Zopiclone

Also known as

Imovane, zimovane, zimmos, zaleplon, zolpidem, z-drugs, zpc, zimmers, zimmies, zim-zims

Classification

Sedative

Overview

Zopiclone is a novel hypnotic agent used in the treatment of insomnia. Its mechanism of action is based on modulating benzodiazepine receptors. In addition to zopiclone's benzodiazepine pharmacological properties it also has some barbiturate like properties .

Medical usage

They are prescribed for the short-term management of severe insomnia, they have a sedative effect and should be used to induce sleep for a short period of time only .

What does it look like?

Zopiclone are typically 3.75mg or 7.5mg (white) oval, scored tablets. They come in other colours (3.75mg are usually orange or blue) but have the dose marked on them .

Street price

Between 0.94p and £5 .

Why take it?

Sought after effects

• relaxation,
• euphoria,
• sleepiness .

Undesired effects

• amnesia,
• depression,
• cognitive impairment (confusion) .

Dosage

Therapeutic

The recommended adult dose of zopiclone ranges from 3.75 mg to 7.5 mg .

Abuse

Oral

• threshold 2 - 3.5 mg,
• light 3.5 - 5 mg,
• common 5 - 7.5 mg,
• strong 7.5 - 15 mg,
• heavy 15 - 22 mg + .

How long do its effects last?

Onset of effects

• oral - 10 - 30 minutes .
• all ROA's - 15 minutes .

Duration of effects

• oral - 3.5 - 9 hours .
• all ROA's - 3.5 - 9 hours .

After-effects

• all ROA's - 1 - 12 hours .

Pharmacology

Zopiclone, although structurally different from benzodiazepines, shares an almost identical pharmacological profile to them. Its mechanism of action works by binding to the same site as benzodiazepines and acts as a full agonist, which in turn positively modulates benzodiazepine-sensitive GABAA receptors and enhances GABA binding at the GABAA receptors to produce zopiclone's pharmacological properties. Since GABA functions as the brain's predominant inhibitory neurotransmitter, this activation of receptors results in the sedative and anxiolytic effects of zopiclone .

Pharmacodynamics

Zopiclone is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABABZ) receptor complex. Subunit modulation of the GABABZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zopiclone binds selectively to the brain alpha subunit of the GABA A omega-1 receptor .

Pharmacokinetics

Protein Binding - 45% - 80% .

Absorption

Rapidly absorbed following oral administration .

Metabolism

Extensively metabolised in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance .

Half-life

Elimination half life is approximately 5 hours (range 3.8 to 6.5 hours) and is prolonged to 11.9 hours in patients with hepatic insufficiency .

Elimination

Excretion - respiration (~50%) and urine 7% - 10% .

Lethal dosage

Zopiclone is capable of resulting in death at extremley high doses and is sometimes used as a method of suicide. It has a similar fatality index as benzodiazepine drugs, apart from temazepam, which is particularly toxic in overdose .

LD50 2.6411 mol/kg in rats .

Toxicity

Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agent. Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing .

The toxic dose of Zopiclone is at 150mg or equivalent to ingesting 20 tablets .

Mechanism of action

Zopiclone exerts its action by binding on the benzodiazepine receptor complex and modulation of the GABABZ receptor chloride channel macromolecular complex. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors as full agonists causing an enhancement of the inhibitory actions of GABA to produce the therapeutic (hypnotic and anxiolytic) and adverse effects of zopiclone .

Mode of use

Tablets and capsules are swallowed.

Some users may crush the tablets to inject but this is rare due to this method being very messy and dangerous. These medicines do not dissolve and if attempted to be injected is likely to cause damage to the veins, resulting in abscesses, DVT, aneurysm, ulcers and varicose veins .

Signs of usage

• inability to fall asleep without taking the drug,
• feeling a compulsion to continue consuming the drug despite no medical necessity,
• experiencing withdrawal symptoms after not taking the drug for a period of time,
• increased fatigue due to depression of the central nervous system,
• mood swings,
• increased dizziness and decreased motor coordination,
• reduced performance at home, work, and school,
• financial difficulties,
• legal problems stemming from use of the drug,
• suicidal tendencies or ideation .

Effects

Physical effects

• muscle relaxation,
• motor control loss,
• respiratory depression,
• sedation,
• dizziness .

Cognitive effects

• amnesia,
• anxiety suppression,
• disinhibition,
• emotion suppression,
• information processing suppression,
• thought deceleration .

Visual effects

• drifting,
• acuity suppression,
• external hallucinations .

Common

• a bitter or metallic taste in your mouth,
• a dry mouth,
• daytime sleepiness .

Positive

• helps with insomnia/sleep,
• euphoria and/or dysphoria .

Neutral

• hallucinations, through all physical senses, of varying intensity,
• increased appetite,
• increased or decreased libido,
• uninhibited extroversion in social or interpersonal settings .

Negative

• headaches (mostly withdrawal symptom),
• nausea (mostly withdrawal symptom),
• vomiting (mostly withdrawal symptom),
• dizziness,
• anterograde amnesia,
• delusions,
• altered thought patterns,
• ataxia or poor motor coordination, difficulty maintaining balance,
• increased impulsivity (mostly withdrawal symptom),
• when stopped, rebound insomnia may occur,
• impaired judgment and reasoning .

Risks

Short-term

Overdose - this risk is increased if used with alcohol, opiates or other sedative / depressant substances, risk of coma and death. Zopiclone may interact with a number of other medicines .

Long-term

Dependence, risk of coma and death. Research has shown that, even at prescribed doses, prolonged use of zopiclone may cause cancer that may affect the brain, lung, bowel, breast and bladder. Zopiclone can also have an adverse effect on the immune system increasing the risk of infections and colds, and is not recommended for people with liver or kidney disease, or women who are pregnant or breast-feeding .

Dangerous interactions

Although many drugs are safe on their own, they can become dangerous and even life-threatening when combined with other substances. The list below contains some common potentially dangerous combinations, but may not include all of them. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption .

• Depressants (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
• Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it .

Withdrawal

• lightheadedness,
• cramps,
• shakiness,
• nausea,
• vomiting,
• increased sweating,
• tachycardia,
• trouble sleeping despite being tired,
• increased crying,
• strong cravings,
• higher levels of anxiety and panic,
• hallucinations,
• seizures .

Legality

The Misuse of Drugs Act 1971 (Ketamine Etc.) (Amendment) Order 2014 inserts zopiclone and zaleplon as Class C drugs. They are Prescription Only Medicines . It is illegal to possess (without a legitimate prescription), supply, produce or import .

Harm reduction

The fact that they are more selective in the receptors on which they work seems to make little difference to the outcome in most cases if the drug is taken every night. Many patients who experience difficulties are transferred back to a benzodiazepine, typically valium.

There is a wide variation in the half-life and response to these drugs (such as the degree of sedation) between different individuals (for example, the elderly and people with hepatic impairment).

Hypnotics may be as likely to cause depression as to help it. Some studies suggest that long term users of sedative hypnotic drugs have a markedly raised suicide risk as well as an overall increased mortality risk. The evidence specifically on 'Z drugs' is limited.

'Z drugs', despite the earliest claims of manufacturers, are not free from the risk of 'rebound effect'; the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage.

It is not recommended to take this group of hypnotics for more than a couple of weeks. It is not wise to drive under the influence of this group of drugs and some people have experienced events of which they have little actual recall. In extreme cases this can leave you very vulnerable. If you start to feel very weak and sleepy make sure you are in a safe, contained environment.

There is a considerable risk in mixing 'Z drugs' with alcohol or other CNS depressants, such as the opioids.

Taking 'Z drugs' as a 'downer' to counteract the effects of stimulants is not just a simple antidote, but puts more strain on your body, particularly the heart and liver if you repeat the pattern .

Paraphernalia

If injected - needle and syringe, water, matches or lighter, spoon, tourniquet, swabs .

Addiction treatment options

Flumazenil is the antidote for zopiclone overdose because it competes with the receptor sites of zopiclone in the body, thereby displacing the zopiclone and prevents it from binding on the receptor sites. Flumazenil also displaces the zopiclone substances on the benzodiazepine receptor sites. This treatment rapidly reverses the symptoms of drug overdose .

Detox

Abrupt cessation of zolpidem consumption is not recommended. Depending on how long and how much zolpidem has been consumed, quitting cold turkey can lead to the development of severe side-effects such as seizures. It is highly recommended that people take a step-down approach to stopping their use of the drug.

The primary treatment option for zolpidem addiction is gradual dose reduction over a long period of time. This method minimises withdrawal symptoms so the person can safely stop using the prescription medication. An inpatient zolpidem addiction treatment centre may be the best place to use this method because the person will have limited access to the drug.

However, this method of treatment is not right for every person. Another option is to gradually transition to a benzodiazepine drug and then begin the dose reduction method. Withdrawal symptoms may be less acute when stepping down from the benzodiazepine drug.

For treatment-resistant or difficult-to-treat patients, rapid detox using a drug called Flumazenil may be required. Using this method, the withdrawal process is completed in seven days. This drug may cause withdrawal symptoms to be significantly reduced or absent. However, this drug has been found to induce seizures in 1% to 3% of patients. There may also be other disadvantages to using this treatment method. It is best to speak with a knowledgeable professional about the pros and cons of using Flumazenil for zolpidem addiction treatment.

Detoxifying from zolpidem is essential to achieving sobriety and avoiding relapse. The body must purge the drug and associated toxins from its system in order to begin functioning normally again. Although it can take only days to become addicted to zolpidem, it can take several weeks to a few months to get through the zolpidem detox process.

Zolpidem rehab centres may employ additional therapies that can assist in the detoxification process. These therapies may include putting you on a special diet, engaging alternative medicines like acupuncture, and prescribing cognitive-behavioral therapy. It is best to work closely with an addiction specialist to develop a zolpidem addiction treatment plan that is right for you .

Addiction treatment

Zolpidem treatment facilities will work on helping you overcome your physical and psychological addiction to the drug. Of the two, physical addiction is often the easiest problem to address. Psychological addiction can be more challenging to overcome because of the emotional attachment you may have to taking the drug. Here are a few tips for getting the most out of your zolpidem addiction treatment .

• find the right treatment centre - It is important to pick a treatment centre that addresses your individual needs and wants. The more comfortable you are with the facility, the more likely you will complete the programme,
• participate fully in the treatment - You are likely to have many thoughts and feel a variety of emotions regarding your addiction. Some of these thoughts and feelings may inhibit your participation in the zolpidem addiction treatment. However, you are responsible for your sobriety. If you want to successfully live as a sober person, you must participate fully in your recovery and get the knowledge and life skills needed to stay clean,
• participate in aftercare programs - Getting through zolpidem rehab is the easy part. The real challenge comes when you return to your life and try to live as a sober person. However, people who have strong support networks are less likely to relapse. Look for aftercare programs you can join that will help you maintain your new lifestyle. Twelve-step programs like Narconon can be a reliable source of continuing education and support,
• don't be afraid to ask for help - If you find you are struggling with a certain aspect of your zolpidem addiction treatment or having difficulty assimilating back into society, reach out for help. No man is an island, and every person needs a helping hand at one point or another. Reach out to your support network when you are struggling. That is what it is there for .

When it comes to zolpidem addiction treatment, you get out of it what you put into it. If you work hard and remain focused on the goal of kicking your addiction to zolpidem, you will be successful .

History

Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main worldwide manufacturer. Initially, it was promoted as an improvement on benzodiazepines, but a recent meta-analysis found it was no better than benzodiazepines in any of the aspects assessed . On April 4, 2005, the U.S. Drug Enforcement Administration listed zopiclone under schedule IV, due to evidence that the drug has addictive properties similar to benzodiazepines .

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