Tag: Zaleplon

What is Zopiclone?

Published on by Andrew Marshall7 Comments

Introduction

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping.

Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating benzodiazepine receptors in the same way that benzodiazepine drugs do.

Zopiclone is a sedative. It works by causing a depression or tranquilisation of the central nervous system. After prolonged use, the body can become accustomed to the effects of zopiclone. When the dose is then reduced or the drug is abruptly stopped, withdrawal symptoms may result. These can include a range of symptoms similar to those of benzodiazepine withdrawal. Although withdrawal symptoms from therapeutic doses of zopiclone and its isomers (i.e. eszopiclone) do not typically present with convulsions and are therefore not considered life-threatening, patients may experience such significant agitation or anxiety that they seek emergency medical attention.

In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone is. Zopiclone is a controlled substance in the United States, Japan, Brazil, and some European countries, and may be illegal to possess without a prescription. However, it is readily available in other countries and is not a controlled substance.

Zopiclone is known colloquially as a “Z-drug”. Other Z-drugs include zaleplon and zolpidem and were initially thought to be less addictive than benzodiazepines. However, this appraisal has shifted somewhat in the last few years as cases of addiction and habituation have been presented. Zopiclone is recommended to be taken on a short-term basis, usually no more than a week or two. Daily or continuous use of the drug is not usually advised, and caution must be taken when the compound is used in conjunction with antidepressants, sedatives or other drugs affecting the central nervous system.

Brief 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 04 April 2005, the US Food and Drug Administration (FDA) listed zopiclone under schedule IV, due to evidence that the drug has addictive properties similar to benzodiazepines.

Zopiclone, as traditionally sold worldwide, is a racemic mixture of two stereoisomers, only one of which is active. In 2005, the pharmaceutical company Sepracor of Marlborough, Massachusetts began marketing the active stereoisomer eszopiclone under the name Lunesta in the United States. This had the consequence of placing what is a generic drug in most of the world under patent control in the United States. Generic forms of Lunesta have since become available in the United States. Zopiclone is currently available off-patent in a number of European countries, as well as Brazil, Canada, and Hong Kong. The eszopiclone/zopiclone difference is in the dosage – the strongest eszopiclone dosage contains 3 mg of the therapeutic stereoisomer, whereas the highest zopiclone dosage (10 mg) contains 5 mg of the active stereoisomer. The two agents have not yet been studied in head-to-head clinical trials to determine the existence of any potential clinical differences (efficacy, side effects, developing dependence on the drug, safety, etc.).

Medical Uses

Zopiclone is used for the short-term treatment of insomnia where sleep initiation or sleep maintenance are prominent symptoms. Long-term use is not recommended, as tolerance, dependence, and addiction can occur. One low-quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in shift workers – more research in this area has been recommended.

Specific Populations

Elderly

Zopiclone, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol consumption increases these impairments. Partial, but incomplete tolerance develops to these impairments. Zopiclone increases postural sway and increases the number of falls in older people, as well as cognitive side effects. Falls are a significant cause of death in older people.

An extensive review of the medical literature regarding the management of insomnia and the elderly found that considerable evidence of the effectiveness and lasting benefits of nondrug treatments for insomnia exist. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, such as zopiclone, offer few if any advantages in efficacy or tolerability in elderly persons. Newer agents such as the melatonin receptor agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of nonbenzodiazepine hypnotic drugs remains to be determined.

Liver Disease

Patients with liver disease eliminate zopiclone much more slowly than normal patients and in addition experience exaggerated pharmacological effects of the drug.

Adverse Reactions

Sleeping pills, including zopiclone, have been associated with an increased risk of death. The British National Formulary states adverse reactions as follows: “taste disturbance (some report a metallic like taste); less commonly nausea, vomiting, dizziness, drowsiness, dry mouth, headache; rarely amnesia, confusion, depression, hallucinations, nightmares; very rarely light headedness, incoordination, paradoxical effects […] and sleep-walking also reported”.

Contraindications

Zopiclone causes impaired driving skills similar to those of benzodiazepines. Long-term users of hypnotic drugs for sleep disorders develop only partial tolerance to adverse effects on driving with users of hypnotic drugs even after 1 year of use still showing an increased motor vehicle accident rate. Patients who drive motor vehicles should not take zopiclone unless they stop driving due to a significant increased risk of accidents in zopiclone users. Zopiclone induces impairment of psychomotor function. Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand eye coordination.

EEG and Sleep

It causes similar alterations on EEG readings and sleep architecture as benzodiazepines and causes disturbances in sleep architecture on withdrawal as part of its rebound effect. Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves. Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset. Cognitive behavioural therapy has been found to be superior to zopiclone in the treatment of insomnia and has been found to have lasting effects on sleep quality for at least a year after therapy.

Overdose

Zopiclone is sometimes used as a method of suicide. It has a similar fatality index to that of benzodiazepine drugs, apart from temazepam, which is particularly toxic in overdose. Deaths have occurred from zopiclone overdose, alone or in combination with other drugs. Overdose of zopiclone may present with excessive sedation and depressed respiratory function that may progress to coma and possibly death. Zopiclone combined with alcohol, opiates, or other central nervous system 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, thereby rapidly reversing its effects. Serious effects on the heart may also occur from a zopiclone overdose when combined with piperazine.

Death certificates show the number of zopiclone-related deaths is on the rise. When taken alone, it usually is not fatal, but when mixed with alcohol or other drugs such as opioids, or in patients with respiratory, or hepatic disorders, the risk of a serious and fatal overdose increases.

Interactions

Zopiclone also interacts with trimipramine and caffeine.

Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly. Due to these risks and the increased risk for dependence, alcohol should be avoided when using zopiclone.

Erythromycin appears to increase the absorption rate of zopiclone and prolong its elimination half-life, leading to increased plasma levels and more pronounced effects. Itraconazole has a similar effect on zopiclone pharmacokinetics as erythromycin. The elderly may be particularly sensitive to the erythromycin and itraconazole drug interaction with zopiclone. Temporary dosage reduction during combined therapy may be required, especially in the elderly. Rifampicin causes a very notable reduction in half-life of zopiclone and peak plasma levels, which results in a large reduction in the hypnotic effect of zopiclone. Phenytoin and carbamazepine may also provoke similar interactions. Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone. Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next-day sedation.

Pharmacology

The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant, and myorelaxant properties. Zopiclone and benzodiazepines bind to the same sites on GABAA-containing receptors, causing an enhancement of the actions of GABA to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone called desmethylzopiclone is also pharmacologically active, although it has predominately anxiolytic properties. One study found some slight selectivity for zopiclone on α1 and α5 subunits, although it is regarded as being unselective in its binding to α1, α2, α3, and α5 GABAA benzodiazepine receptor complexes. Desmethylzopiclone has been found to have partial agonist properties, unlike the parent drug zopiclone, which is a full agonist. The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover. A meta-analysis of randomised controlled clinical trials that compared benzodiazepines to zopiclone or other Z drugs such as zolpidem and zaleplon has found few clear and consistent differences between zopiclone and the benzodiazepines in sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness. Zopiclone is in the cyclopyrrolone family of drugs. Other cyclopyrrolone drugs include suriclone. Zopiclone, although molecularly different from benzodiazepines, shares an almost identical pharmacological profile as benzodiazepines, including anxiolytic properties. Its mechanism of action is by binding to the benzodiazepine site and acting 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. In addition to zopiclone’s benzodiazepine pharmacological properties, it also has some barbiturate-like properties.

In EEG studies, zopiclone significantly increases the energy of the beta frequency band and shows characteristics of high-voltage slow waves, desynchronisation of hippocampal theta waves, and an increase in the energy of the delta frequency band. Zopiclone increases both stage 2 and slow-wave sleep (SWS), while zolpidem, an α1-selective compound, increases only SWS and causes no effect on stage 2 sleep. Zopiclone is less selective to the α1 site and has higher affinity to the α2 site than zaleplon. Zopiclone is therefore very similar pharmacologically to benzodiazepines.

Pharmacokinetics

After oral administration, zopiclone is rapidly absorbed, with a bioavailability around 75-80%. Time to peak plasma concentration is 1-2 hours. A high-fat meal preceding zopiclone administration does not change absorption (as measured by AUC), but reduces peak plasma levels and delays its occurrence, thus may delay the onset of therapeutic effects.

The plasma protein-binding of zopiclone has been reported to be weak, between 45 and 80% (mean 52-59%). It is rapidly and widely distributed to body tissues, including the brain, and is excreted in urine, saliva, and breast milk. Zopiclone is partly extensively metabolised in the liver to form an active N-demethylated derivative (N-desmethylzopiclone) and an inactive zopiclone-N-oxide. Hepatic enzymes playing the most significant role in zopiclone metabolism are CYP3A4 and CYP2E1. In addition, about 50% of the administered dose is decarboxylated and excreted via the lungs. In urine, the N-demethyl and N-oxide metabolites account for 30% of the initial dose. Between 7 and 10% of zopiclone is recovered from the urine, indicating extensive metabolism of the drug before excretion. The terminal elimination half-life of zopiclone ranges from 3.5 to 6.5 hours (5 hours on average).

The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, Cmax (time to maximum plasma concentration), area under the plasma time-concentration curve (AUC) and terminal elimination half-life values are higher for the dextrorotatory enantiomers, owing to the slower total clearance and smaller volume of distribution (corrected by the bioavailability), compared with the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the respective antipodes.

The pharmacokinetics of zopiclone are altered by aging and are influenced by renal and hepatic functions. In severe chronic kidney failure, the area under the curve value for zopiclone was larger and the half-life associated with the elimination rate constant longer, but these changes were not considered to be clinically significant. Sex and race have not been found to interact with pharmacokinetics of zopiclone.

Chemistry

The melting point of zopiclone is 178 °C. Zopiclone’s solubility in water, at room temperature (25 °C) are 0.151 mg/mL. The logP value of zopiclone is 0.8.

Detection in Biological Fluids

Zopiclone may be measured in blood, plasma, or urine by chromatographic methods. Plasma concentrations are typically less than 100 μg/l during therapeutic use, but frequently exceed 100 μg/l in automotive vehicle operators arrested for impaired driving ability and may exceed 1000 μg/l in acutely poisoned patients. Post mortem blood concentrations are usually in a range of 0.4-3.9 mg/l in victims of fatal acute overdose.

Society and Culture

Recreational Use

Zopiclone has the potential for non-medical use, dosage escalation, and drug dependence. It is taken orally and sometimes intravenously when used non-medically, and often combined with alcohol to achieve a combined sedative hypnotic – alcohol euphoria. Patients abusing the drug are also at risk of dependence. Withdrawal symptoms can be seen after long-term use of normal doses even after a gradual reduction regimen. The Compendium of Pharmaceuticals and Specialties recommends zopiclone prescriptions not exceed 7 to 10 days, owing to concerns of addiction, tolerance, and physical dependence. Two types of drug misuse can occur: either recreational misuse, wherein the drug is taken to achieve a high, or when the drug is continued long-term against medical advice. Zopiclone may be more addictive than benzodiazepines. Those with a history of substance misuse or mental health disorders may be at an increased risk of high-dose zopiclone misuse. High dose misuse of zopiclone and increasing popularity amongst people who use substances who have been prescribed with zopiclone. The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia, and nervousness.

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 benzodiazepines and zolpidem, are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range and often in combination with other alcohol, illegal, or addictive prescription drugs, suggesting a high degree of potential for non-medical use of benzodiazepines, zolpidem, and zopiclone. Zopiclone, which at prescribed doses causes moderate impairment the next day, has been estimated to increase the risk of vehicle accidents by 50%, causing an increase of 503 excess accidents per 100,000 persons. Zaleplon or other non-impairing sleep aids were recommended be used instead of zopiclone to reduce traffic accidents. Zopiclone, as with other hypnotic drugs, is sometimes used to carry out criminal acts such as sexual assaults.

Zopiclone has cross-tolerance with barbiturates and is able to suppress barbiturate withdrawal signs. It is frequently self-administered intravenously in studies on monkeys, suggesting a high risk of addictive potential.

Zopiclone is in the top ten medications obtained using a false prescription in France.

What is Zaleplon?

Published on by Andrew Marshall6 Comments

Introduction

Zaleplon, sold under the brand names Sonata among others, is a sedative-hypnotic, used to treat insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class.

It is manufactured by King Pharmaceuticals and Gedeon Richter Plc. It has been discontinued in Canada but can be manufactured if a prescription is brought to a compounding pharmacy. It was prescribed rarely in the United Kingdom, with zopiclone being the preferred Z-drug by the National Health Service (NHS) and is now unavailable.

Medical Uses

Zaleplon is slightly effective in insomnia, primarily characterised by difficulty falling asleep. Zaleplon significantly reduces the time required to fall asleep by improving sleep latency and may therefore facilitate sleep induction rather than sleep maintenance. Due to its ultrashort elimination half-life, zaleplon may not be effective in reducing premature awakenings; however, it may be administered to alleviate middle-of-the-night awakenings. However, zaleplon has not been empirically shown to increase total sleep time.

It may result in an impaired ability to drive the next day, though it has proven promising when compared to other sedative/hypnotics and next-day residual sedation. It may have advantages over benzodiazepines with fewer adverse effects.

Neither zaleplon, nor any nonbenzodiazepine hypnotic class medication should be combined with alcohol, as both modulate GABAA receptor sites, and in a synergistic manner increase the chances of fatal respiratory depression and asphyxiation from vomiting.

Special Populations

Zaleplon is not recommended for chronic use in the elderly. The elderly are more sensitive to the adverse effects of zaleplon such as cognitive side effects. Zaleplon may increase the risk of injury among the elderly. It should not be used while in pregnancy or lactation, and in patients with a history of alcohol or drug abuse, psychotic illness or depression, clinicians should devote more attention.

When compared with benzodiazepines, nonbenzodiazepines (including zaleplon) offer few significant advantages in efficacy and tolerability among elderly individuals. Long-term use of sedative/hypnotics for insomnia has traditionally been discouraged for reasons that include concerns about addiction and rebound insomnia, as well to the risk of side effects associated to GABAA agonists, such as cognitive impairment, anterograde amnesia, daytime sedation, musculoskeletal impairment, and subsequently an increased risk of harm to oneself (e.g. falling) and to others (e.g. automotive accidents). Though, quite obviously as the body and brain age, these aforementioned phenomena are expected events, as they occur daily regardless of ingestion of a sedative/hypnotic. Thus, statistically significant and empirical evidence are arguably still absent as dramatic precautions and conclusions are drawn irrespective of the debilitating realities that accompany insomnia and the fact that these medicines do indeed provide assistance to millions of elderly individuals. It is important to distinguish between the extrapolation of potential side effects relative to the vast number of examples, wherein the sedative/hypnotic has proven therapeutically beneficial and appropriate.

In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but nothing concrete suggests long-term use poses any direct harm to a person. Still, as of today neither benzodiazepines nor nonbenzodiazepines are recommended for the long-term treatment of insomnia.

Adverse Effects

The adverse effects of zaleplon are similar to the adverse effects of benzodiazepines, although with less next-day sedation, and in two studies zaleplon use was found not to cause an increase in traffic accidents, as compared to other hypnotics currently on the market.

Sleeping pills, including zaleplon, have been associated with an increased risk of death.

Available data cannot provide a reliable estimate of the incidence of dependence during treatment at recommended doses of zaleplon (typically 5-20 mg before bed). Other sedative/hypnotics have been associated with various signs and symptoms of a withdrawal syndrome, following abrupt discontinuation, ranging from mild dysphoria and insomnia to more serious cases that include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Following abrupt cessation, the seizure threshold is further lowered, wherein coma and death are possible outcomes if untreated.

Some evidence suggests zaleplon is not as chemically reinforcing and exhibits far fewer rebound effects when compared with other nonbenzodiazepines, or Z-drugs.

Interactions

Cimetidine, rifampicin, and thioridazine cause interactions with zaleplon.

Cimetidine and grapefruit are known to increase blood plasma concentrations of benzodiazepines metabolized by the P450 CYP3A4 liver enzyme (e.g. alprazolam) by extending the time by which the drug leaves the body, effectively extending the half-life and enhancing effects to potentially toxic levels. Thus, given the similarities between zaleplon and benzodiazepines, particularly in effect, and not just chemical structure, it is reasonable to take precautions (e.g. inquire at a pharmacy) before one consumes cimetidine (or grapefruit) while also taking zaleplon.

Pharmacology

Mechanism of Action

Zaleplon is a high-affinity ligand of positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills. Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the natural sleep architecture.

A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found few clear and consistent differences between zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.

Zaleplon has a pharmacological profile similar to benzodiazepines, characterized by an increase in slow wave deep sleep (SWDS) with rapid onset of hypnotic action. Zaleplon is a full agonist for the benzodiazepine α1 receptor located on the GABAA receptor complex in the body, with lower affinity for the α2 and α3 subsites. It selectively enhances the action of GABA similar to, but more selectively than benzodiazepines. Zaleplon, although not a benzodiazepine, maintains a very similar pharmacological profile nonetheless, known for inducing hypnotic effects by α1 subreceptor sites, anxiolytic and muscle relaxant effects via α2 and α3 subsites, with negligible anticonvulsant properties (via α5 subsite), as zaleplon action is modulated at benzodiazepine receptor sites. The elimination half-life of zaleplon is about 1-1.5 hours. The absorption rate of zaleplon is rapid and the onset of therapeutic effects is typically breached within 5-15 minutes following ingestion.

Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band.

Pharmacokinetics

Zaleplon is primarily metabolised by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase. Taken orally, zaleplon reaches full concentration in about one hour. It is extensively metabolised into 5-oxozaleplon and 5-oxodesethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine.

Chemistry

Pure zaleplon in its solid state is a white to off-white powder with very low solubility in water, as well as low solubility in ethanol and propylene glycol. It has a constant octanol-water partition coefficient of log P = 1.23 in the pH range between 1 and 7.

It is classified as a pyrazolopyrimidine.

Society and Culture

Recreational Use

Zaleplon has the potential to be a drug of recreational use, and has been found to have an addictive potential similar to benzodiazepine and benzodiazepine-like hypnotics. The mind- and judgement-altering effects of zaleplon are similar to those of many benzodiazepines, but the fast-acting nature and short half-life of the chemical mean high doses set on much more quickly and last for short periods of time (usually from 45 to 60 minutes).

Some individuals use a different delivery method than prescribed, such as insufflation, to induce effects faster.

A common effect of recreational zaleplon use is the occurrence of (typically short-lived) hallucinations. Fewer visual and auditory hallucinations/disruptions occur with the use of zaleplon than with other Z-drugs, like zolpidem.[citation needed] Anterograde amnesia can occur and can cause one to lose track of the amount of zaleplon already ingested, prompting the ingesting of more than originally planned. However, continuous ingestion is extremely unlikely precisely because of zaleplon’s quick onset of action.

The combination of alcohol and zaleplon can result in fatal respiratory depression and asphyxiation from vomiting.

Aviation Use

The US Federal Aviation Administration (FAA) allows zaleplon with a 12-hour wait period and no more than twice a week, which makes it the sleep medication with the shortest allowed waiting period after use. The substances with the 2nd shortest period, which is of 24 hours, are zolpidem and ramelteon.

Military Use

The United States Air Force uses zaleplon as one of the hypnotics approved as a “no-go pill” to help aviators and special-duty personnel sleep in support of mission readiness (with a four-hour restriction on subsequent flight operation). “Ground tests” are required prior to authorisation being issued to use the medication in an operational situation. The other hypnotics used as “no-go pills” are temazepam and zolpidem, which both have longer mandatory recovery periods.