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.][
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Common side effects include daytime sleepiness, headache, nausea, and diarrhea.[ More severe side effects include memory problems and .]
Zolpidem is a nonbenzodiazepine, or Z-drug, which acts as a sedative and hypnotic[ It generally has a half-life of two to three hours.][ This, however, is increased in those with liver problems.][
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Zolpidem was approved for medical use in the United States in 1992.
Medical uses
Zolpidem is labeled for short-term (usually about two to six weeks) treatment of insomnia at the lowest possible dose.[ It may be used for both improving sleep onset, sleep onset latency, and staying asleep.][
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Guidelines from NICE, the European Sleep Research Society, and the American College of Physicians recommend medication for insomnia (including possible zolpidem) only as a second-line treatment after non-pharmacological treatment options have been tried (e.g. cognitive behavioral therapy for insomnia).
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 (FDA) 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 (reported by 7% of people in clinical trials), drowsiness (2%), dizziness (1%), and diarrhea (1%); the most common side effects of long-term use included
drowsiness (8%),
dizziness (5%),
allergy (4%),
sinusitis (4%),
back pain (3%),
diarrhea (3%),
drugged feeling (3%),
dry mouth (3%),
lethargy (3%),
sore throat (3%),
abdominal pain (2%),
constipation (2%),
heart palpitations (2%),
lightheadedness (2%),
rash (2%),
abnormal dreams (1%),
amnesia (1%),
chest pain (1%),
depression (1%),
flu-like symptoms (1%),
and sleep disorder (1%).
Zolpidem increases the risk of depression, falls and bone fracture, poor driving, suppressed respiration and has been associated with an increased risk of death.[
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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.
Sleepwalking and complex sleep behaviors
Zolpidem is associated with complex sleep behaviors (CSBs), defined as activities performed during sleep followed by amnesia. These activities may include sleepwalking, 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,]
Concerns regarding zolpidem-related CSBs have prompted actions by regulatory authorities, including Australia's Therapeutic Goods Administration (TGA) and the U.S. Food and Drug Administration (FDA). In February 2008, the TGA implemented a boxed warning for the drug.
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.[ Abrupt withdrawal may cause delirium, seizures, or other , especially if used for prolonged periods and at high doses.][
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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 GABAA–receptor as an antagonist, thus stopping (and effectively detoxifying) zolpidem from being able to bind as an agonist on GABAA–receptor; slowly drug dependence or addiction to zolpidem will wane.]
Alcoholism may be at increased risk of physical dependency or abuse of zolpidem.[ It is not typically prescribed in people with a history of alcoholism, drug misuse, 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 drug tolerance-inducing properties have shown that zolpidem has less tolerance-producing potential than benzodiazepines, but in , the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines.
Overdose
Overdose can lead to coma or death.[
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Zolpidem overdose can be treated with the GABAA receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABA receptor to rapidly reverse the effects of the zolpidem.[
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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 GABAA receptor, which enhances GABAergic inhibition of neurotransmission in the central nervous system. It selectively binds to α1 Protein subunit of this pentameric ion channel. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties.
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 in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.
Pharmacokinetics
Microsome studies indicate zolpidem is metabolized by CYP3A4 (61%) CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (<3%), and CYP2C19 (<3%).
Interactions
People should not consume alcohol while taking zolpidem, and should not be prescribed opioid drugs nor take such illicit drugs recreationally.[ The U.S. Food and Drug Administration (FDA) is advising that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS).][ ]
Next day sedation can be worsened if people take zolpidem while they are also taking , other sedatives, anxiolytics, antidepressants, anticonvulsants, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.[
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Cytochrome P450 inhibitors, particularly CYP3A4 and CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, and clarithromycin[ Cytochrome P450 activators like St. John's Wort may decrease the activity of zolpidem.][ One study found that caffeine increases the concentration over time curve of zolpidem by about 20% and furthermore found that caffeine cannot adequately compensate for the impaired cognition caused by zolpidem.]
Chemistry
Three chemical syntheses of zolpidem are common. 4-Methylacetophenone is used as a common precursor. This is brominated and reacted with 2-amino-5-methylpyridine to give the imidazopyridine. From here the reactions use a variety of reagents to complete the synthesis, either involving thionyl chloride or sodium cyanide. These reagents are challenging to handle and require thorough safety assessments.
Several major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.
Alpidem is also an imidazopyridine and is an analogue of zolpidem.
History
Zolpidem was used in Europe starting in 1988 and was brought to market there by Synthelabo.[
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In 2015, the American Geriatrics Society said that zolpidem, eszopiclone, and zaleplon met the Beers criteria and should be avoided in individuals 65 and over "because of their association with harms balanced with their minimal efficacy in treating insomnia."[ The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate."]
Society and culture
Prescriptions in the US for all sleeping pills (including zolpidem) steadily declined from around 57 million tablets in 2013, to around 47 million in 2017, possibly due to concern about prescribing addictive drugs amid the opioid crisis.
Military use
As of 2012, the United States Air Force used zolpidem as one of the hypnotics approved as a "no-go pill" with a six-hour restriction on subsequent flight operation to help aviators and special duty personnel sleep in support of mission readiness. (The other hypnotics used are temazepam and zaleplon.) "Ground tests" are required before an authorization is issued to use the medication in an operational situation.
Recreational use
Zolpidem has potential for medical misuse when the drug is continued long term without or against medical advice, or for recreational use when the drug is taken to achieve a "high".[ Recreational use is more prevalent in those having been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures if abrupt withdrawal from zolpidem occurs.]
Other drugs, including benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers.[ Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of excessive-use potential for , zolpidem, and zopiclone.]
, nonmedical use of zolpidem is common for some adolescents. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations.
Regulation
For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like ) is a schedule IV substance under the Controlled Substances Act in the US.
Use in crime
The Z-drugs, including zolpidem, have been used as date rape drugs.[ This use of the drug was highlighted during proceedings against Darren Sharper, who was accused of using the tablets he was prescribed to facilitate a series of rapes.]
Sleepwalking and complex sleep behaviors
Zolpidem has drawn significant media attention due to reports of complex sleep behaviors (CSBs), including sleepwalking, sleep-driving, and other activities performed while not fully conscious. Notable incidents include media reports in the United States concerning events such as Congressman Patrick Kennedy's motor vehicle accident
In May 2018, actress Roseanne Barr attributed a controversial remark on Twitter to the effects of zolpidem. Barr's tweet compared Valerie Jarrett, a Black woman and former advisor to Barack Obama, to an ape. The comparison sparked widespread condemnation and led to the cancellation of Roseanne.
Brand names
As of September 2018, zolpidem is marketed under many brands.
Research
While cases of zolpidem improving aphasia in people with stroke have been described, use for this purpose has unclear benefits.
Animal studies in FDA files for zolpidem showed a dose dependent increase in some types of tumors, although the studies were too small to reach statistical significance.
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