Zopiclone
Encyclopedia
Zopiclone is a non-benzodiazepine
hypnotic
agent used in the treatment of insomnia
. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone
, is sold under the name Lunesta (see History). Zopiclone is a controlled substance in the United States
, Japan
, Brazil
and some Europe
an 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. Zopiclone is a tranquilliser drug. It works by causing a depression or tranquillisation of the Central Nervous System. As zopiclone is sedating it is marketed as a sleeping pill. After regular dampening down of the Central Nervous System the body becomes accustomed to functioning under the influence of zopiclone. When the dose is reduced or the drug is stopped these adaptions which have occurred when a person's body has become addicted to a drug are revealed. The result is rebound withdrawal symptoms which can include a whole host of withdrawal symptoms which are seen in benzodiazepine withdrawal. See http://www.bcnc.org.uk/symptoms.html.
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
and Canada
. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone derivative dosage contains 3 mg of the therapeutic stereoisomer, whereas, the highest zopiclone dosage (7.5 mg) contains 3.75 mg 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.); the significant possibility that the two drugs have identical effects and only differ in dosing and the simple fact that investing in clinical trials is a very expensive undertaking may be responsible for this line of inquiry thus far remaining unpursued.
where sleep initiation or sleep maintenance are prominent symptoms. Long term use is not recommended as tolerance, dependence, addiction can occur with prolonged use.
Zopiclone is sold under a wide variety of brand names world wide.
(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
and Rohypnol. 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.
.
Nervous system: disruption of REM sleep, double vision
, drowsiness, memory impairments, visuospatial impairments, dizziness
, headache
s, and fatigue
. Unexpected mood changes
have been noted, which if experienced should lead to the drug being withdrawn from the patient.
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 delirium
. 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.
To withdraw from Zopiclone sleeping tablets cross over to an equivalent dose of diazepam, the equivalency table by Professor Heather Ashton can be used. To withdraw and reduce the intensity of withdrawal symptoms, including interdose withdrawal symptoms, it is important that the blood levels of a drug remain constant throughout a 24 hour period. This is not possible with zopiclone as it is a short acting drug, therefore users of Zopiclone should cross over to an equivalent dose of diazepam to begin their dose taper. 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.
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 both 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. There have been 15 epidemiological studies which have shown that hypnotic drugs cause increased mortality, mainly due to increased cancer deaths. The cancers included those of the brain, lung, bowel, breast, and bladder. One possible explanation for the increased cancer deaths is that the Z-drugs have an adverse effect on the immune system. The fact that clinical trial subjects taking other Z-drugs (zolpidem
, zaleplon
and eszopiclone
) had an increased rate of infections seems to support this theory. Benzodiazepine hypnotic agents are also associated with an increased risk of cancer in humans, namely ovarian cancer
. Development of malignancy has been associated with zolpidem usage, but the incidence
of neoplasm in zolpidem users is as yet unknown.
Indiplon
, another nonbenzodiazepine
drug has also shown an increased rate of cancers in clinical trials. The review author concluded by 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".
skills which are similar to benzodiazepines. Long term users of hypnotic drugs for sleep disorder
s 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. Zopiclone is known to, in some case, induce a state of amnesia, which is largely related (and not too dissimilar to 'sleep-walking'). This can extend to sleep-eating, sleep-talking (quite naturally), to dangerously 'sleep driving'. It is therefore usually not used as an anti-anxiety drug (such as Benzodiazepines), as the patient may be liable to make very poor judgment decisions (as they are essentially mentally 'asleep') and attempt dangerous activities. - With absolutely no recollection at all of the events.
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.
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.
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 increases these impairments. Partial, but incomplete tolerance develops to these impairments.
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. 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.
, 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. Although it is regarded as being unselective in its binding to alpha1, alpha1, alpha3 and alpha5 GABAA benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist
properties unlike the parent drug zopiclone which is a full agonist. 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.
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.
. 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. 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.
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 combined 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.
and drug dependence. Zopiclone is well known amongst drug addicts as a drug of abuse and they commonly seek it from their doctors. [One addiction centre found that 5.1% of drug addicts at their treatment center reported 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 can be seen 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 who have been prescribed 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 drug
s 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 vehicle 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.
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 when combined with piperazine.
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 such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
agent used in the treatment of insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone
Eszopiclone
Eszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic used as a treatment for insomnia. Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.Eszopiclone is a short acting...
, is sold under the name Lunesta (see History). Zopiclone is a controlled substance in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
and some Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
an countries, and may be illegal to possess without a prescription.
Zopiclone is known colloquially as a "Z-drug
Z-drug
Z-drugs are a group of nonbenzodiazepine drugs with effects similar to benzodiazepines which are used in the treatment of insomnia, and whose names mostly start with the letter "Z". Some Z drugs may have advantages over benzodiazepines...
". Other Z-drugs include zaleplon
Zaleplon
Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
(Sonata) and zolpidem
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
(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. Zopiclone is a tranquilliser drug. It works by causing a depression or tranquillisation of the Central Nervous System. As zopiclone is sedating it is marketed as a sleeping pill. After regular dampening down of the Central Nervous System the body becomes accustomed to functioning under the influence of zopiclone. When the dose is reduced or the drug is stopped these adaptions which have occurred when a person's body has become addicted to a drug are revealed. The result is rebound withdrawal symptoms which can include a whole host of withdrawal symptoms which are seen in benzodiazepine withdrawal. See http://www.bcnc.org.uk/symptoms.html.
History
Zopiclone was first developed and introduced in 1986 by Rhône-PoulencRhône-Poulenc
-History of the company:The Company was founded in 1928 through the merger of Société des Usines Chimiques du Rhône from Lyon and Établissements Poulenc Frères from Paris founded by Étienne Poulenc, a 19th century Parisian apothecary and brought to prominence by his second and third sons Emile...
S.A., now part of Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
, 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
Drug Enforcement Administration
The Drug Enforcement Administration is a federal law enforcement agency under the United States Department of Justice, tasked with combating drug smuggling and use within the United States...
listed zopiclone under Schedule IV
Controlled Substances Act
The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...
, due to evidence that the drug has addictive properties similar to benzodiazepines.
Zopiclone, as traditionally sold worldwide, is a racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture of two stereoisomers, only one of which is active. In 2005, the pharmaceutical company Sepracor
Sepracor
Sepracor, Inc. is a pharmaceutical company founded in 1984 by Tim Barberich. It was originally located in Princeton, New Jersey and then re-located to Marlborough, Massachusetts. On October 12, 2010, the company changed its name to Sunovion.-Company history:The company's initial focus was on the...
of Marlborough, Massachusetts
Marlborough, Massachusetts
Marlborough is a city in Middlesex County, Massachusetts, United States. The population was 38,499 at the 2010 census. Marlborough became a prosperous industrial town in the 19th century and made the transition to high technology industry in the late 20th century after the construction of the...
began marketing the active stereoisomer eszopiclone
Eszopiclone
Eszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic used as a treatment for insomnia. Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.Eszopiclone is a short acting...
under the name Lunesta in the United States. This had the consequence of placing what is a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
and Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
. The eszopiclone/zopiclone difference is in the dosage—the strongest eszopiclone derivative dosage contains 3 mg of the therapeutic stereoisomer, whereas, the highest zopiclone dosage (7.5 mg) contains 3.75 mg 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.); the significant possibility that the two drugs have identical effects and only differ in dosing and the simple fact that investing in clinical trials is a very expensive undertaking may be responsible for this line of inquiry thus far remaining unpursued.
Indications
Zopiclone is indicated for the short term treatment of insomniaInsomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
where sleep initiation or sleep maintenance are prominent symptoms. Long term use is not recommended as tolerance, dependence, addiction can occur with prolonged use.
Availability
- Zalepla - Costa Rica, Ecuador, Guatemala, Panama
- Zimovane - United Kingdom
- Zimovane, Zileze, Zimoclone, Zopitan, Zorclone - Ireland
- Imovane, Apo-Zopiclone, pms-Zopiclone, Ran-Zopiclone, Rhovane, Pro Zopiclone - Canada
- Imovane or Imrest - Australia, New Zealand, Iceland, Italy, Poland, Finland, Sweden, Norway and Brazil.
- Nocturno and Imovane - Israel
- Imovane (Имован); Relaxon (Релаксон); Somnol (Сомнол) - Russia
- Alchera, Imovane, Z-Dorm, Zopimed, Zopivane - South Africa
- Imoclone, Imozop or Imovane - Denmark
- Limovan - Spain
- Ximovan - Germany
- Zopiclon - Netherlands, Bulgaria
- Zopiclona - Argentina
- Zetix - Bolivia, Chile, Ecuador
- Hypnor - Egypt
- Amoban - Japan
Adverse reactions
The side effect most commonly seen in clinical trials is taste alteration or dysgeusiaDysgeusia
Dysgeusia is the distortion of the sense of taste. Dysgeusia is also often associated with ageusia, which is the complete lack of taste, and hypogeusia, which is the decrease in taste sensitivity. An alteration in taste or smell may be a secondary process in various disease states, or it may be...
(bitter, metallic taste, which is usually fleeting in most users but can persist until the drug's half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
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
Triazolam
Triazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia...
and Rohypnol. 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
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
drugs.
More common reactions
Gastrointestinal: taste disturbances including bitter metallic taste, dry mouthXerostomia
Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...
.
Nervous system: disruption of REM sleep, double vision
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
, drowsiness, memory impairments, visuospatial impairments, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, and fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
. Unexpected mood changes
Mood swing
-Associated disorders:Mood swings are commonly associated with mood disorders including bipolar disorder and depression. In patients with cases of bipolar disorder, the patient experiences serious mood swings that last for days or even weeks...
have been noted, which if experienced should lead to the drug being withdrawn from the patient.
Less common reactions
- Gastrointestinal: heartburnHeartburnHeartburn, also known as pyrosis or acid indigestion is a burning sensation in the chest, just behind the breastbone or in the epigastrium...
, constipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, diarrhoea, nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, coated tongue, bad breath, anorexiaAnorexia (symptom)Anorexia is the decreased sensation of appetite...
or increased appetiteAppetiteThe appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
, vomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, epigastric pains, dyspepsiaDyspepsiaDyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
, dehydrationDehydrationIn physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, parageusiaParageusiaParageusia is the medical term for a bad taste in the mouth.One common form of parageusia is a metallic taste of food. This can be a side effect of several medications, such as acetazolamide, eszopiclone, zopiclone, metronidazole, or etoposide....
. - Cardiovascular: palpitationPalpitationA palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself...
s in elderlySenior citizenSenior citizen is a common polite designation for an elderly person in both UK and US English, and it implies or means that the person is retired. This in turn implies or in fact means that the person is over the retirement age, which varies according to country. Synonyms include pensioner in UK...
patients. - Skin: urticariaUrticariaUrticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
, tingling in the arms and legs. - Miscellaneous: blurred vision, frequent micturition, mild to moderate increases in serumBlood plasmaBlood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
transaminaseTransaminaseIn biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. To be specific, this reaction involves removing the amino group from the amino acid, leaving behind an α-keto acid, and transferring it to the...
s and/or alkaline phosphatasePhosphataseA phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
and interstitial nephritisInterstitial nephritisInterstitial nephritis is a form of nephritis affecting the interstitium of the kidneys surrounding the tubules...
have been reported very rarely. - Reproductive: impotence, delayed ejaculationDelayed ejaculationDelayed ejaculation is the inability to ejaculate or persistent difficulty in achieving orgasm despite the presence of normal sexual desire and sexual stimulation...
, anorgasmiaAnorgasmiaAnorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
in both women and men. - Nervous system: agitationPsychomotor agitationPsychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, anxietyAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, loss of memoryMemory lossMemory loss can be partial or total and it is normal when it comes with aging. Sudden memory loss is usually a result of brain trauma and it may be permanent or temporary. When it is caused by medical conditions such as Alzheimers, the memory loss is gradual and tends to be permanent.Brain trauma...
including retrogradeRetrograde amnesiaRetrograde amnesia is a loss of access to events that occurred, or information that was learned, before an injury or the onset of a disease....
and anterograde amnesiaAnterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
, confusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, dizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, weaknessWeaknessWeakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a...
, somnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, asthenia, euphoriaEuphoria (emotion)Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...
and/or dysphoriaDysphoriaDysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
, feeling of drunkenness, depressionDepression (mood)Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, sleep walking, coordination abnormality, hypotoniaHypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, speech disorderSpeech disorderSpeech disorders or speech impediments are a type of communication disorders where 'normal' speech is disrupted. This can mean stuttering, lisps, etc. Someone who is unable to speak due to a speech disorder is considered mute.-Classification:...
, hallucinationHallucinationA hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s of various strengths, usually auditory and visual, behavioural disorders, aggressionAggressionIn psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
, tremorTremorA tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, rebound insomnia, nightmareNightmareA nightmare is an unpleasant dream that can cause a strong negative emotional response from the mind, typically fear or horror, but also despair, anxiety and great sadness. The dream may contain situations of danger, discomfort, psychological or physical terror...
s, hypomaniaHypomaniaHypomania is a mood state characterized by persistent and pervasive elevated or irritable mood, as well as thoughts and behaviors that are consistent with such a mood state...
. DeliriumDeliriumDelirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
can also occur but is a side effect mainly seen in the elderly.
Tolerance, dependence and withdrawal
Zopiclone, a benzodiazepine-like drug was introduced and initially promoted as having less dependence and withdrawal than traditional benzodiazepineBenzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
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
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
.
Publications in the British Medical Journal
British Medical Journal
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
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
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, 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
Midazolam
Midazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
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
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
, 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 delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
. 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
Equivalent dose
The equivalent absorbed radiation dose, usually shortened to equivalent dose, is a computed average measure of the radiation absorbed by a fixed mass of biological tissue, that attempts to account for the different biological damage potential of different types of ionizing radiation...
of diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
(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
Psychomotor agitation
Psychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
, abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, 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
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
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
Triazolam
Triazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia...
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
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
, 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
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, sweating
Sweating
Perspiration is the production of a fluid consisting primarily of water as well as various dissolved solids , that is excreted by the sweat glands in the skin of mammals...
, rebound insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, 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
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
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
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
, drug misuse (illicit or prescription misuse), or in those with history of physical dependency or psychological dependency
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
on sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
-hypnotic drugs.
To withdraw from Zopiclone sleeping tablets cross over to an equivalent dose of diazepam, the equivalency table by Professor Heather Ashton can be used. To withdraw and reduce the intensity of withdrawal symptoms, including interdose withdrawal symptoms, it is important that the blood levels of a drug remain constant throughout a 24 hour period. This is not possible with zopiclone as it is a short acting drug, therefore users of Zopiclone should cross over to an equivalent dose of diazepam to begin their dose taper. While it acts on the same benzodiazepine receptors as the benzodiazepine family of drugs it is not classed as a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
(with which it shares a number of characteristics and effects) due to its differing molecular structure. Zopiclone is classed as a cyclopyrrolone derivative.
Carcinogenicity
Zopiclone may be carcinogenic and mutagenic according to rat, mice and hamster studies. 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 immunocompetentImmunocompetence
Immunocompetence is the ability of the body to produce a normal immune response following exposure to an antigen. Immunocompetence is the opposite of immunodeficiency or immuno-incompetent or immuno-compromised...
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
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
in immunocompetent patients.
A recent analysis of both U.S. Food and Drug Administration (FDA) data and clinical trial data shows that nonbenzodiazepine Z-drugs
Z-drug
Z-drugs are a group of nonbenzodiazepine drugs with effects similar to benzodiazepines which are used in the treatment of insomnia, and whose names mostly start with the letter "Z". Some Z drugs may have advantages over benzodiazepines...
at prescribed doses cause an increased risk of developing cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
in humans. There have been 15 epidemiological studies which have shown that hypnotic drugs cause increased mortality, mainly due to increased cancer deaths. The cancers included those of the brain, lung, bowel, breast, and bladder. One possible explanation for the increased cancer deaths is that the Z-drugs have an adverse effect on the immune system. The fact that clinical trial subjects taking other Z-drugs (zolpidem
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
, zaleplon
Zaleplon
Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
and eszopiclone
Eszopiclone
Eszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic used as a treatment for insomnia. Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.Eszopiclone is a short acting...
) had an increased rate of infections seems to support this theory. Benzodiazepine hypnotic agents are also associated with an increased risk of cancer in humans, namely ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
. Development of malignancy has been associated with zolpidem usage, but the incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of neoplasm in zolpidem users is as yet unknown.
Indiplon
Indiplon
Indiplon is a nonbenzodiazepine, hypnotic sedative being developed in 2 formulations - an immediate release product for sleep onset and a modified-release version for sleep maintenance.- Mode of action :...
, another nonbenzodiazepine
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
drug has also shown an increased rate of cancers in clinical trials. The review author concluded by 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".
Contraindications
Zopiclone causes impaired drivingDriving under the influence
Driving under the influence is the act of driving a motor vehicle with blood levels of alcohol in excess of a legal limit...
skills which are similar to benzodiazepines. Long term users of hypnotic drugs for sleep disorder
Sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person or animal. Some sleep disorders are serious enough to interfere with normal physical, mental and emotional functioning...
s 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. Zopiclone is known to, in some case, induce a state of amnesia, which is largely related (and not too dissimilar to 'sleep-walking'). This can extend to sleep-eating, sleep-talking (quite naturally), to dangerously 'sleep driving'. It is therefore usually not used as an anti-anxiety drug (such as Benzodiazepines), as the patient may be liable to make very poor judgment decisions (as they are essentially mentally 'asleep') and attempt dangerous activities. - With absolutely no recollection at all of the events.
Special precautions
Alcohol should be avoided when using zopiclone as alcohol and zopiclone enhance the effects of each other.Patients with liver disease
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
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.
Patients who suffer from muscle weakness due to myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
or have poor respiratory reserves due to severe chronic bronchitis
Chronic bronchitis
Chronic bronchitis is a chronic inflammation of the bronchi in the lungs. It is generally considered one of the two forms of chronic obstructive pulmonary disease...
, emphysema
Emphysema
Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...
or other lung disease, or have sleep apnoea cannot safely take zopiclone, nor can a patient with any untreated abnormality of the thyroid gland.
Elderly
Zopiclone, similar to other benzodiazepines and nonbenzodiazepineNonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
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 increases these impairments. Partial, but incomplete tolerance develops to these impairments.
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. 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
Developmental disability
Developmental disability is a term used in the United States and Canada to describe lifelong disabilities attributable to mental or physical impairments, manifested prior to age 18. It is not synonymous with "developmental delay" which is often a consequence of a temporary illness or trauma during...
(anterograde amnesia
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
), 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
Nonbenzodiazepine
The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
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.
Pharmacology
The therapeutic pharmacological properties of zopiclone include hypnoticHypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
, anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
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
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone called desmethylzopiclone is also pharmacologically active although it has predominately anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
properties. Like benzodiazepines zopiclone and its active metabolite desmethylzopiclone also inhibit N-methyl-D-aspartate (NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
) 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. Although it is regarded as being unselective in its binding to alpha1, alpha1, alpha3 and alpha5 GABAA benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
properties unlike the parent drug zopiclone which is a full agonist. The mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity
Locomotor activity
Locomotor activity refers to the movement from place to place. In psychopharmacology, locomotor activity of lab animals is often monitored to assess the behavioural effects of these drugs. Locomotor activity is useful and less robust than most behavioural tests such as operant conditioning and...
and on dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
turnover.
A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
of randomised controlled clinical trials which compared benzodiazepines to zopiclone or other Z Drugs such as zolpidem
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
, zaleplon
Zaleplon
Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
has found that there are few clear and consistent differences between zopiclone and the benzodiazepines in terms of sleep onset latency
Sleep onset latency
In sleep science, sleep onset latency is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages.-Sleep latency studies:...
, 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
Suriclone
Suriclone is a sedative and anxiolytic drug in the cyclopyrrolone family of drugs. Other cyclopyrrolone drugs include zopiclone and pagoclone....
. 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
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
like properties.
In EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
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
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
, 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
Zaleplon
Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
. Zopiclone is therefore very similar pharmacologically to benzodiazepines.
EEG and sleep
Similar to other sedative hypnotic drugs zopiclone causes a decrease in the core body temperatureThermoregulation
Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different...
and is effective in decreasing sleep latency. Zopiclone causes similar alterations on EEG readings and sleep architecture
Sleep architecture
Sleep architecture describes the structure and pattern of sleep and encompasses several variables. Sleep quotas refer to the amount of time spent in REM and NREM sleep. Sleep duration is the total time spent asleep in a 24 hour period. The duration of a NREM-REM cycle is also an important aspect...
as benzodiazepines and causes disturbances in sleep architecture on withdrawal as part of its rebound effect
Rebound effect
The rebound effect, or rebound phenomenon, is the tendency of some medications, when discontinued suddenly, to cause a return of the symptoms it relieved, and that, to a degree stronger than they were before treatment first began...
. 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.
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 milkBreast milk
Breast milk, more specifically human milk, is the milk produced by the breasts of a human female for her infant offspring...
. 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. 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
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of the drug before excretion. The terminal elimination half-life (t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
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
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...
(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.
Interactions
Zopiclone also interacts with trimipramineTrimipramine
Trimipramine is a tricyclic antidepressant . It has antidepressant, anxiolytic, antipsychotic, sedative, and analgesic effects.- Indications :...
and caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
.
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
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
. Zaleplon
Zaleplon
Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
had no detrimental effects on driving skills the next day. Carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
also has additive effects when combined with zopiclone with both drugs enhancing the side effects of each other. Erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
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
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
has a similar effect on zopiclone pharmacokinetics as erythromycin. The elderly may be particularly sensitive to the erythromycin and itraconazole drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
with zopiclone. Temporary dosage reduction during combined therapy may be required especially in the elderly.
Rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
causes a very notable reduction in half-life of zopiclone and peak plasma levels which results in a large reduction in the hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
effect of zopiclone. Phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
may also provoke similar interactions. Ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
and sulfaphenazole
Sulfaphenazole
Sulfaphenazole is a sulfonamide antibacterial....
interfere with the metabolism of zopiclone. Nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next day sedation.
Abuse
Zopiclone is a drug with the potential for misuse with the potential for causing dosage escalation, drug abuseDrug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
and drug dependence. Zopiclone is well known amongst drug addicts as a drug of abuse and they commonly seek it from their doctors. [One addiction centre found that 5.1% of drug addicts at their treatment center reported 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 can be seen 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
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
, drug tolerance and physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...
. 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 who have been prescribed with zopiclone The symptoms of zopiclone addiction
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
can include depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, dysphoria
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
, hopelessness, slow thoughts, social isolation
Social isolation
Social isolation refers to a lack of contact with society for members of social species. There may be many causes and individuals in numerous generally social species are isolated at times, it need not be a pathological condition. In human society, in those cases where it is viewed as a pathology,...
, worrying, sexual anhedonia
Sexual anhedonia
Sexual anhedonia, also known as pleasure dissociative orgasmic disorder, is a condition in which an individual cannot feel pleasure from an orgasm. It is thought to be a variant of hypoactive sexual desire disorder.-Overview:...
and nervousness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
.
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
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
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 drug
Prescription drug
A prescription medication is a licensed medicine that is regulated by legislation to require a medical prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...
s of abuse suggesting a high degree of abuse potential for benzodiazepines, zolpidem
Zolpidem
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
and zopiclone. 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 by 503 excess accidents per 100,000 persons. It was recommended that zaleplon
Zaleplon
Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
or other non-impairing sleep aids are used instead of zopiclone to reduce road traffic accidents. Zopiclone as with other hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
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 temazepamTemazepam
Temazepam is an intermediate-acting 3-hydroxy benzodiazepine. It is mostly prescribed for the short-term treatment of sleeplessness in patients who have difficulty maintaining sleep...
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
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, opiates or other CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
depressants may be even more likely to lead to fatal overdoses. Zopiclone overdosage can be treated with the benzodiazepine receptor antagonist flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
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 when combined with piperazine.
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 such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.
Detection in biological fluids
Zopiclone may be measured in blood, plasma or urine by chromatographic methods. Plasma zopiclone concentrations are typically less than 100 μg/L during therapeutic usage, 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. Postmortem blood concentrations are usually in a range of 0.4-3.9 mg/L in victims of fatal acute overdosage.See also
- BenzodiazepineBenzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- Benzodiazepine dependenceBenzodiazepine dependenceBenzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
- Benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
- nonbenzodiazepineNonbenzodiazepineThe nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.-Classes:There are currently three...
- ZaleplonZaleplonZaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
- Z drugs
External links
- Detailed pharmacological information
- Scheduling recommendation (PDFPortable Document FormatPortable Document Format is an open standard for document exchange. This file format, created by Adobe Systems in 1993, is used for representing documents in a manner independent of application software, hardware, and operating systems....
file) - Details on scheduling
- Erowid zopiclone vault
- Support for Zopiclone dependency/addiction