Zopiclone

Substance identification
Zopiclone (IUPAC chemical name: 6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro- 5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate) is a sedative hypnotic drug of the cyclopyrrolone class. Zopiclone has been reported as a white or slightly yellowish powder. Zopiclone is available as pharmaceutical products in tablet form for oral use. Eszopiclone (the S-enantiomer of zopiclone) is marketed as a pharmaceutical product in some countries.

WHO review history
Zopiclone was pre-reviewed by the Committee at its 29th meeting, when it recommended that surveillance be continued but that a critical review was not required. In view of the abuse liability of the drug and the significant number of reports of adverse drug reactions related to zopiclone abuse sent to the WHO international drug monitoring programme, however, zopiclone was pre- reviewed by the Committee at its 33rd meeting, when it recommended a critical review. Zopiclone was critically reviewed at the 34th meeting, in 2006, when the Committee rated its abuse liability as low and its therapeutic usefulness considerable and recommended continued surveillance by WHO. A pre-review was initiated after a proposal was received from an international agency that suggested a significant increase in the reported number of trafficking cases and seizures involving zopiclone.

Similarity to known substances and effects on the central nervous system
Zopiclone binds to the benzodiazepine receptor that forms part of the GABAA receptor complex. It may bind to different parts of the receptor or cause different changes in the GABAA receptor complex than benzodiazepines.

In animals, zopiclone has sedative, anxiolytic, anticonvulsant and muscle relaxant properties similar to those of benzodiazepines. In studies in humans, it was less effective than benzodiazepines for treatment of anxiety.

Dependence potential
Studies in animals show evidence of zopiclone tolerance and withdrawal, indicating the development of physical dependence. A number of published reports have described physical dependence associated with zopiclone use in humans. Withdrawal symptoms such as increased anxiety and insomnia have been described in people who cease zopiclone use, usually after prolonged use and dose escalation from clinical use. Tolerance and withdrawal have also been reported in clinical trials. Dependence is documented in databases on adverse events associated with use of pharmaceutical drugs.

Actual abuse and/or evidence of likelihood of abuse
Studies in animals suggest that zopiclone may have abuse liability similar to that of benzodiazepines such as midazolam, diazepam, nitrazepam and alprazolam. The effects indicative of abuse liability were blocked by the benzodiazepine antagonist flumazenil, indicating a mechanism of action involving the benzodiazepine receptor.

No controlled studies in humans have been reported on the abuse potential of zopiclone. Published reports support its abuse potential, its use with alcohol and other drugs, excessive use and escalation to high-dose use. The extent of harm related to the use of zopiclone is, however, unclear.

Zopiclone is widely used therapeutically in many countries and regions, and it is also listed in databases of adverse events associated with pharmaceutical use. Zopiclone is most likely to be misused by individuals to whom it is prescribed for long periods, who are using other psychoactive drugs or in those with psychiatric comorbidities. While seizures of zopiclone have been reported in multiple countries in several regions, the prevalence of non-medical use of zopiclone by the general population is unknown. Furthermore, there is insufficient evidence that significant public health and social problems related to abuse can be directly attributed to sole use of zopiclone.

Therapeutic usefulness
Zopiclone is a widely used medicine primarily indicated for the short-term treatment of insomnia.

Recommendation
Zopiclone (IUPAC chemical name: 6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro- 5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate) is a sedative hypnotic drug of the cyclopyrrolone class. The Committee noted that concern has been expressed in several countries regarding non-prescription use of zopiclone. While there have been reports of adverse effects, overdose, withdrawal symptoms and an increased number of seizures of the substance, there is still insufficient evidence that zopiclone is or is likely to be abused to such an extent as to constitute a public health and social problem.

The Committee also noted that zopiclone is widely used therapeutically in many countries.

Recommendation: The Committee recommended that zopiclone (IUPAC chemical name: 6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin- 5-yl4-methylpiperazine-1-carboxylate) not proceed to critical review but be kept under surveillance by the WHO Secretariat.