Question: When was Zopiclone first introduced?

Zopiclone



Zopiclone (brand names Imovane, Zimovane, and Dopareel) is a nonbenzodiazepine hypnotic agent used in the treatment of insomnia. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid in the central nervous system, via modulating benzodiazepine receptors in the same way that benzodiazepine drugs do.
As zopiclone is sedating, it is marketed as a sleeping pill. It works by causing a depression or tranquilization of the central nervous system.  After prolonged use, the body can become accustomed to the effects of zopiclone. When the dose is then reduced or the drug is abruptly stopped, withdrawal symptoms may result. These can include a range of symptoms similar to those of benzodiazepine withdrawal. Although withdrawal symptoms from therapeutic doses of zopiclone and its isomers (i.e. eszopiclone) do not typically present with convulsions and are therefore not considered life-threatening, patients may experience such significant agitation or anxiety that they seek emergency medical attention.
In the United States, zopiclone is not commercially available,[2] although its active stereoisomer, eszopiclone, is sold under the name Lunesta. Zopiclone is a controlled substance in the United States, Japan, Brazil, and some European countries, and may be illegal to possess without a prescription. However, it is readily available in other countries where it is marketed under the brand name Imovane, and is not a controlled substance in its available 10mg, 7.5mg, 5mg, and 3.75mg oral tablet formulations.
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 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. Zopiclone is recommended to be taken on a short-term basis, usually a week or less.[3] Daily or continuous use of the drug is not usually advised, and caution must be taken when the compound is used in conjunction with antidepressants, sedatives or other drugs affecting the central nervous system.[4]

Medical uses

Zopiclone is indicated for the short-term treatment of insomnia where sleep initiation or sleep maintenance are prominent symptoms. Long-term use is not recommended, as tolerance, dependence, and addiction can occur with prolonged use.[5][6] One low quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in shift workers - more research in this area has been recommended.[7]
Specific populations
Elderly
Zopiclone, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol consumption increases these impairments. Partial, but incomplete tolerance develops to these impairments.[8] 
Zopiclone increases postural sway and increases the number of falls in older people, as well as cognitive side effects. Falls are a significant cause of death in older people.[9][10][11]
An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly persons. Newer agents such as the melatonin receptor agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of nonbenzodiazepine hypnotic drugs remains to be determined.[12]
Liver disease
Patients with liver disease eliminate zopiclone much more slowly than normal patients and in addition experience exaggerated pharmacological effects of the drug.[13]
Miscellaneous
Patients who suffer from muscle weakness due to myasthenia gravis or have poor respiratory reserves due to severe chronic bronchitis, emphysema, or other lung disease, or have sleep apnoea cannot safely take zopiclone, nor can a patient with any untreated abnormality of the thyroid gland.[14]
Adverse reactions
Sleeping pills, including zopiclone, have been associated with an increased risk of death.[15] The British National Formulary states adverse reactions as follows: "taste disturbance; less commonly nausea, vomiting, dizziness, drowsiness, dry mouth, headache; rarely amnesia, confusion, depression, hallucinations, nightmares; very rarely light headedness, incoordination, paradoxical effects [...] and sleep-walking also reported".[16]
Contraindications
Zopiclone causes impaired driving skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for sleep disorders develop only partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 year of use still showing an increased motor vehicle accident rate.[17] Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of accidents in zopiclone users.[18] Zopiclone induces impairment of psychomotor function.[19][20] Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand eye coordination.[21][22]
EEG and sleep
Similarly to other sedative hypnotic drugs, zopiclone causes a decrease in the core body temperature and is effective in decreasing sleep latency.[23] It causes similar alterations on EEG readings and sleep architecture as benzodiazepines and causes disturbances in sleep architecture on withdrawal as part of its rebound effect.[24][25] Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves.[26] Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset.[27][28] Cognitive behavioral therapy has been found to be superior to zopiclone in the treatment of insomnia and has been found to have lasting effects on sleep quality for at least a year after therapy.[29][30][31][32]
Overdose
Zopiclone is sometimes used as a method of suicide.[33] It has a similar fatality index to that of  benzodiazepine drugs, apart from temazepam, which is particularly toxic in overdose.[34][35][36] Deaths have occurred from zopiclone overdose, alone or in combination with other drugs.[37][38][39] Overdose of zopiclone may present with excessive sedation and depressed respiratory function that may progress to coma and possibly death.[40] Zopiclone combined with alcohol, opiates, or other central nervous system 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 its effects.[41][42] Serious effects on the heart may also occur from a zopiclone overdose[43][44] when combined with piperazine.[45]
Death certificates show the number of zopiclone-related deaths is on the rise.[46] When taken alone, it usually is not fatal, but when mixed with alcohol or other drugs such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.[47][48]
Interactions
Zopiclone also interacts with trimipramine and caffeine.[49][50]
Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly.[51][52] Due to these risks and the increased risk for dependence, alcohol should be avoided when using zopiclone.[51]
Erythromycin appears to increase the absorption rate of zopiclone and prolong its elimination half-life, 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.[53][54]
Rifampicin causes a very notable 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.[55] Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone.[56] Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next-day sedation.[57]
Pharmacology
The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant, and myorelaxant properties.[58] Zopiclone and benzodiazepines bind to the same sites on GABAA-containing receptors, 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 has predominately anxiolytic properties. One study found some slight selectivity for zopiclone on α1 and α5 subunits,[59] although it is regarded as being unselective in its binding to α1, α2, α3, and α5 GABAA benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist properties, unlike the parent drug zopiclone, which is a full agonist.[60] The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover.[61][62]
A meta-analysis of randomised controlled clinical trials that compared benzodiazepines to zopiclone or other Z drugs such as zolpidem and zaleplon has found few clear and consistent differences between zopiclone and the benzodiazepines in sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.[63]
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 by 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.[64][65][66] In addition to zopiclone's benzodiazepine pharmacological properties, it also has some barbiturate-like properties.[67][68]
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.[69]
Pharmacokinetics

After oral administration, zopiclone is rapidly absorbed, with a bioavailability around 75–80%. Time to peak plasma concentration is 1–2 hours. A high-fat meal preceding zopiclone administration does not change absorption (as measured by AUC), but reduces peak plasma levels and delays its occurrence, thus may delay the onset of therapeutic effects.
The plasma protein-binding of zopiclone has been reported to be weak, between 45 and 80% (mean 52–59%). It is rapidly and widely distributed to body tissues, including the brain, and is excreted in urine, saliva, and breast milk. Zopiclone is partly extensively metabolized in the liver to form an active N-demethylated derivative (N-desmethylzopiclone) and an inactive zopiclone-N-oxide. Hepatic enzymes playing the most significant role in zopiclone metabolism are CYP3A4 and CYP2E1. In addition, about 50% of the administered dose is decarboxylated and excreted via the lungs. 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 of zopiclone ranges from 3.5 to 6.5 hours (5 hours on average).[1]
The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), area under the plasma time-concentration curve (AUC) and terminal elimination half-life values are higher for the dextrorotatory enantiomers, 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.[70] In severe chronic renal failure, the area under the curve value for zopiclone was larger and the half-life associated with the elimination rate constant longer, but these changes were not considered to be clinically significant.[71] Sex and race have not been found to interact with pharmacokinetics of zopiclone.[1]
Chemistry
The melting point of zopiclone is 178°C.[72] Zopiclone's solubility in water, at room temperature (25°C) are 0.151mg/mL.[72] The logP value of zopiclone is 0.8.[72]
Detection in biological fluids
Zopiclone may be measured in blood, plasma, or urine by chromatographic methods. Plasma concentrations are typically less than 100 μg/l during therapeutic use, but frequently exceed 100 μg/l in automotive vehicle operators arrested for impaired driving ability and may exceed 1000 μg/l in acutely poisoned patients. Post mortem blood concentrations are usually in a range of 0.4-3.9mg/l in victims of fatal acute overdose.[73][74][75]
History
Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main worldwide manufacturer. Initially, it was promoted as an improvement on benzodiazepines, but a recent meta-analysis found it was no better than benzodiazepines in any of the aspects assessed.[76] On April 4, 2005, the U.S. 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.[77][78] 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. Generic forms of Lunesta have since become available in the United States. Zopiclone is currently available off-patent in a number of European countries, as well as Brazil, Canada, and Hong Kong. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone derivative dosage contains 3mg of the therapeutic stereoisomer, whereas the highest zopiclone dosage (10mg) contains 5mg 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.).
Society and culture
Recreational use
Zopiclone has the potential for misuse and dosage escalation, drug abuse, and drug dependence. It is abused orally and sometimes intravenously, and often combined with alcohol to achieve a combined sedative hypnotic—alcohol euphoria. Patients abusing the drug are also at risk of dependence. Withdrawal symptoms can be seen after long-term use of normal doses even after a gradual reduction regimen. The Compendium of Pharmaceuticals and Specialties recommends zopiclone prescriptions not exceed 7 to 10 days, owing to concerns of addiction, tolerance, and physical dependence.[79] Two types of drug misuse can occur: either recreational misuse, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice.[80][81] Zopiclone may be more addictive than benzodiazepines.[82] Those with a history of substance misuse or mental health disorders may be at an increased risk of high-dose zopiclone misuse.[83] High dose misuse of zopiclone and increasing popularity amongst drug abusers who have been prescribed with zopiclone[84] The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia, and nervousness.[85]
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.[86][87] Zopiclone, which at prescribed doses causes moderate impairment the next day, has been estimated to increase the risk of vehicle accidents by 50%, causing an increase of 503 excess accidents per 100,000 persons. Zaleplon or other nonimpairing sleep aids were recommended be used instead of zopiclone to reduce traffic accidents.[88] Zopiclone as with other hypnotic drugs is sometimes abused to carry out criminal acts such as sexual assaults.[89]
Zopiclone has crosstolerance with barbiturates and is able to suppress barbiturate withdrawal signs. It is frequently self-administered intravenously in studies on monkeys, suggesting a high risk of abuse potential.[90]
Zopiclone is in the top ten medications obtained using a false prescription in France.[1]
See also
Pazinaclone




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