Biology:Zolpidem

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Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems.[1][2] Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after behavioral changes, such as sleep hygiene, have been tried.[3][4][5] It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer.[6] It is taken by mouth and is available as conventional tablets, extended-release tablets, or sublingual tablets.[1]

Common side effects include daytime sleepiness, headache, nausea, and diarrhea.[1] More severe side effects include memory problems and hallucinations.[6] While flumazenil, a GABAA receptor antagonist, can reverse zolpidem's effects, usually supportive care is all that is recommended in overdose.[7]

Zolpidem is a nonbenzodiazepine, or Z-drug, which acts as a sedative and hypnotic[1][7] as a positive allosteric modulator at the GABAA receptor. It is an imidazopyridine and increases GABA effects in the central nervous system by binding to GABAA receptors at the same location as benzodiazepines.[1] It generally has a half-life of two to three hours.[1] This, however, is increased in those with liver problems.[1]

Zolpidem was approved for medical use in the United States in 1992.[1][8] It became available as a generic medication in 2007.[9] Zolpidem is a schedule IV controlled substance in the US under the Controlled Substances Act of 1970 (CSA).[6][10][11] In 2023, it was the 54th most commonly prescribed medication in the United States, with more than 11 million prescriptions.[12][13]

Medical uses

Generic zolpidem tartrate

Zolpidem is labeled for short-term (usually about two to six weeks) treatment of insomnia at the lowest possible dose.[1][2] It may be used for both improving sleep onset, sleep onset latency, and staying asleep.[6]

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).[3][4][5] 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.[14]

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.[2] The U.S. Food and Drug Administration (FDA) recommends lower doses of zolpidem due to impaired function the day after taking it.[15][16][17][18]

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.[19][20]

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.[21]

Adverse effects

Various zolpidem pills

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%).[10]

Zolpidem increases the risk of depression, falls and bone fracture, poor driving, suppressed respiration and has been associated with an increased risk of death.[22] Upper and lower respiratory infections are also common (experienced by 1–10% of people).[2]

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.[7][23] 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.[16][24]

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 walking, driving, eating, having sex, having conversations, and performing other daily activities while asleep.[16][24][25][7] Research by Australia's National Prescribing Service found these activities typically occur after the first dose or within a few days of starting therapy,[26] although they may occur at any time during treatment.[24]

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.[27] 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.[24][25]

Tolerance, dependence and withdrawal

Ambien tablets

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.[2][3][4][5][28] Tolerance to the effects of zolpidem can develop in some people in just a few weeks.[29] Abrupt withdrawal may cause delirium, seizures, or other adverse effects, especially if used for prolonged periods and at high doses.[29][30] 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.[30]

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.[30] 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.[31]

Alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem.[2] It is not typically prescribed to people with a history of alcoholism, recreational drug use, physical dependency, or psychological dependency on sedative-hypnotic drugs.[2] A 2014 review found evidence of drug-seeking behavior, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.[32]

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.[33]

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.[34]

Overdose

Overdose can lead to coma or death.[2]

Zolpidem overdose can be treated with the GABAA receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABAA receptor to rapidly reverse the effects of the zolpidem.[2]

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 30–300 μg/L in persons receiving the drug therapeutically, 100–700 μg/L in those arrested for impaired driving, and 1000–7000 μg/L in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.[35][36][37]

Pharmacology

Site Ki (nM)
GABAA Benzodiazepine Type Ic 25
GABAA Benzodiazepineb 26
GABAA α1 27
GABAA α1β1γ2 111.9
GABAA α1β3γ2 41
GABAA α2 160
GABAA α2β1γ2 760.6
GABAA α2β2γ2a 765
GABAA α3 380
GABAA α3β1γ2 2149.5
GABAA α4β3γ2 > 10,000
GABAA α5β1γ2 > 10,000
GABAA α6β3γ2 > 10,000
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. aHEK293 bRat's cerebral cortex. cRat's hippocampus. Additional sources:[38][39]

Mechanism of action

Zolpidem is a ligand of high-affinity positive modulator sites of GABAA 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.[40] 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.[41] 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.[42][43] 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-, or α6 subunits, and are found primarily in the spine. Thus, zolpidem favours binding to GABAA receptors located in the brain rather than the spine.[44] 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.[45] 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.[46]

Like zaleplon, zolpidem may increase slow-wave sleep but cause no effect on stage 2 sleep.[47]

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.[48]

Pharmacokinetics

Microsome studies indicate zolpidem is metabolized by CYP3A4 (61%) CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (<3%), and CYP2C19 (<3%).[49] Less than 1% is excreted in urine unchanged.[40] It is principally metabolized into three metabolites, none of which are believed to be pharmacologically active. The absolute bioavailability 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.[1][40][50] 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 to testosterone),[51] others do not.[40] 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.[52]

Interactions

People should not consume alcohol or use opioids while using Zolpidem.[53] Use of opioids with zolpidem increases the risk of respiratory depression and death.[2] 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).[54]

Next day sedation can be worsened if people take zolpidem while they are also taking antipsychotics, other sedatives, anxiolytics, antidepressants, anticonvulsants, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.[2]

Cytochrome P450 inhibitors, particularly CYP3A4 and CYP1A2 inhibitors such as fluvoxamine, ciprofloxacin, and clarithromycin[55] will increase the effects of a given dose of zolpidem.[2] Cytochrome P450 activators like St. John's Wort may decrease the activity of zolpidem.[2] 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.[56] Other studies show no effect of caffeine on zolpidem metabolism.[40]

Chemistry

Three chemical syntheses of zolpidem are common. 4-Methylacetophenone is first brominated and that product is treated 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.[57][58][59] 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.[60]

Alpidem is also an imidazopyridine and is an analogue of zolpidem.[61][62][63] Both agents are GABAA receptor positive allosteric modulators.[61][62][63] However, whereas zolpidem is used as a hypnotic and sedative, alpidem was used as an anxiolytic.[61][62][63]

History

Zolpidem was used in Europe starting in 1988 and was brought to market there by Synthelabo.[64] Synthelabo and Searle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name "Ambien".[64][8] It became available as a generic medication in 2007.[9]

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."[19][20] The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate."[20]

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.[65]

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.[66]

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".[67][68] The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur with use, but some believe it may be more likely when used without a clinical recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through insufflation or injection, or when taken for purposes other than as a sleep aid.[67] 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.[69]

Other drugs, including benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers.[7] Many drivers have blood levels far exceeding the therapeutic dose range, suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem, and zopiclone.[35] U.S. Congressman Patrick J. Kennedy says that he was using zolpidem (Ambien) and promethazine (Phenergan) when he was caught driving erratically at 3 a.m.[70] "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, nonmedical use of zolpidem is common for some adolescents. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations.[71][72] Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.[73]

International travel

Zolpidem is among the agents used in the short-term management of insomnia associated with jet lag, typically at doses of 5–10 mg. Its clinical use, similar to that of other hypnotics, is constrained by the potential for adverse effects and dependence, and guidelines generally recommend limiting treatment duration to short periods, usually under one week.[74]

Regulation

For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like Z-drugs) is a schedule IV substance under the Controlled Substances Act in the US.[11] The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.[75]

Use in crime

The Z-drugs, including zolpidem, have been used as date rape drugs.[7][76] Zolpidem is available by prescription, and broadly prescribed unlike other date rape drugs: gamma-hydroxybutyrate (GHB), which is used to treat narcolepsy, or flunitrazepam (Rohypnol), which is only prescribed as a second-line choice for insomnia.[77] Zolpidem can be detected in bodily fluids for 36 hours, though it may be possible to detect it by hair testing much later, which is due to the short elimination half-life of 2.5–3 hours.[7] 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.[77][78]

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[24][79][80] and in Australia following a fatal 20 metres (66 ft) fall from the Sydney Harbour Bridge involving an individual reportedly under the influence of zolpidem.[81][82]

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.[83][84] The incident prompted Sanofi, the manufacturer of Ambien, to issue a public statement clarifying that "racism is not a known side effect" of the medication.[85]

Brand names

As of September 2018, zolpidem is marketed under many brands, examples include: Ambien 5 mg & 10 mg (IR oral tablets), Ambien CR 6.25 mg & 12.5 mg (controlled release tablets), Edluar 5 mg & 10 mg (sublingual tablets), Intermezzo 1.75 mg & 3.5 mg (sublingual tablets), and ZolpiMist 5 mg (oral spray).[86][87][88]

Research

While cases of zolpidem improving aphasia in people with stroke have been described, use for this purpose has unclear benefits.[89] Zolpidem has also been studied in persistent vegetative states with unclear effect.[90] A 2017 systematic review concluded that while there is preliminary evidence of benefit for treating disorders of movement and consciousness other than insomnia (including Parkinson's disease), more research is needed.[91]

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.[92] Some observational epidemiological studies have found a correlation between use of benzodiazepines and certain hypnotics 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 for confounders like cigarette smoking and alcohol use, and some of the studies analyzed were case–controls, which are more prone to some forms of bias.[93] Similarly, a meta-analysis of benzodiazepine drugs also shows their use is associated with increased risk of cancer.[94]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "Zolpidem (Monograph)". The American Society of Health-System Pharmacists. 27 April 2023. https://www.drugs.com/monograph/zolpidem-tartrate.html. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 "Stilnoct 10mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". UK Electronic Medicines Compendium. 21 May 2018. https://www.medicines.org.uk/emc/product/4933/smpc. 
  3. ↑ 3.0 3.1 3.2 "Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia". NICE. 28 April 2004. https://www.nice.org.uk/guidance/ta77/chapter/1-Guidance. 
  4. ↑ 4.0 4.1 4.2 "European guideline for the diagnosis and treatment of insomnia". Journal of Sleep Research 26 (6): 675–700. December 2017. doi:10.1111/jsr.12594. PMID 28875581. 
  5. ↑ 5.0 5.1 5.2 "Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians". Annals of Internal Medicine 165 (2): 125–33. July 2016. doi:10.7326/M15-2175. PMID 27136449. 
  6. ↑ 6.0 6.1 6.2 6.3 "Insomnia: Pharmacologic Therapy". American Family Physician 96 (1): 29–35. July 2017. PMID 28671376. https://www.aafp.org/afp/2017/0701/p29.html. Retrieved 18 August 2018. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 "The clinical and forensic toxicology of Z-drugs". Journal of Medical Toxicology 9 (2): 155–62. June 2013. doi:10.1007/s13181-013-0292-0. PMID 23404347. 
  8. ↑ 8.0 8.1 "Drug Approval Package: Ambien (Zolpidem Tartrate) NDA 19908". 24 December 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/019908_S000_AmbienTOC.cfm. 
  9. ↑ 9.0 9.1 "FDA Approves First Generic Versions of Ambien (Zolpidem Tartrate) for the Treatment of Insomnia". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 6 March 2010. Retrieved 24 January 2010.
  10. ↑ 10.0 10.1 Cite error: Invalid <ref> tag; no text was provided for refs named Ambien FDA label
  11. ↑ 11.0 11.1 "Drug Scheduling". https://www.dea.gov/drug-information/drug-scheduling. 
  12. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
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  15. ↑ "Questions and Answers: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist)". 13 February 2018. https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-risk-next-morning-impairment-after-use-insomnia-drugs-fda-requires-lower. 
  16. ↑ 16.0 16.1 16.2 "FDA Drug Safety Communication: FDA approves new label changes and dosing for zolpidem products and a recommendation to avoid driving the day after using Ambien CR". 11 December 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-approves-new-label-changes-and-dosing-zolpidem-products-and. 
  17. ↑ "FDA Drug Safety Communication: Risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist)". U.S. Food and Drug Administration (FDA). 10 January 2013. https://www.fda.gov/drugs/drugsafety/ucm334033.htm. 
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  19. ↑ 19.0 19.1 "Common Drug Side Effects and Drug-Drug Interactions in Elderly Adults in Primary Care". Journal of the American Geriatrics Society 65 (7): 1578–1585. July 2017. doi:10.1111/jgs.14870. PMID 28326532. 
  20. ↑ 20.0 20.1 20.2 "American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults". Journal of the American Geriatrics Society 63 (11): 2227–46. November 2015. doi:10.1111/jgs.13702. PMID 26446832. https://www.sigot.org/allegato_docs/1057_Beers-Criteria.pdf. Retrieved 29 June 2018. 
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  23. ↑ "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs 18 (5): 297–328. 2004. doi:10.2165/00023210-200418050-00003. PMID 15089115. 
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  25. ↑ 25.0 25.1 "Boxed Warning for risk of serious injuries caused by sleepwalking". 30 April 2019. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-risk-serious-injuries-caused-sleepwalking-certain-prescription-insomnia. 
  26. ↑ "Zolpidem and sleep-related behaviours". NPS Position Statement (National Prescribing Service Limited). July 2008. http://www.nps.org.au/__data/assets/pdf_file/0011/59888/Zolpidem_position_statement_To_print.pdf. 
  27. ↑ "Zolpidem ('Stilnox') – updated information – February 2008". Therapeutic Goods Administration (TGA). 21 February 2008. https://www.tga.gov.au/alerts/stilnox2.htm. 
  28. ↑ "Clinical guideline for the evaluation and management of chronic insomnia in adults". Journal of Clinical Sleep Medicine 4 (5): 487–504. October 2008. doi:10.5664/jcsm.27286. PMID 18853708. 
  29. ↑ 29.0 29.1 "In the Zzz zone: the effects of Z-drugs on human performance and driving". Journal of Medical Toxicology 9 (2): 163–71. June 2013. doi:10.1007/s13181-013-0294-y. PMID 23456542. 
  30. ↑ 30.0 30.1 30.2 "The problems of long-term treatment with benzodiazepines and related substances". Deutsches Ärzteblatt International 112 (1–2): 1–7. January 2015. doi:10.3238/arztebl.2015.0001. PMID 25613443. 
  31. ↑ "Dependence on zolpidem: two case reports of detoxification with flumazenil infusion". International Clinical Psychopharmacology 20 (5): 285–7. September 2005. doi:10.1097/01.yic.0000166404.41850.b4. PMID 16096519. 
  32. ↑ "An update on zolpidem abuse and dependence". Journal of Addictive Diseases 33 (1): 15–23. 2014. doi:10.1080/10550887.2014.882725. PMID 24467433. 
  33. ↑ "Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors". The Journal of Pharmacology and Experimental Therapeutics 317 (1): 369–77. April 2006. doi:10.1124/jpet.105.096701. PMID 16399882. 
  34. ↑ "Zolpidem-related euphoria, addiction and detoxification: A case report and review of the literature". Medicine 103 (44). November 2024. doi:10.1097/MD.0000000000040280. PMID 39496046. 
  35. ↑ 35.0 35.1 "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Therapeutic Drug Monitoring 29 (2): 248–60. April 2007. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081. 
  36. ↑ "Acute zolpidem overdose--report of two cases". Journal of Analytical Toxicology 23 (6): 559–62. October 1999. doi:10.1093/jat/23.6.559. PMID 10517569. 
  37. ↑ Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. 2011. pp. 1836–1838. 
  38. ↑ "Pharmacology of Sleep Disorders in Children". Principles and Practice of Pediatric Sleep Medicine. Elsevier. 2005. pp. 327–338. doi:10.1016/b978-0-7216-9458-0.50033-7. ISBN 978-0-7216-9458-0. "On recombinant receptors, zolpidem displays a high affinity for only the α1-GABAA receptors and an intermediate affinity for α2- and α3-GABAA receptors. It does not bind to α5-GABAA receptors. The sedative action of zolpidem is exclusively mediated by α1-GABA receptors." 
  39. ↑ "7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models". Journal of Medicinal Chemistry 48 (23): 7089–7092. November 2005. doi:10.1021/jm058034a. PMID 16279764. 
  40. ↑ 40.0 40.1 40.2 40.3 40.4 Cite error: Invalid <ref> tag; no text was provided for refs named costahalflife
  41. ↑ "Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface". Scientific Reports 6. June 2016. doi:10.1038/srep28674. PMID 27346730. Bibcode: 2016NatSR...628674C. 
  42. ↑ "Gamma-aminobutyric acidA receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology". Journal of Neurochemistry 54 (5): 1802–4. May 1990. doi:10.1111/j.1471-4159.1990.tb01237.x. PMID 2157817. 
  43. ↑ "Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux". Molecular Pharmacology 59 (5): 1108–18. May 2001. doi:10.1124/mol.59.5.1108. PMID 11306694. 
  44. ↑ "Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies". Psychopharmacology 128 (1): 1–16. November 1996. doi:10.1007/s002130050103. PMID 8944400. http://link.springer.de/link/service/journals/00213/bibs/6128001/61280001.htm. 
  45. ↑ "Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit". Molecular Pharmacology 50 (3): 670–8. September 1996. doi:10.1016/S0026-895X(25)09339-3. PMID 8794909. http://molpharm.aspetjournals.org/cgi/content/abstract/50/3/670. Retrieved 7 October 2007. 
  46. ↑ "Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses". The Journal of Neuroscience 19 (2): 578–88. January 1999. doi:10.1523/JNEUROSCI.19-02-00578.1999. PMID 9880578. 
  47. ↑ "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats". Journal of Pharmacological Sciences 94 (3): 246–51. March 2004. doi:10.1254/jphs.94.246. PMID 15037809. 
  48. ↑ "Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis". Human Psychopharmacology 19 (5): 305–22. July 2004. doi:10.1002/hup.594. PMID 15252823. 
  49. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named micrsome_liver
  50. ↑ "Hypnotic Medications". Principles and Practice of Sleep Medicine (5th ed.). Elsevier. 2011. pp. 483–491. doi:10.1016/b978-1-4160-6645-3.00042-6. ISBN 978-1-4160-6645-3. 
  51. ↑ "Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men". British Journal of Clinical Pharmacology 56 (3): 297–304. September 2003. doi:10.1046/j.0306-5251.2003.01852.x. PMID 12919178. 
  52. ↑ "Zolpidem and Gender: Are Women Really At Risk?". Journal of Clinical Psychopharmacology 39 (3): 189–199. May 2019. doi:10.1097/JCP.0000000000001026. PMID 30939589. 
  53. ↑ "FDA Drug Safety Communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning". U.S. Food and Drug Administration (FDA). 31 August 2016. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-serious-risks-and-death-when-combining-opioid-pain-or. 
  54. ↑ "FDA urges caution about withholding opioid addiction medications". 20 September 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-urges-caution-about-withholding-opioid-addiction-medications.  Public Domain This article incorporates text from this source, which is in the public domain.
  55. ↑ "Effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects". Archives of Pharmacal Research 42 (12): 1101–1106. December 2019. doi:10.1007/s12272-019-01201-5. PMID 31820397. 
  56. ↑ "Pharmacokinetic and pharmacodynamic interactions between zolpidem and caffeine". Clinical Pharmacology and Therapeutics 82 (1): 54–62. July 2007. doi:10.1038/sj.clpt.6100211. PMID 17443132. 
  57. ↑ The art of drug synthesis. Hoboken, N.J.: Wiley-Interscience. 2007. pp. Chapter 15, Section 2. ISBN 978-0-471-75215-8. 
  58. ↑ Rawalnath SR, Crasta Santosh R, Saxena A, "Process for the preparation of zolpidem", IN patent 246080, published 21 December 2005, issued 14 February 2011
  59. ↑ "A simple and efficient synthesis of hypnotic agent, zolpidem and its related substances". Arkivoc 2009 (2): 315–320. 2009. doi:10.3998/ark.5550190.0010.230. 
  60. ↑ "Synthesis and spectral characterization of zolpidem related substances - hypnotic agent". Arkivoc 2009 (7): 143–149. 2009. doi:10.3998/ark.5550190.0010.714. 
  61. ↑ 61.0 61.1 61.2 "Zolpidem and alpidem: two imidazopyridines with selectivity for omega 1- and omega 3-receptor subtypes". Adv Biochem Psychopharmacol 46: 61–72. 1990. PMID 1981304. 
  62. ↑ 62.0 62.1 62.2 "Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes". Neurosci Biobehav Rev 18 (3): 355–72. 1994. doi:10.1016/0149-7634(94)90049-3. PMID 7984354. 
  63. ↑ 63.0 63.1 63.2 "Anxioselective anxiolytics: on a quest for the Holy Grail". Trends Pharmacol Sci 33 (11): 611–20. November 2012. doi:10.1016/j.tips.2012.08.003. PMID 22981367. 
  64. ↑ 64.0 64.1 "Searle Wins Ok To Sell Sleep Aid". Chicago Tribune. 22 December 1992. https://www.chicagotribune.com/1992/12/22/searle-wins-ok-to-sell-sleep-aid/. 
  65. ↑ "Ambien defence: the real side effects of sleeping pills". Financial Times. 1 June 2018. https://www.ft.com/content/cca81c52-6518-11e8-a39d-4df188287fff. 
  66. ↑ "Air Force Special Operations Command Instruction 48-101". e-publishing.af.mil. 30 November 2012. http://static.e-publishing.af.mil/production/1/afsoc/publication/afsoci48-101/afsoci48-101.pdf. 
  67. ↑ 67.0 67.1 "Management of benzodiazepine misuse and dependence". Australian Prescriber 38 (5): 152–5. October 2015. doi:10.18773/austprescr.2015.055. PMID 26648651. 
  68. ↑ "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of Clinical Psychiatry 66 (Suppl 9): 31–41. 2005. PMID 16336040. 
  69. ↑ "[Epileptic seizures as a sign of abstinence from chronic consumption of zolpidem]" (in es). Revista de Neurología 34 (3): 253–6. 2002. doi:10.33588/rn.3403.2001316. PMID 12022074. 
  70. ↑ "Kennedy To Enter Drug Rehab After Car Crash; Congressman Wrecked Car Near Capitol". http://wcco.com/national/Rep.Patrick.Kennedy.2.267357.html. 
  71. ↑ "Ambien Abuse on Rise Among Teens". KSL. https://www.ksl.com/article/588181. 
  72. ↑ "The misuse of Ambien among adolescents: prevalence and correlates in a national sample". Addictive Behaviors 37 (12): 1389–94. December 2012. doi:10.1016/j.addbeh.2012.06.015. PMID 22795592. 
  73. ↑ "Swimming Australia's 'Stilnox six' given final warning as AOC decides not to issue any further sanctions". ABC News (www.abc.net.au). 23 August 2013. http://www.abc.net.au/news/2013-08-23/australian-olympic-committee-will-not-punish-swimmers-further/4908278. 
  74. ↑ "Pharmacological interventions for jet lag.". The Cochrane Database of Systematic Reviews 10. October 2021. doi:10.1002/14651858.CD014611. 
  75. ↑ Kaplan J-P, George P, "Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals", US patent 4382938, published 10 May 1983, issued 17 July 1984, assigned to Synthelabo
  76. ↑ "Zolpidem most frequently used date rape drug in Korea". The Korea Herald. 29 February 2016. http://www.koreaherald.com/view.php?ud=20160229001119. 
  77. ↑ 77.0 77.1 "Darren Sharper case spotlights sleep drug's dark side". USA Today. 26 March 2014. https://www.usatoday.com/story/sports/nfl/2014/03/26/darren-sharper-ambien-zolpidem-insomnia-date-rape-case/6930621/. 
  78. ↑ "In the rape case against Darren Sharper, former LAPD detective says Ambien is used often and can be similar to GHB". New York Daily News. 17 February 2014. http://www.nydailynews.com/sports/football/drug-sharper-common-rapists-article-1.1616611. 
  79. ↑ "Patrick Kennedy admits addiction after car crash". 5 May 2006. https://www.nytimes.com/2006/05/05/world/americas/05iht-web.0505kennedy.html. 
  80. ↑ "Kennedy's Crash Highlights Dangers of Ambien". 5 May 2006. https://abcnews.go.com/Health/story?id=1927026&page=1. 
  81. ↑ "Did a sleeping pill end her brilliant life?". 19 February 2008. https://www.smh.com.au/national/did-a-sleeping-pill-end-her-brilliant-life-20080219-gds1ni.html. 
  82. ↑ "Stilnox blamed for Harbour Bridge death". nineMSN News. 23 February 2007. http://news.ninemsn.com.au/article.aspx?id=381502. 
  83. ↑ "After Racist Tweet, Roseanne Barr's Show Is Canceled by ABC". 29 May 2018. https://www.nytimes.com/2018/05/29/business/media/roseanne-barr-offensive-tweets.html. 
  84. ↑ "Roseanne Barr Says Ambien Played Role In Racist Tweet That Spiked Her Show's Reboot". 30 May 2018. https://www.npr.org/sections/thetwo-way/2018/05/30/615421269/roseanne-barr-says-ambien-played-role-in-racist-tweet-that-spiked-her-shows-rebo. 
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  86. ↑ "International brands for zolpidem". https://www.drugs.com/international/zolpidem.html. 
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  90. ↑ "Vegetative state and minimally conscious state: a review of the therapeutic interventions". Stereotactic and Functional Neurosurgery 88 (4): 199–207. 2010. doi:10.1159/000314354. PMID 20460949. 
  91. ↑ "Zolpidem for the Treatment of Neurologic Disorders: A Systematic Review". JAMA Neurology 74 (9): 1130–1139. September 2017. doi:10.1001/jamaneurol.2017.1133. PMID 28655027. 
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  93. ↑ "Use of Hypnotics and Risk of Cancer: A Meta-Analysis of Observational Studies". Korean Journal of Family Medicine 39 (4): 211–218. July 2018. doi:10.4082/kjfm.17.0025. PMID 29973038. 
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