Zopiclone, effects

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

Voderholzer U, Riemann D, Hornyak M, et al A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin Neurosci 251 117-123, 2001... 

Hebert C, Delaney JA, Hemmelgarn B et al. (2007) Benzodiazepines and elderly drivers a comparison of pharmacoepidemiological study designs. Pharmacoepidemiol Drag Saf 16(8) 845-849 Hemmeter U, Muller M, Bischof R et al. (2000) Effect of zopiclone and temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers. Psychopharmacology (Berl) 147(4) 384-396... 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

Related hypnotics that also act at benzodiazepine receptors are the newer agents zolpidem, a imida-zopyridine, zaleplon a pyrazolopyrimidine and the cyclopyrrolone zopiclone. Zopiclone might have a role for the treatment of benzodiazepine addiction. In patients in whom zopiclone was substituted for a benzodiazepine for 1 month and then itself abmptly terminated, improved sleep was reported during the zopiclone treatment, and withdrawal effects were absent on discontinuation of zopiclone. A series of non-sedating anxiolytic drugs derived from the same structural families as the above mentioned nonbenzodiazepines, have been developed, such as alpi-dem and pagoclone. 

The cyclopyrrolone zopiclone was one of the first compounds other than the benzodiazepines to be shown to bind at the benzodiazepine receptor. More potent compounds have also been developed (e.g., suriclone and pagoclone). The cyclopyrrolones may actually bind to a different domain on the a subunit from the benzodiazepines (Canton and Doble 1992), and this may underlie the pharmacological differences seen in vivo, that is, lack of some side effects and lack of tolerance after long-term dosing. 

Zopiclone. Zopiclone is a full agonist that has been shown to have sedative properties in experimental animals and to be a potent hypnotic in humans. It has a short duration of action and minimal effects on sleep architecture, which means that it has few residual effects on waking. It appears to cause less tolerance and problems on withdrawal than the classic benzodiazepines and is currently marketed as a hypnotic. 

This non-BZD hypnotic, cyciopyrroione, is indicated for short-term management of insomnia. Zopiclone has a BZD-like profile, a short half-life of 3.5 to 6.5 hours, no active metabolites, minimal rebound effects, and less abuse potential than BZDs. The usual therapeutic dose is oral 7.5 mg administered 30 to 60 minutes before bedtime. Zopiclone has a well-documented capacity to reduce sleep latency, improve quality and duration of sleep, and reduce the frequency of nighttime awakenings. In clinical trials, 7.5 mg doses of zopiclone have been found to be as effective as triazolam 0.5 mg, temazepam 20 mg, flurazepam 15-30 mg, and nitrazepam 5 to 10 mg for the short-term treatment of insomnia (136). 

Zopiclone is relatively well tolerated (137). The most common adverse reaction is taste alteration. A postmarketing analysis of 10,000 cases revealed that zopiclone has a relatively low incidence of side effects (about 8%) (138). Like BZDs, zopiclone has a dose-related hangover effect (139). Rebound insomnia has occurred after short-term use (5 to 14 days) but does not appear to be as severe, even after abrupt withdrawal (140, 141). Abuse, tolerance, and physical and psychological dependence have been reported with zopiclone (142). Zopiclone has been shown to be as effective a hypnotic as triazolam in the elderly ( 143). More comparisons with short to medium half-life BZDs for the treatment of insomnia are needed to show that zopiclone has an advantage over the BZDs. 

Lader M, Denney SC. A double-blind study to establish the residual effects of zopiclone on performance in healthy volunteers. Pharmacology 1983 27(suppl 2) 98-108. 

Rettig, H.C. et al., Effects of hypnotics on sleep and psychomotor performance a double-blind randomized study of lormetazepam, midazolam and zopiclone, Anaesthesia, 45, 1079, 1990. 

The rapid resolution of symptoms and correction of the hyponatremia after withdrawal was consistent with an effect of zopiclone. 

FIGURE 7 The effects of selected organic solvents on the enantioselectivity of zopiclone on a -CD-based CSP. (From Ref. 109.)... 

On the other hand, hypnotics, although they improve total sleep time as well as sleep onset latency during short-term use, induce rebound insomnia after cessation of treatment [56, 57], This is pertinent not only for the short half-life benzodiazepines, but also for newer hypnotic drugs such as zolpidem [58], whereas when they were first launched, there were reports of a more favorable profile for rebound insomnia and daytime anxiety [59], Moreover, a recent review of controlled trials that compared benzodiazepines to the Z-drugs (zaleplon, zolpidem and zopiclone), for short-term management of insomnia, concludes that short-term-acting drugs are equally effective [60],... 

Allain H, Bentue-Ferre D, Tarral A, Gandon JM (2004) 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. EurJ Clin Pharmacol 59 179-188... 

The (S)-isomer of zopiclone (eszopiclone) is now available for the treatment of insomnia. (S)-zopiclone is responsible for the hypnotic effect of zopiclone, whereas the (R)-isomer has no hypnotic properties [25], Eszopiclone is rapidly absorbed and achieves peak plasma concentrations 1 h after its administration. Its ti/2, including the N-oxide metabolite, is approximately 5-7 h [26]. 

Zopiclone exhibits an adverse-effect profile similar to that of the shorter acting benzodiazepines. Hence, poor quality of awakening, drowsiness, tiredness, nightmares, and a dry or bitter taste in the mouth have been reported. The bitter taste is the main reason for treatment discontinuation [80], Zopiclone also impairs memory and psychomotor performance within the first few hours after administration [77, 81],... 

Carlson JN, Haskew R,WackerJ, Maisonneuve IM, Glick SD, JerussiTP(2001) Sedative and anxiolytic effects of zopiclone s enantionmers and metabolite. Eur J Pharmacol 415 181-189... 

Mamelak M, Csima A, Price V (1983) Effects of zopiclone on the sleep of chronic insomniacs. Pharmacology 27 156-164... 

Petre Quadens O, Hoffman G, Buytaert G (1983) Effects of zopiclone as compared to flurazepam on sleep in women over 40 years of age. Pharmacology 27 (Suppl 2) 146-155... 

Tiberge M, Calvet U, Khayi N, Delahye C, Arbus L (1988) Comparison of the effects of zopiclone and triazolam on sleep in healthy subjects. Encephale 14 319-324... 

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