zolpidem

Zolpidem
Systematic (IUPAC) name
N,N,6-Trimethyl-2-(4-methylphenyl)- imidazo(1,2-a)pyridine-3-acetamide
Identifiers
CAS number	82626-48-0
ATC code	N05CF02
PubChem	5732
DrugBank	APRD00095
ChemSpider	5530
Chemical data
Formula	C19H21N3O
Mol. mass	307.395 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	70% (oral) 92% bound in plasma
Metabolism	Hepatic - CYP3A4
Half life	2 to 2.6 hours
Excretion	56% renal 34% fecal
Therapeutic considerations
Pregnancy cat.	B3(AU) B(US)
Legal status	Schedule IV(US) Class C / POM (UK)
Routes	Oral

Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic that potentiates gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to gamma-aminobutyric acid (GABA_A) receptors at the same location as benzodiazepines.^[1] It works quickly (usually within 15 minutes) and has a short half-life (2–3 hours). Trade names of zolpidem include Adormix, Ambien, Ambien CR, Edluar, Damixan, Hypnogen, Ivedal, Nytamel, Stilnoct, Stilnox, Sucedal, Zoldem, Zolnod and Zolpihexal.^[2][3][4][5]

Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is molecularly distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine. Flumazenil, a benzodiazepine receptor antagonist, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic and memory impairing effects.^[6][7]

As an anticonvulsant and muscle relaxant, the beneficial effects start to emerge at 10 and 20 times the dose required for sedation, respectively.^[8] For that reason, it has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are more inclined to induce one or more negative side-effects, including hallucinations and/or amnesia.

The patent in the United States on zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.^[9] On April 23, 2007 the U.S. FDA approved 13 generic versions of zolpidem tartrate. Zolpidem is available from several generic manufacturers in the UK, as a generic from Sandoz in South Africa, as well as from other manufacturers such as Ratiopharm (Germany).

Contents 1 Indications 1.1 Insomnia 1.2 Brain injury 1.3 Coma 1.4 Miscellaneous off-label 2 Side effects 3 Tolerance, dependence and withdrawal 4 Special precautions 4.1 Driving 4.2 Elderly 5 Mechanism of action 5.1 Drug-drug interactions 6 Overdose 7 Abuse and recreational use 8 See also 9 References 10 External links

Indications

Insomnia

Zolpidem is approved for the short-term (usually about two to six weeks) treatment of insomnia, and it has been studied for nightly use up to six months in a single-blind trial published in 1991,^[10] an open-label study lasting 180 days published in 1992 (with continued efficacy in patients who had kept taking it as of 180 days after the end of the trial),^[11] and in an open-label trial lasting 179 days published in 1993.^[12]

The United States Air Force uses zolpidem as a substitute for temazepam, under the trade name Ambien, as "no-go pills" to help pilots sleep after a mission.

Brain injury

A case study performed at the Toulouse University Hospital using PET showed zolpidem repeatably improves brain function and mobility of a patient immobilized by akinetic mutism caused by hypoxia.^[13]

Recently, zolpidem has been cited in various medical reports mainly in the United Kingdom as waking persistent vegetative state (PVS) patients, and dramatically improving the conditions of people with brain injuries.^{[14][15][16][17][18]} Results from phase IIa trials were expected in June 2007. The trials are being conducted by Regen Therapeutics of the UK, who have a patent pending on this new use for Zolpidem.^[19][20]

Coma

Zolpidem has recently been very strongly related to certain instances of patients in a minimally conscious coma state being brought to a fully conscious state. While it was initially given to these supposed permanent coma patients to put them to sleep, it actually brought them to a fully conscious state in which they were capable of communicating and interacting for the first time in years. CT scans have shown that the use of the drug actually does dramatically increase the activity in the frontal lobe of the brain in some patients in a minimally conscious state. Large-scale studies are currently being done to see whether it has the same universal effect on all or most patients in a minimally conscious state.^[21] It may be that zolpidem's ability to stimulate the brain, particularly in the semi-comatose, may be related to one of its side-effects, which sometimes causes sleepwalking and other activity while asleep, that appears to observers to be fully conscious activity.

Miscellaneous off-label

Zolpidem is also used off-label to treat restless leg syndrome.

As is the case with many prescription sedative/hypnotic drugs, it is sometimes used by stimulant users to "come down" after the use of stimulants such as amphetamines (including methamphetamine), cocaine, and MDMA (ecstasy).^[22]

Side effects

Side-effects at any dose may include:

• Anterograde amnesia
• Hallucinations, through all physical senses, of varying intensity
• Delusions
• Altered thought patterns
• Ataxia or poor motor coordination, difficulty maintaining balance^[23]
• Euphoria and/or dysphoria
• Increased appetite
• Increased libido
• Amnesia
• Impaired judgment and reasoning
• Uninhibited extroversion in social or interpersonal settings
• Increased impulsivity
• When stopped, rebound insomnia may occur
• Headaches, in some people

A clinical trial found that after administration of zolpidem trial subjects tended to feel weak, fatigued and developed an antagonistic mood.^[24]

Some users take zolpidem recreationally for some of these side-effects, notably sedation, hallucinations and euphoria. However, the abuse of zolpidem may be less common than benzodiazepine abuse. Zolpidem can become addictive if taken for extended periods of time, due to drug tolerance and physical dependence or the euphoria it can sometimes produce. As with most addictive drugs, a tolerance in the zolpidem user develops and increases all the more quickly the longer the user has been regularly taking it. Under the influence of the drug, it is common for one to take more zolpidem than is necessary, due to either forgetting that one has already taken a pill (elderly users are particularly at risk here) or knowingly taking more than the prescribed dosage. The release of AmbienCR (zolpidem tartrate extended release) in the United States renewed interest in the drug among recreational drug users.

Some users have reported unexplained sleepwalking while using zolpidem, and a few have reported driving, binge eating, sleep talking, and performing other daily tasks while sleeping. The sleepwalker can sometimes perform these tasks as normally as they might if they were awake. They can sometimes carry on complex conversations and respond appropriately to questions or statements so much so that the observer may believe the sleepwalker to be awake. This is similar to, but unlike, typical sleep talking, which can usually be identified easily and is characterised by incoherent speech that often has no relevance to the situation or that is so disorganised as to be completely unintelligible. These effects make a strong suggestion to schizophasia, one of many symptoms commonly seen in individuals suffering from schizophrenia. A person under the influence of this medication may seem fully aware of their environment even though they are still asleep. This can bring about concerns for the safety of the sleepwalker and others. These side-effects may be related to the mechanism that also causes zolpidem to produce its hypnotic properties.^[25] It is unclear whether the drug is responsible for the behavior, but a class-action lawsuit was filed against Sanofi-Aventis in March 2006 on behalf of those that reported symptoms.^[26]

Residual 'hangover' effects such as sleepiness, impaired psychomotor and cognitive after nighttime administration may persist into the next day which may impair the ability of users to drive safely, increase risks of falls and hip fractures.^[27]

The Sydney Morning Herald in Australia reported in 2007 that a man who fell 30 meters to his death from a high-rise unit balcony may have been sleepwalking under the influence of Stilnox. The coverage prompted over 40 readers to contact the newspaper with their own accounts of Stilnox-related automatism, and as of March 2007^[update], the drug was under review by the Adverse Drug Reactions Advisory Committee.^[28]

In February 2008, the australian Therapeutic Goods Administration attached a Black Box Warning to zolpidem, stating that "Zolpidem may be associated with potentially dangerous complex sleep-related behaviours which may include sleep walking, sleep driving and other bizarre behaviours. Zolpidem is not to be taken with alcohol. Caution is needed with other CNS depressant drugs. Limit use to four weeks maximum under close medical supervision."^[29]

Tolerance, dependence and withdrawal

A review medical publication found that long term use of zolpidem is associated with drug tolerance, drug dependence, rebound insomnia and CNS related adverse effects. It was recommended that zolpidem be used for short periods of time using the lowest effective dose. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.^[30] Animal studies of the tolerance inducing properties have shown that in rodents zolpidem has less tolerance producing potential than benzodiazepines but in primates the tolerance producing potential of zolpidem was the same as that of benzodiazepines.^[31] Tolerance can develop in some people to the effects of zolpidem in just a few weeks. Abrupt withdrawal of zolpidem may cause delirium, seizures or other severe effects, especially if used for prolonged periods and at high dosages.^[32][33][34] When drug tolerance and physical dependence to zolpidem has developed, treatment usually entails a gradual dose reduction over a period of months in order to minimise withdrawal symptoms which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method which may be necessary for some patients is a switch to a benzodiazepine equivalent dose of a longer acting benzodiazepine drug such as diazepam or chlordiazepoxide followed by a gradual reduction in dosage of the long acting benzodiazepine. Sometimes for difficult to treat patients an inpatient flumazenil rapid detoxification program can be used to detox from a zolpidem drug dependence or addiction.^[35] However, it should be noted that this treatment approach closely parallels that of the highly controversial rapid opiate detoxification therapy, which critics claim lacks long-term efficacy and can actually be detrimental to a patient's long-term recovery. Additionally, there have been many questions raised about the ethics as well as safety of rapid detox following a number of deaths resulting from the procedure.^[36][37]

Alcohol has cross tolerance with GABAa receptor positive modulators such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason alcoholics or recovering alcoholics may be at increased risk of physical dependency on zolpidem. Also, alcoholics and drug abusers may be at increased risk of abusing and or becoming psychologically dependent on zolpidem. Zolpidem should be avoided in those with a history of Alcoholism, drug misuse, or in those with history of physical dependency or psychological dependency on sedative-hypnotic drugs.

Special precautions

Driving

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.^[38]

Elderly

The elderly are more sensitive to the effects of hypnotics including zolpidem. Zolpidem causes an increased risk of falls and may induce cognitive adverse effects.^[39]

An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine (including zolpidem) sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.^[40]

Mechanism of action

Zolpidem due to its selective binding has very weak anxiolytic, myorelaxant and anticonvulsant properties but very strong hypnotic properties.^[41] Zolpidem binds with high affinity to the α₁ containing GABA_A receptors, about 10-fold lower affinity for those containing the α₂ - and α₃ - GABA_A receptor subunits, and with no appreciable affinity for α₅ subunit containing receptors.^[42] ω₁ type GABA_A receptors are the α₁ containing GABA_A receptors and ω₂ GABA_A receptors are the α₂, α₃, α₄, α₅ and α₆ containing GABA_A receptors. ω₁ GABA_A receptors are primarily found in the brain whereas ω₂ receptors are primarily found in the spine. Thus zolpidem has a preferential binding for the GABA_A-benzodiazepine receptor complex in the brain but a low affinity for the GABA_A-benzodiazepine receptor complex in the spine.^[43]

Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α₄ and α₆ subunit-containing receptors.^[44] Zolpidem positively modulates GABA_A receptors, probably by increasing the GABA_A receptor complexes apparent affinity for GABA, without affecting desensitization or peak current.^[45] Zolpidem increases slow wave sleep and caused no effect on stage 2 sleep in laboratory tests.^[46]

A meta-analysis of the randomised controlled clinical trials that compared benzodiazepines against Z-drugs such as zolpidem has shown that there are 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.^[47]

Drug-drug interactions

Notable drug-drug interactions with the pharmacokinetics of zolpidem include the following drugs chlorpromazine, cimetidine, fluconazole, imipramine, itraconazole, ketoconazole, rifampicin, ritonavir. Interactions with carbamazepine and phenytoin can be expected based on their metabolic pathways but have not yet been studied.^[48] Zolpidem effects can increase and intensify if mixed with other substances like alcohol and cannabis.^{[citation needed]}

Overdose

Overdose of zolpidem may present with excessive sedation, pin-point pupils, depressed respiratory function, which may progress to coma and possibly death. Zolpidem combined with alcohol, opiates or other CNS depressants may be even more likely to lead to fatal overdoses. Zolpidem overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zolpidem from its binding site the benzodiazepine receptor and therefore rapidly reverses the effects of zolpidem.^[49]

Abuse and recreational use

Zolpidem has a potential for either medical misuse when the drug is continued long term without or against medical advice, or recreational use when the drug is taken to achieve a high.^[50] The transition from medical use of zolpidem to high dose addiction or drug dependence can occur when used without a doctor's recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed by inhalation or injection, or when taken for purposes other than as a sleep aid. Abuse is more prevalent in those that have 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 high dose abusers are more likely to have a severe physical dependence on the drug which may cause severe withdrawal symptoms including seizures if abrupt withdrawal from zolpidem occurs.^[51]

One case history report involved a woman detoxing off a high dose of zolpidem experiencing a generalized seizure, with clinical withdrawal and dependence effects reported to be similar to the benzodiazepine withdrawal syndrome.^[52]

In the U.S., recreational use of zolpidem is becoming more common. Recreational users claim that "fighting" the effects of the drug by forcing themselves to stay awake will sometimes cause vivid visuals and a body high.^{[citation needed]} Some users report decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations.^[53]

Zolpidem and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other drugs including the 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 benzodiazepines, zolpidem and zopiclone.^[54] U.S. Congressman Patrick J. Kennedy says that he was using Zolpidem (Ambien) and Phenergan when caught driving erratically at 3AM. ^[55] "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 Ambien's patent expired April 21, 2007, 13 new generic versions were approved, which do not have the "protective cover" present on the Sanofi name-brand Ambien they once previously had to prevent users from crushing, snorting, or injecting the drugs.

In the comedy film Role Models, Wheeler (one of the two main characters) convinces a woman to recreationally take Ambien with him.

See also

• Alpidem
• Imidazopyridine
• Nonbenzodiazepine
• Rebound effect
• Z-drugs

References

External links

Wikimedia Commons has media related to: Zolpidem

• "Prescription Sleep Aid AMBIEN CR". Sanofi-Aventis. http://www.ambiencr.com. Retrieved on 2009-05-21. "Ambien CR official website" 
• "Ambien Cr (zolpidem tartrate) Tablet, Coated". DailyMed. U.S. National Library of Medicine, National Institutes of Health, Health & Human Services. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=5420. Retrieved on 2009-05-21. 
• "Zolpidem (Ambien)". The Vaults of Erowid. 2007-07-19. http://www.erowid.org/pharms/zolpidem/zolpidem.shtml. Retrieved on 2009-05-21. 
• Angelettie L, Kelley-Soderholm E. "Ambien Abuse". Mental Health Site. BellaOnline, Minerva WebWorks LLC. http://www.bellaonline.com/articles/art22470.asp. Retrieved on 2009-05-21. 

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