Zolpidem was approved for medical use in the United States in 1992.[13][25] It became available as ageneric medication in 2007.[26] Zolpidem is aschedule IV controlled substance in the US under theControlled Substances Act of 1970 (CSA).[7][8][27] In 2023, it was the 54th most commonly prescribed medication in the United States, with more than 11million prescriptions.[28][29]
Zolpidem is labeled for short-term (usually about two to six weeks) treatment ofinsomnia at the lowest possible dose.[13][20] It may be used for both improvingsleep onset,sleep onset latency, and staying asleep.[7]
Guidelines fromNICE, the European Sleep Research Society, and theAmerican 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).[21][22][23] 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.[30]
Use of zolpidem may impair driving skills with a resultant increased risk ofroad traffic accidents. This adverse effect is not unique to zolpidem but also occurs with otherhypnotic drugs. Caution should be exercised by motor vehicle drivers.[20] The U.S.Food and Drug Administration (FDA) recommends lower doses of zolpidem due to impaired function the day after taking it.[31][32][33][34]
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 asdelirium andneurocognitive disorder.[35][36]
Animal studies have revealed evidence of incompleteossification and increasedintrauterine 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 incord blood at delivery. Zolpidem is recommended for use during pregnancy only when the benefits outweigh the risks.[37]
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 includeddrowsiness (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%).[8]
Zolpidem increases the risk ofdepression, falls and bone fracture, poor driving, suppressed respiration and has been associated with an increased risk of death.[38] Upper and lower respiratory infections are also common (experienced by 1–10% of people).[20]
Residual 'hangover' effects, such as sleepiness andimpaired psychomotor andcognitive 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.[24][39] 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.[32][40]
Zolpidem is associated with complex sleep behaviors (CSBs), defined as activities performed during sleep followed by amnesia. These activities may includewalking, driving,eating, having sex, having conversations, and performing other daily activities while asleep.[32][40][41][24] Research by Australia'sNational Prescribing Service found these activities typically occur after the first dose or within a few days of starting therapy,[42] although they may occur at any time during treatment.[40]
Concerns regarding zolpidem-related CSBs have prompted actions by regulatory authorities, including Australia'sTherapeutic Goods Administration (TGA) and the U.S. Food and Drug Administration (FDA). In February 2008, the TGA implemented aboxed warning for the drug.[43] 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.[40][41]
Rodent studies of thetolerance-inducing properties have shown that zolpidem has less tolerance-producing potential than benzodiazepines, but inprimates, the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines.[49]
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 asseizures,tremors,delirium, andirritability. Management typically involves tapering or substitution with long-acting benzodiazepines, occasionally withflumazenil orcholinesterase inhibitors, alongsidepsychosocial therapies such asmindfulness-basedcognitive therapy. While organ toxicity is rare, high doses can cause severe central nervous system effects.[50]
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, involvegas orliquidchromatography.[51][52][53]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All values are for human receptors unless otherwise specified.aHEK293bRat'scerebral cortex.c Rat'shippocampus. Additional sources:[55][56]
Zolpidem is aligand of high-affinitypositive modulator sites ofGABAA receptors, which enhancesGABAergic inhibition of neurotransmission in the central nervous system. It selectively binds toα1subunits of thispentamericion channel. Accordingly, it has stronghypnotic properties and weakanxiolytic,myorelaxant, andanticonvulsant properties.[10] Opposed todiazepam, zolpidem is able to bind to binary αβGABA receptors, where it was shown to bind to the α1–α1 subunit interface.[57] Zolpidem has about 10-fold lower affinity for theα2- andα3- subunits than for α1, and no appreciable affinity forα5 subunit-containing receptors.[58][59] ω1 type GABAA receptors are the α1-containing GABAA receptors and are found primarily in the brain, the ω2 receptors are those that contain the α2-, α3-,α4-, α5-, orα6 subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABAA receptors located in the brain rather than the spine.[60] 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.[61] Zolpidem modulates the receptor presumably by inducing a receptor conformation that enables an increased binding strength of theorthosteric agonist GABA towards its cognate receptor without affectingdesensitization or peak currents.[62]
Microsome studies indicate zolpidem is metabolized byCYP3A4 (61%)CYP2C9 (22%),CYP1A2 (14%),CYP2D6 (<3%), andCYP2C19 (<3%).[19] Less than 1% is excreted in urine unchanged.[10] It is principally metabolized into three metabolites, none of which are believed to be pharmacologically active. The absolutebioavailability of zolpidem is about 70%. The drug reaches peak concentration in about 2 hours and has a half-life in healthy adults of about 2–3 hours.[13][10][14] Zolpidem's half life is decreased in children and increased in the elderly and people with liver issues. While some studies show men metabolize zolpidem faster than women (possibly due totestosterone),[65] others do not.[10] A review found only a 33% lower clearance in women compared to men, suggesting the FDA's dosage reduction of 50% for women may have been too large.[66]
People should not consumealcohol or useopioids while using Zolpidem.[67] Use of opioids with zolpidem increases the risk of respiratory depression and death.[20] The U.S. Food and Drug Administration (FDA) is advising that the opioid addiction medicationsbuprenorphine andmethadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS).[68]
Next day sedation can be worsened if people take zolpidem while they are also takingantipsychotics, other sedatives, anxiolytics, antidepressants, anticonvulsants, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.[20]
Cytochrome P450 inhibitors, particularly CYP3A4 and CYP1A2 inhibitors such asfluvoxamine,ciprofloxacin, andclarithromycin[69] will increase the effects of a given dose of zolpidem.[20] Cytochrome P450 activators likeSt. John's Wort may decrease the activity of zolpidem.[20] 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.[70] Other studies show no effect of caffeine on zolpidem metabolism.[10]
Threechemical 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 theimidazopyridine. From here the reactions use a variety of reagents to complete the synthesis, either involvingthionyl chloride orsodium cyanide. These reagents are challenging to handle and require thorough safety assessments.[71][72][73] Though such safety procedures are common in the industry, they make clandestine manufacture difficult.
Several major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.[74]
Alpidem is also an imidazopyridine and is ananalogue of zolpidem.[75][76][77] Both agents are GABAA receptor positive allosteric modulators.[75][76][77] However, whereas zolpidem is used as a hypnotic and sedative, alpidem was used as ananxiolytic.[75][76][77]
Zolpidem was used in Europe starting in 1988 and was brought to market there bySynthelabo.[78] Synthelabo andSearle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name "Ambien".[78][25] It became available as ageneric medication in 2007.[26]
In 2015, theAmerican Geriatrics Society said that zolpidem,eszopiclone, andzaleplon met theBeers criteria and should be avoided in individuals 65 and over "because of their association with harms balanced with their minimal efficacy in treating insomnia."[35][36] The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate."[36]
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 theopioid crisis.[79]
As of 2012, theUnited 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 aretemazepam andzaleplon.) "Ground tests" are required before an authorization is issued to use the medication in an operational situation.[80]
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".[81][82] The transition from medical use of zolpidem to high-dose addiction ordrug dependence can occur with use, but some believe it may be more likely when used without a clinical recommendation to continue using it, when physiologicaldrug tolerance leads to higher doses than the usual 5mg or 10mg, when consumed through insufflation or injection, or when taken for purposes other than as a sleep aid.[81] Recreational use is more prevalent in those having been dependent on other drugs in the past, but tolerance anddrug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to developphysical dependence on the drug, which may cause severe withdrawal symptoms, including seizures if abrupt withdrawal from zolpidem occurs.[83]
Other drugs, including benzodiazepines andzopiclone, are also found in high numbers of suspected drugged drivers.[24] Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of excessive-use potential forbenzodiazepines, zolpidem, and zopiclone.[51] U.S. CongressmanPatrick J. Kennedy says that he was using zolpidem (Ambien) andpromethazine (Phenergan) when he was caught driving erratically at 3 a.m.[84] "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said.
As of 2009[update], nonmedical use of zolpidem is common for some adolescents. Some users have reported decreased anxiety, mildeuphoria, perceptual changes, visual distortions, and hallucinations.[85][86] Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.[87]
Zolpidem has been shown to be effective in reducingjet lag from rapid travel across multiple timezones, such astransatlantic flights between the West Coast of the United States and Europe.[88][89] The most effective results have been shown to be at dosages taken for 3 consecutive nights upon arrival at the traveler's new location, at the new local bedtime, thereby forcing an initial circadian shift toward the new timezone.[90]
For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-likeZ-drugs) is a schedule IV substance under theControlled Substances Act in the US.[27] The United States patent for zolpidem was held by the French pharmaceutical corporationSanofi-Aventis.[91]
TheZ-drugs, including zolpidem, have been used asdate rape drugs.[24][92] Zolpidem is available by prescription, and broadly prescribed unlike other date rape drugs:gamma-hydroxybutyrate (GHB), which is used to treatnarcolepsy, orflunitrazepam (Rohypnol), which is only prescribed as a second-line choice for insomnia.[93] Zolpidem can be detected in bodily fluids for 36 hours, though it may be possible to detect it byhair testing much later, which is due to the shortelimination half-life of 2.5–3 hours.[24] This use of the drug was highlighted during proceedings againstDarren Sharper, who was accused of using the tablets he was prescribed to facilitate a series of rapes.[93][94]
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 CongressmanPatrick Kennedy's motor vehicle accident[40][95][96] and in Australia following a fatal 20 metres (66 ft) fall from theSydney Harbour Bridge involving an individual reportedly under the influence of zolpidem.[97][98]
In May 2018, actressRoseanne Barr attributed a controversial remark onTwitter to the effects of zolpidem. Barr's tweet comparedValerie Jarrett, a Black woman and former advisor to Barack Obama, to an ape. The comparison sparked widespread condemnation and led to the cancellation ofRoseanne.[99][100] The incident promptedSanofi, the manufacturer of Ambien, to issue a public statement clarifying that "racism is not a known side effect" of the medication.[101]
While cases of zolpidem improvingaphasia in people withstroke have been described, use for this purpose has unclear benefits.[103] Zolpidem has also been studied inpersistent vegetative states with unclear effect.[104] A 2017systematic review concluded that while there is preliminary evidence of benefit for treating disorders of movement and consciousness other than insomnia (includingParkinson's disease), more research is needed.[105]
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.[106] Some observational epidemiological studies have found a correlation between use of benzodiazepines and certainhypnotics including zolpidem and an increased risk of getting cancer, but others have found no correlation; a 2017 meta-analysis of such studies found a correlation, stating that use of hypnotics was associated with a 29% increased risk of cancer, and that "zolpidem use showed the strongest risk of cancer" with an estimated 34% increased risk, but noted that the results were tentative because some of the studies failed to control forconfounders like cigarette smoking and alcohol use, and some of the studies analyzed werecase–controls, which are more prone to some forms of bias.[107] Similarly, a meta-analysis of benzodiazepine drugs also shows their use is associated with increased risk of cancer.[108]
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