Eszopiclone
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Eszopiclone
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| Systematic (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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| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C17H17ClN6O3 |
| Mol. mass | 388.808 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Protein binding | 52-59% |
| Metabolism | Hepatic oxidation and demethylation (CYP3A4 and CYP2E1-mediated) |
| Half life | 6 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
C(US) |
| Legal status | |
| Routes | 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 cyclopyrrones.
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.[1] 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.[2]
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[edit] Pharmacology
Eszopiclone acts on benzodiazepine receptors as an agonist.[3] Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between 1 and 1.3 hours.[4] 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.[5] In terms of benzodiazepine receptor binding and relavent potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.[6]
[edit] Indications
Eszopiclone is prescribed for the management of insomnia. Sedative hypnotic agents including eszopiclone are among the most studied drugs to treat insomnia. Eszopiclone's mechamism 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.[7]
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.[8]
[edit] Side Effects
The following side effects may occur from usage of eszopiclone (lunesta):[9]
Common side effects can include:
- unpleasant bitter or metallic taste/smell
- headaches
- cold-like symptoms
- pain
- daytime drowsiness
- lightheadedness
- dizziness
- loss of coordination
- upset stomach
- vomiting
- decreased sexual desire
- painful menstruation (periods)
- breast enlargement in males
- heartburn
- unusual dreams
Less common side effects can include:
- rashes
- itching
- chest pain
- swelling of the hands, feet, ankles, or lower legs
- painful or frequent urination
- bloody or cloudy urine
- back pain
neuropsychiatric adverse effects reported include;[10]
- 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 hypothesised 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 contrindicated 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.[11]
[edit] Carcinogenicity
Eszopiclone may be carcinogenic and mutagenic according to rat, mice and hamster studies. A human study in immunocompromised patients taking eszopiclone demonstrated evidence that eszopiclone is carcinogenic. The author added that it may take decades in immunocompetent people before carcinogenic effects from past eszopiclone use develop. It was suggested that further research and monitoring was required into the potential for eszopiclone to cause cancer.[12]
A recent analysis of FDA and clinical trial data found that nonbenzodiazepine Z-drugs may cause an increased risk 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 and 3 epidemiologic studies which found no association. 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 of cancer but ultimately changed their mind and approved the drugs despite their original 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 due to indications that zopiclone caused 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 has also shown an increased rate of cancers in clinical trials. The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer".[13]
[edit] 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.[14] 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.[15]
[edit] 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[16]
[edit] 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).[9]
[edit] 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:[17]
- anxiety
- unusual dreams
- dizziness
- stomach and muscle cramps
- upset stomach
- vomiting
- sweating
- shakiness
- insomnia
- seizures (rare)
[edit] Overdose
Eszopiclone is dangerous in overdose. Signs of eszopiclone overdose reported included dulled mental status and a prolonged coma (lasting up to 48 hours).[18] 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.[19]
[edit] 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 in industry-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 is 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."[20]
[edit] References
- ^ McCrae CS; Ross A, Stripling A, Dautovich ND (2007). "Eszopiclone for late-life insomnia". Clin Interv Aging 2 (3): 313-26. PMID 18044182.
- ^ McKenzie WS; Rosenberg M (2007). "What every dentist should know about the "z-sedatives"". J Mass Dent Soc 56 (53): 44-5. PMID 18069595.
- ^ Jufe GS (Jul-Aug 2007). "[New hypnotics: perspectives from sleep physiology]". Vertex 18 (74): 294-9. PMID 18265473.
- ^ Halas CJ (1). "Eszopiclone". Am J Health Syst Pharm 63 (1): 41-8. doi:. PMID 16373464.
- ^ Najib J (Apr 2006). "Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia". Clin Ther 28 (4): 491-516. doi:. PMID 16750462.
- ^ Professor Ashton (Apr 2007). BENZODIAZEPINE EQUIVALENCE TABLE. Retrieved on 21 Mar 2008.
- ^ Becker PM (Sep 2006). "Treatment of sleep dysfunction and psychiatric disorders". Curr Treat Options Neurol 8 (5): 367-75. doi:. PMID 16901376.
- ^ "Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone--Sepracor" (2005). Drugs R D 6 (2): 111-5. PMID 15777104.
- ^ a b rxlist. Lunesta. Retrieved on 22 Mar 2008.
- ^ Duggal HS (2007). "New-onset transient hallucinations possibly due to eszopiclone: a case study". Prim Care Companion J Clin Psychiatry 9 (6): 468-9. PMID 18185832.
- ^ Kripke DF (21). "Greater incidence of depression with hypnotic use than with placebo". BMC Psychiatry 7: 42. pubmed. doi:. PMID 17711589.
- ^ Stebbing J; Waters L, Davies L, Mandalia S, Nelson M, Gazzard B, Bower M (1). "Incidence of cancer in individuals receiving chronic zopiclone or eszopiclone requires prospective study". J Clin Oncol 23 (31): 8134-6. doi:. PMID 16258120.
- ^ Kripke, Daniel F (2008). "Evidence That New Hypnotics Cause Cancer" (PDF). Department of Psychiatry, UCSD. University of California. “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.”
- ^ Tariq SH, Pulisetty S (Feb 2008). "Pharmacotherapy for insomnia". Clin Geriatr Med 24 (1): 93-105, vii. doi:. PMID 18035234.
- ^ Bain KT (Jun 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168-92. doi:. PMID 16860264.
- ^ Brielmaier BD (Jan 2006). "Eszopiclone (Lunesta): a new nonbenzodiazepine hypnotic agent". Proc (Bayl Univ Med Cent). 19 (1): 54-9. PMID 16424933.
- ^ MedlinePlus (8). Eszopiclone. National Institutes of Health. Retrieved on 21 Mar 2008.
- ^ Lovett B; Watts D, Grossman M (Jul 2007). "Prolonged coma after eszopiclone overdose". Am J Emerg Med 25 (6): 735 (e5-6). doi:. PMID 17606111.
- ^ Forrester MB (Oct 2007). "Eszopiclone ingestions reported to Texas poison control centers, 2005 2006". Hum Exp Toxicol 26 (10): 795-800. doi:. PMID 18025051.
- ^ Kripke DF (15). "Who should sponsor sleep disorders pharmaceutical trials?". J Clin Sleep Med 3 (7): 671-3. PMID 18198797.
[edit] See also
[edit] External links
- National Institute of Health - Medline Plus - (Eszopiclone)
- Eszopiclone labeling text (PDF)
- Sepracor.com
- Lunesta.com
