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Zopiclone

Clinical data
Trade names	Imovane, Zimovane
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral tablets, 3.75mg (UK), 5 or 7.5 mg
ATC code	N05CF01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: Schedule IV
Pharmacokinetic data
Bioavailability	52-59% bound to plasma protein
Metabolism	Various cytochrome P450 liver enzymes
Elimination half-life	~6 hours ~9 hours for over 65
Excretion	Urine
Identifiers
IUPAC name (RS)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolopyrazin-5-yl 4-methylpiperazine-1-carboxylate
CAS Number	43200-80-2
PubChem CID	5735
DrugBank	DB01198
ChemSpider	5533
UNII	03A5ORL08Q
KEGG	D01372
ChEBI	CHEBI:32315
ChEMBL	ChEMBL135400
CompTox Dashboard (EPA)	DTXSID4041155
ECHA InfoCard	100.051.018
Chemical and physical data
Formula	C17H17ClN6O3
Molar mass	388.808 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES O=C(OC3c1nccnc1C(=O)N3c2ncc(Cl)cc2)N4CCN(C)CC4
InChI InChI=1S/C17H17ClN6O3/c1-22-6-8-23(9-7-22)17(26)27-16-14-13(19-4-5-20-14)15(25)24(16)12-3-2-11(18)10-21-12/h2-5,10,16H,6-9H2,1H3 Key:GBBSUAFBMRNDJC-UHFFFAOYSA-N
(verify)

Zopiclone (brand name Imovane in Canada, Australia and Zimovane in the UK) is a non-benzodiazepine hypnotic (a cyclopyrrolone, which increases the normal transmission of the signal substance GABA in the central nerve system, as benzodiazepines do, however in a rather different way) agent used in the treatment of insomnia. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta (see History). Zopiclone is a controlled substance in the United States, Japan, Brazil and some European countries, and may be illegal to possess without a prescription.

Zopiclone is known colloquially as a "Z-drug". Other Z-drugs include zaleplon (Sonata) and zolpidem (Ambien and AmbienCR) and were initially thought to be less addictive and/or habit-forming than benzodiazepines. However, this appraisal has shifted somewhat in the last few years as cases of addiction and habituation have been presented. It is recommended that zopiclone be taken on a short-term basis, usually a week or less. Daily or continuous use of the drug is not usually advised. Zopiclone is a tranquillizer drug. It works by causing a depression or tranquilization of the Central Nervous System. As zopiclone is sedating it is marketed as a sleeping pill. After regular dampening down of the Central Nervous System the body becomes accustomed to functioning under the influence of zopiclone. When the dose is reduced or the drug is stopped these adaptions which have occurred when a person's body has become addicted to a drug are revealed. The result is rebound withdrawal symptoms that can include a range of withdrawal symptoms seen in benzodiazepine withdrawal.

History

Zopiclone was first developed and introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main worldwide manufacturer of the drug. Initially it was promoted as being an improvement on benzodiazepines. A recent meta analysis found that zopiclone had no superiority over benzodiazepines in any of the aspects assessed. On April 4, 2005, the United States Drug Enforcement Administration 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 mixture of two stereoisomers, only one of which is active. In 2005, the pharmaceutical company Sepracor of Marlborough, Massachusetts 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 in most of the world under patent control in the United States. Although it was expected to be available in generic form by 2010, no generic has become available there at present. However, Zopiclone is currently available off-patent in a number of European countries, as well as Brazil and Canada. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone derivative dosage contains 3 mg of the therapeutic stereoisomer, whereas, the highest zopiclone dosage (7.5 mg) contains 3.75 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.); the significant possibility that the two drugs have identical effects and only differ in dosing and the simple fact that investing in clinical trials is a very expensive undertaking may be responsible for this line of inquiry thus far remaining unpursued.

Indications

Zopiclone is indicated 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, addiction can occur with prolonged use.

Availability

Zopiclone is sold under a wide variety of brand names world wide.

• Zalepla - Costa Rica, Ecuador, Guatemala, Panama
• Zimovane - United Kingdom
• Zimovane, Zileze, Zimoclone, Zopitan, Zorclone - Ireland
• Imovane, Apo-Zopiclone, pms-Zopiclone, Ran-Zopiclone, Rhovane, Pro Zopiclone - Canada
• Imovane or Imrest - Australia, New Zealand, Iceland, Italy, Poland, Finland, Sweden, Norway and Brazil.
• Nocturno and Imovane - Israel
• Imovane (Имован); Relaxon (Релаксон); Somnol (Сомнол) - Russia
• Alchera, Imovane, Z-Dorm, Zopimed, Zopivane - South Africa
• Imoclone, Imozop or Imovane - Denmark
• Somnols; Imovane; Zopitin - Lithuania
• Limovan - Spain
• Ximovan - Germany
• Zopicon - India (by Intas Pharma)
• Zopiclon - Netherlands, Bulgaria
• Zopiclona - Argentina
• Zetix - Bolivia, Chile, Ecuador
• Hypnor - Egypt
• Amoban - Japan
• Zopilcone Actavis Norway

Adverse reactions

The side effect most commonly seen in clinical trials is taste alteration or dysgeusia (bitter, metallic taste, which is usually fleeting in most users but can persist until the drug's half-life has expired). Palpitations may occur in the daytime following withdrawal from the drug after prolonged periods of use (especially when taken for more than two weeks).

Zopiclone induces amnesia type memory impairments similar to triazolam and Rohypnol. Impairment of driving skills with a resultant increased risk of road traffic accidents is probably the most important side effect. This side effect is not unique to zopiclone but also occurs with other hypnotic drugs. A study assessing the impact of zopiclone on driving skills the next day found that the impairments on driving skills are double that of a social dose of alcohol. Zaleplon had no detrimental effects on driving skills the next day.

More common reactions

Gastrointestinal: taste disturbances including bitter metallic taste, dry mouth. Nervous system: disruption of REM sleep, double vision, drowsiness, memory impairments, visuospatial impairments, dizziness, headaches, and fatigue. Unexpected mood changes have been noted, which if experienced should lead to the drug being withdrawn from the patient.

Less common reactions

• Gastrointestinal: heartburn, constipation, diarrhoea, nausea, coated tongue, bad breath, anorexia or increased appetite, vomiting, epigastric pains, dyspepsia, dehydration, parageusia.
• Cardiovascular: palpitations in elderly patients.
• Skin: urticaria, tingling in the arms and legs.
• Miscellaneous: blurred vision, frequent micturition, nocturnal enuresis, mild to moderate increases in serum transaminases and/or alkaline phosphatase and interstitial nephritis have been reported very rarely.
• Reproductive: impotence, delayed ejaculation, anorgasmia in both women and men.
• Nervous system: agitation, anxiety, loss of memory including retrograde and anterograde amnesia, confusion, dizziness, weakness, somnolence, asthenia, euphoria and/or dysphoria, feeling of drunkenness, depression, sleep walking, coordination abnormality, hypotonia, speech disorder, hallucinations of various strengths, usually auditory and visual, behavioural disorders, aggression, tremor, rebound insomnia, nightmares, hypomania. Delirium can also occur but is a side effect mainly seen in the elderly.

Tolerance, dependence and withdrawal

Zopiclone, a benzodiazepine-like drug was introduced and initially promoted as having less dependence and withdrawal than traditional benzodiazepine drugs. However, zopiclone may have an even greater addictive potential than benzodiazepines and has been described as a "benzodiazepine in disguise". Tolerance to the effects of zopiclone can develop after a few weeks. Long term use should be avoided. Abrupt withdrawal particularly with prolonged and high doses can in severe cases cause seizures and delirium.

Publications in the British Medical Journal do not give any evidence to the claim that zopiclone has a low dependence potential. In fact, physical dependence and recreational abuse and withdrawal syndromes similar to those seen in benzodiazepine withdrawal are frequently encountered. Withdrawal symptoms included anxiety, tachycardia, tremor, sweats, flushes, palpitations, derealisation, and further insomnia. Suspected withdrawal convulsions during detoxification from zopiclone has been reported, however the individual was a high dose zopiclone misuser.

The risk of dependency on zopiclone when used for less than 2 weeks or only used occasionally is low. However, this is disputed by one study of low dose zopiclone taken for only 7 nights. It found that discontinuation of zopiclone caused significant rebound insomnia. Furthermore when midazolam taken for 7 nights was discontinued no rebound insomnia occurred suggesting that zopiclone may have even more significant problems of tolerance and dependence than the benzodiazepines. After 3 weeks of use mild to moderate rebound withdrawal symptoms appear upon discontinuation of zopiclone. Due to the risk of tolerance and physical dependence, zopiclone is only recommended for short term (1–4 weeks max) relief of insomnia, or alternatively, long term infrequent use. Long-term zopiclone users who have become physically dependent should not discontinue their medication abruptly as severe withdrawal symptoms may occur such as delirium. If zopiclone has been taken for more than a few weeks then the medication should be gradually reduced or preferably to cross over to an equivalent dose of diazepam (Valium), which has a much longer half-life which makes withdrawal easier and then gradually taper their dosage over a period of several months in order to avoid extremely severe and unpleasant withdrawal symptoms (e.g., inner restlessness, psychomotor agitation, abdominal pain, hypertension, hallucinations, seizures, anxiety, depression, psychosis, etc.) which can last up to two years after withdraw if the withdrawal is done too abruptly. After 4 weeks of nightly use of zopiclone day time withdrawal related anxiety begin to emerge in some users. However, the day time withdrawal anxiety does not appear to be as intense as that seen with the much shorter acting triazolam which provokes even more profound day time withdrawal anxiety symptoms in long term users.

According to the World Health Organisation, zopiclone, although molecularly is not a benzodiazepine, binds unselectively with high affinity to the same benzodiazepine sites that the benzodiazepine class of drugs do. The World Health Organisation also stated that zopiclone is cross tolerant with benzodiazepines and one can substitute one for the other. In the review of zopiclone by the World Health Organisation they found that the appearance of withdrawal symptoms usually occurred either when the drug was misused in excessive doses or when use of zopiclone was prolonged. The withdrawal symptoms from zopiclone reported included anxiety, tachycardia, tremor, sweating, rebound insomnia, derealisation, convulsions, palpitations and flushes.

Zopiclone is cross tolerant with benzodiazepines. 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 zopiclone. Also, alcoholics and drug abusers may be at increased risk of abusing and or becoming psychologically dependent on zopiclone. Zopiclone should be avoided in those with a history of Alcoholism, drug misuse (illicit or prescription misuse), or in those with history of physical dependency or psychological dependency on sedative-hypnotic drugs.

Withdrawing from Zopiclone sleeping tablets has been recommended to be done via a cross over to an equivalent dose of diazepam. This is because diazepam is available in low potency tablets, is cross-tolerant with zopiclone and is longer acting than zopiclone, which allows for a smoother withdrawal and for the body to adjust to a constant dose. While zopiclone acts on the same benzodiazepine receptors as the benzodiazepine family of drugs it is not classed as a benzodiazepine (with which it shares a number of characteristics and effects) due to its differing molecular structure. Zopiclone is classed as a cyclopyrrolone derivative.

Carcinogenicity

Zopiclone may be carcinogenic and mutagenic according to rat, mice and hamster studies. At 100 mg per kg of bodyweight per day, the experimental dosage was considerably higher than the therapeutic dose for humans. The authors of an uncontrolled study of zopiclone said that it may take decades in immunocompetent people before carcinogenic effects from past zopiclone use develops. It was suggested that further research and monitoring was required into the potential for zopiclone to cause cancer in immunocompetent patients.

A recent analysis of both U.S. Food and Drug Administration (FDA) data and clinical trial data shows that nonbenzodiazepine Z-drugs at prescribed doses cause an increased risk of developing cancer in humans. There have been 15 epidemiological studies which have shown that hypnotic drugs cause increased mortality, mainly due to increased cancer deaths. The cancers included those of the brain, lung, bowel, breast, and bladder. One possible explanation for the increased cancer deaths is that the Z-drugs have an adverse effect on the immune system. The fact that clinical trial subjects taking other Z-drugs (zolpidem, zaleplon and eszopiclone) had an increased rate of infections seems to support this theory. Benzodiazepine hypnotic agents are also associated with an increased risk of cancer in humans, namely ovarian cancer. Development of malignancy has been associated with zolpidem usage, but the incidence of neoplasm in zolpidem users is as yet unknown.

Indiplon, another nonbenzodiazepine drug has also shown an increased rate of cancers in clinical trials. The review author concluded by saying: "The likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer".

Contraindications

Zopiclone causes impaired driving skills which are similar to benzodiazepines. Long term users of hypnotic drugs for sleep disorders only develop partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 years use still showing an increased motor vehicle accident rate. Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of road traffic 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. Patients with a history of substance abuse should not be prescribed zopiclone, as it has a very high potential for problematic drug misuse. Zopiclone is known to, in some case, induce a state of amnesia, which is largely related (and not too dissimilar to 'sleep-walking'). This can extend to sleep-eating, sleep-talking (quite naturally), to dangerously 'sleep driving'. It is therefore usually not used as an anti-anxiety drug (such as Benzodiazepines), as the patient may be liable to make very poor judgment decisions (as they are essentially mentally 'asleep') and attempt dangerous activities. - With absolutely no recollection at all of the events.

Special precautions

Alcohol should be avoided when using zopiclone as alcohol and zopiclone enhance the effects of each other and the risk of dependence could increase.

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

Zopiclone increases 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.

Patients who suffer from muscle weakness due to myasthenia gravis or have poor respiratory reserves due to severe chronic bronchitis, emphysema or other lung disease, or have sleep apnoea cannot safely take zopiclone, nor can a patient with any untreated abnormality of the thyroid gland.

Elderly

Zopiclone, similar to other benzodiazepines and nonbenzodiazepine hypnotic 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 increases these impairments. Partial, but incomplete tolerance develops to these impairments.

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 lasting benefits of non-drug treatments for insomnia. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer little if any advantages in efficacy or tolerability in elderly persons. It was found that newer agents such as the melatonin 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), 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. It was concluded that further research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Pharmacology

The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant and myorelaxant properties. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABA_A containing receptors as full agonists causing an enhancement of the actions of GABA to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone called desmethylzopiclone is also pharmacologically active although it has predominately anxiolytic properties. Like benzodiazepines zopiclone and its active metabolite desmethylzopiclone also inhibit N-methyl-D-aspartate (NMDA) receptors and nicotinic acetylcholine (nAChRs) receptors which might play a role in the addictive properties of these drugs. One study however, found some slight selectivity for zopiclone on α1 and α5 subunits. Although it is regarded as being unselective in its binding to α1, α2, α3 and α5 GABA_A benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist properties unlike the parent drug zopiclone which is a full agonist. The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover. A meta-analysis of randomised controlled clinical trials which compared benzodiazepines to zopiclone or other Z Drugs such as zolpidem, zaleplon has found that there are few clear and consistent differences between zopiclone and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness. Zopiclone is in the cyclopyrrolone 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 via binding to the benzodiazepine site and acting as a full agonist which in turn positively modulates benzodiazepine sensitive GABA_A receptors and enhances GABA binding at the GABA_A receptors to produce zopiclone's pharmacological properties. In addition to zopiclone's benzodiazepine pharmacological properties it also has some barbiturate like properties.

In EEG studies, zopiclone significantly increases the energy of the beta frequency band and shows characteristics of high-voltage slow waves, desynchronization of hippocampal theta waves and an increase in the energy of the delta frequency band. Zopiclone increases both stage 2 and slow wave sleep (SWS), while zolpidem, an α1-selective compound, increases only SWS and causes no effect on stage 2 sleep. 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.

EEG and sleep

Similar to other sedative hypnotic drugs zopiclone causes a decrease in the core body temperature and is effective in decreasing sleep latency. Zopiclone 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. 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 as well as delaying its onset. Cognitive behavioral therapy 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.

Pharmacokinetics

After oral administration, zopiclone is rapidly absorbed, with a bioavailability of approximately 80%. The plasma protein binding of zopiclone has been reported to be between 45 and 80%. Zopiclone is rapidly and widely distributed to body tissues including the brain, and is excreted in urine, saliva and breast milk. Zopiclone is partly metabolised in the liver to form an inactive N-demethylated derivative and an active N-oxide metabolite. In addition, approximately 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 (t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), AUC (area under the plasma time-concentration curve) and t1/2z values are higher for the dextrorotatory enantiomer owing to the slower total clearance and smaller volume of distribution (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. The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions.

Interactions

Zopiclone also interacts with trimipramine and caffeine. Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly. Erythromycin appears to increase the absorption rate of zopiclone and prolong the elimination half-life of zopiclone leading to increased plasma levels and more pronounced effects. Itraconazole has a similar effect on zopiclone pharmacokinetics as erythromycin. The elderly may be particularly sensitive to the erythromycin and itraconazole drug interaction with zopiclone. Temporary dosage reduction during combined therapy may be required especially in the elderly. Rifampicin 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 and carbamazepine may also provoke similar interactions. Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone. Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next day sedation.

Abuse

Zopiclone is a drug with the potential for misuse with the potential for causing dosage escalation, drug abuse and drug dependence. Zopiclone is well known amongst drug addicts as a drug of abuse and they commonly seek it from their doctors. It is abused orally and sometimes intravenously and often combined with alcohol to achieve a combined sedative hypnotic - alcohol euphoria. Patients who do abuse 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 regime. The Compendium of Pharmaceuticals and Specialties recommends that zopiclone prescriptions do not exceed 7 – 10 days due to concerns of addiction, drug tolerance and physical dependence. Two types of drug misuse can occur; either recreational misuse, where 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. Those with a history of substance misuse or mental health disorders may be at an increased risk of high dose zopiclone misuse. High dose misuse of zopiclone and increasing popularity amongst drug abusers who have been prescribed with zopiclone The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia and nervousness.

Zopiclone and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other drugs including the 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 other alcohol, illegal or prescription drugs of abuse suggesting a high degree of abuse potential for 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. It was recommended that zaleplon or other non-impairing sleep aids are used instead of zopiclone to reduce road traffic accidents. Zopiclone as with other hypnotic drugs is sometimes abused to carry out criminal acts such as sexual assaults.

Zopiclone has cross tolerance with barbiturates and is able to suppress barbiturate withdrawal signs. Zopiclone is frequently self administered intravenously in studies on monkeys suggesting a high risk of abuse potential.

Zopiclone is in the top ten medications obtained using false prescription in France.

However, due to its distinctly bitter taste it is unlikely to be covertly administered to facilitate drug-related crime such as robbery, sexual assault etc. The tablets are coated with a film to mask the taste when swallowed, but crushing destroys this film. Also, a common side-effect is a bitter, metallic taste following ingestion, so a person who has administered zopiclone is likely to be aware that they are under the influence of this drug.

Overdose

Zopiclone is sometimes used as a method of suicide. Zopiclone has a similar fatality index as benzodiazepine drugs, apart from temazepam which is particularly toxic in overdosage. Deaths have occurred from zopiclone overdose, alone or in combination with other drugs. Overdose of zopiclone may present with excessive sedation, depressed respiratory function which may progress to coma and possibly death. Zopiclone combined with alcohol, opiates or other CNS depressants may be even more likely to lead to fatal overdoses. Zopiclone overdosage can be treated with the benzodiazepine receptor antagonist flumazenil which displaces zopiclone from its binding site on the benzodiazepine receptor thereby rapidly reversing the effects of zopiclone. Serious effects on the heart may also occur from a zopiclone overdose when combined with piperazine.

Death certificates show the number of zopiclone related deaths is on the rise. Zopiclone when taken alone usually is not fatal, however, when mixed with alcohol or other drugs such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.

Detection in biological fluids

Zopiclone may be measured in blood, plasma or urine by chromatographic methods. Plasma zopiclone concentrations are typically less than 100 μg/L during therapeutic usage, 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. Postmortem blood concentrations are usually in a range of 0.4-3.9 mg/L in victims of fatal acute overdosage.

See also

• Benzodiazepine
• Benzodiazepine dependence
• Benzodiazepine withdrawal syndrome
• nonbenzodiazepine
• Zaleplon
• Z drugs

References

1. http://www.drugs.com/cons/zopiclone.html
2. http://www.nice.org.uk/nicemedia/pdf/TA077publicinfoenglish.pdf
3. Van, Der, Kleijn, E (1989). "Effects of zopiclone and temazepam on sleep, behaviour and mood during the day". European journal of clinical pharmacology. 36 (3): 247–51. doi:10.1007/BF00558155. ISSN 0031-6970. PMID 2744064. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
4. Holbrook AM, Crowther R, Lotter A, Cheng C, King D (2000). "Meta-analysis of benzodiazepine use in the treatment of insomnia". CMAJ. 162 (2): 225–33. PMC 1232276. PMID 10674059. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
5. Blaschke, G; Hempel, G; Müller, We (1993). "Preparative and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site". Chirality. 5 (6): 419–21. doi:10.1002/chir.530050605. ISSN 0899-0042. PMID 8398600. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
6. Fernandez, C; Maradeix, V; Gimenez, F; Thuillier, A; Farinotti, R (1993). "Pharmacokinetics of zopiclone and its enantiomers in Caucasian young healthy volunteers". Drug metabolism and disposition: the biological fate of chemicals. 21 (6): 1125–8. ISSN 0090-9556. PMID 7905394. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
7. http://insomnia.emedtv.com/lunesta/generic-lunesta.html
8. "What's wrong with prescribing hypnotics?". Drug Ther Bull. 42 (12): 89–93. 2004. doi:10.1136/dtb.2004.421289. PMID 15587763. {{cite journal}}: Unknown parameter |month= ignored (help)
9. Touitou Y (2007). "". Ann Pharm Fr (in French). 65 (4): 230–8. PMID 17652991. {{cite journal}}: Unknown parameter |month= ignored (help)
10. "Benzodiazepine Names". Retrieved 26 July 2008.
11. Gorenstein C, Tavares SM, Gentil V, Peres C, Moreno RA, Dreyfus JF (1990). "Psychophysiological effects and dose equivalence of zopiclone and triazolam administered to healthy volunteers. Methodological considerations". Braz. J. Med. Biol. Res. 23 (10): 941–51. PMID 2101059.{{cite journal}}: CS1 maint: multiple names: authors list (link)
12. Gustavsen I, Bramness JG, Skurtveit S, Engeland A, Neutel I, Mørland J (2008). "Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam". Sleep Med. 9 (8): 818–22. doi:10.1016/j.sleep.2007.11.011. PMID 18226959. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
13. Verster JC, Veldhuijzen DS, Patat A, Olivier B, Volkerts ER (2006). "Hypnotics and driving safety: meta-analyses of randomized controlled trials applying the on-the-road driving test". Curr Drug Saf. 1 (1): 63–71. doi:10.2174/157488606775252674. PMID 18690916. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
14. Vermeeren A, Riedel WJ, van Boxtel MP, Darwish M, Paty I, Patat A (2002). "Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol". Sleep. 25 (2): 224–31. PMID 11905433. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
15. Giercksky, Ke; Wickstrom, E (1980). "A dose-response study in situational insomnia with zopiclone, a new tranquilizer". Clinical therapeutics. 3 (1): 21–7. ISSN 0149-2918. PMID 6996815. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
16. Ratrema M, Guy C, Nelva A; et al. (2001). "". Therapie (in French). 56 (1): 41–50. PMID 11322016. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
17. Nicholson, An; Stone, Bm (1982). "Zopiclone: sleep and performance studies in healthy man". International pharmacopsychiatry. 17 Suppl 2: 92–7. ISSN 0020-8272. PMID 7188378. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
18. Subhan, Z; Hindmarch, I (1984). "Effects of zopiclone and benzodiazepine hypnotics on search in short-term memory". Neuropsychobiology. 12 (4): 244–8. doi:10.1159/000118146. ISSN 0302-282X. PMID 6152563. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
19. Channer, Ks; Dent, M; Roberts, Cj (1984). "The effect of posture at the time of administration on the central depressant effects of the new hypnotic zopiclone". British Journal of Clinical Pharmacology. 18 (6): 879–86. ISSN 0306-5251. PMC 1463687. PMID 6529528. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
20. Monchesky, Tc; Billings, Bj; Phillips, R (1986). "Zopiclone: a new nonbenzodiazepine hypnotic used in general practice". Clinical therapeutics. 8 (3): 283–91. ISSN 0149-2918. PMID 3521857. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
21. Bocca ML, Denise P (2000). "Residual effects of hypnotics on disengagement of spatial attention". J. Psychopharmacol. (Oxford). 14 (4): 401–5. doi:10.1177/026988110001400409. PMID 11198059.
22. Hussain N, MacKinnon M, Akbari A (2003). "Zopiclone-induced acute interstitial nephritis". Am. J. Kidney Dis. 41 (5): E17. doi:10.1016/S0272-6386(03)00382-2. PMID 12778435. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
23. Moloney I, Breen EG, El Hassan H, Kelly BD (2007). "Extreme agitation occurring with zopiclone". Ir Med J. 100 (6): 511. PMID 17668690. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
24. Ferentinos P, Paparrigopoulos T (2009). "Zopiclone and sleepwalking". Int. J. Neuropsychopharmacol. 12 (1): 141–2. doi:10.1017/S1461145708009541. PMID 18925983. {{cite journal}}: Unknown parameter |month= ignored (help)
25. Warot, D; Bensimon, G; Danjou, P; Puech, Aj (1987). "Comparative effects of zopiclone, triazolam and placebo on memory and psychomotor performance in healthy volunteers". Fundamental & clinical pharmacology. 1 (2): 145–52. doi:10.1111/j.1472-8206.1987.tb00553.x. ISSN 0767-3981. PMID 3679064. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
26. Fava GA (1996). "Amnestic syndrome induced by zoplclone". Eur. J. Clin. Pharmacol. 50 (6): 509. doi:10.1007/s002280050149. PMID 8858280.
27. Silva A, Collao A, Orellana M, Meléndez J, Caviedes P, Cárdenas AM (2003). "Zopiclone, but not brotizolam, impairs memory storage during sleep". Neurosci. Res. 47 (2): 241–3. doi:10.1016/S0168-0102(03)00170-6. PMID 14512149. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
28. David M, Breton JL, Guy I, Vandel S (1998). "". Therapie (in French). 53 (1): 78–80. PMID 9773104.{{cite journal}}: CS1 maint: multiple names: authors list (link)
29. Bramness JG (1998). "". Tidsskrift for den Norske laegeforening. 118 (13): 2029–32. PMID 9656789. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
30. Luty S, Sellman D (1993). "Imovane—a benzodiazepine in disguise". N. Z. Med. J. 106 (959): 293. PMID 8321452. {{cite journal}}: Unknown parameter |month= ignored (help)
31. Deveaux M, Chèze M, Pépin G (2008). "The role of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to test blood and urine samples for the toxicological investigation of drug-facilitated crimes". Ther Drug Monit. 30 (2): 225–8. doi:10.1097/FTD.0b013e3181676186. PMID 18367985. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
32. "Hypnotic dependence: zolpidem and zopiclone too". Prescrire Int. 10 (51): 15. 2001. PMID 11503851. {{cite journal}}: Unknown parameter |month= ignored (help)
33. Wong CP, Chiu PK, Chu LW (2005). "Zopiclone withdrawal: an unusual cause of delirium in the elderly" (PDF). Age Ageing. 34 (5): 526–7. doi:10.1093/ageing/afi132. PMID 16107464. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
34. Jones IR, Sullivan G (1998). "Physical dependence on zopiclone: case reports". BMJ. 316 (7125): 117. PMC 2665371. PMID 9462317. {{cite journal}}: Unknown parameter |month= ignored (help)
35. Aranko, K; Henriksson, M; Hublin, C; Seppäläinen, Am (1991). "Misuse of zopiclone and convulsions during withdrawal". Pharmacopsychiatry. 24 (4): 138–40. doi:10.1055/s-2007-1014457. ISSN 0176-3679. PMID 1754610. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
36. Anderson, Aa (1987). "Zopiclone and nitrazepam: a multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice". Sleep. 10 Suppl 1: 54–62. ISSN 0161-8105. PMID 3326116. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
37. Begg, Ej; Robson, Ra; Frampton, Cm; Campbell, Je (1992). "A comparison of efficacy and tolerance of the short acting sedatives midazolam and zopiclone". The New Zealand medical journal. 105 (944): 428–9. ISSN 0028-8446. PMID 1297939. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
38. Dorian, P; Sellers, Em; Kaplan, H; Hamilton, C (1983). "Evaluation of zopiclone physical dependence liability in normal volunteers". Pharmacology. 27 Suppl 2: 228–34. doi:10.1159/000137931. ISSN 0031-7012. PMID 6669632. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
39. Mendelson WB, Jain B (1995). "An assessment of short-acting hypnotics". Drug Saf. 13 (4): 257–70. doi:10.2165/00002018-199513040-00005. PMID 8573298. {{cite journal}}: Unknown parameter |month= ignored (help)
40. Harter C, Piffl-Boniolo E, Rave-Schwank M (1999). "". Psychiatr Prax (in German). 26 (6): 309. PMID 10627964. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
41. sanofi-aventis Canada Inc (October 30, 2008). "IMOVANE (zopiclone) Tablets, 5.0 mg and 7.5 mg" (PDF).
42. Kahlert I (2001). "". Dtsch Med Wochenschr. 126 (22): 653–4. doi:10.1055/s-2001-14488. PMID 11450624. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
43. Professor Heather Ashton. "BENZODIAZEPINES: HOW THEY WORK AND HOW TO WITHDRAW".
44. Fontaine, R; Beaudry, P; Le, Morvan, P; Beauclair, L; Chouinard, G (1990). "Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety". International clinical psychopharmacology. 5 (3): 173–83. doi:10.1097/00004850-199007000-00002. ISSN 0268-1315. PMID 2230061. {{cite journal}}: |format= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
45. ^ WHO (2006). "World Health Organisation - Assessment of Zopiclone" (PDF). who.int.
46. Cohen, C; Sanger, Dj (1994). "Tolerance, cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps". Psychopharmacology. 115 (1–2): 86–94. doi:10.1007/BF02244756. ISSN 0033-3158. PMID 7862917. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
47. http://www.cks.nhs.uk/benzodiazepine_and_z_drug_withdrawal/management/scenario_benzodiazepine_and_z_drug_withdrawal/view_full_scenario
48. http://www.benzo.org.uk/manual/
49. EQUIVALENCY TABLE
50. Elie, R; Deschenes, Jp (1982). "Efficacy and tolerance of zopiclone in insomniac geriatric patients". International pharmacopsychiatry. 17 Suppl 2: 179–87. ISSN 0020-8272. PMID 7188374. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
51. Stebbing J (November 1, 2005). "Incidence of cancer in individuals receiving chronic zopiclone or eszopiclone requires prospective study". J Clin Oncol. 23 (31): 8134–6. doi:10.1200/JCO.2005.03.5881. PMID 16258120. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
52. ^ Kripke, Daniel F (2008). "Evidence That New Hypnotics Cause Cancer" (PDF). Department of Psychiatry, UCSD. University of California. the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer.
53. Staner L, Ertlé S, Boeijinga P; et al. (2005). "Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring" (PDF). Psychopharmacology (Berl.). 181 (4): 790–8. doi:10.1007/s00213-005-0082-8. PMID 16025317. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
54. Barbone F, McMahon AD, Davey PG; et al. (1998). "Association of road-traffic accidents with benzodiazepine use". Lancet. 352 (9137): 1331–6. doi:10.1016/S0140-6736(98)04087-2. PMID 9802269. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
55. Yasui M (2005). "". Nihon Shinkei Seishin Yakurigaku Zasshi. 25 (3): 143–51. PMID 16045197. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
56. Rettig, Hc; De, Haan, P; Zuurmond, Ww; Von, Leeuwen, L (1990). "Effects of hypnotics on sleep and psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone". Anaesthesia. 45 (12): 1079–82. doi:10.1111/j.1365-2044.1990.tb14896.x. ISSN 0003-2409. PMID 2278337. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
57. Lader, M; Denney, Sc (1982). "A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers". International pharmacopsychiatry. 17 Suppl 2: 98–108. ISSN 0020-8272. PMID 7188379. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
58. Billiard, M; Besset, A; De, Lustrac, C; Brissaud, L (1987). "Dose-response effects of zopiclone on night sleep and on nighttime and daytime functioning". Sleep. 10 Suppl 1: 27–34. ISSN 0161-8105. PMID 3326113. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
59. Bannan N, Rooney S, O'connor J (2007). "Zopiclone misuse: an update from Dublin". Drug Alcohol Rev. 26 (1): 83–5. doi:10.1080/09595230601052777. PMID 17364840. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
60. G. A. Fava (1996). "Amnestic syndrome induced by zopiclone". European Journal of Clinical Pharmacology. 50 (6). doi:10.1007/s002280050149.
61. Kuitunen T (1990). "Actions and interactions of hypnotics on human performance: single doses of zopiclone, triazolam and alcohol". Int Clin Psychopharmacol. 5 (Suppl 2): 115–30. PMID 2201724. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
62. Parker, G; Roberts, Cj (1983). "Plasma concentrations and central nervous system effects of the new hypnotic agent zopiclone in patients with chronic liver disease". British Journal of Clinical Pharmacology. 16 (3): 259–65. ISSN 0306-5251. PMC 1428012. PMID 6626417. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
63. Tada, K; Sato, Y; Sakai, T; Ueda, N; Kasamo, K; Kojima, T (1994). "Effects of zopiclone, triazolam, and nitrazepam on standing steadiness". Neuropsychobiology. 29 (1): 17–22. doi:10.1159/000119057. ISSN 0302-282X. PMID 8127419. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
64. Allain H, Bentué-Ferrer D, Tarral A, Gandon JM (2003). "Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized, cross-over, double-blind study versus placebo" (PDF). Eur. J. Clin. Pharmacol. 59 (3): 179–88. doi:10.1007/s00228-003-0591-5. PMID 12756510. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
65. Antai-Otong D (2006). "The art of prescribing. Risks and benefits of non-benzodiazepine receptor agonists in the treatment of acute primary insomnia in older adults". Perspect Psychiatr Care. 42 (3): 196–200. doi:10.1111/j.1744-6163.2006.00070.x. PMID 16916422. {{cite journal}}: Unknown parameter |month= ignored (help)
66. Upfal, Jonathan (2000) . The Australian Drug Guide (5 ed.). Melbourne: Bookman Press Pty Ltd. p. 743. ISBN 1-86395-170-9.
67. Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (2010). "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Med Rev. 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127. {{cite journal}}: Unknown parameter |month= ignored (help)
68. Bain KT (2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother. 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264. {{cite journal}}: Unknown parameter |month= ignored (help)
69. Röschke, J; Mann, K; Aldenhoff, Jb; Benkert, O (1994). "Functional properties of the brain during sleep under subchronic zopiclone administration in man". European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology. 4 (1): 21–30. doi:10.1016/0924-977X(94)90311-5. ISSN 0924-977X. PMID 8204993. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
70. Fleck MW (2002). "Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone" (PDF). J. Pharmacol. Exp. Ther. 302 (2): 612–8. doi:10.1124/jpet.102.033886. PMID 12130723. {{cite journal}}: Unknown parameter |month= ignored (help)
71. Mikkelsen JD, Søderman A, Kiss A, Mirza N (2005). "Effects of benzodiazepines receptor agonists on the hypothalamic-pituitary-adrenocortical axis". Eur. J. Pharmacol. 519 (3): 223–30. doi:10.1016/j.ejphar.2005.06.049. PMID 16125698. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
72. Petroski RE, Pomeroy JE, Das R; et al. (2006). "Indiplon is a high-affinity positive allosteric modulator with selectivity for alpha1 subunit-containing GABAA receptors" (PDF). J. Pharmacol. Exp. Ther. 317 (1): 369–77. doi:10.1124/jpet.105.096701. PMID 16399882. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
73. Atack, JR. (2003). "Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site". Curr Drug Targets CNS Neurol Disord. 2 (4): 213–32. doi:10.2174/1568007033482841. PMID 12871032. {{cite journal}}: Unknown parameter |month= ignored (help)
74. Liu HJ (1985). "Pharmacologic studies of the central action of zopiclone: effects on locomotor activity and brain monoamines in rats". Int J Clin Pharmacol Ther Toxicol. 23 (3): 121–8. PMID 2581904. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
75. Sato K (1985). "Pharmacologic studies of central actions of zopiclone: influence on brain monoamines in rats under stressful condition". Int J Clin Pharmacol Ther Toxicol. 23 (4): 204–10. PMID 2860074. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
76. Dündar, Y (2004). "Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis". Hum Psychopharmacol. 19 (5): 305–22. doi:10.1002/hup.594. PMID 15252823. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
77. Blanchard JC (1983). "Suriclone: a new cyclopyrrolone derivative recognizing receptors labeled by benzodiazepines in rat hippocampus and cerebellum". J Neurochem. 40 (3): 601–7. doi:10.1111/j.1471-4159.1983.tb08023.x. PMID 6298365. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
78. Skerritt, Jh; Johnston, Ga (1983). "Enhancement of GABA binding by benzodiazepines and related anxiolytics". European Journal of Pharmacology. 89 (3–4): 193–8. doi:10.1016/0014-2999(83)90494-6. ISSN 0014-2999. PMID 6135616. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
79. De, Deyn, Pp; Macdonald, Rl (1988). "Effects of non-sedative anxiolytic drugs on responses to GABA and on diazepam-induced enhancement of these responses on mouse neurones in cell culture". British Journal of Pharmacology. 95 (1): 109–20. ISSN 0007-1188. PMC 1854132. PMID 2905900. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
80. Julou L (1983). "Pharmacological studies on zopiclone". Pharmacology. 27 (2): 46–58. doi:10.1159/000137911. PMID 6142468. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
81. Blanchard JC (1983). "Brain receptors and zopiclone". Pharmacology. 27 (2): 59–69. doi:10.1159/000137912. PMID 6322210. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
82. Noguchi H (2004). "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats" (pdf). J Pharmacol Sci. 94 (3): 246–51. doi:10.1254/jphs.94.246. PMID 15037809. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
83. Holmes AL, Gilbert SS, Dawson D (2002). "Melatonin and zopiclone: the relationship between sleep propensity and body temperature". Sleep. 25 (3): 301–6. PMID 12003160. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
84. Trachsel L, Dijk DJ, Brunner DP, Klene C, Borbély AA (1990). "Effect of zopiclone and midazolam on sleep and EEG spectra in a phase-advanced sleep schedule". Neuropsychopharmacology. 3 (1): 11–8. PMID 2306331. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
85. Mann K, Bauer H, Hiemke C, Röschke J, Wetzel H, Benkert O (1996). "Acute, subchronic and discontinuation effects of zopiclone on sleep EEG and nocturnal melatonin secretion". Eur Neuropsychopharmacol. 6 (3): 163–8. doi:10.1016/0924-977X(96)00014-4. PMID 8880074. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
86. Wright NA, Belyavin A, Borland RG, Nicholson AN (1986). "Modulation of delta activity by hypnotics in middle-aged subjects: studies with a benzodiazepine (flurazepam) and a cyclopyrrolone (zopiclone)". Sleep. 9 (2): 348–52. PMID 3505734. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
87. Kim YD, Zhuang HY, Tsutsumi M, Okabe A, Kurachi M, Kamikawa Y (1993). "Comparison of the effect of zopiclone and brotizolam on sleep EEG by quantitative evaluation in healthy young women". Sleep. 16 (7): 655–61. PMID 8290860. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
88. Kanno O, Watanabe H, Kazamatsuri H (1993). "Effects of zopiclone, flunitrazepam, triazolam and levomepromazine on the transient change in sleep-wake schedule: polygraphic study, and the evaluation of sleep and daytime condition". Prog. Neuropsychopharmacol. Biol. Psychiatry. 17 (2): 229–39. doi:10.1016/0278-5846(93)90044-S. PMID 8430216. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
89. "Cognitive therapy superior to zopiclone for insomnia". J Fam Pract. 55 (10): 845. 2006. PMID 17089469. {{cite journal}}: Unknown parameter |month= ignored (help)
90. Baillargeon L, Landreville P, Verreault R, Beauchemin JP, Grégoire JP, Morin CM (2003). "Discontinuation of benzodiazepines among older insomniac adults treated with cognitive-behavioural therapy combined with gradual tapering: a randomized trial". CMAJ. 169 (10): 1015–20. PMC 236226. PMID 14609970. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
91. Sivertsen B, Omvik S, Pallesen S; et al. (2006). "Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial". JAMA. 295 (24): 2851–8. doi:10.1001/jama.295.24.2851. PMID 16804151. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
92. Morgan K (2004). "Psychological treatment for insomnia in the regulation of long-term hypnotic drug use" (PDF). Health Technol Assess. 8 (8). National Institute for Health Research: 1–68. PMID 14960254. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
93. Gaillot, J; Heusse, D; Hougton, Gw; Marc, Aurele, J; Dreyfus, Jf (1982). "Pharmacokinetics and metabolism of zopiclone". International pharmacopsychiatry. 17 Suppl 2: 76–91. ISSN 0020-8272. PMID 7188377. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
94. Caille, G; Du, Souich, P; Spenard, J; Lacasse, Y; Vezina, M (1984). "Pharmacokinetic and clinical parameters of zopiclone and trimipramine when administered simultaneously to volunteers". Biopharmaceutics & drug disposition. 5 (2): 117–25. doi:10.1002/bdd.2510050205. ISSN 0142-2782. PMID 6743780. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
95. Mattila, Me; Mattila, Mj; Nuotto, E (1992). "Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects". Pharmacology & toxicology. 70 (4): 286–9. doi:10.1111/j.1600-0773.1992.tb00473.x. ISSN 0901-9928. PMID 1351673. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
96. Kuitunen, T; Mattila, Mj; Seppala, T (1990). "Actions and interactions of hypnotics on human performance: single doses of zopiclone, triazolam and alcohol". International clinical psychopharmacology. 5 Suppl 2: 115–30. ISSN 0268-1315. PMID 2201724. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
97. Koski A, Ojanperä I, Vuori E (2003). "Interaction of alcohol and drugs in fatal poisonings". Hum Exp Toxicol. 22 (5): 281–7. doi:10.1191/0960327103ht324oa. PMID 12774892. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
98. Aranko, K; Luurila, H; Backman, Jt; Neuvonen, Pj; Olkkola, Kt (1994). "The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone". British Journal of Clinical Pharmacology. 38 (4): 363–7. ISSN 0306-5251. PMC 1364781. PMID 7833227. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
99. Jalava KM, Olkkola KT, Neuvonen PJ (1996). "Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone". Eur. J. Clin. Pharmacol. 51 (3–4): 331–4. doi:10.1007/s002280050207. PMID 9010708.{{cite journal}}: CS1 maint: multiple names: authors list (link)
100. Villikka K, Kivistö KT, Lamberg TS, Kantola T, Neuvonen PJ (1997). "Concentrations and effects of zopiclone are greatly reduced by rifampicin". Br J Clin Pharmacol. 43 (5): 471–4. doi:10.1046/j.1365-2125.1997.00579.x. PMC 2042775. PMID 9159561. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
101. Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, Jaillon P (1999). "Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism". Drug Metab. Dispos. 27 (9): 1068–73. PMID 10460808. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
102. Alderman CP, Gebauer MG, Gilbert AL, Condon JT (2001). "Possible interaction of zopiclone and nefazodone". Ann Pharmacother. 35 (11): 1378–80. doi:10.1345/aph.1A074. PMID 11724087. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
103. Cimolai N (2007). "Zopiclone: is it a pharmacologic agent for abuse?". Can Fam Physician. 53 (12): 2124–9. PMC 2231551. PMID 18077750. {{cite journal}}: Unknown parameter |month= ignored (help)
104. Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.
105. Hoffmann F, Pfannkuche M, Glaeske G (2008). "". Nervenarzt (in German). 79 (1): 67–72. doi:10.1007/s00115-007-2280-6. PMID 17457554. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
106. Bramness JG, Olsen H (1998). "". Tidsskr. Nor. Laegeforen. (in Norwegian). 118 (13): 2029–32. PMID 9656789. {{cite journal}}: Unknown parameter |month= ignored (help)
107. Ströhle A, Antonijevic IA, Steiger A, Sonntag A (1999). "". Nervenarzt (in German). 70 (1): 72–5. doi:10.1007/s001150050403. PMID 10087521. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
108. Sikdar S (1998). "Physical dependence on zopiclone. Prescribing this drug to addicts may give rise to iatrogenic drug misuse". BMJ. 317 (7151): 146. PMC 1113504. PMID 9657802. {{cite journal}}: Unknown parameter |month= ignored (help)
109. Kuntze MF, Bullinger AH, Mueller-Spahn F (2002). "Excessive use of zopiclone: a case report" (PDF). Swiss Med Wkly. 132 (35–36): 523. PMID 12506335. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
110. Jones AW (2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Ther Drug Monit. 29 (2): 248–60. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
111. Bramness JG, Skurtveit S, Mørland J (1999). "". Tidsskr. Nor. Laegeforen. (in Norwegian). 119 (19): 2820–1. PMID 10494203. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
112. Menzin J, Lang KM, Levy P, Levy E (2001). "A general model of the effects of sleep medications on the risk and cost of motor vehicle accidents and its application to France". PharmacoEconomics. 19 (1): 69–78. doi:10.2165/00019053-200119010-00005. PMID 11252547. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
113. Kintz P, Villain M, Ludes B (2004). "Testing for the undetectable in drug-facilitated sexual assault using hair analyzed by tandem mass spectrometry as evidence". Ther Drug Monit. 26 (2): 211–4. doi:10.1097/00007691-200404000-00022. PMID 15228167. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
114. Yanagita T. (1982). "Dependence potential of zopiclone studied in monkeys". International pharmacopsychiatry. 17 (2): 216–27. PMID 6892368. {{cite journal}}: Cite has empty unknown parameters: |month= and |coauthors= (help)
115. Mannaert E, Tytgat J, Daenens P (1996). "Detection and quantification of the hypnotic zopiclone, connected with an uncommon case of drowning". Forensic Sci. Int. 83 (1): 67–72. doi:10.1016/0379-0738(96)02018-X. PMID 8939015. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
116. Relative toxicity of benzodiazepines in overdose
117. Buckley NA, Dawson AH, Whyte IM, McManus P, Ferguson N.Correlations between prescriptions and drugs taken in self-poisoning: Implications for prescribers and drug regulation.Med J Aust (in press)
118. Buckley NA, Dawson AH, Whyte IM, O'Connell DL. (1995). "[Relative toxicity of benzodiazepines in overdose.]". BMJ. 310 (6974): 219–21. doi:10.1136/bmj.310.6974.219. PMC 2548618. PMID 7866122.{{cite journal}}: CS1 maint: multiple names: authors list (link)
119. Meatherall RC (1997). "Zopiclone fatality in a hospitalized patient". J. Forensic Sci. 42 (2): 340–3. PMID 9068198. {{cite journal}}: Unknown parameter |month= ignored (help)
120. Van Bocxlaer J, Meyer E, Clauwaert K, Lambert W, Piette M, De Leenheer A (1996). "Analysis of zopiclone (Imovane) in postmortem specimens by GC-MS and HPLC with diode-array detection". J Anal Toxicol. 20 (1): 52–4. PMID 8837952.{{cite journal}}: CS1 maint: multiple names: authors list (link)
121. Yamazaki M, Terada M, Mitsukuni Y, Yoshimura M (1998). "". Nihon Hoigaku Zasshi (in Japanese). 52 (4): 245–52. PMID 9893443. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
122. Boniface PJ, Russell SG (1996). "Two cases of fatal zopiclone overdose". J Anal Toxicol. 20 (2): 131–3. PMID 8868406.
123. Cienki, JJ (2005). "Zopiclone overdose responsive to flumazenil". Clin Toxicol (Phila). 43 (5): 385–6. PMID 16235515. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
124. Pounder, Dj; Davies, Ji (1994). "Zopiclone poisoning: tissue distribution and potential for postmortem diffusion". Forensic Science International. 65 (3): 177–83. doi:10.1016/0379-0738(94)90273-9. ISSN 0379-0738. PMID 8039775. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
125. Regouby Y, Delomez G, Tisserant A (1990). "". Therapie (in French). 45 (2): 162. PMID 2353332.{{cite journal}}: CS1 maint: multiple names: authors list (link)
126. Regouby Y, Delomez G, Tisserant A (1989). "". Therapie (in French). 44 (5): 379–80. PMID 2814922.{{cite journal}}: CS1 maint: multiple names: authors list (link)
127. Dart, Richard C. (2003). Medical Toxicology. p. 889. ISBN 978-0-7817-2845-4. {{cite book}}: Cite has empty unknown parameter: |coauthors= (help)
128. Carlsten, A (2003). "The role of benzodiazepines in elderly suicides". Scand J Public Health. 31 (3): 224–8. doi:10.1080/14034940210167966. PMID 12850977. {{cite journal}}: Cite has empty unknown parameter: |month= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
129. Harry P (1997). "". Rev Prat. 47 (7): 731–5. PMID 9183949. {{cite journal}}: Unknown parameter |month= ignored (help)
130. Bramness JG, Arnestad M, Karinen R, Hilberg T (2001). "Fatal overdose of zopiclone in an elderly woman with bronchogenic carcinoma". J. Forensic Sci. 46 (5): 1247–9. PMID 11569575. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
131. Kratzsch C, Tenberken O, Peters FT et al. Screening, library-assisted identification and validated quantification of 23 benzodiazepines, flumazenil, zaleplone, zolpidem and zopiclone in plasma by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization. J. Mass Spec. 39: 856-872, 2004.
132. Gustavsen I, Al-Sammurraie M, Mørland J, Bramness JG. Impairment related to blood drug concentrations of zopiclone and zolpidem compared to alcohol in apprehended drivers. Accid. Anal. Prev. 41: 462-466, 2009.
133. R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1677-1679.

External links

• Detailed pharmacological information
• Scheduling recommendation (PDF file)
• Details on scheduling
• Erowid zopiclone vault
• Support for Zopiclone dependency/addiction

• Cyclopyrrolones
• Pyrrolopyrazines
• Lactams
• Pyridines
• Organochlorides
• Carbamates
• Piperazines
• Sanofi
• Nonbenzodiazepines