|Systematic (IUPAC) name|
|Routes||Oral (tablet), Sublingual, Oromucosal (spray), Rectal|
|Bioavailability||70% (oral) 92% bound in plasma|
|Metabolism||Hepatic – CYP3A4|
|Half-life||2 to 3 hours|
|Mol. mass||307.395 g/mol|
|(what is this?)|
Zolpidem (brand names Ambien, Ambien CR, Intermezzo, Stilnox, Stilnoct, Sublinox, Hypnogen, Zonadin, Sanval and Zolsana) is a prescription medication used for the treatment of insomnia and some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates GABA, an inhibitory neurotransmitter, by binding to GABAA receptors at the same location as benzodiazepines. It works quickly, usually within 15 minutes, and has a short half-life of two to three hours.
Zolpidem has not adequately demonstrated effectiveness in maintaining sleep, unless delivered in a controlled-release (CR) form. However, it is effective in initiating sleep. 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.
As a muscle relaxant and anticonvulsant, the drug's effects are not evident until dosages 10 and 20 times those required for sedation, respectively, are reached. For that reason, zolpidem has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are also more inclined to induce one or more of the drug's adverse side effects, including hallucinations and amnesia. Contrary to early studies, more recent research has indicated that zolpidem is in fact a potent anticonvulsant. The anticonvulsant effects are not realized until the normal dosage range has been surpassed (meaning sedation would still be a major side effect) but the threshold for this effect is now believed to be considerably lower than original estimates.
The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. On April 23, 2007, the U.S. Food and Drug Administration (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 and TEVA in Israel, as well as from other manufacturers such as Ratiopharm and Takeda GmbH (both Germany).
In 2012, a study published in the BMJ Open journal revealed that sleeping pills, including zolpidem, are associated with a higher risk of death and cancer diagnosis. Nevertheless, the study showed only a link, and did not prove the deaths were caused by the pills or by other symptoms related to insomnia.
On January 10, 2013, the Food and Drug Administration announced it is requiring the manufacturer of Ambien and Zolpimist to cut the recommended dosage for women in half, after laboratory studies showed that the medicines can leave patients drowsy in the morning and at risk for car accidents. The FDA recommended that manufacturers extend the new dosage cuts to men as well, who process the drug at a faster rate; however, the reasons men and women metabolize the drugs at different rates are still unknown. In May 2013, the FDA approved label changes specifying new dosage recommendations for zolpidem products because of concerns regarding next-morning impairment.
- 1 Medical uses
- 2 Adverse effects
- 3 Special precautions
- 4 Mechanism of action
- 5 Chemistry
- 6 Misuse
- 7 Usage
- 8 Research
- 9 References
- 10 Further reading
- 11 External links
Clinicians prescribe zolpidem for short-term (usually about two to six weeks) treatment of insomnia. Zolpidem has not proven effective in maintaining sleep, but addresses sleep-initiation problems. The effect over placebo is of marginal clinical benefit.
Side effects may include:
- Headaches (mostly withdrawal symptom)
- Nausea (mostly withdrawal symptom)
- Vomiting (mostly withdrawal symptom)
- Anterograde amnesia
- Hallucinations, through all physical senses, of varying intensity
- Delusions
- Altered thought patterns
- Ataxia or poor motor coordination, difficulty maintaining balance
- Euphoria or dysphoria
- Increased appetite
- Increased or decreased libido
- Impaired judgment and reasoning
- Uninhibited extroversion in social or interpersonal settings
- Increased impulsivity (mostly withdrawal symptom)
- When stopped, rebound insomnia may occur
Some users have reported unexplained sleepwalking[original research?] while using zolpidem, as well as sleep driving, binge eating 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. Rare reports of sexual parasomnia episodes related to zolpidem intake have also been reported. Sleepwalkers 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 observers may believe them to be awake. This is in contrast to "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.
Those under the influence of this medication may seem fully aware of their environments, though they are still asleep. This can bring about concerns for the safety of the sleepwalkers and others. These side effects may be related to the mechanism that also causes zolpidem to produce its hypnotic properties. 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 who reported symptoms. Conversely, it is possible some users believed they were asleep during these events because they do not remember the events, due to the short-term memory loss and anterograde amnesia side-effects.
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.
The Sydney Morning Herald in Australia in 2007 reported 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.[needs update]
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 behaviors 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." This report received widespread media coverage after the death of Australian student Mairead Costigan, who fell 20 m from the Sydney Harbour Bridge while under the influence of Stilnox.
Tolerance, dependence, and withdrawal
A review medical publication found 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. 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. The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.
Nonpharmacological treatment options (e.g. cognitive behavioral therapy for insomnia), however, were found to have sustained improvements in sleep quality. 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. 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.
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.
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. It should be avoided in those with a history of alcoholism, drug misuse, physical dependency, or psychological dependency on sedative-hypnotic drugs. Zolpidem has rarely been associated with drug-seeking behavior, the risk of which is amplified in patients with a history of drug or alcohol abuse.
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.
Detection in body fluids
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.
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. 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.
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.
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.
Gastroesophageal reflux disease
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.
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. 
Mechanism of action
Zaleplon and zolpidem both are agonists at the GABA A ɣ 1 subunit. Due to its selective binding, zolpidem has very weak anxiolytic, myorelaxant, and anticonvulsant properties but very strong hypnotic properties. Zolpidem binds with high affinity and acts as a full agonist at the α1-containing GABAA receptors, about 10-fold lower affinity for those containing the α2- and α3- GABAA receptor subunits, and with no appreciable affinity for α5 subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and ω2 GABAA receptors are the α2-, α3-, α4-, α5-, and α6-containing GABAA receptors. ω1 GABAA receptors are found primarily in the brain, whereas ω2 receptors are found primarily in the spine. Thus, zolpidem has a preferential binding for the GABAA-benzodiazepine receptor complex in the brain but a low affinity for the GABAA-benzodiazepine receptor complex in the spine.
Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α4 and α6 subunit-containing receptors. Zolpidem positively modulates GABAA receptors, it is presumed by increasing the GABAA receptor complex's apparent affinity for GABA without affecting desensitization or peak current. Like zaleplon (Sonata), zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep.
A meta-analysis of the randomised, controlled, clinical trials that compared benzodiazepines against nonbenzodiazepines such as zolpidem 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.
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. 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.
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. 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.
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". 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 through inhalation or injection, or when taken for purposes other than as a sleep aid. Misuse 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.
One case history reported a woman detoxifying from a high dose of zolpidem experiencing a generalized seizure, with clinical withdrawal and dependence effects reported to be similar to the benzodiazepine withdrawal syndrome.
Nonmedical use of zolpidem is increasingly common in the U.S., Canada, and the UK. Recreational users report that resisting the drug's hypnotic effects can in some cases elicit vivid visuals and a body high. Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations.
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. U.S. Congressman Patrick J. Kennedy says that he was using Zolpidem (Ambien) and Phenergan when caught driving erratically at 3AM. "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said.
Zolpidem, along with the other benzodiazepine-like Z-drugs is a Schedule IV controlled substance in the U.S., according to the Controlled Substances Act, given its potential for abuse and dependence.
The United States Air Force uses zolpidem as one of the hypnotics approved as "no-go pills" to help aviators and special duty personnel sleep in support of mission readiness (the other hypnotics used are temazepam and zaleplon during war time). "Ground tests" are required prior to authorization issued to use the medication in an operational situation.
Zolpidem may provide short-lasting but effective improvement in symptoms of aphasia present in some survivors of stroke. The mechanism for improvement in these cases remains unexplained and is the focus of current research by several groups, to explain how a drug that acts as a hypnotic-sedative in people with normal brain function, can increase speech ability in people recovering from severe brain injury. Use of zolpidem for this application remains experimental at this time, and is not officially approved by any pharmaceutical manufacturers of zolpidem or medical regulatory agencies worldwide.
- "Home Office circular 039 / 2003". Archived from the original on 2010-11-24.
- Du B, Shan A, Zhang Y, Zhong X, Chen D, Cai K (2014). "Zolpidem Arouses Patients in Vegetative State After Brain Injury". The American Journal of the Medical Sciences 347 (3): 178–82. doi:10.1097/MAJ.0b013e318287c79c. PMID 23462249.
- "Prescribing Information" (PDF). sanofi-aventis. 2007. Retrieved 2011-08-29.
- Lemmer B (2007). "The sleep-wake cycle and sleeping pills". Physiol. Behav. 90 (2–3): 285–93. doi:10.1016/j.physbeh.2006.09.006. PMID 17049955.
- Rosenberg RP (2006). "Sleep maintenance insomnia: strengths and weaknesses of current pharmacologic therapies". Ann Clin Psychiatry 18 (1): 49–56. doi:10.1080/10401230500464711. PMID 16517453.
- Patat A, Naef MM, van Gessel E, Forster A, Dubruc C, Rosenzweig P (October 1994). "Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic". Clin Pharmacol Ther 56 (4): 430–6. doi:10.1038/clpt.1994.157. PMID 7955804.
- Wesensten NJ, Balkin TJ, Davis HQ, Belenky GL (September 1995). "Reversal of triazolam- and zolpidem-induced memory impairment by flumazenil". Psychopharmacology (Berl) 121 (2): 242–9. doi:10.1007/BF02245635. PMID 8545530.
- Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, Bartholini G (1986). "Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects". J. Pharmacol. Exp. Ther. 237 (2): 649–58. PMID 2871178.
- Vlainić J, Pericić D (15 January 2010). "Zolpidem is a potent anticonvulsant in adult and aged mice". Brain Research 1310: 181–8. doi:10.1016/j.brainres.2009.11.018. PMID 19914223.
- US 4382938, Kaplan J-P, George P, "Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals", published 1983-05-10, issued 1984-07-17, assigned to Synthelabo
- "FDA Approves First Generic Versions of Ambien (Zolpidem Tartrate) for the Treatment of Insomnia". Retrieved 2010-01-24.
- Boseley, Sarah (2012-02-27). "Sleeping pills increase risk of death, study suggests | Science". London: The Guardian. Retrieved 2014-01-31.[unreliable medical source?]
- Kripke, D. F.; Langer, R. D.; Kline, L. E. (27 February 2012). "Hypnotics' association with mortality or cancer: a matched cohort study". BMJ Open 2 (1): e000850–e000850. doi:10.1136/bmjopen-2012-000850.
- "FDA tells drugmakers to lower doses for Ambien, other sleeping pills". CBS News. Retrieved 10 January 2013.
- "FDA Changes Dosing on Ambien, Ambien CR, Zolpidem and Edluar". Lawyersandsettlements.com. 2013-05-15. Retrieved 2014-01-31.
- "Ambien". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN (Dec 17, 2012). "Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration". BMJ (Clinical research ed.) 345: e8343. doi:10.1136/bmj.e8343. PMC 3544552. PMID 23248080.
- Yasui M, Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K (2005). "[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]" [Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]. Nihon Shinkei Seishin Yakurigaku Zasshi = Japanese Journal of Psychopharmacology (in Japanese) 25 (3): 143–51. PMID 16045197.
- Weil, Ellery (2011-01-17). "An Account of Sharing an Ambien with a Girl I Met One Week Prior at a Party". Thought Catalog. Retrieved 2014-01-31.
- NPS Position Statement: Zolpidem and sleep-related behaviours (2008). Available at http://nps.org.au/news_and_media/media_releases/repository/zolpidem_stilnox_info_for_prescribers
- Schenck CH, Arnulf I, Mahowald MW (2007). "Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences". Sleep 30 (6): 683–702. PMC 1978350. PMID 17580590.
- Dolder CR, Nelson MH (2008). "Hypnosedative-induced complex behaviours : incidence, mechanisms and management". CNS Drugs 22 (12): 1021–36. doi:10.2165/0023210-200822120-00005. PMID 18998740.
- "Perchance To ... Eat?".[title incomplete]
- Vermeeren A (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID 15089115.
- Gilmore, Heath (2007-03-11). "Sleeping pill safety under federal review". the Sydney Morning Herald. Retrieved 2007-03-11.
- "Zolpidem ("Stilnox") – updated information – February 2008". www.tga.gov.au. Archived from the original on 2007-08-12. Retrieved 2009-06-22.
- <--Staff editor(s);no by-line--> (August 11, 2008). "Stilnox warnings upgraded". The Sydney Morning Herald. Retrieved 2014-02-01.
- "Stilnox blamed for Harbour Bridge death". nineMSN News. February 23, 2007. Archived from the original on 2007-06-15.
- Perlis ML, McCall WV, Krystal AD, Walsh JK (2004). "Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia". The Journal of clinical psychiatry 65 (8): 1128–1137. doi:10.4088/jcp.v65n0816. PMID 15323600.
- Scharf MB, Roth T, Vogel GW, Walsh JK (1994). "A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia". The Journal of clinical psychiatry 55 (5): 192–199. PMID 8071269.
- Kirkwood CK (1999). "Management of insomnia". J Am Pharm Assoc (Wash) 39 (5): 688–96; quiz 713–4. PMID 10533351.[title missing]
- Petroski RE, Pomeroy JE, Das R, Bowman H, Yang W, Chen AP, Foster AC (April 2006). "Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors" (PDF). J. Pharmacol. Exp. Ther. 317 (1): 369–77. doi:10.1124/jpet.105.096701. PMID 16399882.
- Harter C, Piffl-Boniolo E, Rave-Schwank M (November 1999). "[Development of drug withdrawal delirium after dependence on zolpidem and zoplicone]" [Development of drug withdrawal delirium after dependence on zolpidem and zoplicone]. Psychiatr Prax (in German) 26 (6): 309. PMID 10627964.
- "Hypnotic dependence: zolpidem and zopiclone too". Prescrire Int 10 (51): 15. February 2001. PMID 11503851.
- Sethi PK, Khandelwal DC (February 2005). "Zolpidem at supratherapeutic doses can cause drug abuse, dependence and withdrawal seizure" (PDF). J Assoc Physicians India 53: 139–40. PMID 15847035.
- Quaglio G, Lugoboni F, Fornasiero A, Lechi A, Gerra G, Mezzelani P (September 2005). "Dependence on zolpidem: two case reports of detoxification with flumazenil infusion". Int Clin Psychopharmacol 20 (5): 285–7. doi:10.1097/01.yic.0000166404.41850.b4. PMID 16096519.
- Lheureux P, Debailleul G, De Witte O, Askenasi R (1990). "Zolpidem intoxication mimicking narcotic overdose: response to flumazenil". Human & Experimental Toxicology 9 (2): 105–7. doi:10.1177/096032719000900209. PMID 2111156.
- Jones AW, Holmgren A, Kugelberg FC (2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Ther. Drug Monit 29 (2): 248–260. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081.
- Gock SB, Wong SH, Nuwayhid N, Venuti SE, Kelley PD, Teggatz JR, Jentzen JM (1999). "Acute zolpidem overdose—report of two cases". J. Anal. Toxicol 23 (6): 559–562. doi:10.1093/jat/23.6.559. PMID 10517569.
- R. Baselt (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 1836–1838.
- Gustavsen I, Bramness JG, Skurtveit S, Engeland A, Neutel I, Mørland J (December 2008). "Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam". Sleep Med. 9 (8): 818–22. doi:10.1016/j.sleep.2007.11.011. PMID 18226959.
- "FDA Requires Lower Dosing of Zolpidem". The Medical Letter on Drugs and Therapeutics (The Medical Letter) 55 (1408): 5. January 21, 2013. Retrieved April 14, 2013.
- 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). FDA. January 10, 2013. Retrieved April 14, 2013
- Antai-Otong D (August 2006). "The art of prescribing. Risks and benefits of non-benzodiazepine receptor agonists in the treatment of acute primary insomnia in older adults". Perspect Psychiatr Care 42 (3): 196–200. doi:10.1111/j.1744-6163.2006.00070.x. PMID 16916422.
- Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.
- Gagliardi GS, Shah AP, Goldstein M, Denua-Rivera S, Doghramji K, Cohen S, Dimarino AJ (September 2009). "Effect of zolpidem on the sleep arousal response to nocturnal esophageal acid exposure". Clin. Gastroenterol. Hepatol. 7 (9): 948–52. doi:10.1016/j.cgh.2009.04.026. PMID 19426833.
- Drugsdb.eu. "Zolpidem Pregnancy Warnings". Retrieved 2014-02-01.
- Salvà P, Costa J (September 1995). "Clinical pharmacokinetics and pharmacodynamics of zolpidem. Therapeutic implications". Clin Pharmacokinet 29 (3): 142–53. doi:10.2165/00003088-199529030-00002. PMID 8521677.
- Pritchett DB, Seeburg PH (1990). "Gamma-aminobutyric acidA receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology". J. Neurochem. 54 (5): 1802–4. doi:10.1111/j.1471-4159.1990.tb01237.x. PMID 2157817.
- Smith AJ, Alder L, Silk J, Adkins C, Fletcher AE, Scales T, Kerby J, Marshall G, Wafford KA, McKernan RM, Atack JR (2001). "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". Mol. Pharmacol. 59 (5): 1108–18. PMID 11306694.
- Rowlett JK, Woolverton WL (November 1996). "Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies". Psychopharmacology (Berl.) 128 (1): 1–16. doi:10.1007/s002130050103. PMID 8944400.[dead link]
- Wafford KA, Thompson SA, Thomas D, Sikela J, Wilcox AS, Whiting PJ (1996). "Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit". Mol. Pharmacol. 50 (3): 670–8. PMID 8794909.
- Perrais D, Ropert N (1999). "Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses". J. Neurosci. 19 (2): 578–88. PMID 9880578.
- Noguchi H, Kitazumi K, Mori M, Shiba T (2004). "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats". J. Pharmacol. Sci. 94 (3): 246–51. doi:10.1254/jphs.94.246. PMID 15037809. "WARNING: The reference indicates that zaleplon-Sonata, not zolpidem, increases Slow-wave sleep"
- Dündar Y, Dodd S, Strobl J, Boland A, Dickson R, Walley T (2004). "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. doi:10.1002/hup.594. PMID 15252823.
- Johnson DS, Li JJ (2007). The art of drug synthesis. Hoboken, N.J.: Wiley-Interscience. pp. Chapter 15, Section 2. ISBN 9780471752158.
- IN 246080, Rawalnath, Sakhardande Rajiv; Richard Crasta Santosh & ALOK SAXENA, "Process for the preparation of zolpidem", published 21-Dec-2005, issued 14-Feb-2011
- Sumalatha, Y. (2009). "A simple and efficient synthesis of hypnotic agent, zolpidem and its related substances". Arkivoc 2009 (2): 315–320. doi:10.3998/ark.5550190.0010.230.
- Sumalatha, Y. (2009). "Synthesis and spectral characterization of zolpidem related substances - hypnotic agent". Arkivoc 2009 (7): 143–149. doi:10.3998/ark.5550190.0010.714.
- Hulhoven R, Desager JP, Harvengt C, Hermann P, Guillet P, Thiercelin JF (1988). "Lack of interaction between zolpidem and H2 antagonists, cimetidine and ranitidine". International journal of clinical pharmacology research 8 (6): 471–476. PMID 3253224.
- Wang JS, DeVane CL (2003). "Pharmacokinetics and drug interactions of the sedative hypnotics" (PDF). Psychopharmacol Bull 37 (1): 10–29. doi:10.1007/BF01990373. PMID 14561946. Archived from the original on 2007-07-09.
- Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.
- Barrero-Hernández FJ, Ruiz-Veguilla M, López-López MI, Casado-Torres A (2002). "[Epileptic seizures as a sign of abstinence from chronic consumption of zolpidem]" [Epileptic seizures as a sign of abstinence from chronic consumption of zolpidem]. Rev Neurol (in Spanish; Castilian) 34 (3): 253–6. PMID 12022074.
- Cubała WJ, Landowski J (2007). "Seizure following sudden zolpidem withdrawal". Prog. Neuropsychopharmacol. Biol. Psychiatry 31 (2): 539–40. doi:10.1016/j.pnpbp.2006.07.009. PMID 16950552.
- "ksl.com – Ambien Abuse on Rise Among Teens". www.ksl.com. Retrieved 2009-06-22.
- Jones AW, Holmgren A, Kugelberg FC (2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Therapeutic drug monitoring 29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081.
- "Kennedy To Enter Drug Rehab After Car Crash; Congressman Wrecked Car Near Capitol".[dead link]
- "Home | GIPdatabank". Gipdatabank.nl. 2013-11-15. Retrieved 2014-01-31.
- Clauss R, Nel W (2006). "Drug induced arousal from the permanent vegetative state". NeuroRehabilitation 21 (1): 23–8. PMID 16720934.
- Whyte J, Myers R (May 2009). "Incidence of clinically significant responses to zolpidem among patients with disorders of consciousness: a preliminary placebo controlled trial". American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists 88 (5): 410–8. doi:10.1097/PHM.0b013e3181a0e3a0. PMID 19620954.
- Hall SD, Yamawaki N, Fisher AE, Clauss RP, Woodhall GL, Stanford IM (April 2010). "GABA(A) alpha-1 subunit mediated desynchronization of elevated low frequency oscillations alleviates specific dysfunction in stroke--a case report". Clinical Neurophysiology : Official Journal of the International Federation of Clinical Neurophysiology 121 (4): 549–55. doi:10.1016/j.clinph.2009.11.084. PMID 20097125.
- Nyakale NE, Clauss RP, Nel W, Sathekge M (2010). "Clinical and brain SPECT scan response to zolpidem in patients after brain damage". Arzneimittel-Forschung 60 (4): 177–81. doi:10.1055/s-0031-1296269. PMID 20486466.
- Machado C, Estévez M, Pérez-Nellar J, Gutiérrez J, Rodríguez R, Carballo M, Chinchilla M, Machado A, Portela L, García-Roca MC, Beltrán C (March 2011). "Autonomic, EEG, and behavioral arousal signs in a PVS case after Zolpidem intake". The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques 38 (2): 341–4. PMID 21320843.
- Snyman N, Egan JR, London K, Howman-Giles R, Gill D, Gillis J, Scheinberg A (2011). "Zolpidem for Persistent Vegetative State - A Placebo-Controlled Trial in Pediatrics". Neuropediatrics 41 (5): 223–227. doi:10.1055/s-0030-1269893. PMID 21210338.
- Whyte J, Myers R (2009). "Incidence of Clinically Significant Responses to Zolpidem Among Patients with Disorders of Consciousness". American Journal of Physical Medicine & Rehabilitation 88 (5): 410–418. doi:10.1097/PHM.0b013e3181a0e3a0. PMID 19620954.
- Interlandi, Jeneen (December 1, 2011). "A Drug That Wakes the Near Dead". New York Times.
- Joel Lamoure RPh. BScPhm.,FASCP. "How Is Zolpidem Dependence Managed?". Medscape Pharmacists Ask the Expert. WebMD. Retrieved 2010-03-05. (login required)
- "Prescription Sleep Aid AMBIEN CR". Sanofi-Aventis. Ambien CR official website. April 2013. Retrieved 2009-05-21.
- "Ambien Cr (zolpidem tartrate) Tablet, Coated". DailyMed. U.S. National Library of Medicine, National Institutes of Health, Health & Human Services. Retrieved 2009-05-21.[dead link]
- "Zolpidem (Ambien)". The Vaults of Erowid. 2007-07-19. Retrieved 2009-05-21.
- Angelettie L, Kelley-Soderholm E. "Ambien Abuse". Mental Health Site. BellaOnline, Minerva WebWorks LLC. Retrieved 2009-05-21.
- U.S. National Library of Medicine: Drug Information Portal – Zolpidem
Media related to Zolpidem at Wikimedia Commons