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

sleeping problems Dyssomnias are a broad classification of sleeping disorders involving difficulty getting to sleep, remaining asleep, or of excessive sleepiness. Dyssomnias are primary disorders of initiating or maintaining sleep or of excessive sleepiness and ar ...

. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavioral changes, such as

sleep hygiene Sleep hygiene is a behavioral and environmental practice developed in the late 1970s as a method to help people with mild to moderate insomnia. Clinicians assess the sleep hygiene of people with insomnia and other conditions, such as depression, ...

, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray. Common side effects include daytime sleepiness, headache, nausea, and diarrhea. More severe side effects include memory problems and

hallucinations A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...

. The previously recommended dose was decreased in 2013, by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA), to the immediate-release 10mg for men, and 5mg for women, in an attempt to reduce next-day

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

. Newer extended-release formulations include the 6.25mg for women, and 12.5mg or 6.25mg for men, which also cause next-day somnolence when used in higher doses. Additionally, driving the next morning is not recommended with either higher doses or the long-acting formulation. While flumazenil, a GABA_A–receptor

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

, can reverse zolpidem's effects, usually

supportive care Symptomatic treatment, supportive care, supportive therapy, or palliative treatment is any medical therapy of a disease that only affects its symptoms, not the underlying cause. It is usually aimed at reducing the signs and symptoms for the comf ...

is all that is recommended in overdose. Zolpidem is a nonbenzodiazepine which acts as a

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...

and

hypnotic Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...

. Zolpidem is a GABA_A receptor agonist of the imidazopyridine class. It works by increasing GABA effects in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

by binding to GABA_A receptors at the same location as

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

. It generally has a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

of two to three hours. This, however, is increased in those with liver problems. Zolpidem was approved for medical use in the United States in 1992. It became available as a generic medication in 2007. Zolpidem is a Schedule IV controlled substance under the

Controlled Substances Act of 1970 The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...

(CSA). More than ten million prescriptions are filled each year in the United States, making it one of the most commonly used treatments for sleeping problems. In 2020, it was the 47th most commonly prescribed medication in the United States, with more than 14million prescriptions.

Medical uses

Zolpidem is labelled for short-term (usually about two to six weeks) treatment of

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

at the lowest possible dose. It may be used for both improving sleep onset, sleep onset latency, and staying asleep. Guidelines from

NICE Nice ( , ; Niçard: , classical norm, or , nonstandard, ; it, Nizza ; lij, Nissa; grc, Νίκαια; la, Nicaea) is the prefecture of the Alpes-Maritimes department in France. The Nice agglomeration extends far beyond the administrative ...

, the European Sleep Research Society, and the

American College of Physicians The American College of Physicians (ACP) is a national organization of internists, who specialize in the diagnosis, treatment, and care of adults.Sokanu "What is an Internist?" Retrieved October 20, 2014 With 161,000 members, ACP is the largest ...

recommend medication for insomnia (including possibly zolpidem) only as a second line treatment after non-pharmacological treatment options have been tried (e.g. cognitive behavioral therapy for insomnia). This is based in part on a 2012 review which found that zolpidem's effectiveness is nearly as much due to psychological effects as to the medication itself. A lower-dose version (3.5mg for men and 1.75mg for women) is given as a tablet under the tongue and used for middle-of-the-night awakenings. It can be taken if there are at least 4 hours between the time of administration and when the person must be awake.

Contraindications

Zolpidem should not be taken by people with obstructive sleep apnea,

myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...

, severe liver disease,

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

; or by children, or people with psychotic illnesses. It should not be taken by people who are or have been addicted to other substances. 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

drugs. Caution should be exercised by motor vehicle drivers. In 2013, the FDA recommended the dose for women be reduced and that prescribers should consider lower doses for men due to impaired function the day after taking the drug. Zolpidem should not be prescribed to older people, who are more sensitive to the effects of hypnotics including zolpidem and are at an increased risk of falls and adverse cognitive effects, such as

delirium Delirium (also known as acute confusional state) is an organically caused decline from a previous baseline of mental function that develops over a short period of time, typically hours to days. Delirium is a syndrome encompassing disturbances ...

and neurocognitive disorder. Zolpidem has not been assigned to a

pregnancy category The pregnancy category of a medication is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does ''not'' include any risks conferred by pharmaceutical agents or their ...

by the FDA. Animal studies have revealed evidence of incomplete

ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in ...

and increased intrauterine fetal death 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.

Adverse effects

The most common adverse effects of short-term use include headache (reported by 7% of people in clinical trials), drowsiness (2%), dizziness (1%), and diarrhea (1%); the most common side effects of long-term use included drowsiness (8%), dizziness (5%), allergy (4%), sinusitis (4%), back pain (3%), diarrhea (3%), drugged feeling (3%), dry mouth (3%), lethargy (3%), sore throat (3%), abdominal pain (2%), constipation (2%), heart palpitations (2%), lightheadedness (2%), rash (2%), abnormal dreams (1%), amnesia (1%), chest pain (1%), depression (1%), flu-like symptoms (1%), and sleep disorder (1%). Zolpidem increases risk of depression, falls and bone fracture, poor driving, suppressed respiration, and has been associated with an increased risk of death. Upper and lower respiratory infections are also common (experienced by between 1 and 10% of people). 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. Around 3% of people taking zolpidem are likely to break a bone as a result of a fall due to impaired coordination caused by the drug. 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 Established in March 1998, NPS MedicineWise (known prior to 2009 as the National Prescribing Service) is an Australian not-for-profit organisation whose programs are funded by the national Department of Health. Since July 2012, the organisation h ...

found these events occur mostly after the first dose taken, or within a few days of starting therapy. In February 2008, the Australian Therapeutic Goods Administration attached a

boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that i ...

concerning this adverse effect.

Tolerance, dependence and withdrawal

As zolpidem is associated with

drug tolerance Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, furthe ...

and substance dependence, its prescription guidelines are only for severe insomnia and short periods of use at the lowest effective dose. Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause

, seizures, or other

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...

s, especially if used for prolonged periods and at high doses. When drug tolerance and physical dependence to zolpidem develop, treatment usually entails a gradual dose reduction over a period of months to minimize withdrawal symptoms, which can resemble those seen during

benzodiazepine withdrawal Benzodiazepine withdrawal syndrome often abbreviated to benzo withdrawal or BZD withdrawal is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines, either medically or recreationally develops a phy ...

. Failing that, an alternative method may be necessary for some people, such as a switch to a

benzodiazepine equivalent The below tables contain a sample list of benzodiazepines and benzodiazepine Analog (chemistry), analogs that are commonly prescribed, with their basic pharmacological characteristics, such as half-life and equivalent doses to other benzodiazepine ...

dose of a longer-acting benzodiazepine drug, as for diazepam or chlordiazepoxide, followed by a gradual reduction in dose of the long-acting benzodiazepine. In people who are difficult to treat, an inpatient flumazenil administration allows for rapid competitive binding of flumazenil to GABA_A–receptor as an

, thus stopping (and effectively detoxifying) zolpidem from being able to bind as an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

on GABA_A–receptor; slowly

drug dependence Substance dependence, also known as drug dependence, is a biopsychological situation whereby an individual's functionality is dependent on the necessitated re-consumption of a psychoactive substance because of an adaptive state that has develope ...

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...

to zolpidem will wane. Alcohol has

cross tolerance Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor ...

with GABA_A receptor positive allosteric modulators, such as the

and the nonbenzodiazepine drugs. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependency or abuse of zolpidem. It is not typically prescribed in people with a history of alcoholism,

recreational drug use Recreational drug use indicates the use of one or more psychoactive drugs to induce an altered state of consciousness either for pleasure or for some other casual purpose or pastime by modifying the perceptions and emotions of the user. When a ...

, physical dependency, or psychological dependency on sedative-hypnotic drugs. A 2014 review found evidence of drug-seeking behavior, with prescriptions for zolpidem making up 20% of falsified or forged prescriptions.

Rodent Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are n ...

studies of the

tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...

-inducing properties have shown that zolpidem has less tolerance-producing potential than

, but in

primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians ( monkeys and apes, the latter includin ...

s, the tolerance-producing potential of zolpidem was the same as seen with benzodiazepines, therefore further research is necessary.

Overdose

Overdose can lead to coma or death. When overdose occurs, there are often other drugs in the person's system. Zolpidem overdose can be treated with the GABA_A receptor antagonist flumazenil, which displaces zolpidem from its binding site on the GABA_A receptor to rapidly reverse the effects of the zolpidem. It is unknown if dialysis is helpful.

Detection in body fluids

Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in people who are hospitalized, to provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300μg/L in persons receiving the drug therapeutically, 100–700μg/L in those arrested for impaired driving, and 1000–7000μg/L in victims of acute overdosage. Analytical techniques, in general, involve gas or

liquid A liquid is a nearly incompressible fluid that conforms to the shape of its container but retains a (nearly) constant volume independent of pressure. As such, it is one of the four fundamental states of matter (the others being solid, gas, ...

chromatography.

Pharmacology

Mechanism of action

Zolpidem is a

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

of high-affinity positive modulator sites of GABA_A receptors, which enhances

GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...

inhibition of neurotransmission in the central nervous system. It selectively binds to α₁ subunits of this pentameric

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...

. Accordingly, it has strong

properties and weak anxiolytic, myorelaxant, and

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...

properties. Opposed to diazepam, zolpidem is able to bind to binary αβ

GABA receptor The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and ...

s, where it was shown to bind to the α1–α1 subunit interface. 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. ω₁ type GABA_A receptors are the α₁-containing GABA_A 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 GABA_A receptors located in the brain rather than 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 α₄ and α₆. 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. Like

zaleplon Zaleplon, sold under the brand names Sonata among others, is a sedative- hypnotic, used to treat insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. It is manufactured by King Pharmaceuticals and Gedeon Richte ...

, zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep. A

meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...

that compared benzodiazepines against nonbenzodiazepines has shown few consistent differences between zolpidem and

in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance,

rebound insomnia The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...

, and daytime alertness.

Pharmokinetics

Microsome studies indicate zolpidem is metabolized by

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

(61%)

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the pro ...

(22%), CYP1A2 (14%), CYP2D6 (<3%), and CYP2C19 (<3%). It is principally metabolized into three metabolites, none of which are believed to be pharmocologically active. The absolute bioavailability of zolpidem is about 70%. The drug reaches peak concentration in about 2 hours and has a half life in healthly adults of about 2-3 hours. Zolpidem's half life is decreased in children and increased in the elderly and people with liver issues. While some studies show men metabolize zolipdem faster than women (possibly due to testosterone), others do not. A review found only a 33% lower clearance in women compared to men, suggesting the FDA's dosage reduction of 50% for women may have been too large.

Interactions

People should not consume alcohol while taking zolpidem, and should not be prescribed

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

drugs nor take such illicit drugs recreationally. Opioids can also increase the risk of becoming psychologically dependent on zolpidem. Use of opioids with zolpidem increases the risk of respiratory depression and death. The US Food and Drug Administration (FDA) is advising that the opioid addiction medications buprenorphine and methadone should not be withheld from patients taking benzodiazepines or other drugs that depress the central nervous system (CNS). Next day sedation can be worsened if people take zolpidem while they are also taking

antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...

s, other sedatives, anxiolytics, antidepressant agents, antiepileptic drugs, and antihistamines. Some people taking antidepressants have had visual hallucinations when they also took zolpidem.

Cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

inhibitors, particularly CYP3A4 and CYP1A2 inhibitors such as fluvoxamine,

ciprofloxacin Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin i ...

, and clarithromycin will increase the effects of a given dose of zolpidem. Cytochrome P450 activators like St. John's Wort may decrease the activity of zolpidem. One study found that caffeine increases the concentration over time curve of zolpidem by about 20% and furthermore found that caffeine cannot adequately compensate for the impaired cognition caused by zolpidem.

Chemistry

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.

History

Zolpidem was used in Europe starting in 1988, and was brought to market there by Synthelabo. Synthelabo and Searle collaborated to bring it to market in the US, and it was approved in the United States in 1992 under the brand name "Ambien". It became available as a generic medication in 2007. In 2015, the

American Geriatrics Society The American Geriatrics Society (AGS) is a non-profit professional society founded on June 11, 1942, for health care professionals practicing geriatric medicine. Among the founding physicians were Dr. Ignatz Leo Nascher, who coined the term "ger ...

said that zolpidem, eszopiclone and

met the

Beers criteria The Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, commonly called the Beers List, are guidelines published by the American Geriatrics Society (AGS) for healthcare professionals to help improve the safety of prescribi ...

and should be avoided in individuals 65 and over "because of their association with harms balanced with their minimal efficacy in treating insomnia." The AGS stated the strength of the recommendation that older adults avoid zolpidem is "strong" and the quality of evidence supporting it is "moderate."

Society and culture

Prescriptions in the US for all sleeping pills (including zolpidem) steadily declined from around 57 million tablets in 2013, to around 47 million in 2017, possibly in relation to concern about prescribing addictive drugs in the midst of the opioid crisis.

Military use

The

United States Air Force The United States Air Force (USAF) is the air service branch of the United States Armed Forces, and is one of the eight uniformed services of the United States. Originally created on 1 August 1907, as a part of the United States Army Si ...

uses zolpidem as one of the hypnotics approved as a " no-go pill" (with a six-hour restriction on subsequent flight operation) to help aviators and special duty personnel sleep in support of mission readiness. (The other hypnotics used are temazepam and

.) "Ground tests" are required prior to authorization issued to use the medication in an operational situation.

Recreational use

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". The transition from medical use of zolpidem to high-dose addiction or

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

leads to higher doses than the usual 5mg or 10mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Recreational use is more prevalent in those having been dependent on other drugs in the past, but tolerance and

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. Other drugs, including benzodiazepines and

zopiclone Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases th ...

, 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

, zolpidem and zopiclone. US Congressman Patrick J. Kennedy says that he was using zolpidem (Ambien) and promethazine (Phenergan) when caught driving erratically at 3 a.m. "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said. Nonmedical use of zolpidem is increasingly common in the US, Canada, and the UK. Some users have reported decreased anxiety, mild

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and d ...

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

Regulation

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 The Controlled Substances Act (CSA) is the statute establishing federal U.S. drug policy under which the manufacture, importation, possession, use, and distribution of certain substances is regulated. It was passed by the 91st United States ...

in the US. The United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.

Use in crime

The

Z-drugs Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep problem ...

including zolpidem have been used as

date rape drugs A date rape drug is any drug that incapacitates another person and renders that person vulnerable to sexual assault, including rape. The substances are associated with date rape because of reported incidents of their use in the context of two ...

. Zolpidem is available legally by prescription, and broadly prescribed unlike other date rape drugs:

gamma-hydroxybutyrate ''gamma''-Hydroxybutyric acid (or γ-hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid) is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. ...

(GHB), which is used to treat narcolepsy, or

flunitrazepam Flunitrazepam, also known as Rohypnol among other names, is a benzodiazepine used to treat severe insomnia and assist with anesthesia. As with other hypnotics, flunitrazepam has been advised to be prescribed only for short-term use or by those ...

(Rohypnol), which is only prescribed as a second-line choice for insomnia. Zolpidem can typically be detected in bodily fluids for 36 hours, though it may be possible to detect it by hair testing much later, which is due to the short

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...

of 2.5–3 hours. This use of the drug was highlighted during proceedings against Darren Sharper, who was accused of using the tablets he was prescribed to facilitate a series of rapes.

Sleepwalking

Zolpidem received widespread media coverage in Australia after the death of a student who fell from the Sydney Harbour Bridge while under the influence of zolpidem.

Brands

As of September 2018, zolpidem was marketed under many brands: Adorma, Albapax, Ambien, Atrimon, Belbien, Bikalm, Cymerion, Dactive, Dalparan, Damixan, Dormeben, Dormilam, Dormilan, Dormizol, Eanox, Edluar, Flazinil, Fulsadem, Hypnogen, Hypnonorm, Intermezzo, Inzofresh, Ivadal, Ivedal, Le Tan, Lioram, Lunata, Medploz, Mondeal, Myslee, Nasen, Niterest, Nocte, Nottem, Noxidem, Noxizol, Nuo Bin, Nytamel, Nyxe, Olpitric, Onirex, Opsycon, Patz, Polsen, Sanval, Semi-Nax, Sleepman, Somex, Somidem, Somit, Somnil, Somnipax, Somnipron, Somno, Somnogen, Somnor, Sonirem, Sove, Soza, Stilnoct, Stilnox, Stilpidem, Stimin, Sublinox, Sucedal, Sumenan, Vicknox, Viradex, Xentic, Zasan, Zaviana, Ziohex, Zipsoon, Zodem, Zodenox, Zodium, Zodorm, Zolcent, Zoldem, Zoldorm, Zoldox, Zolep, Zolfresh, Zolip, Zolman, Zolmia, Zolnox, Zolnoxs, Zolodorm, Zolnyt, Zolpeduar, Zolpel, Zolpi, Zolpi-Q, Zolpic, Zolpidem, Zolpidem tartrate, Zolpidemi tartras, Zolpidemtartraat, Zolpidemtartrat, Zolpidemum, Zolpigen, Zolpihexal, Zolpimist, Zolpineo, Zolpinox, Zolpirest, Zolpistar, Zolpitop, Zolpitrac, Zolpium, Zolprem, Zolsana, Zolta, Zoltar, Zolway, Zomnia, Zonadin, Zonoct, Zopid, Zopidem, Zopim, and Zorimin.

Research

While cases of zolpidem improving

aphasia Aphasia is an inability to comprehend or formulate language because of damage to specific brain regions. The major causes are stroke and head trauma; prevalence is hard to determine but aphasia due to stroke is estimated to be 0.1–0.4% in ...

in people with

stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

have been described, use for this purpose has unclear benefit. Zolpidem has also been studied in persistent vegetative states with unclear effect. A 2017

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on t ...

concluded that while there is preliminary evidence of benefit for treating disorders of movement and consciousness other than insomnia (including

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

), more research is needed. More recent research has found zolpidem treatment to be effective in the short term, but only in a small proportion of cases (estimated at around 5%) and only when the brain injury is of a specific type. Tolerance to the beneficial effects also develops rapidly, and so for these reasons while zolpidem may sometimes be used as a "last resort" treatment, it has numerous disadvantages and research continues into novel treatments that might provide the same kind of benefits in a larger proportion of patients, and with a more sustained benefit. Animal studies in FDA files for zolpidem showed a dose dependent increase in some types of tumors, although the studies were too small to reach statistical significance. Some observational epidemiological studies have found a correlation between use of benzodiazepines and certain

s including zolpidem and an increased risk of getting cancer, but others have found no correlation; a 2017 meta-analysis of such studies found a correlation, stating that use of hypnotics was associated with a 29% increased risk of cancer, and that "zolpidem use showed the strongest risk of cancer" with an estimated 34% increased risk, but noted that the results were tentative because some of the studies failed to control for

confounder In statistics, a confounder (also confounding variable, confounding factor, extraneous determinant or lurking variable) is a variable that influences both the dependent variable and independent variable, causing a spurious association. Con ...

s like cigarette smoking and alcohol use, and some of the studies analyzed were case–controls, which are more prone to some forms of bias. Similarly, a meta-analysis of benzodiazepine drugs also shows their use is associated with increased risk of cancer.

References

External links

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