Zopiclone
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Zopiclone, sold under the brand name Imovane among others, is a
nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...
, specifically a
cyclopyrrolone Cyclopyrrolones are a family of hypnotic and anxiolytic nonbenzodiazepine drugs with similar pharmacological profiles to the benzodiazepine derivatives. Although cyclopyrrolones are chemically unrelated to benzodiazepines, they function via the G ...
, used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a
cyclopyrrolone Cyclopyrrolones are a family of hypnotic and anxiolytic nonbenzodiazepine drugs with similar pharmacological profiles to the benzodiazepine derivatives. Although cyclopyrrolones are chemically unrelated to benzodiazepines, they function via the G ...
. However, zopiclone increases the normal transmission of the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
gamma-aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...
(GABA) in the central nervous system, via modulating GABAA receptors similarly to the way
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
drugs do inducing sedation but not with the anti-anxiety properties of the benzodiazepines. Zopiclone is a
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...
. It works by causing a depression or tranquilization of the central nervous system. After prolonged use, the body can become accustomed to the effects of zopiclone. When the dose is then reduced or the drug is abruptly stopped, withdrawal symptoms may result. These can include a range of symptoms similar to those of
benzodiazepine withdrawal Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stop ...
. Although withdrawal symptoms from therapeutic doses of zopiclone and its isomers (i.e., eszopiclone) do not typically present with convulsions and are therefore not considered life-threatening, patients may experience such significant agitation or anxiety that they seek emergency medical attention. In the United States, zopiclone is not commercially available, although its active
stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
, eszopiclone, is. Zopiclone is a controlled substance in the United States, Japan, Brazil, New Zealand and some European countries, and may be illegal to possess without a prescription. Zopiclone is known colloquially as a "
Z-drug Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...
". Other Z-drugs include
zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
and
zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...
and were initially thought to be less addictive than benzodiazepines. However, this appraisal has shifted somewhat in the last few years as cases of addiction and habituation have been presented. Zopiclone is recommended to be taken at the lowest effective dose, with a duration of 2–3 weeks for short-term insomnia. Daily or continuous use of the drug is not usually advised, and caution must be taken when the compound is used in conjunction with benzodiazepines, sedatives or other drugs affecting the central nervous system.


Medical uses

Zopiclone is used for the short-term treatment of insomnia where sleep initiation or sleep maintenance are prominent symptoms. Long-term use is not recommended, as tolerance, dependence, and addiction can occur. One low-quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in
shift work Shift work is an employment practice designed to keep a service or production line operational at all times. The practice typically sees the day divided into shifts, set periods of time during which different groups of workers perform their ...
ers, and more research in this area has been recommended.
Cognitive behavioral therapy Cognitive behavioral therapy (CBT) is a form of psychotherapy that aims to reduce symptoms of various mental health conditions, primarily depression, PTSD, and anxiety disorders. Cognitive behavioral therapy focuses on challenging and chang ...
has been found to be superior to zopiclone in the treatment of insomnia and has been found to have lasting effects on sleep quality for at least a year after therapy.


Specific populations


Elderly

Zopiclone, similar to other benzodiazepines and
nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
consumption increases these impairments. Partial, but incomplete tolerance develops to these impairments. Zopiclone increases postural sway and increases the number of falls in older people, as well as cognitive side effects. Falls are a significant cause of death in older people. An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly persons. Newer agents such as the melatonin receptor agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (
anterograde amnesia In neurology, anterograde amnesia is the inability to create new memories after an event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. Thi ...
), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of nonbenzodiazepine hypnotic drugs remains to be determined.


Liver disease

Patients with liver disease eliminate zopiclone much more slowly than normal patients and in addition experience exaggerated pharmacological effects of the drug.


Adverse reactions

Sleeping pills, including zopiclone, have been associated with an increased risk of death. The
British National Formulary The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medicin ...
states adverse reactions as follows: "taste disturbance (some report a metallic taste); less commonly nausea, vomiting, dizziness, drowsiness, dry mouth, headache; rarely amnesia, confusion, depression, hallucinations, nightmares; very rarely light headedness, incoordination, paradoxical effects ..and sleep-walking also reported".


Contraindications

Zopiclone causes
impaired driving Driving under the influence (DUI) is the crime of driving, operating, or being in control of a vehicle while one is impaired from doing so safely by the effect of either alcohol (see drunk driving) or some other drug, whether recreational or ...
skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for
sleep disorder A sleep disorder, or somnipathy, is a medical disorder affecting an individual's sleep patterns, sometimes impacting physical, mental, social, and emotional functioning. Polysomnography and actigraphy are tests commonly ordered for diagnosing sle ...
s develop only partial tolerance to adverse effects on driving, with users of hypnotic drugs even after one year of use still showing an increased motor vehicle accident rate. Patients who drive motor vehicles should not take zopiclone as there is a significantly increased risk of accidents in zopiclone users. Zopiclone induces impairment of psychomotor function. Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand-eye coordination. A
double-blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...
study on the effect on performance of several hypnotic medications, relevant to military personnel who may have to be awakened to carry out duties, found that drugs listed in increasing order of performance impact duration were melatonin (with no impact), zaleplon, temazepam, and zopiclone. The effects on serial reaction time (SRT), logical reasoning (LRT), serial subtraction (SST), and multitask (MT) were measured. For zaleplon (10 mg), zopiclone (7.5 mg) and temazepam (15 mg) respectively the times to recover normal performance for SRT were 3.25, , and 5.25 hours; for LRT 3.25, , and 4.25 hours; for SST 2.25, , and 4.25 hours; and for MT 2.25, , and 3.25 hours. The study did not consider the effectiveness of the drugs on sleep.


EEG and sleep

It causes similar alterations on EEG readings and sleep architecture as benzodiazepines and causes disturbances in sleep architecture on withdrawal as part of its
rebound effect 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- ...
. Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves. Zopiclone reduces the total amount of time spent in
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
as well as delaying its onset. In EEG studies, zopiclone significantly increases the energy of the beta frequency band, increasing stage 2. Zopiclone is less selective to the α1 site and has higher affinity to the α2 site than zaleplon. Zopiclone is therefore very similar pharmacologically to benzodiazepines.


Overdose

Zopiclone is sometimes used as a method of suicide. It has a similar fatality index to that of benzodiazepine drugs, apart from
temazepam Temazepam, sold under the brand name Restoril among others, is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypn ...
, which is particularly toxic in overdose. Deaths have occurred from zopiclone overdose, alone or in combination with other drugs. Overdose of zopiclone may present with excessive sedation and depressed respiratory function that may progress to coma and possibly death. Zopiclone combined with
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
,
opiates An opiate is an alkaloid substance derived from opium (or poppy straw). It differs from the similar term ''opioid'' in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain ( ...
, or other central nervous system depressants may be even more likely to lead to fatal overdoses. Zopiclone overdosage can be treated with the GABAA receptor benzodiazepine site antagonist
flumazenil Flumazenil, also known as flumazepil, is a selective GABAA receptor, GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (partic ...
, which displaces zopiclone from its binding site, thereby rapidly reversing its effects. Serious effects on the heart may also occur from a zopiclone overdose when combined with
piperazine Piperazine () is an organic compound with the formula . In term of its structure, it can be described as cyclohexane with the 1- and 4-CH2 groups replaced by NH. Piperazine exists as deliquescent solid with a saline taste. Piperazine is freely sol ...
. Death certificates show the number of zopiclone-related deaths is on the rise. When taken alone, it usually is not fatal, but when mixed with alcohol or other drugs such as
opioids Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...
, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.


Interactions

Zopiclone also interacts with trimipramine and
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
. Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly. Due to these risks and the increased risk for dependence, alcohol should be avoided when using zopiclone.
Erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...
appears to increase the absorption rate of zopiclone and prolong its
elimination half-life Biological half-life (elimination half-life, pharmacological 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 blood plasma. ...
, leading to increased plasma levels and more pronounced effects.
Itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...
has a similar effect on zopiclone pharmacokinetics as erythromycin. The elderly may be particularly sensitive to the erythromycin and itraconazole
drug interaction In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect ...
with zopiclone. Temporary dosage reduction during combined therapy may be required, especially in the elderly.
Rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...
causes a very notable reduction in half-life of zopiclone and peak plasma levels, which results in a large reduction in the hypnotic effect of zopiclone.
Phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...
and
carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...
may also provoke similar interactions.
Ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...
and sulfaphenazole interfere with the metabolism of zopiclone. Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next-day sedation.


Pharmacology

The therapeutic pharmacological properties of zopiclone include
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
,
anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
,
anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...
, and
myorelaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therap ...
properties. Zopiclone and benzodiazepines bind to the same sites on GABAA receptors, causing an enhancement of the actions of
GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...
to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone desmethylzopiclone is also pharmacologically active, although it has predominately anxiolytic properties. One study found some slight selectivity for zopiclone on α1 and α5 subunits, although it is regarded as being unselective in its binding to GABAA receptors containing α1, α2, α3, and α5 subunits. Desmethylzopiclone has been found to have
partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...
properties, unlike the parent drug zopiclone, which is a full agonist. The
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
and
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
turnover. A
meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
of randomised controlled
clinical trials Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
that compared benzodiazepines to zopiclone or other Z drugs such as zolpidem and zaleplon has found few clear and consistent differences between zopiclone and the benzodiazepines in
sleep onset latency In sleep science, sleep onset latency (SOL) is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages. Sleep latency studies Pioneering Stanford Univers ...
, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness. Zopiclone is in the
cyclopyrrolone Cyclopyrrolones are a family of hypnotic and anxiolytic nonbenzodiazepine drugs with similar pharmacological profiles to the benzodiazepine derivatives. Although cyclopyrrolones are chemically unrelated to benzodiazepines, they function via the G ...
family of drugs. Other cyclopyrrolone drugs include suriclone. Zopiclone, although molecularly different from benzodiazepines, shares an almost identical pharmacological profile as benzodiazepines, including anxiolytic properties. Its mechanism of action is by binding to the benzodiazepine site and acting as a
full 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 agoni ...
, which in turn positively modulates benzodiazepine-sensitive GABAA receptors and enhances GABA binding at the GABAA receptors to produce zopiclone's pharmacological properties. In addition to zopiclone's benzodiazepine pharmacological properties, it also has some
barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...
-like properties.


Pharmacokinetics

After oral administration, zopiclone is rapidly absorbed, with a
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
around 75–80%. Time to peak plasma concentration is 1–2 hours. A high-fat meal preceding zopiclone administration does not change absorption (as measured by AUC), but reduces peak plasma levels and delays its occurrence, thus may delay the onset of therapeutic effects. The plasma protein-binding of zopiclone has been reported to be weak, between 45 and 80% (mean 52–59%). It is rapidly and widely distributed to body tissues, including the brain, and is excreted in urine, saliva, and
breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a var ...
. Zopiclone is partly extensively metabolized in the liver to form an active ''N''-demethylated derivative (''N''-desmethylzopiclone) and an inactive zopiclone-''N''-oxide. Hepatic enzymes playing the most significant role in zopiclone metabolism are
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
and
CYP2E1 Cytochrome P450 2E1 (abbreviated CYP2E1, ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, inclu ...
. In addition, about 50% of the administered dose is decarboxylated and excreted via the lungs. In urine, the ''N''-demethyl and ''N''-oxide metabolites account for 30% of the initial dose. Between 7 and 10% of zopiclone is recovered from the urine, indicating extensive metabolism of the drug before excretion. The terminal elimination half-life of zopiclone ranges from 3.5 to 6.5 hours (5 hours on average). The
pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...
of zopiclone in humans are stereoselective. After oral administration of the
racemic mixture In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...
, Cmax (time to maximum plasma concentration), area under the plasma time-concentration curve ( AUC) and terminal elimination half-life values are higher for the dextrorotatory
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
s, owing to the slower total clearance and smaller
volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...
(corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the ''N''-demethyl and ''N''-oxide metabolites are higher than those of the respective
antipodes In geography, the antipode () of any spot on Earth is the point on Earth's surface diametrically opposite to it. A pair of points ''antipodal'' () to each other are situated such that a straight line connecting the two would pass through Ea ...
. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. In severe chronic
kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
, the area under the curve value for zopiclone was larger and the half-life associated with the elimination rate constant longer, but these changes were not considered to be clinically significant. Sex and race have not been found to interact with pharmacokinetics of zopiclone.


Chemistry

The
melting point The melting point (or, rarely, liquefaction point) of a substance is the temperature at which it changes state of matter, state from solid to liquid. At the melting point the solid and liquid phase (matter), phase exist in Thermodynamic equilib ...
of zopiclone is 178 °C. Zopiclone's solubility in water, at room temperature (25 °C) are 0.151 mg/mL. The logP value of zopiclone is 0.8.


Detection in biological fluids

Zopiclone may be measured in blood, plasma, or urine by chromatographic methods. Plasma concentrations are typically less than 100 μg/L during therapeutic use, but frequently exceed 100 μg/L in automotive vehicle operators arrested for impaired driving ability and may exceed 1000 μg/L in acutely poisoned patients. ''Post mortem'' blood concentrations are usually in a range of 400 to 3900 μg/L in victims of fatal acute overdose.


History

Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
, the main worldwide manufacturer. Initially, it was promoted as an improvement on benzodiazepines, but a recent meta-analysis found it was no better than benzodiazepines in any of the aspects assessed. On April 4, 2005, the U.S.
Drug Enforcement Administration The Drug Enforcement Administration (DEA) is a Federal law enforcement in the United States, United States federal law enforcement agency under the U.S. Department of Justice tasked with combating illicit Illegal drug trade, drug trafficking a ...
listed zopiclone under schedule IV, due to evidence that the drug has addictive properties similar to benzodiazepines. Zopiclone, as traditionally sold worldwide, is a
racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...
mixture of two
stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
s, only one of which is active. In 2005, the pharmaceutical company Sepracor of
Marlborough, Massachusetts Marlborough is a city in Middlesex County, Massachusetts, United States. The population was 41,793 at the 2020 United States census, 2020 census. Marlborough became a prosperous industrial town in the 19th century and made the transition to high ...
, began marketing the active stereoisomer eszopiclone under the name Lunesta in the United States. This had the consequence of placing what is a
generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
in most of the world under patent control in the United States. Generic forms of Lunesta have since become available in the United States. Zopiclone is currently available off-patent in a number of European countries, Brazil, Canada, Hong Kong, and New Zealand. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone dosage contains 3 mg of the therapeutic stereoisomer, whereas the highest zopiclone dosage (10 mg) contains 5 mg of the active stereoisomer. The two agents have not yet been studied in head-to-head clinical trials to determine the existence of any potential clinical differences (efficacy, side effects, developing dependence on the drug, safety, etc.).


Society and culture


Recreational use

Zopiclone has the potential for non-medical use, dosage escalation, and drug dependence. It is taken orally and sometimes intravenously when used non-medically, and often combined with alcohol to achieve euphoria. Patients abusing the drug are also at risk of dependence. Withdrawal symptoms can be seen after long-term use of normal doses even after a gradual reduction regimen. The Compendium of Pharmaceuticals and Specialties recommends zopiclone prescriptions not exceed 7 to 10 days, owing to concerns of addiction, tolerance, and physical dependence. Two types of drug misuse can occur: either recreational misuse, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice. Zopiclone may be more addictive than
benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...
. Those with a history of substance misuse or
mental health disorders The ''Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition'' (DSM-5), is the 2013 update to the ''Diagnostic and Statistical Manual of Mental Disorders'', the taxonomic and diagnostic tool published by the American Psychiatri ...
may be at an increased risk of high-dose zopiclone misuse. High dose misuse of zopiclone and increasing popularity amongst people who use substances who have been prescribed with zopiclone The symptoms of zopiclone addiction can include depression,
dysphoria Dysphoria (; ) is a profound state of unease or dissatisfaction. It is the semantic opposite of euphoria. In a psychiatric context, dysphoria may accompany depression, anxiety, or agitation. In psychiatry Intense states of distress and uneas ...
,
hopelessness Depression is a mental state of low mood and aversion to activity. It affects about 3.5% of the global population, or about 280 million people worldwide, as of 2020. Depression affects a person's thoughts, behavior, feelings, and sense o ...
, slow thoughts,
social isolation Social isolation is a state of complete or near-complete lack of contact between an individual and society. It differs from loneliness, which reflects temporary and involuntary lack of contact with other humans in the world. Social isolation c ...
, worrying, sexual anhedonia, and
nervousness Anxiety is an emotion characterised by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different from fear in that fear is defined as the emotional response to a present threat, where ...
. Zopiclone and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other sedating drugs, including benzodiazepines and zolpidem, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range and often in combination with alcohol, illegal, or addictive
prescription drug A prescription drug (also prescription medication, prescription medicine or prescription-only medication) is a pharmaceutical drug that is permitted to be dispensed only to those with a medical prescription. In contrast, over-the-counter drugs c ...
s, suggesting a high degree of potential for non-medical use of benzodiazepines, zolpidem, and zopiclone. Zopiclone, which at prescribed doses causes moderate impairment the next day, has been estimated to increase the risk of vehicle accidents by 50%, causing an increase of 503 excess accidents per 100,000 persons.
Zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
or other nonimpairing sleep aids were recommended be used instead of zopiclone to reduce traffic accidents. Zopiclone, as with other hypnotic drugs, is sometimes used to carry out criminal acts such as
sexual assaults Sex is the trait that determines whether a sexually reproducing organism produces male or female gametes. Sex, SEX or sexual may also refer to: *Sexual intercourse, a sexual activity Arts and entertainment Film and television * ''Sex'' (1920 ...
. Zopiclone has crosstolerance with barbiturates and is able to suppress barbiturate withdrawal symptoms. It is frequently self-administered intravenously in studies on monkeys, suggesting a high risk of addictive potential. Zopiclone is in the top ten medications obtained using a false prescription in France.


References


External links


Detailed pharmacological information

Scheduling recommendation
(
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file)
Details on scheduling



Support for zopiclone dependency/addiction
{{GABAAR PAMs Carbamates Cyclopyrrolones Lactams Nonbenzodiazepines Chloropyridines 4-Methylpiperazin-1-yl compounds Pyrrolopyrazines Sanofi GABAA receptor positive allosteric modulators Hallucinogens Disubstituted pyridines