Zopiclone: A New Breed.

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Before Zopiclone: The Benzo Age

The Benzo Age

In the past, and for a long time benzodiazepines (AKA Benzos) were the ‘go-to’ drugs of choice to treat insomnia.

In fact, it wasn’t until awareness on the associated risks of taking benzos that people became aware about the dangers. 

 

Many concerns about benzos were raised due to their adverse effects, which turned people to hypnotics – such as Zopiclone [1].

 

More importantly, hypnotics, like that of Zopiclone, are now:

 

the most common type of drug prescribed to older adults [1].

Beyond Benzodiazepines

Beyong Benzos

As of now, there are currently three FDA approved commercially sold non-benzodiazepine drugs that are available for the treatment of insomnia; these include, Zaleplon, Zolpidem and Eszopiclone [2].

 

As of 2013 the FDA recorded a staggering 3 million prescriptions of eszopiclone.

 

For the treatment of insomnia, the FDA approves several z-drugs, including: Lunesta (eszopiclone), Ambien (zolpidem), Edluar (zolpidem), Intermezzo (zolpidem), Sonata (zaleplon) and Zolpimist (zolpidem) [3]. 

Short History of Zopiclone

zopiclone history

Historically, zopiclone was first developed by a company called Sepracor and introduced by a company known as Rhone-Poulenc S.A, in 1986.

 

At that time this Z-drug was marketed as an improvement on traditional benzodiazepines [4]. 

 

In 2015, the US Drug Enforcement Administration placed zopiclone as a schedule 4 drug, brought on by the fact that evidence suggested zopiclone had addictive properties [4;5]. 

Zopiclone has been documented as having anxiolytic, anticonvulsant and muscle relaxant activity [6]. 

How Zopiclone Works

binding site zopiclone

To begin with,  Z-drugs (also known as non-benzodiazepines) bind to the same binding site as benzodiazepines.

This common receptor is known as the GABA receptor

When a drug binds to a receptor and causes a biological response, it’s called an Agonist.

Z-drugs are agonists at the same gamma-aminobutyric acid-type A (GABA) receptor – just as many inhibitory or sedating drugs such as Valium do.

 

Of all the z-drugs, zopiclone is known to produce the longest duration of action (half life). 

 

Furthermore, zopiclone reduces sleep onset latency, thereby increasing the total sleep time of an individual – reducing the overall night time awakenings [6].

However, among these functions of zopiclone it is uncertain if zopiclone extends total sleep time [2].

Uptake & Metabolism of Zopiclone

Zopiclone Pharmacokinetics

uptake and metabolism of Zopiclone

Pharmacokinetics is the scientific term in pharmacology for describing how a drug is absorbed into your body, and distributed to where it needs to go.

Then it details a drugs metabolism into a desirable form for your body to use.

The final step in pharmacokinetics is excretion.

Zopiclone Adsorbtion

zopiclone adsorbtion

Once zopiclone is taken, it is rapidly absorbed by the body [7].

Moreover, zopiclone has been reported to have a bioavailability, that is, the amount of drug available to the body to use, of approximately 80% [7]. 

Bioavailability is a need to know.

 

Zopiclone’s has a bioavailability of approximately 80%

 

Understanding bioavailability is an inseparable part of how a drug should be administered.

In addition, knowing the bioavailability of a z-drug like zopiclone can better define its possible interactions that may inhibit its activity in the body [8]

When we take Paracetamol, for example, we don’t often ask if what you’ve taken has reached the location it’s meant to, to alleviate pain, etc.

But we know that once we’ve taken our medication it seems to work, and sometimes last for hours.

This is the knowledge and importance of a defined bioavailability (or absorption) of that particular drug.

Zopiclone Metabolism

zopiclone metabolism

Zopiclone is metabolized in the liver, where it then undergoes a series of chemical changes that results in the formation of smaller metabolites [7].

 

Zopiclone’s half-life (time it spends in the body) is around 5-6 hours [9]. 

 

Once taken orally, zopiclone binds to the same recognition site on its GABA(A) receptor [6].

Zopiclone’s metabolism in the liver involves a series of chemical steps that are eventually excreted in the urine [2; 3]. 

Importantly, zopiclone is modified into two main metabolites [10]:

  • N-desmethyl-zopiclone which is ‘inactive’ (accounting for around 16% of the original dose).
  • Zopiclone N-oxide which ‘weakly active’ (accounting for around 11-12% of original dose).

 

zopiclone metabolites

Figure 1. Chemical structures of (top) zopiclone, (bottom left) N-desmethyl-zopiclone, and (bottom right) zopiclone N-oxide.

Zopiclone Distribution

zopiclone distribution

Drug distribution may be an unfamiliar term to many…

Essentially, what it refers to is the process, and time taken for a drug to be delivered to the many bodily ‘tissues’ once it has entered the bloodstream [11].

 

zopiclone first pass

Figure 1. Uptake of a drug, or medication involves three major processes: absorption, distribution and elimination or excretion. This model of drug ‘processing’ allows for a clearer insight into the organ-specific and molecular mechanisms which a drug can take. Image source: https://abdominalkey.com/principles-of-drug-therapy-dosing-and-prescribing-in-chronic-kidney-disease-and-renal-replacement-therapy/.

 

Fortuitously, Zopiclone – taken orally – is reported to be distributed around the body quite readily [1].

Once a 7.5mg oral dose of zopiclone is taken, for example:

 

peak blood concentrations have been observed in around 30 minutes.

 

In addition, once absorbed, zopiclone therapeutic blood concentrations of a 7.5mg dose can range between 60-90 nanograms per mL [12].  

Zopiclone Excretion

Zopiclone neurones

Zopiclone is rapidly excreted mainly through liver metabolism.

 

A single zopiclone dose has been reported to have an elimination half-life of just over 5 hours after administration [12]. 

 

This means that half the Zopiclone is remains in the blood after 5 hours.

In addition to the excretion of the main zopiclone molecule, the N-desmethyl-zopiclone metabolite takes just over 7 hours to fully eliminate.

Moreover, the N-oxide-zopiclone metabolite takes just over 4 hours to be excreted [12]. 

Eszopiclone (Lunesta) & Enantiomers

The FDA approved the S-enantiomer of Zopiclone (Eszopiclone), sold commonly as Lunesta in 2013.

Eszopiclone (Lunesta) is the active enantiomer of Zopiclone.

An enantiomer is one of two molecules (in this case, zopiclone AND eszopiclone) that are mirror images of each other; however you cannot superimpose them (place one directly over the other) – since they wouldn’t match

Sorry if that seems a little confusing..

…Figure 1 below is a visual representation of the two Zopiclone enatiomers:

 

zopiclone enantiomers

 

The interesting thing about enantiomers is that they are chemically identical with the same physical properties, and one couldn’t tell them apart if one saw them.

New & Improved: Eszopiclone (Lunesta)

lunesta

It is important to understand that once a patent on a particular drug is near its end date, a pharmaceutical company will then switch to marketing a single enantiomer (Lunesta), as opposed to a mixture of two enantiomers in a single drug formulation. 

 

Often, this move is at the cost to the consumer and not necessarily the best formulation.

 

The danger here is that these companies might claim the ‘new and improved’ enantiomer has better activity in the body and is less toxic.

However this may not always be the case.

For this reason, the FDA requires all companies to diligently describe and disclose all individual components of a new and existing drug [13]. 

Zopiclone: Prescribing and Doses

zopiclone prescribing

Zopiclone, depending on the manufacturer of this drug, is available in a series of oral doses.

For starters, doses of zopiclone include:

  • 3.75mg
  • 5mg
  • 7.5mg
  • 10mg (generics only)

 

Zolpidem is available in doses ranging from 5-10mg, whereas zopiclone comes in doses ranging from 3.75-7.5mg [14].  

 

Z-drug Dose (for older adults) Effects on sleep Adverse effects Formulations
Zopiclone (Eszopiclone) 1mg (sleep latency)

2mg (sleep maintenance)

sleep-onset latency 

Sleep maintenance 

Headache, unpleasant taste, dizziness, dry mouth Oral tablet 
Zolpidem 2.5mg sleep-onset latency  Headache, dry mouth, dizziness, hallucinations, delirium, nausea, vomiting. Immediate-release tablet 

Controlled-release (CR) tablet

Sublingual tablet

Oral spray mist

Zaleplon  5mg sleep-onset latency  Headache, vomiting, abdominal pain, rhinitis, dizziness, CNS-depressant effects. Sonata capsules (5mg and 10mg)

Table adapted from data taken from [15] [16][17][18]

Prescribing Zopiclone

Prescribing Zopiclone doctor

In medicine there is the concept of ‘good prescribing’ of z-drugs [14].

This approach ensures that factors, such as costs, existing illnesses, age and response to therapy are considered before dosing on drugs like zopiclone.

For the best results, it is crucial to see and consult with your medical professional on particular z-drugs as your doctor would best know when to stop or cut-back on your dose [19].

 

Please Take zopiclone as your doctor has indicated to you.

Before Taking Zopiclone

Sometimes it’s best to NOT to take Zopiclone.

In these cases, it is always better to take the safe route and consult your doctor.

Especially if you are or have any of the following:

  • pregnant 
  • breathing (respiratory) problems 
  • have a history of drug addiction
  • mental health problems
  • problems with liver 
  • allergic reaction to medicines
  • currently taking any other medications.

 

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

References

[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  

  • UPDATED

    4th May 2020 – date of the last edit to this article.

  • AUTHOR
  • SCIENCE

    This article uses only evidence based information.

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NHS UK

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