Zopiclone

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Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine, specifically a cyclopyrrolone, 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 GABA_A receptors similarly to the way benzodiazepine drugs do inducing sedation but not with the anti-anxiety properties of the benzodiazepines.

Zopiclone is a sedative. It works by causing a depression or tranquilization 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. Template:Citation needed

In the United States, zopiclone is not commercially available,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> although its active stereoisomer, eszopiclone, is. Zopiclone is a controlled substance in the United States, Japan, Brazil, New Zealand and some European countries, and may be illegal to possess without a prescription. Template:Citation needed

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 at the lowest effective dose, with a duration of 2–3 weeks for short-term insomnia.<ref>Template:Citation Current as of 8 June 2023</ref> Daily or continuous use of the drug is not usually advised, and caution must be taken when the compound is used in conjunction with benzodiazepines, sedatives or other drugs affecting the central nervous system.<ref>Template:Cite journal</ref>

Medical uses

File:Zopiclone 7.5mg.jpg

A 7.5 mg zopiclone tablet.

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> One low-quality study found that zopiclone is ineffective in improving sleep quality or increasing sleep time in shift workers, and more research in this area has been recommended.<ref>Template:Cite journal</ref>

Cognitive behavioral 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="Mets-2010">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Liver disease

Patients with liver disease eliminate zopiclone much more slowly than normal patients and in addition experience exaggerated pharmacological effects of the drug.<ref>Template:Cite journal</ref>

Adverse reactions

Sleeping pills, including zopiclone, have been associated with an increased risk of death.<ref>Template:Cite journal</ref> The British National Formulary states adverse reactions as follows: "taste disturbance (some report a metallic 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".<ref name=bnf>Template:Citation</ref>

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 one year of use still showing an increased motor vehicle accident rate.<ref>Template:Cite journal</ref> Patients who drive motor vehicles should not take zopiclone as there is a significantly increased risk of accidents in zopiclone users.<ref>Template:Cite journal</ref> Zopiclone induces impairment of psychomotor function.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Driving or operating machinery should be avoided after taking zopiclone as effects can carry over to the next day, including impaired hand-eye coordination.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

A double-blind study on the effect on performance of several hypnotic medications, relevant to military personnel who may have to be awakened to carry out duties, found that drugs listed in increasing order of performance impact duration were melatonin (with no impact), zaleplon, temazepam, and zopiclone. The effects on serial reaction time (SRT), logical reasoning (LRT), serial subtraction (SST), and multitask (MT) were measured. For zaleplon (10 mg), zopiclone (7.5 mg) and temazepam (15 mg) respectively the times to recover normal performance for SRT were 3.25, Template:Em, and 5.25 hours; for LRT 3.25, Template:Em, and 4.25 hours; for SST 2.25, Template:Em, and 4.25 hours; and for MT 2.25, Template:Em, and 3.25 hours. The study did not consider the effectiveness of the drugs on sleep.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Zopiclone reduces both delta waves and the number of high-amplitude delta waves whilst increasing low-amplitude waves.<ref>Template:Cite journal</ref> Zopiclone reduces the total amount of time spent in REM sleep as well as delaying its onset.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In EEG studies, zopiclone significantly increases the energy of the beta frequency band, increasing stage 2. 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.<ref>Template:Cite journal</ref>

Overdose

Zopiclone is sometimes used as a method of suicide.<ref>Template:Cite journal</ref> It has a similar fatality index to that of benzodiazepine drugs, apart from temazepam, which is particularly toxic in overdose.<ref>Buckley NA, Dawson AH, Whyte IM, McManus P, Ferguson N.Correlations between prescriptions and drugs taken in self-poisoning: Implications for prescribers and drug regulation. Med J Aust (in press)</ref><ref name="pmid12474705">Template:Cite journal</ref> Deaths have occurred from zopiclone overdose, alone or in combination with other drugs.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Overdose of zopiclone may present with excessive sedation and depressed respiratory function that may progress to coma and possibly death.<ref>Template:Cite journal</ref> 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 GABA_A receptor benzodiazepine site antagonist flumazenil, which displaces zopiclone from its binding site, thereby rapidly reversing its effects.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Serious effects on the heart may also occur from a zopiclone overdose<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> when combined with piperazine.<ref>Template:Cite book</ref>

Death certificates show the number of zopiclone-related deaths is on the rise.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Interactions

Zopiclone also interacts with trimipramine and caffeine.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Alcohol has an additive effect when combined with zopiclone, enhancing the adverse effects including the overdose potential of zopiclone significantly.<ref name="pmid2201724" /><ref>Template:Cite journal</ref> Due to these risks and the increased risk for dependence, alcohol should be avoided when using zopiclone.<ref name="pmid2201724">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone.<ref>Template:Cite journal</ref> Nefazodone impairs the metabolism of zopiclone leading to increased zopiclone levels and marked next-day sedation.<ref>Template:Cite journalTemplate:Dead link</ref>

Pharmacology

The therapeutic pharmacological properties of zopiclone include hypnotic, anxiolytic, anticonvulsant, and myorelaxant properties.<ref>Template:Cite journal</ref> Zopiclone and benzodiazepines bind to the same sites on GABA_A receptors, causing an enhancement of the actions of GABA to produce the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone desmethylzopiclone is also pharmacologically active, although it has predominately anxiolytic properties. One study found some slight selectivity for zopiclone on α1 and α5 subunits,<ref>Template:Cite journal</ref> although it is regarded as being unselective in its binding to GABA_A receptors containing α1, α2, α3, and α5 subunits. Desmethylzopiclone has been found to have partial agonist properties, unlike the parent drug zopiclone, which is a full agonist.<ref>Template:Cite journal</ref> The mechanism of action of zopiclone is similar to benzodiazepines, with similar effects on locomotor activity and on dopamine and serotonin turnover.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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 GABA_A receptors and enhances GABA binding at the GABA_A receptors to produce zopiclone's pharmacological properties.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In addition to zopiclone's benzodiazepine pharmacological properties, it also has some barbiturate-like properties.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Pharmacokinetics

File:Zopiclone metabolism.svg

Two major zopiclone metabolites.

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 metabolized 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).<ref name = "Assessment" />

The pharmacokinetics of zopiclone in humans are stereoselective. After oral administration of the racemic mixture, C_max (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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> Sex and race have not been found to interact with pharmacokinetics of zopiclone.<ref name = "Assessment" />

Chemistry

The melting point of zopiclone is 178 °C.<ref name="Pubchem Zopiclone">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Zopiclone's solubility in water, at room temperature (25 °C) are 0.151 mg/mL.<ref name="Pubchem Zopiclone" /> The logP value of zopiclone is 0.8.<ref name="Pubchem Zopiclone" />

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 400 to 3900 μg/L in victims of fatal acute overdose.<ref name="pmid15329838">Template:Cite journal</ref><ref name="pmid19393793">Template:Cite journal</ref><ref>Template:Cite book</ref>

History

Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi, 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.<ref>Template:Cite journal</ref> 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.

Zopiclone, as traditionally sold worldwide, is a racemic mixture of two stereoisomers, only one of which is active.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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, Brazil, Canada, Hong Kong, and New Zealand. 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 stereoisomerTemplate:Citation needed. The two agents have not yetTemplate:When 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.).

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 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Zopiclone may be more addictive than benzodiazepines.<ref>Template:Cite journal</ref> Those with a history of substance misuse or mental health disorders may be at an increased risk of high-dose zopiclone misuse.<ref>Template:Cite journal</ref> High dose misuse of zopiclone and increasing popularity amongst people who use substances who have been prescribed with zopiclone<ref>Template:Cite journal</ref>Template:Clarification needed The symptoms of zopiclone addiction can include depression, dysphoria, hopelessness, slow thoughts, social isolation, worrying, sexual anhedonia, and nervousness.<ref>Template:Cite journal</ref>

Zopiclone and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other sedating drugs, including 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 alcohol, illegal, or addictive prescription drugs, suggesting a high degree of potential for non-medical use of benzodiazepines, zolpidem, and zopiclone.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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 nonimpairing sleep aids were recommended be used instead of zopiclone to reduce traffic accidents.<ref>Template:Cite journal</ref> Zopiclone, as with other hypnotic drugs, is sometimes used to carry out criminal acts such as sexual assaults.<ref>Template:Cite journal</ref>

Zopiclone has crosstolerance with barbiturates and is able to suppress barbiturate withdrawal symptoms. It is frequently self-administered intravenously in studies on monkeys, suggesting a high risk of addictive potential.<ref>Template:Cite journal</ref>

Zopiclone is in the top ten medications obtained using a false prescription in France.<ref name = "Assessment" />

External links

• Detailed pharmacological information Template:Webarchive
• Scheduling recommendation (PDF file)
• Details on scheduling
• Erowid zopiclone vault
• Support for zopiclone dependency/addiction Template:Webarchive

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   | group5 = Imidazoles
   | list5 =

• Etomidate
• Metomidate
• Propoxate

   | group6 = Monoureides
   | list6 =

• Acecarbromal
• Apronal (apronalide)
• Bromisoval
• Capuride
• Carbromal
• Ectylurea

   | group7 = Neuroactive steroids
   | list7 =

• Acebrochol
• Allopregnanolone
• Alphadolone
• Alphaxolone
• Eltanolone
• Hydroxydione
• Minaxolone
• Progesterone

   | group8 = Nonbenzodiazepines
   | list8 =

• Eszopiclone
• Indiplon
• Lirequinil
• Necopidem
• Pagoclone
• Pazinaclone
• Saripidem
• Suproclone
• Suriclone
• Zaleplon
• Zolpidem
• Zopiclone

   | group9 = Phenols
   | list9 =

• Propofol

   | group10 = Piperidinediones
   | list10 =

• Glutethimide
• Methyprylon
• Pyrithyldione
• Piperidione

   | group11 = Quinazolinones
   | list11 =

• Afloqualone
• Cloroqualone
• Diproqualone
• Etaqualone
• Mebroqualone
• Mecloqualone
• Methaqualone
• Methylmethaqualone
• Nitromethaqualone
• SL-164

   | group12 = Others
   | list12 =

• Acetophenone
• Acetylglycinamide chloral hydrate
• Bromide compounds
  • Lithium bromide
  • Potassium bromide
  • Sodium bromide
• Centalun
• Chloral betaine
• Chloral hydrate
• Chloralose
• Clomethiazole
• Dichloralphenazone
• Gaboxadol
• Kavalactones
• Loreclezole
• Paraldehyde
• Petrichloral
• Sulfonylalkanes
  • Sulfonmethane (sulfonal)
  • Tetronal
  • Trional
• Triclofos
• Sesquiterpene
  • Isovaleramide
  • Isovaleric acid
  • Valerenic acid

 }}

 | group2 = GABAB
 | list2 =

• 1,4-Butanediol
• 4-Fluorophenibut
• Aceburic acid
• Baclofen
• GABOB
• GHB (sodium oxybate)
• GBL
• GVL
• Phenibut
• Tolibut

 | group3 = H1
 | list3 = {{#invoke:navbox|navbox|child
 | groupstyle = text-align:center;

   | group1 = Antihistamines
   | list1 =

• Captodiame
• Cyproheptadine
• Diphenhydramine
• Doxylamine
• Hydroxyzine
• Methapyrilene
• Perlapine
• Pheniramine
• Promethazine
• Propiomazine

   | group2 = Antidepressants
   | list2 =

• Serotonin antagonists and reuptake inhibitors
  • Etoperidone
  • Nefazodone
  • Trazodone
• Tricyclic antidepressants
  • Amitriptyline
  • Doxepin
  • Trimipramine, etc.
• Tetracyclic antidepressants
  • Mianserin
  • Mirtazapine, etc.

   | group3 = Antipsychotics
   | list3 =

• Typical antipsychotics
  • Chlorpromazine
  • Thioridazine, etc.
• Atypical antipsychotics
  • Olanzapine
  • Quetiapine
  • Risperidone, etc.

 }}

 | group5 = α2-Adrenergic
 | list5 =

• Clonidine
• Detomidine
• Dexmedetomidine
• Lofexidine
• Medetomidine
• Romifidine
• Tizanidine
• Xylazine

 | group6 = 5-HT2A
 | list6 = {{#invoke:navbox|navbox|child
 | groupstyle = text-align:center;

   | group1 = Antidepressants
   | list1 =

• Trazodone
• Tricyclic antidepressants
  • Amitriptyline
  • Doxepin
  • Trimipramine, etc.
• Tetracyclic antidepressants
  • Mianserin
  • Mirtazapine, etc.

   | group2 = Antipsychotics
   | list2 =

• Typical antipsychotics
  • Chlorpromazine
  • Thioridazine, etc.
• Atypical antipsychotics
  • Olanzapine
  • Quetiapine
  • Risperidone, etc.

   | group3 = Others
   | list3 =

• Niaprazine

 }}

 | group7 = Melatonin
 | list7 =

• Agomelatine
• Melatonin
• Ramelteon
• Tasimelteon

 | group8 = Orexin
 | list8 =

• Daridorexant
• Lemborexant
• Suvorexant

 | group9 = [[Gabapentinoid|Template:Abbr Template:Abbr]]
 | list9 = 

• Gabapentin
• Gabapentin enacarbil
• Mirogabalin
• Phenibut
• Pregabalin

 | group10 = Others
 | list10 =

• Cannabidiol
  • Cannabis
• Chlorophenylalkyldiols
  • Fenpentadiol
  • Metaglycodol
  • Phenaglycodol
• Diethylpropanediol
• Evoxine
• Fenadiazole
• Guaifenesin-related muscle relaxants
  • Chlorphenesin
  • Mephenesin
  • Mephenoxalone
  • Metaxalone
  • Methocarbamol
• Midaflur
• Opioids (e.g., morphine)
• Passion flower
• Scopolamine
• Trazodone
• UMB68
• Valnoctamide

}} Template:Insomnia pharmacotherapies Template:GABAAR PAMs