Zopiclone

Zopiclone (pronunciation perhaps Sanofi-Aventis, the main worldwide manufacturer of the drug. Zopiclone is a controlled substance in the United States, Canada and some European countries and may be illegal to possess without a prescription.

While it acts on the BZ¹ receptor and is a short-acting hypnotic agent, it is not a cyclopyrrolone derivative, belonging to a novel chemical class which is structurally unrelated to existing hypnotics.

On April 4, 2005, the United States DEA listed zopiclone under Schedule IV, due to some evidence that the drug has addictive properties similar to benzodiazepines.

Zopiclone, as traditionally sold worldwide, is a 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 been studied via head-to-head clinical trials to determine if any clinical differences exist (e.g., efficacy, side-effects, developing dependence on the drug, and safety, etc.).

Zopiclone is known colloquially as a "Z drug", Other Z drugs include zolpidem (Ambien and AmbienCR) and were thought in initial studies to be less addictive and less habit forming than benzodiazepines. This appraisal has shifted somewhat in the last few years, as cases of addiction and habituation have been presented. It is recommended that zopiclone is taken on a "when required" basis, and daily or continuous use of the drug is not usually advised.

Adverse reactions

The side-effect most commonly seen in clinical trials is taste alteration or dysgeusia (bitter, metallic taste, which is usually fleeting in most users but can persist until the drug's half-life has expired). Palpitations may occur in the daytime after withdrawal from the drug after prolonged periods of use (>4 weeks).

More common reactions

Gastrointestinal: bitter metallic taste, dry mouth. Nervous system: drowsiness, headaches, and fatigue. Unexpected mood changes have been noted, which if experienced should lead to the drug being withdrawn from the patient.

Less common reactions

• Gastrointestinal: heartburn, constipation, diarrhoea, nausea, coated tongue, bad breath, anorexia or increased appetite, vomiting, epigastric pains, dyspepsia, dehydration, parageusia.
• Cardiovascular: palpitations in elderly patients.
• Skin: urticaria, tingling in the arms and legs.
• Miscellaneous: blurred vision, frequent micturition, mild to moderate increases in serum phosphatase have been reported very rarely.
• Reproductive: impotence, ejaculation failure, 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.

Pharmacokinetics

Zopiclone is a cyclopyrrolone hypnotic agent. It possesses a chiral centre and is commercially available as a carbamazepine.

Pharmacology

The mechanism of action of zopiclone is similar to serotonin turnover.^[1][2] A meta-analysis of randomised controlled clinical trials which compared benzodiazepines to Zopiclone or other Z Drugs such as benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness.^[3] Zopiclone is in the barbiturate like properties.^[5][6]

In zaleplon. Zopiclone is therefore very similar pharmacologically to benzodiazepines.^[7]

Dependence and withdrawal

Zopiclone was introduced and initially promoted as having less dependence and withdrawal than traditional GABAa containing receptors. Zopiclone has high affinity for the alpha¹ subunit GABAa receptor and a low to intermediate action on α² and α³. receptors.^[9] The alpha1 alpha2 and alpha3 GABAa receptors make up over 90% of all GABAa receptors in humans. The differences in receptor affinity and binding of zopiclone compared with benzodiazepines have led some to claims of a lower dependency risk with zopiclone.

Publications in the British Medical Journal have cast some doubt on the claim that zopiclone has a low dependence potential. Physical dependence and recreational abuse and withdrawal syndromes similar to those seen in benzodiazepine withdrawal have been described. Withdrawal symptoms included anxiety, tachycardia, tremor, sweats, flushes, palpitations, derealisation, and further insomnia.^[10]

High dose misuse of zopiclone and increasing popularity amongst drug abusers has also been described with zopiclone^[11] Due to the risk of tolerance and physical dependence zopiclone is only recommended for the short term (2–4 weeks) relief of insomnia, or alternatively, long term infrequent use. Long-term zopiclone users who have become physically dependent are usually recommended to cross over to an equivalent dose of 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.^[12]

The risk of dependency on zopiclone when used for less than 4 weeks or used occasionally is very low.^{[citation needed]}

Alcohol has cross tolerance with GABAa receptor positive modulators such as 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.

Cognitive Behavioural Therapy

Zopiclone, nitrazepam are the most frequently prescribed hypnotics in the United Kingdom. Hypnotic drugs are of poor value for the management of chronic insomnia. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous sedative hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly which compounds the problem of chronic hypnotic drug use. Chronic hypnotic drug consumption has been shown to reduce work performance, increase absenteeism, increase road traffic accidents, increase morbidity, increase mortality and is associated with increased deliberate self harm. In the elderly increases in falls and fractures associated with sedative hypnotic drug use has been found. Cognitive behavioral therapy (CBT) has been found to be more effective for the long term management of insomnia than sedative hypnotic drugs.^{[citation needed]} No formal withdrawal programs for benzodiazepines exists with local providers. A meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A large scale trial utilising cognitive behavioural therapy in chronic users of sedative hypnotics including nitrazepam, temazepam and zopiclone found that CBT to be a more effective long term treatment for chronic insomnia. Persisting improvements in sleep quality, sleep latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3, 6 and 12 month follow up was found in those receiving cognitive behavioural therapy. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia was flexible, practical and cost effective treatment for the treatment of insomnia and that CBT leads to a reduction of benzodiazepine drug intake in significant number of patients.^[13]

Special precautions

Zopiclone induces impairment of motor function.^[14] Driving or operating machinery should be avoided after taking zopiclone.

Abuse

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 zolpidem and zopiclone.^[15]

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.^[16]

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 and therefore rapidly reverses the effects of zopiclone.^[17]

Death certificates show that fatal zopiclone overdoses are on the rise.^[18]

Availability

Zopiclone is also sold under a wide variety of other brand names world wide including:

• Insomnium - Argentina
• Sedolox and Somnal - Austria
• Rhovane - Canada
• Alpaz, Losopil, Nuctane, Zetix, Zometic and Zonix - Chile
• Imovane, Imoclone and Imozop - Denmark
• Zopinox, Imovane - Finland
• Optidorm, Ximovan, Zodurat, Zop, Zopi-Puren, Zopicalm and Zopiclodura - Germany
• Somnosan - Germany, Portugal
• Amvey, Eurovan, Zolief and Zomni - Hong Kong
• Zopicon - India
• Zileze, Zimoclone, Zopitan and Zorclone - Republic of Ireland
• Zimovane - Republic of Ireland, United Kingdom
• Nocturno - Israel
• Imovane (Имован) - Argentina, Australia, Belgium, Brazil, Canada, Chile, Czech Republic, Denmark, Finland, France, Greece, Hong Kong, Hungary, Iceland, Israel, Italy, Malaysia, Mexico, Netherlands, Norway, New Zealand, Russia, South Africa, Singapore, Sweden, Switzerland, Turkey, Venezuela
• Relaxon (Релаксон) and Somnol (Сомнол) - Russia
• Alchera, Z-Dorm, Zopimed and Zopivane - South Africa
• Datolan, Limovan, Siaten and Zopicalma - Spain
• Zopiklon - Denmark, Norway
• Amoban - Japan
• Hypnor - Egypt

References