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Zopiclone 1

Zopiclone

Zopiclone

Systematic (IUPAC) name

( RS )-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylateClinical data

Trade names Imovane, Zimovane

AHFS/Drugs.com International Drug Names[1]

Pregnancy cat. C (US)

Legal status POM (UK) Schedule IV (US)

Routes Oral tablets, 3.75mg (UK), 5 or 7.5 mg

Pharmacokinetic data

Bioavailability 52-59% bound to plasma protein

Metabolism Various cytochrome P450 liver enzymes

Half-life ~6 hours

~9 hours for over 65

Excretion Urine

Identifiers

CAS number 43200-80-2[2]

ATC code N05CF01[3]

PubChemCID 5735

[4]

DrugBank DB01198[5]

ChemSpider 5533[6]

UNII 03A5ORL08Q[7]

KEGG D01372[8]

ChEBI CHEBI:32315[9]

ChEMBL CHEMBL135400[10]

Chemical data

Formula C17

H17

Cl N6O

3

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Zopiclone 2

Mol. mass 388.808 g/mol

(what is this?) (verify)[11]

Zopiclone (brand name Imovane in Canada and Australia, and Zimovane in the UK) is a non-benzodiazepine

hypnotic agent used in the treatment of insomnia. It is a cyclopyrrolone , which increases the normal transmission of the signal substance GABA in the central nervous system, as benzodiazepines do, but in a different way.

As zopiclone is sedating it is marketed as a sleeping pill. 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 stopped, withdrawal symptoms may result. These can include a range of

symptoms similar to those of benzodiazepine withdrawal.

In the United States, zopiclone is not commercially available, [12] 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. [13] Daily or continuous use of the

drug is not usually advised. [14]

Medical usesZopiclone 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 and addiction can occur with

prolonged use. [15][16]

Adverse reactionsThe 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 [17] 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. [18][19] 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 doseof alcohol. Zaleplon had no detrimental effects on driving skills the next day. [20] Daytime withdrawal related anxiety

can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone. [21]

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Zopiclone 3

More common

Gastrointestinal: taste disturbances including bitter metallic taste, dry mouth. [22][23] Nervous system: disruption of

REM sleep, double vision, drowsiness, memory impairments, visuospatial impairments, dizziness, headaches, and

fatigue. [24][25][26][27][28] Unexpected mood changes have been noted, which if experienced should lead to the drug

being withdrawn from the patient.

Less common

• 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. [29]

• Reproductive : impotence, delayed ejaculation, anorgasmia in both women and men.

• Nervous system : agitation, [30] anxiety, loss of memory including retrograde and anterograde amnesia, confusion,

dizziness, weakness, somnolence, asthenia, euphoria and/or dysphoria, feeling of drunkenness, depression, sleep

walking, [31] coordination abnormality, hypotonia, speech disorder, hallucinations of various strengths, usually

auditory and visual, behavioural disorders, aggression, tremor, rebound insomnia, nightmares,

hypomania. [32][33][34] Delirium can also occur but is a side effect mainly seen in the elderly. [35]

Tolerance, dependence and withdrawalZopiclone, 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". [36][37][38] Tolerance to the effects of

zopiclone can develop after a few weeks. Long term use should be avoided. Abrupt withdrawal particularly withprolonged and high doses can in severe cases cause seizures and delirium. [39][40]

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. [41] Suspected withdrawal

convulsions during detoxification from zopiclone has been reported, however the individual was a high dose

zopiclone misuser. [42]

The risk of dependency on zopiclone when used for less than 2 weeks or only used o ccasi onally is low. [43] How ever,

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 si gnificant problems of tolerance and dependence

than the benzodiazepines. [44] After 3 weeks of use mild to moderate rebound withdrawal symptoms appear upon

discontinuation of zopiclone. [45] 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. [46]

Long-term zopiclone users w ho have become physi cally dependent sh ould not discontinue their medication abruptly

as severe withdrawal symptoms may occur such as delirium. [47] 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. [48][49][50] After

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Zopiclone 4

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. [51]

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 substituteone 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. [52]

Zopiclone is cross tolerant with benzodiazepines. [53] Alcohol has cross tolerance with GABAA

receptor positive

modulators such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason alcoholics or recovering

alcoholics may be at increased risk of physical dependency on 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. [54][55][56] 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. [57]

Carcinogenicity

A recent analysis of both U.S. Food and Drug Administration (FDA) data and clinical tri al data shows thatnonbenzodiazepine 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. [58]

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 andpatients should be warned that hypnotics possibly place patients at higher risk for cancer". [58]

ContraindicationsZopiclone causes impaired driving skills which are similar to benzodiazepines. Long-term users of hypnotic drugs

for sleep disorders develop only 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. [59] 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. [60] Zopiclone induces impairment of psychomotor function. [61][62] Driving or operating machinery should be

avoided after taking zopiclone as effects can carry over to the next day including impaired hand eyecoordination. [63][64] Patients with a history of substance abuse should not be prescribed zopiclone, as it has a very

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Zopiclone 5

high potential for problematic drug misuse. [65] 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. [66]

Special precautionsAlcohol should be avoided when using zopiclone, as alcohol and zopiclone enhance the effects of each other and the

risk of dependence could increase. [67]

Patients with liver disease eliminate zopiclone much slower than normal patients and in addition experience

exaggerated pharmacological effects of the drug. [68]

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. [69][70][71]

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 apatient with any untreated abnormality of the thyroid gland. [72]

ElderlyZopiclone, 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. [73]

An extensive review of the medical literature regarding the management of insomnia and the elderly fou nd that ther e

is considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia. Compared withthe benzodiazepines, the nonbenzodiazepine sedative -hypnoti cs, 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. [74]

PharmacologyThe therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant and

myorelaxant properties. [75] Both zopiclone and benz odiazepin es act indiscriminately at the benzodiazepine binding

site on ‚1, ‚2, ‚3 and ‚5 GABAA

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 altho ugh it has pre dominately 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. [76][77] One study however, found some slight selectivity for zopiclone on ‚1 and ‚5 subunits. [78] Although it

is regarded as being unselective in its binding to ‚1, ‚2, ‚3 and ‚5 GABAA

benzodiazepine receptor complexes.

Desmethylzopiclone has been found to have partial agonist properties unlike the parent drug zopiclone which is a

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Zopiclone 6

full agonist. [79] The mechanism of a ction of zopiclone is s imilar to benzodiazepines, with similar effects on

locomotor activity and on dopamine and serotonin turnover. [80][81] 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. [82] 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

GABAA

receptors and enhances GABA binding at the GABAA

receptors to produce zopiclone's pharmacological

properties. [83][84][85] In addition to zopiclone's benzodiazepine pharmacological properties it also has some

barbiturate like properties. [86][87]

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 ‚1-selective

compound, increases only SWS and causes no effect on stage 2 sleep. Zopiclone is less selective to the ‚1 site andhas higher affinity to the ‚2 site than zaleplon. Zopiclone is therefore very similar pharmacologically to

benzodiazepines. [88]

EEG and sleepSimilar to other sedative hypnotic drugs zopiclone causes a decrease in the core body temperature and is effective in

decreasing sleep latency. [89] 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. [90][91]

Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude

waves. [92] Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset. [93][94]

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. [95][96][97][98]

PharmacokineticsAfter 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 t he 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 theurine 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. [99]

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Zopiclone 7

InteractionsZopiclone also interacts with trimipramine and caffeine. [100][101] Alcohol has an additive effect when combined with

zopiclone, enhancing the adverse e ff ects including the overdose potential of zopiclone significantly. [102][103]

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 ha s a similar effe ct on zopiclone

pharmacokineti cs as erythromyci n. The elderly may be parti cularly sensitive to the erythromycin and itraconazoledrug interaction with zopiclone. Temporary dosage reduction during combined therapy may be required especially in

the elderly. [104][105] 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. [106] Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone. [107]

Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next day

sedation. [108]

History

Zopiclone was developed, and first introduced in 1986, by Rhƒne-Poulenc S.A., now part of Sanofi-Aventis, themain worldwide manufacturer. Initially it was promoted as an improvement on benzodiazepines but a recent meta

analysis found that zopiclone was no better than benzodiazepines in any of the aspects assessed. [109] On April 4,

2005, the U.S. 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. [110][111] 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 mo st of the world under paten t co ntrol in the United St ates. Although it was expected to be

available in generic form by 2010, no generic has become available there at present. [112] However, Zopiclone is

currently available off-patent in a number of European countries, as well as Brazi l, Canada and H ong Kong. Theeszopiclone/zop iclone difference i s i n the dosage • the strong est 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.

Recreational useZopiclone 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. [One addictio n centre f ound that 5.1% o f drug addicts at their tr eatment center reported a zopiclone

addiction.] 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 dependen ce. Withdrawal

symptoms can be seen after long t erm use of normal doses ev en after a gradual reduction regime. The Compendium

of Pharmaceuticals and Specialties recommends that zopiclone prescriptions not exceed 7 to 10 days, owing to

concerns of addiction, drug tolerance and physical dependence. [113] 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.[114][115]

Zopiclone may be more addictive than benzodiazepines.[116]

Those with a history ofsubstance misuse or mental health disorders may be at an increased risk of high dose zopiclone misuse. [117] High

dose misuse of zopiclone and increasing popularity amongst drug abusers who have been prescribed with

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Zopiclone 8

zopiclone [118] The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts,

social isolation, worrying, sexual anhedonia and nervousness. [119]

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 forbenzodiazepines, zolpidem and zopiclone. [120][121] Zopiclone which at prescribed doses causes moderate impairment

the next day has been estimated to increase the risk of vehicle accidents by 50 percent, causing an increase of 503

excess accidents per 100,000 persons. It was recommended that zaleplon or other nonimpairing sleep aids be used

instead of zopiclone to reduce road traffic accidents. [122] Zopiclone as with other hypnotic drugs is sometimes

abused to carry out criminal acts such as sexual assaults. [123]

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. [124]

Zopiclone is in the top ten medications obtained using false prescription in France. [52]

However, due to its distinctly bitter taste it is unlikely to be covertly administered to facilitate drug-related crime

such as robbery and sexual assault. 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 he is under the influence of this drug.

OverdoseZopiclone is sometimes used as a method of suicide. [125] Zopiclone has a similar fatality index as benzodiazepine

drugs, apart from temazepam which is particularly toxic in overdosage. [126][127][128] Deaths have occurred from

zopiclone overdose, alone or in combination with other drugs. [129][130][131] Overdose of zopiclone may present with

excessive sedation, depressed respiratory function which may progress to coma and possibly death. [132] 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. [133][134] Serious effects on the heart may also occur from a zopiclone overdose [135][136] when combined

with piperazine. [137]

Death certificates show the number of zopiclone related deaths is on the rise. [138] 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. [139][140]

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Zopiclone 9

Detection in biological fluidsZopiclone may be measured in blood, plasma, or urine by chromatographic methods. Plasma zopiclone

concentrations are typically less than 100 „g/L during therapeutic usage, but frequently exceed 100 „g/L in

automotive vehicle operators arrested for impaired driving ability and may exceed 1000 „g/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. [141][142][143]

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External links• Detailed pharmacological information (http:/ / www. mentalhealth. com/ drug/ p30-i01. html)

• Scheduling recommendation (http:/ / www. erowid. org/ pharms/ zopiclone/ zopiclone_law1. pdf) (PDF file)

• Details on scheduling (http:/ / www. deadiversion. usdoj. gov/ fed_regs/ rules/ 2005/ fr0404. htm)

• Erowid zopiclone vault (http:/ / www. erowid. org/ pharms/ zopiclone/ zopiclone. html)

• Support for Zopiclone dependency/addiction (http:/ / www. non-benzodiazepines.org. uk/ )

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Article Sources and Contributors 15

Article Sources and ContributorsZopiclone Source : http://en.wikipedia.org/w/index.php?oldid=533127879 Contributors : AManWithNoPlan, Achowat, Albert Wincentz, Andrew73, Angemedic, Anthony Blunt, Aramgutang,Arcadian, Arthena, Avalyn, Axel92, BD2412, Bachrach44, Barent, Beetstra, Belovedfreak, Black-Velvet, Bobo192, BoomerAB, Bushing, Cantaloupe2, Carpetman2007, Casforty, Cerkit,Ceyockey, Chowbok, Chris the speller, Chrysaor, Cmdrjameson, CommonsDelinker, Conti, CtrlAltPoodles, DMacks, DanBealeCocks, David Kernow, Davidruben, Deskana, Dreadstar, Dvmedis,Edgar181, Ericoides, Everything Else Is Taken, Ezeu, Fotb, Furtado1, Fuzzform, Gaius Cornelius, Galaxiaad, Gr 50 10, Grafen, Ground Zero, Has4, Hetoi, Historian932, Honey, Hypnocil,Ikosse, J.delanoy, JTaylor44, Jamison Lofthouse, Jmh649, JohnCoxon, Jpo, JŠ, Kay Dekker, Kazlow101, Keithonearth, KirrVlad, Kwamikagami, Law Lord, Leandrod, Little Professor, Loudsox,Lproven, Marknagel, Markus451, Martpol, Matthew Buckley, Mentifisto, Meodipt, Mewaqua, Mgiganteus1, Mqa, MrADHD, Mykhal, Nasnema, Navicular, Necromance, Nirmos,

NotAnIP83:149:66:11, Pacula, Pashihiko, Plutonium27, Ponyo, Pseudomonas, Puck35, Qwertyasdf99, R'n'B, RedGKS, Regaudio, Rich Farmbrough, Richard Arthur Norton (1958- ), Rjwilmsi,Rmky87, Roger Roger, Ronhjones, Rudimae, Sannse, Selket, SemanticMantis, Shisha-Tom, SimonD, Smsnarr, Snowgrouse, SpiderJon, Spiral5800, StaceyGrove, Stilldoggy, Sun Creator,Sunray, Tassedethe, The Thing That Should Not Be, Thickslab, Tiagofassoni, Tins128, Tmrussell, Toddst1, Troed, Uthbrian, Vlad, Votani, Vslashg, WWGB, Waldir, Wheels1967, Wobble,Woohookitty, Wtshymanski, €•‚ƒ „…† ‡ ˆ ‰ , 196 anonymous edits

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