Introduction to Zopiclone

Zopiclone was introduced in 1986 as a safer alternative to benzodiazepine drugs, as it was believed to have less potential than benzodiazepines for developing tolerance, dependance and abuse. Zopiclone has pharmacological effects very similar to benzodiazepines. It is sedating, anxiety reducing, anticonvulsant and muscle relaxing. Zopiclone increases the action of GABA because it is a type A gamma-aminobutyric acid (GABA) receptor agonist.[2][3] Zopiclone improves sleep continuity by increasing total sleep time, reducing the time it takes to fall asleep, and reducing the number of awakenings in both insomniacs and healthy individuals. Many, but not all, studies have found zopiclone increases slow wave sleep; some report zopiclone causes a reduction of REM sleep similar to that of benzodiazepines.[4]

Using Zopiclone

Zopiclone is prescribed in oral formulation, in 5.0 mg and 7.5 mg doses.
Eszopiclone (Lunesta), the active stereoisomer of zopiclone, is prescribed in oral formulation in 1 mg, 2 mg, and 3mg doses.

Ways of Administration

Oral administration of Zopiclone

Zopiclone has oral bioavailability >75%, so oral administration is standard and effective. The standard therapeutic dose of zopiclone is 3.75-15 mg, taken shortly before bed for insomnia.[5]

Snorting Zopiclone

Insufflation (snorting) is not a recommended route of administration because zopiclone is not water soluable, and so will not be absorbed by the mucous membranes. Any sedative effect from snorting zopiclone will result from it dripping down to the stomach and being absorbed.[6]

Plugging Zopiclone

Effects of Zopiclone

As a sedative/hypnotic zopiclone reduces central nervous system activity and causes relaxation and drowsiness. Taken as prescribed, zopiclone will reduce sleep latency (the time it takes to fall asleep), increase total sleep time, and reduce REM sleep. A bad metalic taste and amnesia are commonly reported side-effects of zopiclone use.[7]

Combinations with Zopiclone

Central nervous system depressants like alcohol and benzodiazepines have an additive effect if taken with zopiclone, significantly increasing the risk of adverse sedative effects. Opiate and opioid drugs can also have an additive effect when combined with zopiclone, raising the risk of adverse effects such as respiratory depression.
Zopiclone is known to interact with a number of medications. Medications which increase zopiclone's effects are erythromycin (antibiotic), itraconazole (antifungal), sulfaphenazole (antibacterial).[8][9]
Medications which decrease zopiclone's effects are rifampicin (antibiotic), ketoconazole (antifungal), phenytoin (anticonvulsant) and carbamazepine (anticonvulsant).[10][11]

Different Uses for Zopiclone

Pharmacology of Zopiclone

Zopiclone is hypnotic, anti-anxiety, anticonvulsant, and muscle relaxing in its effects. Both slow wave and Stage 2 sleep are increased by zopiclone.[12] Although it is not a benzodiazapine, zopiclone acts in a pharmacologically similar way, enhancing GABA through binding at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors. Both zopiclone and its active metabolite desmethylzopiclone also inhibit NMDA and nAChRs receptors. It has been theorized that zopiclone's inhibition of NMDA and nAChRs receptors is implicated in the addictive properties of zopiclone.[13]
Zopiclone is metabolized in the liver by demethylation, decarboxylation, and side chain oxidation producing metabolites including a weakly active N-oxide derivative and an inactive N-desmethyl metabolite. Approximately half of a dose of zopiclone is converted to other inactive metabolites via decarboxylation. Zopiclone has a half-life of between 3.5 and 8 hours.[14]

Chemistry of Zopiclone

Column 1	Column 2
Systematic (IUPAC) name:	6-(5-chloropyridin-2-yl)-7-oxo-5H,6H,7H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate
Synonyms:	4-methyl-1-piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester, 6-(5-chloropyridin-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, RP-27267, Amoban, Imovane, Limovan, Sopivan, Ximovan, Zimovane, (±)-Zopiclone, Rhovane, Zopiclona, Zopiclonum; Eszopiclone, Estorra, Lunesta (S-form)
Molecular Formula:	C17H17ClN6O3
Molar mass:	388.81 g/mol
CAS Registry Number:	43200-80-2, 138729-47-2 (S-form)
Melting Point:	178°C, 206.5°C (S-form)
Boiling Point:	no data
Flash Point:	no data
Solubility:	freely soluble in chloroform and methylene chloride; soluble in dimethylformamide and 0.1 N hydrochloric acid; slightly soluble in acetone; nearly insoluble in water, ethanol, or ethyl ether. (not verified)
Additionnal data:	none
Notes:	freebase crystallized from acetonitrile/diisopropyl ether 1:1; S-form crystallized from acetonitrile

[1]

The Dangers of Zopiclone

Physical health risks

Withdrawal Seizures

Zopiclone withdrawal involves risk of seizure, especially if zopiclone is abruptly stopped or when doses of zopiclone have been increased beyond normal therapeutic amounts.[15]

Next day impairment

A single 7.5 mg dose of zopiclone has been demonstrated to disrupt cognition, memory, and driving and psychomotor performance the morning following bedtime administration.[16]

Others

Severe drowsiness, dyspnea, skin rash.[17]

Zopiclone Overdose

Reported deaths

Deaths due to zopiclone toxicity have been reported but are rare. The fatal toxicity rate for zopiclone is not significantly different from that for benzodiazepines as a group, though lower than alprazolam (xanax) and chlormethiazole. Hypnosedatives like zopiclone are more frequently contributory factors rather than primary substances in poisoning deaths.[18]

Mental health risks

Aggressiveness, loss of inhibitions, confusion, and daytime anxiety

Behaviorial changes associated with use of zopiclone including aggressiveness and extroversion, loss of inhibitions, confusion, daytime anxiety and/or restlessness.[19]

Disturbed thought patterns and amnesia

Zopiclone use is associated with disturbed cognition, including abnormal thoughts, depersonalization, hallucinations, and illusions, and extreme agitation.[20][21]

Sleep-walking and other complex behaviours

There have been many reports of people engaging in complex behaviors while still asleep from taking zopiclone, include sleepwalking, preparing food and eating and even driving cars.[22]

ZopicloneAddiction

Physical Addiction of Zopiclone

Zopiclone should not be abruptly stopped, as this can cause withdrawal symptoms similar to those seen in benzodiazapine withdrawal, including anxiety, rebound insomnia, tremors, tachycardia, and seizures.[23]

Mental Addiction of Zopiclone

Zopiclone presents some risk of dependence, tolerance and abuse, though the level of risk has been found to be significantly lower for zopiclone than that of benzodiazapines prescribed for sleep difficulties.[24][25]

Legal Status of Zopiclone

Zopiclone is a controlled substance 21 CFR 1308.14

United Nations

Australia

Canada

Zopiclone is not a scheduled substance in Canada's Controlled Drugs and Substances Act (March 2012), but is a Schedule F drug under Canada's Food and Drugs Act, which means zopiclone may only be dispensed to someone with a prescription.

EU

Germany

UK

Zopiclone is a prescription only medication (POM) in the UK and may only be despensed with a valid doctors prescription[26][27]

Ireland

Zopiclone is a Prescription only drug, not controlled under the 1977 Misuse of drugs act or any subsequent amendments [28]

New Zealand

USA

The United States Drug Enforcement Administration lists zopiclone under Schedule IV, due to evidence that zopiclone has addictive properties similar to benzodiazepines.
Zopiclone is not commercially available in the United States, though oral preparations of zopiclone's active stereoisomer eszopiclone are commercially available (Lunesta).

History of Zopiclone

More Zopiclone Sections

References

1. ^Skerritt, Jh; Johnston, Ga. Enhancement of GABA binding by benzodiazepines and related anxiolytics. European Journal of Pharmacology. 1983;89(3-4):193–8.
2. ^Skerritt, Jh; Johnston, Ga. Enhancement of GABA binding by benzodiazepines and related anxiolytics. European Journal of Pharmacology. 1983;89(3-4):193–8.
3. ^Cimolai N. Zopiclone: Is it a pharmacological agent for abuse? Canadian Family Physician. 2007;53(12):2124–9.
4. ^Hemmeter, U., Müller, M., Bischof, R., Annen, B., Holsboer-Trachsler, E. Effect of zopiclone and temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers. Psychopharmacology. 2000;147(4):384-396.
5. ^ Gaillot J, Heusse D, Hougton GW, Marc Aurele J, Dreyfus JF. Pharmacokinetics and metabolism of zopiclone. Pharmacology. 1983;27(Suppl 2):76-91.
6. ^ Gaillot J, Heusse D, Hougton GW, Marc Aurele J, Dreyfus JF. Pharmacokinetics and metabolism of zopiclone. Pharmacology. 1983;27(Suppl 2):76-91.
7. ^ Warot, D; Bensimon, G; Danjou, P; Puech, Aj. Comparative effects of zopiclone, triazolam and placebo on memory and psychomotor performance in healthy volunteers. Fundamental & Clinical Pharmacology. 1987;1(2):145–52.
8. ^Aranko, K; Luurila, H; Backman, Jt; Neuvonen, Pj; Olkkola, Kt. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone. British Journal of Clinical Pharmacology. 1994; 38(4): 363–7.]
9. ^Jalava KM, Olkkola KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone. European Journal of Clinical Pharmacology. 1996;51(3-4):331–4.]
10. ^Villikka K, Kivistö KT, Lamberg TS, Kantola T, Neuvonen PJ. Concentrations and effects of zopiclone are greatly reduced by rifampicin. British Journal of Clinical Pharmacology. 1997; 43(5): 471–4.
11. ^Becquemont L, Mouajjah S, Escaffre O, Beaune P, Funck-Brentano C, Jaillon P. Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism. Drug Metabolism and Disposition. 1999;27(9):1068–73.
12. ^Röschke, J; Mann, K; Aldenhoff, Jb; Benkert, O. Functional properties of the brain during sleep under subchronic zopiclone administration in man. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology. 1994;4(1):21–30.
13. ^Fleck MW. Molecular actions of (S)-desmethylzopiclone (SEP-174559), an anxiolytic metabolite of zopiclone. Journal of Pharmacology and Experimental Therapeutics. 2002;302(2):612–18.
14. ^Gaillot, J; Heusse, D; Hougton, Gw; Marc, Aurele, J; Dreyfus, Jf. Pharmacokinetics and metabolism of zopiclone. Pharmacology. 1982;17(Suppl. 2):76–91.
15. ^Cubała WJ, Landowski J. Seizure following sudden zolpidem withdrawal. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:539–540.
16. ^Mets, Monique A J; De Vries, Juna M; De Senerpont Domis, Lieke M; Volkerts, Edmund R; Olivier, Berend; Verster, Joris C. Next-day effects of ramelteon (8 mg), zopiclone (7.5 mg), and placebo on highway driving performance, memory functioning, psychomotor performance, and mood in healthy adult subjects. Sleep. 2011;34(10):1327-34.
17. ^Monchesky, Tc; Billings, Bj; Phillips, R. Zopiclone: a new nonbenzodiazepine hypnotic used in general practice. Clinical Therapeutics. 1986;8(3):283–91.
18. ^Reith DM; Fountain J; McDowell R; Tilyard M. Comparison of the fatal toxicity index of zopiclone with benzodiazepines. Journal Of Toxicology. Clinical Toxicology. 2003;41(7):975-80.
19. ^ Monchesky, Tc; Billings, Bj; Phillips, R. Zopiclone: a new nonbenzodiazepine hypnotic used in general practice. Clinical Therapeutics. 1986;8(3):283–91.
20. ^Moloney I, Breen EG, El Hassan H, Kelly BD. Extreme agitation occurring with zopiclone. Irish Medical Journal. 2007; 100(6): 511.
21. ^Monchesky, Tc; Billings, Bj; Phillips, R. Zopiclone: a new nonbenzodiazepine hypnotic used in general practice. Clinical Therapeutics. 1986;8(3):283–91.
22. ^Ferentinos P, Paparrigopoulos T. Zopiclone and sleepwalking. International Journal of Neuropsychopharmacology. 2009;12(1):141–2.
23. ^Cimolai N. Zopiclone: Is it a pharmacological agent for abuse? Canadian Family Physician. 2007;53(12):2124–9.
24. ^Hajak, G; Müller, WE; Wittchen, HU; D. Pittrow, D; Kirch, W. Abuse and Dependence Potential for the Non-benzodiazepine Hypnotics Zolpidem and Zopiclone: A Review of Case Reports and Epidemiological Data. Addiction. 2003;98:1371–1378.
25. ^Hajak, G. A comparative assessment of the risks and benefits of zopiclone: a review of 15 years' clinical experience. Drug safety: an international journal of medical toxicology and drug experience. 1999;21(6):457-69.
26. ^Mims.co.uk
27. ^The Prescription Only Medicines (Human Use) Order 1997.
28. ^Zopiclone misuse: an update from Dublin. Drug and Alcohol Review. 26(1):83-5.

[1]Merck Index, fifteenth edition (2013)