Zolpidem

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Zolpidem
Clinical data
Trade namesAmbien and Ambien CR, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa693025
License data
Pregnancy
category
Dependence
liability		Physical: High
sedative-hypnotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability70% (by mouth)
Protein binding92%[9]
MetabolismLiver through CYP3A4 (~60%), CYP2C9 (~20%), and CYP1A2 (~14%)[10]
Metabolites(ZCA) zolpidem 6-carboxylic acid; (ZPCA) zolpidem phenyl-4-carboxylic acid
Onset of action≤ 30 Minutes
Elimination half-life2.0 - 3 hours[4][9]
Duration of action3 hours
ExcretionKidney (56%)
fecal (34%)
Identifiers
  • N,N-Dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetamide hemitartrate
JSmol)
Melting point193–197 °C (379–387 °F) [9]
  • CN(C)C(=O)Cc1c(nc2ccc(C)cn12)c3ccc(C)cc3
  • InChI=1S/C19H21N3O/c1-13-5-8-15(9-6-13)19-16(11-18(23)21(3)4)22-12-14(2)7-10-17(22)20-19/h5-10,12H,11H2,1-4H3 checkY
  • Key:ZAFYATHCZYHLPB-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of

oral spray.[4]

Common side effects include daytime

supportive care is all that is recommended in overdose.[15]

Zolpidem is a

liver problems.[4]

Zolpidem was approved for medical use in the United States in 1992.

Controlled Substances Act of 1970 (CSA).[7][8] More than ten million prescriptions are filled each year in the United States, making it one of the most commonly used treatments for sleeping problems.[18][19] In 2021, it was the 63rd most commonly prescribed medication in the United States, with more than 10 million prescriptions.[20][21]

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.[4][11] It may be used for both improving sleep onset, sleep onset latency, and staying asleep.[7]

Guidelines from

NICE, the European Sleep Research Society, and the American College of Physicians recommend medication for insomnia (including possibly zolpidem) only as a second line treatment after non-pharmacological treatment options have been tried (e.g. cognitive behavioral therapy for insomnia).[12][13][14] 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.[22]

Contraindications

Zolpidem should not be taken by people with

psychotic illnesses. It should not be taken by people who are or have been addicted to other substances.[11]

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.[11] In 2013, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men due to impaired function the day after taking the drug.[23][24]

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

neurocognitive disorder.[25][26]

Zolpidem has not been assigned to a

teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is recommended for use during pregnancy only when benefits outweigh risks.[27]

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%).[8]

Zolpidem increases risk of depression, falls and bone fracture, poor driving, suppressed respiration, and has been associated with an increased risk of death.[28] Upper and lower respiratory infections are also common (experienced by 1–10% of people).[11]

Residual 'hangover' effects, such as sleepiness 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.[15][29] Around 3% of people taking zolpidem are likely to break a bone as a result of a fall due to impaired coordination caused by the drug.[30]

Some users have reported unexplained

National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy.[31] In February 2008, the Australian Therapeutic Goods Administration attached a boxed warning concerning this adverse effect.[32]

Tolerance, dependence and withdrawal

Ambien tablets

As zolpidem is associated with

drug dependence or addiction to zolpidem will wane.[36]

drug-seeking behavior, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.[37]

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.[38]

Overdose

Overdose can lead to coma or death.[11] When overdose occurs, there are often other drugs in the person's system.[11][15]

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.[11]

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.[39][40][41]

Pharmacology

Mechanism of action

Zolpidem is a

orthosteric agonist GABA towards its cognate receptor without affecting desensitization or peak currents.[47]

Like

rebound insomnia, and daytime alertness.[49]

Pharmacokinetics

Microsome studies indicate zolpidem is metabolized by CYP3A4 (61%) CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (<3%), and CYP2C19 (<3%).[10] Less than 1% is excreted in urine unchanged.[9] 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.[4][9] 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),[50] others do not.[9] 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.[51]

Interactions

People should not consume alcohol while taking zolpidem, and should not be prescribed opioid drugs nor take such illicit drugs recreationally.[52] Opioids can also increase the risk of becoming psychologically dependent on zolpidem.[medical citation needed] Use of opioids with zolpidem increases the risk of respiratory depression and death.[11] The US 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).[53]

Next day sedation can be worsened if people take zolpidem while they are also taking antipsychotics, other sedatives, anxiolytics, antidepressant agents, antiepileptic drugs, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.[11]

St. John's Wort may decrease the activity of zolpidem.[11] 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.[55] Other studies show no effect of caffeine on zolpidem metabolism.[9]

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.[56][57][58] Though such safety procedures are common in industry, they make clandestine manufacture difficult.

A number of major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.[59]

Alpidem is also an imidazopyridine and is an analogue of zolpidem.[60][61][62] Both agents are GABAA receptor positive allosteric modulators.[60][61][62] However, whereas zolpidem is used as a hypnotic and sedative, alpidem was used as an anxiolytic.[60][61][62]

History

Zolpidem was used in Europe starting in 1988, and was brought to market there by

generic medication in 2007.[17]

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."[25][26] The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate."[26]

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 in relation to concern about prescribing addictive drugs in the midst of the

opioid crisis.[64]

Military use

The

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 prior to authorization issued to use the medication in an operational situation.[65]

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".

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.[68]

Other drugs, including benzodiazepines and

benzodiazepines, zolpidem and zopiclone.[39] US Congressman Patrick J. Kennedy says that he was using zolpidem (Ambien) and promethazine (Phenergan) when caught driving erratically at 3 a.m.[69]
"I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said.

Nonmedical use of zolpidem is increasingly common in the US, Canada, and the UK. Some users have reported decreased anxiety, mild

euphoria, perceptual changes, visual distortions, and hallucinations.[70] Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.[71]

Regulation

For the stated reason of its potential for recreational use and dependence, zolpidem (along with the other benzodiazepine-like

Sanofi-Aventis.[72]

Use in crime

The

elimination half-life of 2.5–3 hours.[15] 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.[74][75]

Sleepwalking

Zolpidem received widespread media coverage in Australia after the death of a student who fell 20 metres (66 ft) from the Sydney Harbour Bridge while under the influence of zolpidem.[76]

Brand names

As of September 2018, zolpidem is marketed under many brands.[1]

Research

While cases of zolpidem improving

persistent vegetative states with unclear effect.[78] 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.[79] More recent research has found zolpidem treatment to be effective in the short term, but only in a small proportion of cases (estimated at around 5%) and only when the brain injury is of a specific type. Tolerance to the beneficial effects also develops rapidly, and so for these reasons while zolpidem may sometimes be used as a "last resort" treatment, it has numerous disadvantages and research continues into novel treatments that might provide the same kind of benefits in a larger proportion of patients, and with a more sustained benefit.[80]

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.

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.[82] Similarly, a meta-analysis of benzodiazepine drugs also shows their use is associated with increased risk of cancer.[83]

References

  1. ^ a b "International brands for zolpidem". Drugs.com. Retrieved 15 March 2018.
  2. ^ a b "Zolpidem Use During Pregnancy". Drugs.com. 30 June 2020. Retrieved 14 August 2020.
  3. ISBN 9783319414003
    .
  4. ^ a b c d e f g h i j k l m "Zolpidem (Monograph)". The American Society of Health-System Pharmacists. 27 April 2023. Retrieved 10 March 2024.
  5. ^ "Scheduling of zolpidem (Stilnox)". Therapeutic Goods Administration (TGA). 21 February 2008. Retrieved 15 August 2020.
  6. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 3 August 2023.
  7. ^
    PMID 28671376
    .
  8. ^ a b c "Ambien- zolpidem tartrate tablet, film coated". DailyMed. 29 August 2019. Retrieved 15 August 2020.
  9. ^
    S2CID 23391285
    .
  10. ^
    PMID 10383565
    .
  11. ^ a b c d e f g h i j k l m n o "Stilnoct 10mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". UK Electronic Medicines Compendium. 21 May 2018. Archived from the original on 20 August 2018. Retrieved 19 August 2018.
  12. ^ a b c "Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia". NICE. 28 April 2004.
  13. ^
    PMID 28875581. Open access icon
  14. ^
    PMID 27136449. Open access icon
  15. ^
    PMID 23404347
    .
  16. ^ a b "Drug Approval Package: Ambien (Zolpidem Tartrate) NDA 19908". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 15 August 2020.
  17. ^ a b "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.
  18. ^ "Zolpidem". LiverTox. Archived from the original on 16 March 2018. Retrieved 15 March 2018.
  19. ^ "Some Sleep Drugs Can Impair Driving". U.S. Food and Drug Administration (FDA). 13 June 2013. Retrieved 15 March 2018.
  20. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  21. ^ "Zolpidem - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  22. PMID 23248080
    .
  23. PMID 23348358
    . Retrieved 14 April 2013.
  24. ^ "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. Archived from the original on 22 July 2017. Retrieved 14 April 2013.
  25. ^
    S2CID 6621392. Open access icon
  26. ^
    S2CID 38797655.{{cite journal}}: CS1 maint: numeric names: authors list (link
    )
  27. ^ Drugsdb.eu. "Zolpidem Pregnancy Warnings". Archived from the original on 18 August 2018. Retrieved 1 February 2014.
  28. S2CID 7946506
    .
  29. S2CID 25592318
    .
  30. S2CID 4701575
    .
  31. ^ "Zolpidem and sleep-related behaviours" (PDF). NPS Position Statement. National Prescribing Service Limited. July 2008. Archived from the original (PDF) on 10 April 2012.
  32. ^ "Zolpidem ("Stilnox") – updated information – February 2008". Therapeutic Goods Administration (TGA). 21 February 2008. Archived from the original on 3 June 2009. Retrieved 22 June 2009.
  33. PMID 18853708
    .
  34. ^
    PMID 23456542
    .
  35. ^
    PMID 25613443
    .
  36. PMID 16096519
    .
  37. S2CID 30959471
    .
  38. S2CID 46510829
    .
  39. ^
    S2CID 25511804
    .
  40. PMID 10517569
    .
  41. ^ Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 1836–1838.
  42. PMID 27346730
    .
  43. S2CID 86674799
    .
  44. S2CID 86156878
    .
  45. S2CID 25654504. Archived from the original
    on 12 January 2002.
  46. PMID 8794909. Archived from the original
    on 8 January 2009. Retrieved 7 October 2007.
  47. PMID 9880578
    .
  48. PMID 15037809
    . WARNING: The reference indicates that zaleplon-Sonata, not zolpidem, increases Slow-wave sleep
  49. S2CID 10888200
    .
  50. PMID 12919178
    .
  51. S2CID 92998845
    .
  52. ^ "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. Retrieved 18 August 2018.
  53. ^ "FDA urges caution about withholding opioid addiction medications". U.S. Food and Drug Administration. 20 September 2017. Retrieved 15 August 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  54. S2CID 209164976
    .
  55. S2CID 46250744
    .
  56. ISBN 9780471752158
    .
  57. ^ IN 246080, Rawalnath SR, Crasta Santosh R, Saxena A, "Process for the preparation of zolpidem", published 21 December 2005, issued 14 February 2011 
  58. hdl:2027/spo.5550190.0010.230
    .
  59. hdl:2027/spo.5550190.0010.714
    .
  60. ^
    PMID 1981304
    .
  61. ^
    S2CID 11612995
    .
  62. ^
    PMID 22981367
    .
  63. ^ a b Morris S (22 December 1992). "Searle Wins Ok To Sell Sleep Aid". Chicago Tribune.
  64. ^ Crow D (1 June 2018). "Ambien defence: the real side effects of sleeping pills". Financial Times. Archived from the original on 10 December 2022.
  65. ^ "Air Force Special Operations Command Instruction 48-101" (PDF). e-publishing.af.mil. 30 November 2012. Archived from the original (PDF) on 11 June 2014. Retrieved 8 March 2014.
  66. ^
    PMID 26648651
    .
  67. PMID 16336040
    .
  68. PMID 12022074
    .
  69. ^ "Kennedy To Enter Drug Rehab After Car Crash; Congressman Wrecked Car Near Capitol". Archived from the original on 28 March 2020. Retrieved 23 June 2009.
  70. ^ Mulvihill K. "Ambien Abuse on Rise Among Teens". KSL. Archived from the original on 20 February 2009. Retrieved 22 June 2009.
  71. ^ "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. Retrieved 3 August 2016.
  72. ^ US 4382938, Kaplan J-P, George P, "Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals", published 10 May 1983, issued 17 July 1984, assigned to Synthelabo 
  73. ^ "Zolpidem most frequently used date rape drug in Korea". The Korea Herald. 29 February 2016.
  74. ^ a b Schrotenboer B (26 March 2014). "Darren Sharper case spotlights sleep drug's dark side". USA Today.
  75. ^ Red C (17 February 2014). "In the rape case against Darren Sharper, former LAPD detective says Ambien is used often and can be similar to GHB". Daily News. New York.
  76. ^ "Stilnox blamed for Harbour Bridge death". nineMSN News. 23 February 2007. Archived from the original on 15 June 2007.
  77. S2CID 38304960
    .
  78. PMID 20460949
    .
  79. S2CID 10756280
    .
  80. PMID 32979847
    .
  81. PMID 27303633
    .
  82. PMID 29973038
    .
  83. PMID 27667780
    .

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