Eszopiclone

drugbox
IUPAC_name = (5S)-6-(5-Chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazin-5-yl 4-methyl-1-piperazinecarboxylate

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CAS_number = 138729-47-2
ATC_prefix = N05
ATC_suffix = CF04
ATC_supplemental = [cite web |url=http://www.whocc.no/atcddd/new_atc_ddd.html#ATCDDD_FINAL |title=ATC/DDD Classification (FINAL): New ATC 5th level codes |date=August 27, 2008 |author=WHO International Working Group for Drug Statistics Methodology |publisher=WHO Collaborating Centre for Drug Statistics Methodology |accessdate=2008-09-05]
PubChem = 969472
DrugBank = APRD00431
C = 17 |H = 17 |Cl = 1 |N = 6 |O = 3
molecular_weight = 388.808 g/mol
smiles = CN1CCN(C(=O)O [C@@H] 2NC(=O)c3nccnc23)C(C1)c1ccc(Cl)cn1
bioavailability =
protein_bound = 52-59%
metabolism = Hepatic oxidation and demethylation (CYP3A4 and CYP2E1-mediated)
elimination_half-life = 6 hours
excretion = Renal
pregnancy_US = C
legal_US = Schedule IV
routes_of_administration = Oral

Eszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic agent (viz., a sedative) used as a treatment for insomnia. Eszopiclone is the active stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.

Eszopiclone is a short acting nonbenzodiazepine sedative hypnotic. It has been shown to be safe and effective short term treatment in the elderly and safe in younger adults for 6 - 12 months. All clinical trials of eszopiclone published so far are industry funded by the pharmaceutical manufacturer of eszopiclone, Sepracor. [cite journal | journal = Clin Interv Aging | year = 2007 | volume = 2 | issue = 3 | pages = 313–26 | title = Eszopiclone for late-life insomnia | author = McCrae CS | coauthors = Ross A, Stripling A, Dautovich ND | pmid = 18044182] Eszopiclone (Lunesta) along with other "Z Drugs" including zolpidem (Ambien), zaleplon (Sonata) are the most commonly prescribed sedative hypnotics in the USA. There were 43 million prescriptions issued for insomnia medications during 2005 in the USA which generated a total of $2.7 billion for pharmaceutical companies. [cite journal | journal = J Mass Dent Soc | year = 2007 | volume = 56 | issue = 53 | pages = 44–5 | title = What every dentist should know about the "z-sedatives" | author =McKenzie WS | coauthors = Rosenberg M | pmid = 18069595]

Pharmacology

Eszopiclone acts on benzodiazepine receptors as an agonist. [cite journal | journal = Vertex | year = 2007 | month = Jul-Aug | volume = 18 | issue = 74 | pages = 294–9 | title = [New hypnotics: perspectives from sleep physiology] | author =Jufe GS | pmid = 18265473] Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between 1 and 1.3 hours. [cite journal | journal = Am J Health Syst Pharm | year = 2006 | month = Jan | date = 1 | volume = 63 | issue = 1 | pages = 41–8 | title = Eszopiclone | author = Halas CJ | pmid = 16373464 | doi = 10.2146/ajhp050357] The elimination half-life of eszopiclone is approximately 6 hours and is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. [cite journal | journal = Clin Ther | year = 2006 | month = Apr | volume = 28 | issue = 4 | pages = 491–516 | title = Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia | author = Najib J | pmid = 16750462 | doi = 10.1016/j.clinthera.2006.04.014] In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam. [cite web
url= http://www.benzo.org.uk/bzequiv.htm |title= BENZODIAZEPINE EQUIVALENCE TABLE |accessdaymonth= 21 Mar |accessyear= 2008 |author= Professor Ashton |year= 2007 |month= Apr]

Indications

Eszopiclone's mechanism of action is via the benzodiazepine receptor-GABA complex. Other drugs which are similar to eszopiclone and also work via the benzodiazepine receptor-GABA complex include benzodiazepines, zaleplon, and zolpidem. Behavioral therapies, particularly cognitive behavioral therapy, and lifestyle changes show significant long-term efficacy as treatments for chronic insomnia. [cite journal | journal = Curr Treat Options Neurol | year = 2006 | month = Sep | volume = 8 | issue = 5 | pages = 367–75 | title = Treatment of sleep dysfunction and psychiatric disorders | author = Becker PM | pmid = 16901376 | doi = 10.1007/s11940-006-0026-6]

Dosages

For treatment to improve sleep onset and/or sleep maintenance the recommended dose is 2mg-3mg for adult patients (aged 18-64 years) and 2mg for older adult patients aged 65 years or older. The 1mg dose is for older adult patients whose problems are related to sleep onset. [cite journal | journal = Drugs R D | year = 2005 | volume = 6 | issue = 2 | pages = 111–5 | title = Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone--Sepracor | pmid = 15777104 | doi = 10.2165/00126839-200506020-00006 | author = &Na;,]

ide Effects

The following side effects may occur from usage of eszopiclone (lunesta):cite web |url= http://www.rxlist.com/cgi/generic/lunesta_ad.htm |title= Lunesta |accessdaymonth= 22 Mar |accessyear= 2008 |author= rxlist]

Common side effects can include:

* unpleasant bitter or metallic taste
* headaches
* chest pain
* cold-like symptoms
* pain
* dry mouth
* daytime drowsiness
* lightheadedness
* dizziness
* upset stomach
* decreased sexual desire
* painful menstruation (periods)
* heartburn

Less common side effects can include:

* rashes
* itching
* incoordination
* swelling of the hands, feet, ankles, or lower legs
* painful or frequent urination
* back pain

neuropsychiatric adverse effects reported include; [cite journal | journal = Prim Care Companion J Clin Psychiatry | year = 2007 | volume = 9 | issue = 6 | pages = 468–9 | title = New-onset transient hallucinations possibly due to eszopiclone: a case study |url =http://www.psychiatrist.com/pcc/pccpdf/v09n06/v09n0611.pdf#page=5 |type =PDF |author =Duggal HS | pmid = 18185832]

* more outgoing behavior
* aggressive behavior
* confusion
* agitation
* auditory and visual hallucinations
* worsening of depression
* suicidal thoughts
* depersonalisation
* amnesia

If a person does not sleep immediately after taking their Eszopiclone (Lunesta) or if they get up shortly after taking their medication they may experience dizziness, lightheadedness, hallucinations (seeing things or hearing voices that are not there), as well as experience problems with coordination and memory.

Increased risk of depression

It has been claimed that insomnia causes depression and hypothesized that insomnia medications may help to treat depression. However, an analysis of data of clinical trials submitted to the FDA concerning the drugs zolpidem, zaleplon and eszopiclone found that these sedative hypnotic drugs more than doubled the risks of developing depression compared to those taking placebo pills. Hypnotic drugs therefore may be contraindicated in patients suffering from or at risk of depression. Hypnotics were found to be more likely to cause depression than to help it. Studies have found that long term users of sedative hypnotic drugs have a markedly raised suicide risk as well as an overall increased mortality risk. Cognitive-behavioral therapy (CBT) for insomnia on the other hand has been found to both improve sleep quality as well as general mental health. [cite journal | journal = BMC Psychiatry | year = 2007 | month= Aug |date= 21 |volume= 7 | title= Greater incidence of depression with hypnotic use than with placebo |url =http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17711589 |publisher=pubmed |author =Kripke DF | pmid = 17711589 | doi= 10.1186/1471-244X-7-42 | pages= 42]

Elderly

Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects. [cite journal | journal = Clin Geriatr Med | year = 2008 | month = Feb | volume = 24 | issue = 1 | pages = 93–105, vii | title = Pharmacotherapy for insomnia | author = Tariq SH, Pulisetty S | pmid = 18035234 | doi = 10.1016/j.cger.2007.08.009] 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 durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been 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 these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia. [cite journal | journal = Am J Geriatr Pharmacother | year = 2006 | month = Jun | volume = 4 | issue = 2 | pages = 168–92 | title = Management of chronic insomnia in elderly persons | author = Bain KT | pmid = 16860264 | doi = 10.1016/j.amjopharm.2006.06.006]

Dependence

Eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of benzodiazepines and similar benzodiazepine-like drugs such as eszopiclone may lead to physical and psychological dependence. The risk of abuse and dependence increases with the dose and duration of usage and concomitant use of other psychoactive drugs. The risk is also greater in patients with a history of alcohol or drug abuse or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks.Eszopiclone was studied for up to 6 months in a group of patients which showed no signs of tolerance or dependence in a study funded and carried out by Sepracor. Insomnia itself can result from dependence or substance withdrawal symptoms. Causes of insomnia include chronic anxiety, depression, alcohol or substance abuse or withdrawal, adverse or withdrawal effects from medication, or age-related changes in sleep [cite journal | journal = Proc (Bayl Univ Med Cent). | year = 2006 | month = Jan | volume = 19 | issue = 1 | pages = 54–9 | title = Eszopiclone (Lunesta): a new nonbenzodiazepine hypnotic agent | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16424933#B1 | author = Brielmaier BD | pmid = 16424933]

Abuse

A study of abuse potential of eszopiclone found that eszopiclone at doses of 6 and 12 mg produced euphoric effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia and hallucinations was observed for both eszopiclone (lunesta) as well as for diazepam (Valium).cite web |url= http://www.rxlist.com/cgi/generic/lunesta_ad.htm |title= Lunesta |accessdaymonth= 22 Mar |accessyear= 2008 |author= rxlist]

Withdrawal Symptoms

If a person has taken Eszopiclone for longer than 1 - 2 weeks they should not stop taking the medication abruptly and should consult their doctor. Usually doctors will direct a slow reduction in dosage to minimise withdrawal symptoms. Particularly after abrupt cessation of medication, withdrawal symptoms may include: [cite web |url= http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a605009.html |title= Eszopiclone |accessdaymonth= 21 Mar |accessyear= 2008 |author= MedlinePlus |coauthors= |date= 8 |year= 2001 |month= Jan |format= |publisher= National Institutes of Health]

*anxiety
*unusual dreams
*dizziness
*stomach and muscle cramps
*upset stomach
*vomiting
*sweating
*shakiness
*insomnia
*seizures (rare)

Overdose

Eszopiclone is dangerous in overdose. Signs of eszopiclone overdose reported included dulled mental status and a prolonged coma (lasting up to 48 hours). [cite journal | journal = Am J Emerg Med | year = 2007 | month = Jul | volume = 25 | issue = 6 | pages = 735 (e5–6) | title = Prolonged coma after eszopiclone overdose | author = Lovett B | coauthors = Watts D, Grossman M | pmid = 17606111 | doi = 10.1016/j.ajem.2006.12.021] Texas poison control centers reported that during 2005-2006 there were 525 total eszopiclone overdoses recorded by them in the state of Texas with the majority of which being intentional suicide attempts. [cite journal | journal = Hum Exp Toxicol | year = 2007 | month = Oct | volume = 26 | issue = 10 | pages = 795–800 | title = Eszopiclone ingestions reported to Texas poison control centers, 2005 2006 | author = Forrester MB | pmid = 18025051 | doi = 10.1177/0960327107084045]

Controversy

The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications including eszopiclone. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry inindustry-sponsored trials was 3.6 times higher than non-industry-sponsored studies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. The author was concerned that there is no discussion of adverse effects of sedative hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in eszopiclone and other sedative hypnotic drugs and an overemphasis on the positive effects. The author concluded by stating that "major hypnotic trials are needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." [cite journal | journal = J Clin Sleep Med | year = 2007 | month = Dec | date = 15 | volume = 3 | issue = 7 | pages = 671–3 | title = Who should sponsor sleep disorders pharmaceutical trials? | author = Kripke DF | pmid = 18198797]

References

ee also

* Zopiclone
* Benzodiazepines

External links

* [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a605009.html National Institute of Health - Medline Plus - (Eszopiclone)]
* [http://www.lunesta.com/PostedApprovedLabelingText.pdf Eszopiclone labeling text (PDF)]
* [http://www.sepracor.com/ Sepracor.com]
* [http://www.lunesta.com/ Lunesta.com]