Zolpidem, sold under the brand name Ambien, among others,[1] is a sedative primarily used for the treatment of trouble sleeping.[3] It is typically only recommended if sleep hygiene is not effective.[2] It decreases the time to sleep onset by about 15 minutes and at larger doses helps people stay asleep longer.[2] It is taken by mouth and is available in a long acting formulation.[3] Common side effects include sleepiness, headache, nausea, and diarrhea.[3] Other side effects include memory problems, hallucinations, and abuse.[2] The recommended dose was decreased in 2013 due to next-morning impairment.[4] Additionally driving the next morning is not recommended with either higher doses or the long acting formulation.[4] While flumazenil can reverse zolpidem's effects usually supportive care is all that is recommended in overdose.[5] Zolpidem is a nonbenzodiazepine of the imidazopyridine class.[3] It works by increasing GABA effects in the central nervous system by binding to GABAA receptors at the same location as benzodiazepines.[3] It generally has a half-life of two to three hours.[3] This, however, is increased in those with liver problems.[3] Zolpidem was approved for medical use in the United States in 1992.[3] It became available as a generic medication in 2007.[6] In the United States it has a monthly cost of about US$8 for immediate release and US$66 for controlled release medication, as of 2017.[2] In that country more than 10 million prescriptions are filled a year, making it one of the most commonly used treaments for sleeping problems.[7][8] Zolpidem is typically only recommended for short-term (usually about two to six weeks) treatment of insomnia.[9] It may be used for both improving sleep onset and staying asleep.[2] Also, a 2012 review found that zolpidem's effectiveness is nearly as much due to psychological effects as to the medication itself, so "increased attention should be directed at psychological intervention of insomnia."[10] A lower-dose version (3.5 mg for men and 1.75 mg for women) is administered as a sub-lingual tablet and used for middle-of-the night awakenings. It can be taken if there is at least 4 hours between the time of administration and when the person must be awake.[11] Zolpidem has some muscle relaxant and anticonvulsant properties, but has not been approved for use in muscle relaxation or seizure prevention. This is because the dosage of drug needed to cause muscle relaxation is 10 times the sedating dose, while early studies indicated that the dosage needed for preventing seizures is 20 times the sedating dose.[12] The most common side effects for 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 dry mouth (3%), allergy (4%), back pain (3%), flu-like symptoms (1%), chest pain (1%), heart palpitations (2%), drowsiness (8%), dizziness (5%), lethargy (3%), drugged feeling (3%), lightheadedness (2%), depression (1%), abnormal dreams (1%), amnesia (1%), sleep disorder (1%), diarrhea (3%), abdominal pain (2%), constipation (2%), sinusitis (4%), sore throat (3%), and rash (2%).[13] Some users have reported unexplained sleepwalking[14] while using zolpidem, as well as sleep driving,[14] night eating syndrome while asleep, and performing other daily tasks while sleeping. Research by Australia's National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy.[15] Rare reports of sexual parasomnia (sleep sex) episodes related to zolpidem intake have also been reported.[16] Sleepwalkers can sometimes perform these tasks as normally as they might if they were awake. 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.[14][17] In February 2008, the Australian Therapeutic Goods Administration attached a boxed warning to zolpidem, stating that "Zolpidem may be associated with potentially dangerous complex sleep-related behaviours that may include sleep walking, sleep driving, and other bizarre behaviours. Zolpidem is not to be taken with alcoholic beverages. Caution is needed with other CNS-depressant drugs. Limit use to four weeks maximum under close medical supervision."[18] A review medical publication found long-term use of zolpidem is associated with drug tolerance, substance 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. Zolpidem 10 mg is effective in treating insomnia when used intermittently no fewer than three and no more than five pills per week for a period of 12 weeks.[19] Nonpharmacological treatment options (e.g. cognitive behavioral therapy for insomnia), however, were found to have sustained improvements in sleep quality.[20] 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.[21] Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other severe effects, especially if used for prolonged periods and at high dosages.[22][23][24] When drug tolerance and physical dependence to zolpidem has developed, treatment usually entails a gradual dose reduction over a period of months to minimise withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some patients, such as 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 detoxify from a zolpidem drug dependence or addiction.[25] 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 recreational drug users may have an increased likelihood of abuse and or becoming psychologically dependent on zolpidem.[26][27][28] It is not typically prescribed in those with a history of alcoholism, recreational drug use, physical dependency, or psychological dependency on sedative-hypnotic drugs. Zolpidem has rarely been associated with drug-seeking behavior,[citation needed] the likelihood of which is amplified in patients with a history of recreational use of drugs or alcohol. An overdose of zolpidem may cause excessive sedation, pin-point pupils, or depressed respiratory function, which may progress to coma, and possibly death. Combined with alcohol, opiates, or other CNS depressants, it 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 on the benzodiazepine receptor to rapidly reverse the effects of the zolpidem.[29] Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, 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.[30][31][32] 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.[33] Studies showed that eight hours after a bedtime dose of 10 mg, 15% of women and 3% of men would have blood levels that produce impaired driving skills; for an extended-release dose of 12.5 mg, the risk increased to 33% and 25%, respectively. As a consequence, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men.[34][35] The elderly are more sensitive to the effects of hypnotics including zolpidem. Zolpidem causes an increased risk of falls and may induce adverse cognitive effects.[36] 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 nondrug treatments for insomnia in adults of all ages, and these interventions are underused. 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. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, were found to 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. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[37] Patients suffering from gastroesophageal reflux disease (GERD) had reflux events measured to be significantly longer when taking zolpidem than on placebo. The same trend was found for reflux events in patients without GERD. This is assumed to be due to suppression of arousal during the reflux event, which would normally result in a swallowing reflex to clear gastric acid from the esophagus. Patients with GERD experience significantly higher esophageal exposure to gastric acid, which increases the likelihood of their developing esophageal cancer.[38] Zolpidem has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of incomplete ossification and increased postimplantation fetal loss 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 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. [39] Zolpidem is a high-affinity positive modulator of GABAA receptors. 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 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 meta-analysis that compared benzodiazepines against nonbenzodiazepines has shown 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] Three 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.[49][50][51] 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.[52] Notable drug–drug interactions with the pharmacokinetics of zolpidem include chlorpromazine, fluconazole, imipramine, itraconazole, ketoconazole, rifampicin, and ritonavir. Interactions with carbamazepine and phenytoin can be expected based on their metabolic pathways, but have not yet been studied. There does not appear to be any interaction between zolpidem and cimetidine or ranitidine.[53][54] However, it was noted in the same study that cimetidine did appear to prolong the hypnotic effects of Zolpidem beyond its typical 3 hour duration, which is indicative of some sort of metabolic interaction.[53] Zolpidem is one of the most common GABA-potentiating sleeping medications prescribed in the Netherlands, with a total of 582,660 prescriptions dispensed in 2008.[55] The United States Air Force uses zolpidem as one of the hypnotics approved as a "no-go pill" (with a 6-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.[56] Zolpidem has potential for either 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".[57][58] 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 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 through inhalation or injection, or when taken for purposes other than as a sleep aid.[57] 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.[59] Other drugs, including the benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers.[60] Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone.[61] U.S. Congressman Patrick J. Kennedy says that he was using Zolpidem (Ambien) and Phenergan when caught driving erratically at 3 am.[62] "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 U.S., Canada, and the UK. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations.[63] Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.[64] 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 U.S. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.[65] Zolpidem has become one of many date rape drugs.[66][67] Unlike Rohypnol ("roofies"), which was banned in 1996, zolpidem is available legally by prescription, and unlike gamma-hydroxybutyrate, which is used to treat a rare form of narcolepsy, zolpidem was prescribed 43.8 million times in the U.S. in 2012.[66] It dissolves readily in liquids such as wine,[66] and can typically be detected in bodily fluids for only 36 hours, though it may be possible to detect it by hair testing much later;[66] this is due to the short elimination half-life of 2.5–3 hours.[68] This application 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.[66][67] Zolpidem received widespread media coverage in Australia after the death of a student who fell 20 m from the Sydney Harbour Bridge while under the influence of zolpidem.[69] While cases of zolpidem improving aphasia in people with stroke have been described, use for this purpose has unclear benefit.[70] Zolpidem has also been studied in persistent vegetative states with unclear effect.[71] 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.[72] Media related to Zolpidem at Wikimedia Commons

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