Brand name:
Zopiclone Imovane, Zimovane and Zopinox
,Eszopiclone , Lunesta
Zopiclone is known under various different brand names around the
world. The brand names of Zopiclone are as follows:
Alchera, Alpaz, Amvey, Datolan, Eurovan, Imoclone, Insomnium, Imovane,
Imozop, Limovan, Losopil, Nocturno, Nuctane, Optidorm, Relaxon
Rhovane, Sedolox, Siaten, Somnal, Somnol (??????), Somnosan, Ximovan,
Z-Dorm, Zetix, Zileze, Zimoclone, Zimovane, Zodurat, Zolief, Zometic,
Zomni, Zonix, Zop, Zopicalm, Zopicalma, Zopiclodura, Zopicon, Zopimed,
Zopinox, Zopi-Puren, Zopitan, Zopivane, Zorclone - all available a
prescription with/out.
Zopiclone - is a novel hypnotic agent used in the treatment of insomnia.
Zopiclone is a controlled substance in the United States, Canada and
some European countries, and may be illegal to possess without a prescription.
Coming off Zopiclone can be a difficult task to accomplish. This page
gives some background information on Zopiclone and a suggested withdrawal
schedule. There have been growing concerns about zopiclone addiction,
including concerns about tolerance, physical dependence, severe withdrawal
symptoms and recreational abuse potential. Zopiclone is in the Z drug
family of sedative hypnotics. Included in the Z drug family of so called
nonbenzodiazepines are Zolpidem, Zaleplon and Zopiclone. The World
Health Organisation has stated that Zopiclone binds to benzodiazepine
receptors and is cross tolerant with benzodiazepines.
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.[1] 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
Zopiclone was first developed by Sepracor and introduced in 1986 by
Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main worldwide
manufacturer of the drug. 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.[3][4] In 2005, the
pharmaceutical company Sepracor of Marlborough, Massachusetts began
marketing the active stereoisomer eszopiclone under the name Lunesta
in the United States. This had the consequence of placing what is a
generic drug in most of the world under patent control in the United
States, although it is expected to be available in generic form in
that country by 2010. It is already available off-patent in a number
of European countries as well as Brazil. The eszopiclone/zopiclone
difference is in the dosage—the strongest eszopiclone derivative
dosage contains 3mg of the therapeutic stereoisomer, whereas, the highest
zopiclone dosage (7.5mg) contains 3.75mg of the active stereoisomer.
The two agents have not yet been studied in head-to-head clinical trials
to determine the existence of any potential clinical differences (efficacy,
side effects, developing dependence on the drug, safety, etc).
Withdrawing From Zopiclone
Withdrawing from Zopiclone must be carried out over a period of time
to avoid severe withdrawal side effects which can include seizures
and psychosis. The withdrawal syndrome of zopiclone seems to be identical
to benzodiazepine withdrawal and similar to alcohol withdrawal.
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 occured when a persons 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 this page BENZODIAZEPINE
WITHDRAWAL SYMPTOMS.
To withdraw from Zopiclone sleeping tablets cross over to an equivalent
dose of diazepam. We have found the equivalency table by Professor
Heather Ashton to be the most reliable and accurate. You can visit
this page and view her EQUIVALENCY TABLE to locate the approximate
equivalent dose of zopiclone to diazepam. 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. See the explaination by
Dr JG McConnell in his article called The Clinicopharmacotherapeutics
of Benzodiazepine and Z drug dose Tapering Using Diazepam.
The cross over from zopiclone to diazepam should take about 4 weeks.
After cross over it is recommended that the individual remains on the
diazepam dose for a further 4 weeks to allow the diazepam to accumulate
and the individual to stabalise on a fixed blood plasma level of zopiclone.
90% of diazepam accumulation occurs after 4 weeks and Diazepam stops
accumulating in the blood stream after 6 weeks after which time it
plateau's at a constant dose level.
Below is a simple withdrawal plan for Zopiclone in a table schedule
format. It is important for the reader to note that this is only a
guide and is not a schedule that should be seen as carved in stone.
The rate of withdrawal should be determined by the individual who can
judge what speed of reduction is right for them. We believe that the
individual has to take responsibilty for their own withdrawal program.
Readers may notice that we recommend day time use of zopiclone even
though it is marketed and prescribed for night time use. This is because
the reader who is withdrawing from zopiclone will be suffering from
a physical addiction to zopiclone secondary to insomnia and it is essential
to keep blood levels stable to prevent day time anguish of withdrawal
symptoms. This is only a temporay measure until the user has fully
crossed over to diazepam. The table uses the example of someone dependent
on 30 mg of zopiclone
Pharmacology
Both zopiclone and benzodiazepines act indiscriminately at a1, a2,
a3 and a5 GABAA containing receptors.[5] In addition to hypnotic
properties zopiclone is anxiolytic, anticonvulsant and myorelaxant.[6]
The mechanism of action of zopiclone is similar to benzodiazepines,
with similar effects on locomotor activity and on dopamine and serotonin
turnover.[7][8] 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.[9] 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.[10][11][12]
In addition to zopiclone's benzodiazepine pharmacological properties
it also has some barbiturate like properties.[13][14]
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 a1-selective
compound, increases only SWS and causes no effect on stage 2 sleep.
Zopiclone is less selective to the a1 site and has higher affinity
to the a2 site than zaleplon. Zopiclone is therefore very similar pharmacologically
to benzodiazepines
After oral administration, zopiclone is rapidly absorbed, with a bioavailability
of approximately 80%. The plasma protein binding of zopiclone has been
reported to be between 45 and 80%. Zopiclone is rapidly and widely
distributed to body tissues including the brain, and is excreted in
urine, saliva and breast milk. Zopiclone is partly metabolised in the
liver to form an inactive N-demethylated derivative and an active N-oxide
metabolite. In addition, approximately 50% of the administered dose
is decarboxylated and excreted via the lungs. Less than 7% of the administered
dose is renally excreted as unchanged zopiclone. In urine, the N-demethyl
and N-oxide metabolites account for 30% of the initial dose. Between
7 and 10% of zopiclone is recovered from the urine indicating extensive
metabolism of the drug before excretion. The terminal elimination half-life
(t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics
of zopiclone in humans are stereoselective. After oral administration
of the racemic mixture, Cmax (time to maximum plasma concentration),
AUC (area under the plasma time-concentration curve) and t1/2z values
are higher for the dextrorotatory enantiomer owing to the slower total
clearance and smaller volume of distribution (corrected by the bioavailability),
compared with the levorotatory enantiomer. In urine, the concentrations
of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites
are higher than those of the respective antipodes. The pharmacokinetics
of zopiclone are altered by aging and are influenced by renal and hepatic
functions
Side effects
The side effect most commonly seen in clinical trials
is taste alteration or dysgeusia (bitter, metallic taste, which is
usually fleeting in most users but can persist until the drug's half-life
has expired). Palpitations may occur in the daytime following withdrawal
from the drug after prolonged periods of use (especially when taken
for more than two weeks).
Less common reactions
* Gastrointestinal: heartburn, constipation, diarrhoea, nausea, coated
tongue, bad breath, anorexia or increased appetite, vomiting, epigastric
pains, dyspepsia, dehydration, parageusia.
* Cardiovascular: palpitations in elderly patients.
* Skin: urticaria, tingling in the arms and legs.
* Miscellaneous: blurred vision, frequent micturition, mild to moderate
increases in serum transaminases and/or alkaline phosphatase have been
reported very rarely.
* Reproductive: impotence, delayed ejaculation, anorgasmia in both
women and men.[citation needed]
* Nervous system: agitation, anxiety, loss of memory including retrograde
and anterograde amnesia, confusion, dizziness, weakness, somnolence,
asthenia, moderate to severe euphoria and/or dysphoria, feeling of
drunkenness, depression, coordination abnormality, hypotonia, speech
disorder, hallucinations of various strengths, usually auditory and
visual, behavioural disorders, aggression, tremor, rebound insomnia,
nightmares, hypomania.carcinogenic and mutagenic according to rat,
mice and hamster studies. It should be noted that, at 100 mg per kg
of bodyweight per day, the experimental dosage was considerably higher
than the therapeutic dose for humans. The authors of an uncontrolled
study of Zopiclone said that it may take decades in immunocompetent
people before carcinogenic effects from past zopiclone use develops.
It was suggested that further research and monitoring was required
into the potential for zopiclone to cause cancer in immunocompetant
patients.[23]
A recent analysis of U.S. Food and Drug Administration (FDA) data
and clinical trial data shows that nonbenzodiazepine Z-drugs at prescribed
doses cause an increased risk of developing cancer in humans. The data
shows that trial subjects receiving hypnotic drugs had an increased
the risk of developing cancer and malignancies. There have been 15
epidemiologic studies which have shown that hypnotic drugs cause increased
mortality, mainly due to increased cancer deaths. The cancers included
cancer of the brain, lung, bowel, breast, and bladder, and neoplasms.
Initially FDA reviewers did not want to approve the drugs due to concerns
over cancer but ultimately changed their mind and approved the drugs
despite the concerns. FDA data has shown that zolpidem, zaleplon and
eszopiclone are clastogenic and cause cancer in rodents. Benzodiazepine
agonists are associated with an increased risk of ovarian cancer in
humans. Zopiclone was reportedly refused a product license by the FDA
in the USA due to indications that zopiclone could cause the development
of cancer. Development of a malignant neoplasm has been associated
with zolpidem usage but the rate of incidence of neoplasm in zolpidem
users is as yet unknown. The rates, in clinical trials for the nonbenzodiazepine
Z drugs, of malignancies and neoplasms are significantly higher in
hypnotic groups than in placebo groups. Also the analysis of clinical
trials and FDA data showed that eszopiclone, zaleplon, and zolpidem
appeared to have an adverse effect on the immune system, causing an
increased rate of infections and colds in hypnotic users. Suppression
of immune function might be the cause of the increased rate of cancer
in nonbenzodiazepine hypnotic users. Indiplon another nonbenzodiazepine
drug has also shown an increased rate of cancers in clinical trials.
Overdose
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.Death certificates
show the number of zopiclone related deaths is on the rise. Zopiclone,
when taken alone usually is not fatal however, when mixed with alcohol
or other drugs eg opioids or in patients with respiratory or hepatic
disorders the risk of a serious and life threatening overdose increases
