Zopiclone

Zopiclone, sold as Imovane, Zimovane Zopinox in Europe and Canada and Amoban in Japan, and as the eszopiclone analogue Lunesta in the United States, is a novel hypnotic agent used in the treatment of insomnia. Zopiclone is a controlled substance in the United States, Canada, Japan and some European countries, and may be illegal to possess without a prescription.

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 and/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. It is recommended that zopiclone be taken on an "as needed" basis. Daily or continuous use of the drug is not usually advised. While it acts on the same benzodiazepine receptors as the benzodiazepine family of drugs it is not classed as a benzodiazepine (with which it shares a number of characteristics and effects) due to its differing molecular structure. Zopiclone is classed as a cyclopyrrolone derivative.

History
Zopiclone 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. Initially it was promoted as being an improvement on benzodiazepines. A recent meta analysis found that zopiclone had no superiority over benzodiazepines in any of the aspects assessed. On April 4, 2005, the United States 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. 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 it is expected to be available in generic form in that country by 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&mdash;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 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).

Indications
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, addiction can occur with prolonged use.

Pharmacology
The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant and myorelaxant properties. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors as full agonists 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. Like benzodiazepines zopiclone and its active metabolite desmethylzopiclone also inhibit N-methyl-D-aspartate (NMDA) receptors and nicotinic acetylcholine (nAChRs) receptors which might play a role in the addictive properties of these drugs. One study however, found some slight selectivity for zopiclone on α1 and α5 subunits. The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover. 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. 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 via 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. In addition to zopiclone's benzodiazepine pharmacological properties it also has some barbiturate like properties.

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.

Pharmacokinetics
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. Between 7 and 10% of zopiclone is recovered from the urine indicating extensive metabolism of the drug before excretion. 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.

EEG and sleep
Similar to other sedative hypnotic drugs zopiclone causes a decrease in the core body temperature and is effective in decreasing sleep latency. Zopiclone 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. Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves. Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset. 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.

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 following withdrawal from the drug after prolonged periods of use (especially when taken for more than two weeks).

Zopiclone induces amnesia type memory impairments similar to triazolam. Impairment of driving skills with a resultant increased risk of road traffic accidents is probably the most important side effect. This side effect is not unique to zopiclone but also occurs with other hypnotic drugs.

More common reactions
Gastrointestinal: taste disturbances including bitter metallic taste, dry mouth. Nervous system: disruption of REM sleep, double vision, drowsiness, memory impairments, visuospatial impairments, dizziness, headaches, and fatigue. Unexpected mood changes have been noted, which if experienced should lead to the drug being withdrawn from the patient.

Less common reactions

 * Gastrointestinal: heartburn, constipation, diarrhoea, nausea, coated tongue, bad breath, anorexia or increased appetite, vomiting, epigastric pains, dyspepsia, dehydration, parageusia.
 * Cardiovascular: palpitations in elderly patients.
 * Skin: urticaria, tingling in the arms and legs.
 * Miscellaneous: blurred vision, frequent micturition, mild to moderate increases in serum transaminases and/or alkaline phosphatase and interstitial nephritis have been reported very rarely.
 * Reproductive: impotence, delayed ejaculation, anorgasmia in both women and men.
 * Nervous system: agitation, anxiety, loss of memory including retrograde and anterograde amnesia, confusion, dizziness, weakness, somnolence, asthenia, moderate to severe euphoria and/or dysphoria, feeling of drunkenness, depression, sleep walking, coordination abnormality, hypotonia, speech disorder, hallucinations of various strengths, usually auditory and visual, behavioural disorders, aggression, tremor, rebound insomnia, nightmares, hypomania.  Delirium can also occur but is a side effect mainly seen in the elderly.

Contraindications
Zopiclone causes impaired driving skills which are similar to benzodiazepines. Long term users of hypnotic drugs for sleep disorders only develop partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 years use still showing an increased motor vehicle accident rate. Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of road traffic accidents in zopiclone users. Zopiclone induces impairment of psychomotor function. Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day including impaired hand eye coordination. Patients with a history of substance abuse should not be prescribed zopiclone, as it has a very high potential for problematic drug misuse.

Special precautions
Alcohol should be avoided when using zopiclone as alcohol and zopiclone enhance the effects of each other.

Patients with liver disease eliminate zopiclone much slower than normal patients and in addition experience exaggerated pharmacological effects of the drug.

Zopiclone increases 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.

Zopiclone use by the elderly
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and lasting benefits of non-drug treatments for insomnia such as cognitive behavioural therapy in adults of all age groups and that these therapies are under used. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer little if any advantages in efficacy or tolerability in elderly persons. It was found that newer agents such as the melatonin 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. It was concluded that further research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.

Interactions
Zopiclone also interacts with trimipramine and caffeine. Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly. A study assessing the impact of zopiclone on driving skills the next day found that the impairments on driving skills are double that of a social dose of alcohol. Zaleplon had no detrimental effects on driving skills the next day. Carbamazepine also has additive effects when combinded with zopiclone with both drugs enhancing the side effects of each other. Erythromycin appears to increase the absorption rate of zopiclone and prolong the elimination half life of zopiclone 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. 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. Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone. Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next day sedation.

Availability


Zopiclone is also sold under a wide variety of other brand names world wide.
 * Imozop - Denmark, 3,75 mg and 7,5 mg by Sandoz A/S.

It is sold under the following brand names in English speaking countries.


 * Rhovane and Imovane - Canada
 * Zimovane - United Kingdom
 * Imovane - Australia, New Zealand
 * Zileze, Zimoclone, Zimovane, Zopitan, Zorclone - Ireland
 * Alchera, Imovane, Z-Dorm, Zopimed, Zopivane - South Africa

Tolerance, dependence and withdrawal
Zopiclone, a benzodiazepine-like drug 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 and has been described as a "benzodiazepine in disguise". Tolerance to the effects of zopiclone can develop after a few weeks. Long term use should be avoided. Abrupt withdrawal particularly with prolonged and high doses can in severe cases cause seizures and delirium.

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. Suspected withdrawal convulsions during detoxification from zopiclone has been reported, however the individual was a high dose zopiclone misuser.

The risk of dependency on zopiclone when used for less than 2 weeks or only used occasionally is low. However, this is disputed by one study of low dose zopiclone taken for only 7 nights. It found that discontinuation of zopiclone caused significant rebound insomnia. Furthermore when midazolam taken for 7 nights was discontinued no rebound insomnia occurred suggesting that zopiclone may have even more significant problems of tolerance and dependence than the benzodiazepines. After 3 weeks of use mild to moderate rebound withdrawal symptoms appear upon discontinuation of zopiclone. Due to the risk of tolerance and physical dependence, zopiclone is only recommended for short term (1 - 4 weeks max) relief of insomnia, or alternatively, long term infrequent use. Long-term zopiclone users who have become physically dependent should not discontinue their medication abruptly as severe withdrawal symptoms may occur such as delerium. If zopiclone has been taken for more than a few weeks then the medication should be gradually reduced or preferably to cross over to an equivalent dose of diazepam (Valium), which has a much longer half life which makes withdrawal easier and then gradually taper their dosage over a period of several months in order to avoid extremely severe and unpleasant withdrawal symptoms (e.g., inner restlessness, psychomotor agitation, abdominal pain, hypertension, hallucinations, seizures, anxiety, depression, psychosis, etc.) which can last up to two years after withdraw if the withdrawal is done too abruptly. After 4 weeks of nightly use of zopiclone day time withdrawal related anxiety begin to emerge in some users. However, the day time withdrawal anxiety does not appear to be as intense as that seen with the much shorter acting triazolam which provokes even more profound day time withdrawal anxiety symptoms in long term users.

According to the World Health Organisation, Zopiclone, although molecularly is not a benzodiazepine, binds unselectively with high affinity to the same benzodiazepine sites that the benzodiazepine class of drugs 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.

Zopiclone is cross tolerant with benzodiazepines. 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.

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 experimental 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 immunocompetent patients.

A recent analysis of U.S. Food and Drug Administration (FDA) data and clinical trial data shows that nonbenzodiazepine Z-drugs at prescribed doses cause an increased risk of developing cancer in humans. The data shows that trial subjects receiving hypnotic drugs had an increased 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 over 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 could cause the development of 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 another nonbenzodiazepine drug 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".

Abuse
Zopiclone is a drug with the potential for misuse with the potential for causing dosage escalation, drug abuse and drug dependence. Zopiclone is well known amongst drug addicts as a drug of abuse and commonly seek it from their doctors with over 5% of drug addicts at treatment centers reporting a zopiclone addiction. It is abused orally and sometimes intravenously and often combined with alcohol to achieve a combined sedative hypnotic - alcohol euphoria. Patients who do abuse the drug are also at risk of dependence. Withdrawal symptoms are frequent after long term use of normal doses even after a gradual reduction regime. The Compendium of Pharmaceuticals and Specialties recommends that zopiclone prescriptions do not exceed 7 - 10 days due to concerns of addiction, drug tolerance and physical dependence. Two types of drug misuse can occur; either recreational misuse, where the drug is taken to achieve a high, or when the drug is continued long term against medical advice. Zopiclone may be more addictive than benzodiazepines. Those with a history of substance misuse or mental health disorders may be at an increased risk of high dose zopiclone misuse. High dose misuse of zopiclone and increasing popularity amongst drug abusers has been described with zopiclone The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia and nervousness.

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. Zopiclone which at prescribed doses causes moderate impairment the next day has been estimated to increase the risk of vehicile accidents by 50%, causing an increase by 503 excess accidents per 100,000 persons. It was recommended that zaleplon or other non-impairing sleep aids are used instead of zopiclone to reduce road traffic accidents. Zopiclone as with other hypnotic drugs is sometimes abused to carry out criminal acts such as sexual assaults.

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.

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

Overdose
Zopiclone is sometimes used as a method of suicide. Zopiclone has a similar fatality index as benzodiazepine drugs, apart from alprazolam which is particularly toxic in overdosage. Deaths have occurred from zopiclone overdose, alone or in combination with other drugs. 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 thereby rapidly reversing the effects of zopiclone. Serious effects on the heart may also occur from a zopiclone overdose.

Death certificates show the number of zopiclone related deaths is on the rise. Zopiclone, when taken alone usually is not fatal however, when mixed with alcohol or other drugs eg opioids or in patients with respiratory or hepatic disorders the risk of a serious and fatal overdose increases significantly.