Zopiclone and the Treatment of Insomnia: A Comprehensive Clinical and Historical Overview

Before Zopiclone: The Benzodiazepine Era

Before the introduction of Zopiclone, benzodiazepines were the standard medicines used to treat insomnia and anxiety. From the 1960s onwards, medicines such as diazepam, nitrazepam, lorazepam and temazepam became widely prescribed because they helped patients fall asleep more quickly and reduced anxiety.

Initially these medicines were regarded as a significant improvement over older sedatives such as barbiturates, which carried a much higher risk of overdose. Benzodiazepines offered a better safety profile and quickly became one of the most frequently prescribed medicines worldwide.

Over time, however, researchers and healthcare professionals recognised several important limitations associated with long-term benzodiazepine use. Patients could develop tolerance, meaning higher doses were needed to achieve the same effect, while prolonged use also increased the likelihood of physical dependence and withdrawal symptoms when treatment was stopped.

Other recognised concerns included:

  • Morning drowsiness
  • Reduced alertness
  • Poor concentration
  • Memory impairment
  • Increased risk of falls in older adults
  • Slower reaction times
  • Reduced driving performance

These concerns encouraged researchers to search for newer medicines capable of improving sleep while reducing some of the unwanted effects associated with benzodiazepines.

Beyond Benzodiazepines

The search for improved insomnia treatments resulted in the development of a newer class of medicines commonly known as Z-drugs. Although these medicines are chemically different from benzodiazepines, they act on many of the same receptors within the brain.

The three medicines in this group are:

Medicine Common Brand Primary Use
Zopiclone Zimovane Difficulty falling asleep and staying asleep
Zolpidem Ambien Sleep-onset insomnia
Zaleplon Sonata Short-term difficulty falling asleep

Rather than acting broadly throughout the central nervous system, these medicines were designed to bind more selectively to receptors involved in promoting sleep.

Potential advantages include:

  • Faster sleep onset
  • Reduced night-time waking
  • Improved sleep continuity
  • Shorter duration of next-day sedation in suitable patients
  • Effective short-term insomnia treatment

Although often better tolerated than many older sedatives, Z-drugs are still prescription medicines and should only be used for short periods under appropriate medical supervision.

A Short History of Zopiclone

Zopiclone was introduced during the 1980s following years of pharmaceutical research into alternative hypnotic medicines. Scientists aimed to develop a treatment that retained the sleep-promoting effects of benzodiazepines while improving tolerability for suitable patients.

Following clinical development, Zopiclone became available in many countries as a short-term treatment for insomnia. It quickly gained popularity because many patients experienced:

  • Faster sleep initiation
  • Longer sleep duration
  • Fewer night awakenings
  • Improved overall sleep quality

Today, Zopiclone remains one of the most commonly prescribed hypnotic medicines for the short-term management of insomnia. In the United Kingdom it is classified as a Prescription Only Medicine (POM) and should only be supplied after assessment by an appropriately qualified healthcare professional.

How Zopiclone Works

Sleep is regulated by a complex network of neurotransmitters that either stimulate or calm brain activity. One of the body’s most important calming neurotransmitters is gamma-aminobutyric acid (GABA).

GABA acts as the brain’s natural braking system by slowing nerve activity and promoting relaxation.

Zopiclone works by attaching to GABA-A receptors located throughout the central nervous system. Once attached, it enhances the effects of naturally occurring GABA, reducing excessive neuronal activity and making it easier for the body to transition into sleep.

As GABA activity increases, many patients experience:

  • Faster sleep onset
  • Reduced sleep latency
  • Longer uninterrupted sleep
  • Fewer night awakenings
  • Improved overall sleep efficiency

Unlike medicines designed to treat anxiety throughout the day, Zopiclone is intended to be taken immediately before bedtime when the patient is able to obtain a full night’s sleep, usually between seven and eight hours.

Although highly effective for short-term treatment, Zopiclone should not be used continuously for prolonged periods because tolerance and dependence may still develop. Healthcare professionals generally recommend using the lowest effective dose for the shortest possible duration alongside lifestyle changes and non-drug treatments such as Cognitive Behavioural Therapy for Insomnia (CBT-I).

Uptake and Metabolism of Zopiclone

Once a Zopiclone tablet is swallowed, the medicine begins a carefully regulated journey through the body. Pharmacologists describe this process using the term pharmacokinetics, which explains how a medicine is absorbed, distributed, metabolised, and eventually eliminated.

Understanding these processes helps explain why Zopiclone begins working relatively quickly, how long its effects last, and why the medicine should only be taken immediately before bedtime.

Unlike some medicines that require several doses before becoming effective, Zopiclone is rapidly absorbed after oral administration. After entering the bloodstream, it is transported throughout the body before reaching the brain, where it enhances the activity of gamma-aminobutyric acid (GABA), the neurotransmitter responsible for reducing nerve activity and promoting sleep.

The body then gradually breaks the medicine down into inactive or weakly active metabolites, which are removed primarily through the kidneys.

The four major stages include:

  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Together, these processes determine both the effectiveness and duration of the medicine.

Understanding Zopiclone Pharmacokinetics

Pharmacokinetics refers to what the body does to a medicine after it has been taken. Every medicine follows the same four-step pathway.

  • Stage 1 – Absorption: The medicine moves from the digestive tract into the bloodstream.
  • Stage 2 – Distribution: Blood circulation transports the medicine to organs and tissues throughout the body.
  • Stage 3 – Metabolism: The liver chemically converts the medicine into compounds that are easier for the body to eliminate.
  • Stage 4 – Excretion: The kidneys remove the medicine and its metabolites through urine.

Each stage influences how quickly the medicine begins working, how effective it becomes and how long its effects continue.

Zopiclone Absorption

Following oral administration, Zopiclone is absorbed rapidly from the gastrointestinal tract.

Clinical studies indicate that the medicine has a relatively high oral bioavailability, meaning that a large proportion of the swallowed dose successfully reaches the bloodstream rather than being destroyed during digestion.

Several factors influence absorption, including:

  • Whether the medicine is taken with food
  • Individual digestive function
  • Liver function
  • Age
  • Other medicines being taken

After a standard oral dose, blood concentrations usually increase quickly, allowing many patients to begin feeling sleepy within approximately 30 to 60 minutes.

For this reason, healthcare professionals recommend taking Zopiclone immediately before going to bed rather than earlier in the evening.

Property Information
Administration Oral tablet
Absorption Rapid
Bioavailability Approximately 75–80%
Time to peak concentration Around 1–2 hours

Zopiclone Distribution

Once absorbed, Zopiclone enters the bloodstream and is distributed throughout the body.

Distribution refers to the movement of a medicine from the blood into tissues where it produces its therapeutic effect.

Zopiclone readily crosses the blood–brain barrier, allowing it to reach receptors within the central nervous system.

After binding to GABA-A receptors, nerve activity slows, helping the brain transition naturally towards sleep.

Factors affecting distribution include:

  • Blood flow
  • Body composition
  • Age
  • Liver function
  • Kidney function
  • Plasma protein binding

Older adults often process medicines more slowly, which is one reason lower starting doses are usually recommended for elderly patients.

Zopiclone Metabolism

After exerting its effects, Zopiclone is transported to the liver where specialised enzymes begin breaking the medicine into smaller compounds.

This process is known as drug metabolism.

The liver converts Zopiclone into several metabolites, the two principal ones being:

  • N-desmethyl Zopiclone: This metabolite has little or no hypnotic activity and represents one of the major breakdown products.
  • Zopiclone N-oxide: This metabolite retains only weak pharmacological activity compared with the parent medicine.

The liver enzyme CYP3A4 plays a major role in metabolising Zopiclone.

Because of this, medicines that strongly affect CYP3A4 may alter blood concentrations of Zopiclone and increase the likelihood of side effects or reduce effectiveness.

Examples include certain:

  • Antibiotics
  • Antifungal medicines
  • Anti-seizure medicines
  • HIV medicines

Patients should always tell their prescriber about every medicine and supplement they are taking before starting Zopiclone.

Zopiclone Excretion

The final stage of pharmacokinetics is excretion.

Once metabolism has occurred, the body removes both the original medicine and its metabolites.

Most elimination occurs through the kidneys in urine, while a smaller proportion leaves the body through faeces.

The average elimination half-life of Zopiclone is approximately five hours, although this may vary depending on:

  • Age
  • Liver disease
  • Kidney disease
  • Overall health
  • Concomitant medicines

A half-life of five hours means that approximately half of the medicine has been removed from the bloodstream after this period.

Although blood concentrations continue falling overnight, some individuals—particularly older adults—may still experience residual drowsiness the following morning.

Characteristic Typical Value
Main route of elimination Kidneys (urine)
Secondary route Faeces
Average half-life About 5 hours
Duration of clinical effect Approximately 6–8 hours
Complete elimination Usually within 24–48 hours, depending on individual factors

Why Pharmacokinetics Matters

Understanding how Zopiclone moves through the body helps explain why healthcare professionals recommend taking the medicine only immediately before bedtime and only when a full night’s sleep is possible.

Correct timing reduces the risk of next-day drowsiness while allowing the medicine to produce its intended hypnotic effect.

Knowledge of absorption, metabolism and elimination also helps clinicians determine appropriate dosing for older adults and patients with liver or kidney impairment, ensuring treatment remains both effective and as safe as possible.

Eszopiclone (Lunesta) and Enantiomers

Modern pharmaceutical research has shown that some medicines exist in two mirror-image forms known as enantiomers. Although these molecules share the same chemical formula, they may behave differently inside the human body.

Zopiclone contains two enantiomers:

  • S-enantiomer (Eszopiclone)
  • R-enantiomer

The S-enantiomer is considered to contribute most of the medicine’s sleep-promoting activity. For this reason, researchers developed Eszopiclone, which contains only the active S-enantiomer and is marketed in several countries under the brand name Lunesta.

Unlike standard Zopiclone, which contains both molecular forms, Eszopiclone contains only the active component.

Potential characteristics include:

  • Improved receptor selectivity
  • Reliable sleep induction
  • Reduced night-time awakenings
  • Longer sleep maintenance in suitable patients

Although chemically related, the availability of Eszopiclone varies between countries, and prescribing practices differ according to national regulatory guidance.

Understanding Enantiomers

An enantiomer is a molecule that is a mirror image of another molecule, much like a person’s left and right hands.

Although both versions contain identical atoms, their three-dimensional arrangement differs.

This difference may influence:

  • Drug activity
  • Receptor binding
  • Side effects
  • Drug metabolism
  • Duration of action

Many medicines contain mixtures of enantiomers, while others are developed using only the more active form.

For Zopiclone:

  • Standard Zopiclone contains both R and S enantiomers.
  • Eszopiclone contains only the active S-enantiomer.

Researchers continue studying whether single-enantiomer medicines offer meaningful clinical advantages over racemic mixtures in different patient groups.

Eszopiclone (Lunesta): Development and Clinical Use

Eszopiclone was developed to isolate the more active component of Zopiclone.

It is prescribed primarily for adults experiencing:

  • Difficulty falling asleep
  • Frequent waking during the night
  • Poor sleep maintenance
  • Chronic insomnia requiring medical treatment

Clinical studies suggest that Eszopiclone may improve both sleep onset and sleep maintenance in selected patients.

However, as with all hypnotic medicines, treatment should be:

  • Individualised
  • Regularly reviewed
  • Used for the shortest appropriate duration
  • Combined with non-medicinal approaches whenever possible

Behavioural therapies and healthy sleep habits remain the cornerstone of long-term insomnia management.

Zopiclone Prescribing and Available Doses

In the United Kingdom, Zopiclone is classified as a Prescription Only Medicine (POM).

It should only be supplied following assessment by an appropriately qualified healthcare professional.

Treatment is generally reserved for:

  • Severe insomnia
  • Short-term sleep disturbance
  • Sleep problems causing significant daytime impairment

Typical tablet strengths include:

  • 3.75 mg: Older adults or patients requiring a lower dose
  • 7.5 mg: Standard adult dose
  • 10 mg: Not routinely recommended in UK clinical practice

Treatment is normally limited to two to four weeks, including gradual dose reduction where appropriate.

Principles of Safe Prescribing

Healthcare professionals consider many factors before prescribing Zopiclone.

These include:

  • Patient age
  • Medical history
  • Liver function
  • Kidney function
  • Pregnancy status
  • Current medicines
  • Alcohol consumption
  • Previous history of dependence
  • Mental health conditions

The aim is always to prescribe the lowest effective dose for the shortest possible period while minimising potential risks.

Regular review is recommended to determine whether continued treatment remains necessary.

Before Taking Zopiclone

Although Zopiclone is effective for many people, it is not suitable for everyone.

Patients should inform their healthcare professional if they:

  • Are pregnant or planning pregnancy
  • Are breastfeeding
  • Have liver disease
  • Have kidney disease
  • Have breathing disorders such as sleep apnoea
  • Have myasthenia gravis
  • Have severe depression
  • Have a history of alcohol misuse
  • Have previously experienced dependence on medicines
  • Take other medicines that cause drowsiness

Your prescriber may recommend an alternative treatment if Zopiclone is considered unsuitable.

Important Safety Advice

To reduce the likelihood of side effects:

  • Take Zopiclone immediately before going to bed.
  • Ensure at least 7–8 hours are available for sleep.
  • Avoid alcohol while taking the medicine.
  • Never exceed the prescribed dose.
  • Do not combine with other sedative medicines unless advised by a healthcare professional.
  • Avoid driving or operating machinery if you feel sleepy the following morning.

Stopping treatment suddenly after prolonged use may result in withdrawal symptoms. Patients who have used Zopiclone regularly should seek medical advice before discontinuing treatment.

Frequently Asked Questions

How quickly does Zopiclone work?
Most people begin feeling sleepy within 30 to 60 minutes after taking a tablet.

How long does Zopiclone remain active?
The medicine generally provides sleep support for around 6 to 8 hours, although individual responses vary.

Can Zopiclone be taken every night?
It is intended for short-term treatment only. Long-term continuous use is generally not recommended because of the potential for tolerance, dependence, and withdrawal symptoms.

Is Zopiclone addictive?
There is a risk of physical and psychological dependence, particularly with prolonged use or higher doses. Following the prescribed dose and duration helps reduce this risk.

Can I drink alcohol while taking Zopiclone?
No. Alcohol can increase the sedative effects of Zopiclone, raising the risk of excessive drowsiness, impaired coordination, and breathing difficulties.

It is ALWAYS best practice, and responsible practice to consult your medical professional before taking ANY hypnotic or z-drug for insomnia [20]. 

[1] https://www.ncbi.nlm.nih.gov/pubmed/8837952

[2] http://www.scielo.br/scielo.php?pid=S1807-59322016000100005&script=sci_arttext

[3] https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/sleep-12 disorder-sedative-hypnotic-drug-information

[4] http://pharmapedia.wikidot.com/zopiclone#toc0

[5] https://www.deadiversion.usdoj.gov/fed_regs/rules/2005/fr0214.htm

[6] https://www.ncbi.nlm.nih.gov/pubmed/9506247

[7] https://link.springer.com/article/10.2165/00003088-199529060-00004

[8] https://pdfs.semanticscholar.org/1dab/823b1923a9a8313abd43beb3706cac12425a.pdf 

[9] https://www.drugbank.ca/drugs/DB01198

[10] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657020/pdf/13181_2013_Article_292.pdf

[11] https://link.springer.com/content/pdf/10.1007%2Fs40263-017-0445-9.pdf  

[12] https://www.deadiversion.usdoj.gov/fed_regs/rules/2005/fr0214.htm

[13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614593/  

[14] https://www.acnr.co.uk/2019/05/the-misprescribing-of-z-drugs-for-insomnia/ 

[15] https://www.clinicaltherapeutics.com/article/S0149-2918(16)30733-0/pdf 

[16] https://www.clinicaltherapeutics.com/article/S0149-2918(16)30733-0/pdf]

[17] http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con2023057.pdf] 

[18] https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020859s011lbl.pdf  

[19] https://www.webmd.com/drugs/2/drug-17524/zaleplon-oral/details  

[20] https://patient.info/medicine/zopiclone-tablets-zimovane