Zolpidem addresses sleep-initiation problems, but is not effective in maintaining sleep. Clinicians prescribe zolpidem for short-term (usually about two to six weeks) treatment of insomnia. Also, a 2012 NIH study showed that zolpidem's effectiveness is nearly as much due to psychological effects as to the drug itself, so "increased attention should be directed at psychological intervention of insomnia.".
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.
On April 23, 2007, the U.S. Food and Drug Administration (FDA) approved 13 generic versions of zolpidem tartrate. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. 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).
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. This adverse effect is not unique to zolpidem but also occurs with other hypnotic drugs. Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. Caution should be exercised by motor vehicle drivers. As a consequence, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men.
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. It was recommended that zolpidem be used for short periods of time using the lowest effective dose. A review medical publication found long-term use of zolpidem is associated with drug tolerance, substance dependence, rebound insomnia, and CNS -related adverse effects.
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.
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 2013, the Food and Drug Administration required manufacturers to decrease the recommended dose for women by half, after studies showed that the medicines can leave people drowsy in the morning and at risk for motor vehicle collisions. The underlying mechanism involves GABA. In May 2013, the FDA approved label changes specifying new dosage recommendations for zolpidem products because of concerns regarding next-morning impairment.
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. Zolpidem was used by Australian Olympic swimmers at the London Olympics in 2012, leading to controversy.
Zolpidem causes an increased risk of falls and may induce adverse cognitive effects. The elderly are more sensitive to the effects of hypnotics including zolpidem.
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. Like zaleplon, zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep.
While cases of zolpidem improving aphasia in people with stroke have been described, use for this purpose has unclear benefit. 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. Zolpidem has also been studied in persistent vegetative states with unclear effect.
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. 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.
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.
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. 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.
ω 1 type GABA A receptors are the α 1 -containing GABA A receptors and are found primarily in the brain, the ω 2 receptors are those that contain the α 2 -, α 3 -, α 4 -, α 5 -, or α 6 subunits, and are found primarily in the spine. Zolpidem is a high-affinity positive modulator of GABA A receptors. Thus, zolpidem favours binding to GABAA receptors located in the brain rather the spine. 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 α 4 and α 6. 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. It selectively binds to α 1 subunits of this pentameric ion channel. Zolpidem has about 10-fold lower affinity for the α 2 - and α 3 - subunits than for α 1, and no appreciable affinity for α 5 subunit-containing receptors. Accordingly, it has strong hypnotic properties and weak anxiolytic, myorelaxant, and anticonvulsant properties. 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.
Though such safety procedures are common in industry, they make clandestine manufacture difficult. Three syntheses of zolpidem are common. This is brominated and reacted with 2-amino-5-methylpyridine to give the imidazopyridine. 4-methylacetophenone is used as a common precursor. 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.
Patients with GERD experience significantly higher esophageal exposure to gastric acid, which increases the likelihood of their developing esophageal cancer. 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.
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.
Its hypnotic effects are similar to those of the benzodiazepine class of drugs. However, it is effective in initiating sleep. Zolpidem has not adequay demonstrated effectiveness in maintaining sleep, unless delivered in a controlled-release (CR) form. It usually works within 15 minutes, and has a short half-life of two to three hours. Zolpidem, sold as the brand name Ambien among others, is a sedative primarily used for the treatment of trouble sleeping.
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. There does not appear to be any interaction between zolpidem and cimetidine or ranitidine. 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.
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. 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. 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.
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%).
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. Zolpidem has some muscle relaxant and anticonvulsant properties, but has not been approved for use in muscle relaxation or seizure prevention.
Congressman Patrick J. U.S. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone. Other drugs, including the benzodiazepines and zopiclone, are also found in high numbers of suspected drugged drivers. "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said. Kennedy says that he was using Zolpidem (Ambien) and Phenergan when caught driving erratically at 3 am.
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.
Also, alcoholics and recreational drug users may have an increased likelihood of recreationally using and or becoming psychologically dependent on zolpidem. Alcohol has cross tolerance with GABA A 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. 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, the likelihood of which is amplified in patients with a history of recreational use of drugs or alcohol.
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.
Caution is needed with other CNS-depressant drugs. Limit use to four weeks maximum under close medical supervision.". Zolpidem is not to be taken with alcoholic beverages. 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.
It is a short-acting nonbenzodiazepine compound of the imidazopyridine class that increases the activity of GABA, an inhibitory neurotransmitter, by binding to GABA A receptors at the same location as benzodiazepines. Flumazenil, a benzodiazepine receptor antagonist, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic and memory-impairing effects. It is molecularly distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine.
Media related to Zolpidem at Wikimedia Commons.
Rare reports of sexual parasomnia (sleep sex) episodes related to zolpidem intake have also been reported. Sleepwalkers can sometimes perform these tasks as normally as they might if they were awake. Some users have reported unexplained sleepwalking while using zolpidem, as well as sleep driving, 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.
Sometimes for difficult-to-treat patients, an inpatient flumazenil rapid detoxification program can be used to detoxify from a zolpidem drug dependence or addiction. 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. 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.
A number of major side-products of the sodium cyanide reaction have been characterised and include dimers and mannich products.
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. It dissolves readily in liquids such as wine, 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; this is due to the short elimination half-life of 2.5–3 hours. 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. Zolpidem has become one of many date rape drugs. in 2012.
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. 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. 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". 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.
Abrupt withdrawal may cause delirium, seizures, or other severe effects, especially if used for prolonged periods and at high dosages. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. 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. Nonpharmacological treatment options (e.g. cognitive behavioral therapy for insomnia ), however, were found to have sustained improvements in sleep quality.
Zolpidem has been assigned to pregnancy category C by the FDA. In one case report, zolpidem was found in cord blood at delivery. There are no controlled data in human pregnancy. 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. Zolpidem is recommended for use during pregnancy only when benefits outweigh risks.Ambien