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==Contraindications==
==Contraindications==
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.<ref>{{cite journal |author=Barbone F, McMahon AD, Davey PG, ''et al'' |title=Association of road-traffic accidents with benzodiazepine use |journal=Lancet |volume=352 |issue=9137 |pages=1331–6 |year=1998 |month=October |pmid=9802269 |doi= 10.1016/S0140-6736(98)04087-2|url=http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)04087-2/fulltext}}</ref> Zopiclone induces impairment of psychomotor function.<ref>{{cite journal |author=Yasui M |coauthors=Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K |title=[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes] |volume=25 |issue=3 |pages=143–51 |month=June |year=2005 |pmid=16045197 |journal=Nihon Shinkei Seishin Yakurigaku Zasshi }}</ref><ref>{{ cite journal |pmid=2278337 |url= |format= |year=1990 |month=Dec |author=Rettig, Hc; De, Haan, P; Zuurmond, Ww; Von, Leeuwen, L |title=Effects of hypnotics on sleep and psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone. |volume=45 |issue=12 |pages=1079–82 |issn=0003-2409 |journal=Anaesthesia |doi=10.1111/j.1365-2044.1990.tb14896.x }}</ref> Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day including impaired hand eye coordination.<ref>{{ cite journal |pmid=7188379 |year=1982 |month= |author=Lader, M; Denney, Sc |title=A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers. |volume=17 Suppl 2 |issue= |pages=98–108 |issn=0020-8272 |journal=International pharmacopsychiatry }}</ref><ref>{{ cite journal |pmid=3326113 |url= |year=1987 |month= |author=Billiard, M; Besset, A; De, Lustrac, C; Brissaud, L |title=Dose-response effects of zopiclone on night sleep and on nighttime and daytime functioning. |volume=10 Suppl 1 |issue= |pages=27–34 |issn=0161-8105 |journal=Sleep }}</ref>
Zopiclone causes impaired driving skills. 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.<ref>{{cite journal |author=Staner L, Ertlé S, Boeijinga P, ''et al'' |title=Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring |journal=Psychopharmacology (Berl.) |volume=181 |issue=4 |pages=790–8 |year=2005 |month=October |pmid=16025317 |doi=10.1007/s00213-005-0082-8 |url=http://www.springerlink.com/content/q3742117g8140426/fulltext.pdf |format=PDF}}</ref> 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.<ref>{{cite journal |author=Barbone F, McMahon AD, Davey PG, ''et al'' |title=Association of road-traffic accidents with benzodiazepine use |journal=Lancet |volume=352 |issue=9137 |pages=1331–6 |year=1998 |month=October |pmid=9802269 |doi= 10.1016/S0140-6736(98)04087-2|url=http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)04087-2/fulltext}}</ref> Zopiclone induces impairment of psychomotor function.<ref>{{cite journal |author=Yasui M |coauthors=Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K |title=[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes] |volume=25 |issue=3 |pages=143–51 |month=June |year=2005 |pmid=16045197 |journal=Nihon Shinkei Seishin Yakurigaku Zasshi }}</ref><ref>{{ cite journal |pmid=2278337 |url= |format= |year=1990 |month=Dec |author=Rettig, Hc; De, Haan, P; Zuurmond, Ww; Von, Leeuwen, L |title=Effects of hypnotics on sleep and psychomotor performance. A double-blind randomised study of lormetazepam, midazolam and zopiclone. |volume=45 |issue=12 |pages=1079–82 |issn=0003-2409 |journal=Anaesthesia |doi=10.1111/j.1365-2044.1990.tb14896.x }}</ref> Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day including impaired hand eye coordination.<ref>{{ cite journal |pmid=7188379 |year=1982 |month= |author=Lader, M; Denney, Sc |title=A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers. |volume=17 Suppl 2 |issue= |pages=98–108 |issn=0020-8272 |journal=International pharmacopsychiatry }}</ref><ref>{{ cite journal |pmid=3326113 |url= |year=1987 |month= |author=Billiard, M; Besset, A; De, Lustrac, C; Brissaud, L |title=Dose-response effects of zopiclone on night sleep and on nighttime and daytime functioning. |volume=10 Suppl 1 |issue= |pages=27–34 |issn=0161-8105 |journal=Sleep }}</ref>


==Special precautions==
==Special precautions==

Revision as of 10:01, 20 December 2008

Zopiclone
Clinical data
Routes of
administration		Oral tablets, 5 or 7.5 mg
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability52-59% bound to plasma protein
MetabolismVarious cytochrome P450 liver enzymes
Elimination half-life~6 hours
~9 hours for over 65
ExcretionUrine
Identifiers
  • [8-(5-chloropyridin-2-yl)- 7-oxo-2,5,8-triazabicyclo [4.3.0]nona-1,3,5-trien-9-yl] 4- methylpiperazine-1-carboxylate
CAS Number
PubChem CID
DrugBank
CompTox Dashboard (EPA)
ECHA InfoCard100.051.018 Edit this at Wikidata
Chemical and physical data
FormulaC17H17ClN6O3
Molar mass388.808 g/mol g·mol−1

Zopiclone (pronunciation perhaps /ˈzɒpɪkloʊn/), sold as Imovane, Zimovane and Zopinox in Europe and Canada, and as the eszopiclone analogue Lunesta in the United States, is a novel hypnotic agent used in the treatment of insomnia. Zopiclone is a controlled substance in the United States, Canada 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 an "as needed" basis. Daily or continuous use of the drug is not usually advised.[1] While it 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.[2]

History

Zopiclone was first developed by Sepracor 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.[3] 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.[4][5] 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 is expected to be available in generic form in that country by 2010. It is already available off-patent in a number of European countries as well as Brazil. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone derivative dosage contains 3mg of the therapeutic stereoisomer, whereas, the highest zopiclone dosage (7.5mg) contains 3.75mg 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).

Indications

Zopiclone is indicated for the short term treatment of insomnia.[6]

Pharmacology

The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant and myorelaxant properties.[7] Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 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 although it 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.[8][9] The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover.[10][11] 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.[12] 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.[13][14][15] In addition to zopiclone's benzodiazepine pharmacological properties it also has some barbiturate like properties.[16][17]

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.[18]

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. Less than 7% of the administered dose is renally excreted as unchanged zopiclone. 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.[19]

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).

More common reactions

Gastrointestinal: taste disturbances including bitter metallic taste, dry mouth.[20][21] Nervous system: disruption of REM sleep, double vision, drowsiness, memory impairments, visuospatial impairments, dizziness, headaches, and fatigue.[22][23][24][25][26] Unexpected mood changes have been noted, which if experienced should lead to the drug being withdrawn from the patient.

Less common reactions

Contraindications

Zopiclone causes impaired driving skills. 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.[32] 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.[33] Zopiclone induces impairment of psychomotor function.[34][35] Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day including impaired hand eye coordination.[36][37]

Special precautions

Alcohol should be avoided when using zopiclone as alcohol and zopiclone enhance the effects of each other.[38]

Patients with liver disease eliminate zopiiclone much slower than normal patients and in addition experience exagerated pharmacological effects of the drug.[39]

Zopiclone increases sway which may be of particular concern for older people. Falls are a significant cause of death in older people.[40][41]

Interactions

Zopiclone also interacts with trimipramine and caffeine.[42][43] Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly.[44][45] 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.[46] Carbamazepine also has additive effects when combinded with zopiclone with both drugs enhancing the side effects of each other.[47] 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.[48][49] Rifampicin causes a very notible 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.[50] Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone.[51] Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next day sedation.[52]

Availability

Generic Zopiclone 7.5 mg, as manufactored by Merck & Co

Zopiclone is also sold under a wide variety of other brand names world wide. It is sold under the following brand names in English speaking countries.[53]

  • Rhovane and Imovane - Canada
  • Zimovane - United Kingdom
  • Imovane - Australia, New Zealand
  • Zileze, Zimoclone, Zimovane, Zopitan, Zorclone - Ireland
  • Alchera, Imovane, Z-Dorm, Zopimed, Zopivane - South Africa

Tolerance, dependence and withdrawal

Zopiclone 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.[54] 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 delerium.[55][56]

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.[57] Suspected withdrawal convulsions during detoxification from zopiclone has been reported, however the individual was a high dose zopiclone misuser.[58]

The risk of dependency on zopiclone when used for less than 2 weeks or only used occasionally is low.[59] 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 occured suggesting that zopiclone may have even more significant problems of tolerance and dependence than the benzodiazepines.[60] After 3 weeks of use mild to moderate rebound withdrawal symptoms appear upon discontinuation of zopiclone.[61] 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.[62] Long-term zopiclone users who have become physically dependent should not discontinue their medication abruptly as severe withdrawal symptoms may occur such as delerium.[63] 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.[64][65][66] 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.[67]

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.[68]

Zopiclone is cross tolerant with benzodiazepines.[69] 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.

Carcinogenicity

Zopiclone may be carcinogenic and mutagenic according to rat, mice and hamster studies. It should be noted that, 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 immunocompetant patients.[70]

A recent analysis of 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. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer and malignancies. There have been 15 epidemiologic studies which have shown that hypnotic drugs cause increased mortality, mainly due to increased cancer deaths. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and neoplasms. Initially FDA reviewers did not want to approve the drugs due to concerns over cancer but ultimately changed their mind and approved the drugs despite the concerns. FDA data has shown that zolpidem, zaleplon and eszopiclone are clastogenic and cause cancer in rodents. Benzodiazepine agonists are associated with an increased risk of ovarian cancer in humans. Zopiclone was reportedly refused a product license by the FDA in the USA due to indications that zopiclone could cause the development of cancer. Development of a malignant neoplasm has been associated with zolpidem usage but the rate of incidence of neoplasm in zolpidem users is as yet unknown. The rates, in clinical trials for the nonbenzodiazepine Z drugs, of malignancies and neoplasms are significantly higher in hypnotic groups than in placebo groups. Also the analysis of clinical trials and FDA data showed that eszopiclone, zaleplon, and zolpidem appeared to have an adverse effect on the immune system, causing an increased rate of infections and colds in hypnotic users. Suppression of immune function might be the cause of the increased rate of cancer in nonbenzodiazepine hypnotic users. Indiplon another nonbenzodiazepine drug has also shown an increased rate of cancers in clinical trials. The review author concluded 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".[71]

Abuse

Zopiclone may be more addictive than benzodiazepines.[72] Those with a history of substance misuse or a mental health disorders may be at an increased risk of high dose zopiclone misuse.[73] High dose misuse of zopiclone and increasing popularity amongst drug abusers has been described with zopiclone[74] The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia and nervousness.[75]

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.[76][77] Zopiclone which at prescribed doses causes moderate impairment the next day has been estimated to increase the risk of vehicile accidents by 50%, causing an increase by 503 excess accidents per 100,00 persons. It was recommended that zaleplon or other non-impairing sleep aids are used instead of zopiclone to reduce road traffic accidents.[78] Zopiclone as with other hypnotic drugs sometimes abused to carry out criminal acts such as sexual assaults.[79]

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.[80]

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

Overdose

Zopiclone is sometimes used as a method of suicide.[81] Zopcilone has a similar fatality index as benzodiazepine drugs, apart from alprazolam which is particularly toxic in overdosage.[82] Deaths have occured from zopiclone overdose, alone or in combination with other drugs.[83][84][85] Overdose of zopiclone may present with excessive sedation, depressed respiratory function which may progress to coma and possibly death.[86] 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.[87][88]

Death certificates show the number of zopiclone related deaths is on the rise.[89] Zopiclone, when taken alone usually is not fatal however, when mixed with alcohol or other drugs eg opioids or in patients with respiratory or hepatic disorders the risk of a serious and fatal overdose increases significantly.[90][91]

Zopiclone is a Schedule IV controlled drug.[92]

See also

References

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