Zopiclone insomnia

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. 

Of the non-benzodiazepines that have been introduced recently for the treatment of anxiety and insomnia, buspirone and zopiclone have been the most extensively investigated so far. The pharmacokinetic characteristics of... 

Individuals on very small amounts of heroin are prescribed diazepam for anxiety, agitation or craving, zopiclone or zolpidem for insomnia, hyoscine butylbromide (Buscopan) for stomach cramps, and diphenoxylate/atropine (Lomotil) for diarrhoea, over a seven-day period. The medication schedule provided to the user explains which drug is for which symptoms, and the maximum doses of each that can be taken in a day, which for diazepam varies during the course. The basic medication regime is included in the Appendix. 

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. 

The newer sedative-hypnotics that are not benzodiazepines are rapidly becoming the first-line treatment for insomnia. These agents not only have pharmacodynamic advantages over benzodiazepines in terms of their mechanism of action, but perhaps more importantly, pharmacokinetic advantages as well. Three nonbenzodiazepine sedative-hypnotic agents that are now available are zaleplon (a pyrazolopyrimidine), zopiclone (a cyclopyrrolone not available in the United States), and zolpidem (an imidazopyridine) (Figs. 8—28-8—30 Table 8—4). 

The nonbenzodiazepine sedative-hypnotics zaleplon, zolpidem, and zopiclone are replacing benzodiazepine sedative-hypnotics as first-line treatments for insomnia. Some antidepressants, such as sedating tricyclic antidepressants and trazodone, are also used as sedative-hypnotic agents for the treatment of insomnia. 

A woman with a 2-week history of insomnia took zopiclone 7.5 mg nightly and over the next 9 days became confused, lethargic, and depressed, culminating in an overdose of six zopiclone tablets. Her previous medical history included hypertension and two episodes of diuretic-induced SIADH. Her serum sodium was 129 mmol/1 and 4 days later fell to 113 mmol/1. Her serum osmolality was low (240 mmol/kg) and her urine sodium was 20 mmol/1. The serum sodium returned to normal 12 days after withdrawal of zopiclone. 

Terzano MG, Rossi M, Palomba V, Smerieri A, Parri-no L. New drugs for insomnia comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf. 2003 26 261-282. 

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],... 

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]. 

Noble S, Langtry HD, Lamb H M (1998) Zopiclone An update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia. Drugs 55 277-302... 

Allain H, Delahaye C, Le Coz F, Blin P, Decombe R, Martinet JP (1991) Postmarketing surveillance of zopiclone in insomnia analysis of 20513 cases. Sleep 14 408 -13... 

A range of medications is available to treat insomnia, ranging from herbal preparations such as valerian to the recently introduced z compounds, zopiclone, zolpidem and zaleplon. Many drugs used for other primary purposes have sedative and sleep-inducing properties as side effects these include many tricyclic antidepressants and antihistamines. 

Since 1987 when zopiclone was introduced into clinical practice, extensive evaluations have shown that some rebound changes can be detected in healthy individuals [22-24], In patients with insomnia more than 20 studies have assessed rebound. Rebound can be found in such patients [25,26], but is usually more frequent and present in greater intensity in comparison groups given triazolam. 

Studies in the elderly have been carefully reviewed by Soldatos and his colleagues [27]. Some deterioration in the soundness of sleep has been detected but the amount of rebound insomnia following zopiclone discontinuation is relatively weak. Although one would certainly expect rebound in a hypnotic with a half-life of around 5 h, the frequency and severity of such rebound seems definitely less than those observed with comparative benzodiazepines such as triazolam and temazepam [28],... 

An evaluation has been made of the utility of zopiclone substitution in facilitating the withdrawal of flunitrazepam [31]. Twenty-four volunteers with insomnia and a history of long-term benzodiazepine hypnotic use were assessed with both subjective and objective measures during a 5-week substitution with zopiclone and subsequent withdrawal or continuation on flunitrazepam. Withdrawal from flunitrazepam was accompanied a worsening of sleep quality, both subjectively and objectively. No such deterioration was seen in the zopiclone-substituted groups. 

A very detailed review of zopiclone noted its proven efficacy and good tolerability [34], With respect to withdrawal, clinical trials showed no evidence for significant rebound insomnia. The risk of withdrawal reactions was very low, although dependency and abuse have been reported. 

Post-marketing surveillance and pharmacovigilance data contain few convincing cases of withdrawal from zopiclone. Most consist of rebound insomnia, but there are a few instances of withdrawal convulsions following high-dose dependence. A review of 25 zopiclone discontinuation studies found rebound effects and withdrawal symptoms to be minimal [35],... 

Fontaine R, Beaudry P, Le Morvan P et al. (1988) Efficacy and rebound insomnia of zopiclone and triazolam. Psychopharmacology 96, Suppl 219... 

In human studies, there is some evidence that withdrawal signs such as nervousness, anxiety and vertigo occur following sub-chronic administration of zopiclone but the frequency and intensity of the withdrawal effects are greater after conventional 1,4-benzodiazepines. No rebound effects have been seen in patients with insomnia who received zolpidem daily for 7-180 days. By contrast, after 3 weeks of abercamil treatment of patients with generalized anxiety disorder possible signs of withdrawal resulted, the incidence of these withdrawal effects being related to doses of abercamil administered. 

From the published clinical studies, it would appear that the partial agonists bretazenil and abercamil are less likely to cause physiological dependence, have lower reinforcing effects and a lower incidence of subjective effects associated with abuse liability than the conventional 1,4-benzodiazepine sedative-hypnotics. It is presently unclear whether the full agonists for the GABA-A receptor, zolpidem and zopiclone, offer a real advance in the treatment of insomnia although their adverse effect profiles and abuse liability may be lower than that of the conventional benzodiazepines. 

In addition to the benzodiazepines, there may be a role for the nonbenzodiazepine drugs such as zalaplon, zolpidem or zopiclone in the treatment of anxiety and insomnia in the elderly. These drugs appear to be well tolerated in younger populations of patients, but it is essential to await the outcome of properly conducted trials of these drugs on a substantial number of elderly patients before any conclusions may be drawn regarding their value as alternatives to the benzodiazepines. 

Diazepam is better indicated if insomnia is associated with daytime anxiety. Other benzodiazepines prescribed for insomnia include nitrazepam, flur-azepam, loprazolam, lormetazepam and temazepam. The non-benzodiazepine hypnotics zaleplon, zolpidem and zopiclone are not licensed for long-term use. The sedative antipsychotic promethazine hydrochloride is sometimes used to facilitate sleep, with a 25-50 mg recommended dose. Melatonin has proved effective for some clients, mostly in regulating the sleep/waking cycle. Although evidence of efficacy is limited, some clients use herbs such as valerian and chamomile. If Mr AB will finally be diagnosed with depression, a trial with an antidepressant will be indicated. 

An 86-year-old white woman taking nefazodone for depression started to take zopiclone for insomnia, but subsequently had morning drowsiness (37). The plasma concentration of zopiclone was measured 8 hours after administration on two occasions, during and after nefazodone therapy. After withdrawal of nefazodone, the plasma concentration of the -enantiomer of zopiclone fell from 107 to 17 ng/ml, while the plasma concentration of the i -enantiomer fell from 21 to 1.5 ng/ml. 

National Institute for Health and Clinical Excellence. Zaleplon, zolpidem and zopiclone for the short-term management of insomnia. Technology Appraisal Guidance 2004 77. www.nice.org.uk... 

Tsutsui SZolipidem Study Group. A double-blind comparative study of zolpidem versus zopiclone in the treatment of chronic primary insomnia. J Int Med Res 2001 29(3) 163-77. 

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