Zopiclone

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Zopiclone
Systematic (IUPAC) name
[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
Identifiers
CAS number 43200-80-2
ATC code N05CF01
PubChem 5735
DrugBank APRD00356
Chemical data
Formula C17H17ClN6O3 
Mol. mass 388.808 g/mol
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
Therapeutic considerations
Pregnancy cat.

C(US)

Legal status

POM(UK) Schedule IV(US)

Routes Oral tablets 7.5 mg

Zopiclone (pronunciation perhaps IPA: /ˈzɒpɪkloʊn/) sold as Imovane and Zimovane 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 also available worldwide under various other trade names. It 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. Zopiclone is a controlled substance in the United States, Canada and some European countries and may be illegal to possess without a prescription.

While it acts on the BZ¹ receptor and is a short-acting hypnotic agent, it is not a benzodiazepine (with which it shares a number of characteristics and effects), but a cyclopyrrolone derivative, belonging to a novel chemical class which is structurally unrelated to existing hypnotics.

On April 4, 2005, the United States DEA listed zopiclone under Schedule IV, due to some 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 in that country, it is expected to be available in generic form by the year 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 been studied via head-to-head clinical trials to determine if any clinical differences exist (e.g., efficacy, side-effects, developing dependence on the drug, and safety, etc.).

Zopiclone is known colloquially as a "Z drug", Other Z drugs include zaleplon (Sonata) and zolpidem (Ambien and AmbienCR) and were thought in initial studies to be less addictive and less habit forming than benzodiazepines. This appraisal has shifted somewhat in the last few years, as cases of addiction and habituation have been presented. It is recommended that zopiclone is taken on a "when required" basis, and daily or continuous use of the drug is not usually advised.

Contents

[edit] 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 after withdrawal from the drug after prolonged periods of use (especially when taken more than two weeks).

[edit] More common reactions

Gastrointestinal: bitter metallic taste, dry mouth. Nervous system: drowsiness, headaches, and fatigue. Unexpected mood changes have been noted, which if experienced should lead to the drug being withdrawn from the patient.

[edit] Less common reactions

[edit] 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 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.[1]

A recent analysis of FDA and clinical trial data shows that nonbenzodiazepine Z-drugs at prescribed doses cause 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 of 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 caused 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 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".[2]

[edit] Pharmacokinetics

Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral centre and is commercially available as a racemic mixture. Methods involving high performance liquid chromatography (HPLC), gas chromatography, capillary electrophoresis (CE) and high performance thin layer chromatography have been developed for the quantification of zopiclone and its 2 main metabolites in biological samples. For the chiral determination of the enantiomers of zopiclone and its metabolites, HPLC and CE methods are available. 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. 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. Drug interactions have been observed with erythromycin, trimipramine and carbamazepine.

[edit] Pharmacology

The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover.[3][4] 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.[5] 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 modulating benzodiazepine receptors.[6] In addition to zopiclone's benzodiazepine pharmacological properties it also has some barbiturate like properties.[7][8]

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.[9]

[edit] 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.[10] Benzodiazepines act indiscriminately at α1, α2, α3 and α5 GABAA containing receptors. Zopiclone has high affinity for the α1 subunit GABAA receptor and a low to intermediate action on α2 and α3 receptors.[11] The α1, α2 and α3 GABAA receptors make up over 90% of all GABAA receptors in humans. The differences in receptor affinity and binding of zopiclone compared with benzodiazepines have led some to claims of a lower dependency risk with zopiclone.

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.[12]

High dose misuse of zopiclone and increasing popularity amongst drug abusers has also been described with zopiclone[13] Due to the risk of tolerance and physical dependence, zopiclone is only recommended for short term (less than one week) relief of insomnia, or alternatively, long term infrequent use. Long-term zopiclone users who have become physically dependent are usually recommended to cross over to an equivalent dose of diazepam (Valium), which has a much longer half life, and then gradually taper their dosage over a period of several months in order to avoid extremely severe and unpleasant withdrawal symptoms (e.g., hallucinations, seizures, anxiety, depression, psychosis, etc.) which can last up to two years after withdraw if the withdraw was done too abruptly.

According to the World Health Organisation, Zopiclone, although molecularly is not a benzodiazepine, binds unselectively with high affinity to the same benzodiazepine receptors that benzodiazepines 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.[14]

However, the risk of dependency on zopiclone when used for less than 7 consecutive days or only used occasionally is very low.[citation needed]

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.

[edit] Special precautions

Zopiclone induces impairment of motor function.[15] Driving or operating machinery should be avoided after taking zopiclone.

Zopiclone increases sway in older people. Falls are a significant cause of death in older people.

[edit] Abuse

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 suggesting a high degree of abuse potential for benzodiazepines, zolpidem and zopiclone.[16]

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.[17]

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

[edit] Overdose

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 and therefore rapidly reverses the effects of zopiclone.[18]

Death certificates show the number of zopiclone related deaths are on the rise.[19]

[edit] Availability

Generic Zopiclone 7.5 mg, as manufactored by Merck & Co
Generic Zopiclone 7.5 mg, as manufactored by Merck & Co

Zopiclone is also sold under a wide variety of other brand names world wide including:

  • Insomnium - Argentina
  • Sedolox and Somnal - Austria
  • Rhovane and Imovane - Canada
  • Alpaz, Losopil, Nuctane, Zetix, Zometic and Zonix - Chile
  • Imovane, Imoclone and Imozop - Denmark
  • Zopinox, Imovane - Finland
  • Optidorm, Ximovan, Zodurat, Zop, Zopi-Puren, Zopicalm and Zopiclodura - Germany
  • Somnosan - Germany, Portugal
  • Amvey, Eurovan, Zolief and Zomni - Hong Kong
  • Zopicon - India
  • Zileze, Zimoclone, Zopitan and Zorclone - Republic of Ireland
  • Zimovane - Republic of Ireland, United Kingdom
  • Nocturno - Israel
  • Imovane (Имован) - Argentina, Australia, Belgium, Brazil, Canada, Chile, Czech Republic, Denmark, Finland, France, Greece, Hong Kong, Hungary, Iceland, Israel, Italy, Malaysia, Mexico, Netherlands, Norway, New Zealand, Russia, South Africa, Singapore, Sweden, Switzerland, Turkey, Venezuela
  • Zopiclon - Zentiva - Bulgaria
  • Relaxon (Релаксон) and Somnol (Сомнол) - Russia
  • Alchera, Z-Dorm, Zopimed, Zopivane and Sandoz-Zopiclone - South Africa
  • Datolan, Limovan, Siaten and Zopicalma - Spain
  • Zopiklon - Denmark, Norway
  • Amoban - Japan
  • Hypnor - Egypt

[edit] References

  1. ^ Stebbing J; Waters L, Davies L, Mandalia S, Nelson M, Gazzard B, Bower M (1). "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. 
  2. ^ 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.” 
  3. ^ Liu HJ; Sato K, Shih HC, Shibuya T, Kawamoto H, Kitagawa H. (Mar 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. 
  4. ^ Sato K; Hong YL, Yang MS, Shibuya T, Kawamoto H, Kitagawa H. (Apr 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. 
  5. ^ Dündar, Y; Dodd S, Strobl J, Boland A, Dickson R, Walley T. (Jul 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. PMID 15252823. 
  6. ^ Blanchard JC; Julou L. (Mar 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. 
  7. ^ Julou L; Bardone MC, Blanchard JC, Garret C, Stutzmann JM. (1983). "Pharmacological studies on zopiclone.". Pharmacology. 27 (2): 46-58. PMID 6142468. 
  8. ^ Blanchard JC; Boireau A, Julou L. (1983). "Brain receptors and zopiclone.". Pharmacology. 27 (2): 59-69. PMID 6322210. 
  9. ^ Noguchi H; Kitazumi K, Mori M, Shiba T. (Mar 2004). "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats." (pdf). J Pharmacol Sci. 94 (3 pages = 246-51). doi:10.1254/jphs.94.246. PMID 15037809. 
  10. ^ Bramness JG; Olsen H. (1998). "[Adverse effects of zopiclone]". Tidsskrift for den Norske laegeforening. 118 (13): 2029-32. PMID 9656789. 
  11. ^ Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone
  12. ^ Physical dependence on zopiclone: case reports
  13. ^ Prescribing this drug to addicts may give rise to iatrogenic drug misuse
  14. ^ World Health Organisation - Assessment of Zopiclone
  15. ^ Yasui M; Kato A, Kanemasa T, Murata S, Nishitomi K, Koike K, Tai N, Shinohara S, Tokomura M, Horiuchi M, Abe K. (Jun 2005). "[Pharmacological profiles of benzodiazepinergic hypnotics and correlations with receptor subtypes]" 25 (3): 143-51. PMID 16045197. 
  16. ^ Jones AW; Holmgren A, Kugelberg FC. (Apr 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. 
  17. ^ Yanagita T. (1982). "Dependence potential of zopiclone studied in monkeys.". International pharmacopsychiatry. 17 (2): 216-27. PMID 6892368. 
  18. ^ Cienki, JJ; Burkhart KK, Donovan JW. (2005). "Zopiclone overdose responsive to flumazenil.". Clin Toxicol (Phila). 43 (5): 385-6. PMID 16235515. 
  19. ^ Carlsten, A; Waern M, Holmgren P, Allebeck P. (2003). "The role of benzodiazepines in elderly suicides.". Scand J Public Health. 31 (3): 224-8. PMID 12850977. 

[edit] External links