducing properties have shown that zolpidem has less tolerance-producing potential than benzodiazepines, but in primates, the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines.
Zolpidem misuse has been associated with dependence and addiction, often driven by its euphoric effects. Reported cases include extremely high daily doses, sometimes up to 6,000 mg, with withdrawal symptoms such as seizures, tremors, delirium, and irritability. Management typically involves tapering or substitution with long-acting benzodiazepines, occasionally with flumazenil or cholinesterase inhibitors, alongside psychosocial therapies such as mindfulness-based cognitive therapy. While organ toxicity is rare, high doses can cause severe central nervous system effects.

Overdose

Overdose can lead to coma or death.
Zolpidem overdose can be treated with the GABA_A receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABA_A receptor to rapidly reverse the effects of the zolpidem.

Detection in body fluids

Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in people who are hospitalized, to provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300μg/L in persons receiving the drug therapeutically, 100–700μg/L in those arrested for impaired driving, and 1000–7000μg/L in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.

Pharmacology

Mechanism of action

Zolpidem is a ligand of high-affinity positive modulator sites of GABA_A receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. It selectively binds to α₁ subunits of this pentameric ion channel. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties. Opposed to diazepam, zolpidem is able to bind to binary αβ GABA receptors, where it was shown to bind to the α1–α1 subunit interface. Zolpidem has about 10-fold lower affinity for the α₂- and α₃- subunits than for α₁, and no appreciable affinity for α₅ subunit-containing receptors. ω₁ type GABA_A receptors are the α₁-containing GABA_A receptors and are found primarily in the brain, the ω₂ receptors are those that contain the α₂-, α₃-, α₄-, α₅-, or α₆ subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABA_A receptors located in the brain rather than the spine. Zolpidem has no affinity for γ₁ and γ₃ subunit-containing receptors and, like the vast majority of benzodiazepine-like drugs, it lacks affinity for receptors containing α₄ and α₆. Zolpidem modulates the receptor presumably by inducing a receptor conformation that enables an increased binding strength of the orthosteric agonist GABA towards its cognate receptor without affecting desensitization or peak currents.
Like zaleplon, zolpidem may increase slow-wave sleep but cause no effect on stage 2 sleep.
A 2004 meta-analysis compared benzodiazepines against nonbenzodiazepines and showed few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.