Wikipedia

Clonazepam

Not to be confused withclozapine,clonazolam,orclorazolam.

Clonazepam,sold under the brand nameKlonopinamong others, is abenzodiazepinemedication used to prevent and treatanxiety disorders,seizures,bipolarmania,agitation associated withpsychosis,obsessive–compulsive disorder(OCD), andakathisia.[11]It is a long-acting[12]tranquilizerof thebenzodiazepineclass.[11]It possessesanxiolytic,anticonvulsant,sedative,hypnotic,andskeletal muscle relaxantproperties. It is typically takenorally(swallowed by mouth) but is also usedintravenously.[11][13]Effects begin within one hour and last between eight and twelve hours in adults.[9][1]

Clonazepam
Clinical data
Pronunciationkləˈnazɪpam, kloe-NAZ-e-pam
Trade namesKlonopin, Rivotril, Paxam,[1]others[2]
AHFS/Drugs.comMonograph
MedlinePlusa682279
License data
Pregnancy
category
Dependence
liability		Physical:Very High Psychological:Moderate
Addiction
liability		Moderate[4][5]
Routes of
administration		By mouth,intramuscular,intravenous,sublingual
Drug classBenzodiazepine
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability90%
Protein binding≈85%
MetabolismLiver(CYP3A)[11]
Metabolites7-aminoclonazepam
7-acetaminoclonazepam
3-hydroxy clonazepam[7][8]
Onset of actionWithin an hour[9]
Eliminationhalf-life19–60 hours[10]
Duration of action8–12 hours[9][1]
ExcretionKidney
Identifiers
  • 5-(2-Chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.015.088Edit this at Wikidata
Chemical and physical data
FormulaC15H10ClN3O3
Molar mass315.71g·mol−1
3D model (JSmol)
  • O=C1CN=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N1
  • InChI=1S/C15H10ClN3O3/c16-12-4-2-1-3-10(12)15-11-7-9(19(21)22)5-6-13(11)18-14(20)8-17-15/h1-7H,8H2,(H,18,20)checkY
  • Key:DGBIGWXXNGSACT-UHFFFAOYSA-NcheckY
(verify)

Common side effects may includesleepiness,weakness,poor coordination,difficulty concentrating, and agitation. Clonazepam may alsodecrease memory formation.[11]Long-term usemay result intolerance,dependence,and life-threateningwithdrawal symptomsif stopped abruptly.[11][14]Dependence occurs in one-third of people who take benzodiazepines for longer than four weeks.[10]The risk ofsuicideincreases, particularly in people who are already depressed.[11][15]Use during pregnancy may result in harm to the fetus.[11]Clonazepam binds toGABAAreceptors,thus increasing the effect of the chiefinhibitoryneurotransmitterγ-aminobutyric acid(GABA).[10]

Clonazepam was patented in 1960 and went on sale in 1975 in the United States fromRoche.[16][17]It is available as ageneric medication.[11]In 2022, it was the 57th most commonly prescribed medication in the United States, with more than 11million prescriptions.[18][19]In many areas of the world, it is commonly used as arecreational drug.[20][21]

Medical uses

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Clonazepam is prescribed for short-term management ofepilepsy,anxiety,obsessive–compulsive disorder(OCD), andpanic disorderwith or withoutagoraphobia.[22][23][24]

Seizures

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Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects.

Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam.[25]As a result, clonazepam is sometimes used for certain rare childhood epilepsies, but it is ineffective in the control of infantile spasms.[26]Clonazepam is mainly prescribed for the acute management of epilepsy. Clonazepam is effective in the acute control of non-convulsivestatus epilepticus;the benefits, though, tended to be transient in many people, and the addition ofphenytoinfor lasting control was required in these patients.[27]

It is also approved for the treatment of typical and atypical absences (seizures) and infantilemyoclonicandakinetic seizures.[28]A subgroup of people withtreatment-resistant epilepsymay benefit from long-term use of clonazepam; the benzodiazepineclorazepatemay be an alternative due to its slow onset of tolerance.[10][29]

Anxiety disorders

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The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated incontrolled clinical trials.Some long-term trials have suggested a benefit of clonazepam for up to three years without the development oftolerance.[33]Clonazepam is also effective in the management ofacute mania.[34]

Muscle disorders

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Restless legs syndromecan be treated using clonazepam as a third-line treatment option, as the use of clonazepam is still investigational.[35][36]Bruxismalso responds to clonazepam in the short term.[37]REM sleep behavior disorderresponds well to low doses of clonazepam.[38]It is also used for:

Other

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  • Benzodiazepines, such as clonazepam, are sometimes used for the treatment ofmaniaor acutepsychosis-induced aggression. In this context, benzodiazepines are given either alone or in combination with other first-line drugs such aslithium,haloperidol,orrisperidone.[42][43]The effectiveness of taking benzodiazepines along withantipsychotic medicationis unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.[43]
  • Hyperekplexia[44]
  • Many forms ofparasomniaand other sleep disorders are treated with clonazepam.[45]
  • It is not effective for preventingmigraines.[46]

Contraindications

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Adverse effects

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In September 2020, the U.S.Food and Drug Administration(FDA) required theboxed warningbe updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.[48]

Common

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Less common

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  • Confusion[10]
  • Irritability and aggression[50]
  • Psychomotor agitation[51]
  • Lack of motivation[52]
  • Increased libido[53]
  • Loss of libido
  • Impaired motor function
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Cognitive impairments[vague][54]
  • Some users reporthangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up.[58][59][60]While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.[61]After regular use,rebound insomniamay occur when discontinuing clonazepam.[62]
  • Benzodiazepines may cause or worsendepression.[10]

Occasional

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Rare

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Thelong-term effects of clonazepamcan include depression,[10]disinhibition,andsexual dysfunction.[74]

Drowsiness

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Clonazepam, like other benzodiazepines, may impair a person's ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified byalcoholconsumption, so alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.

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  • Anxiety
  • Irritability
  • Insomnia
  • Tremors
  • Headaches
  • Stomach pain
  • Hallucinations
  • Suicidal thoughts or urges
  • Depression
  • Fatigue
  • Dizziness
  • Sweating
  • Confusion
  • Potential to exacerbate existing panic disorder upon discontinuation
  • Seizures[75]similar todelirium tremens(with long-term use of excessive doses)

Benzodiazepines such as clonazepam can be very effective in controllingstatus epilepticus,but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference withcognitivefunctions and behavior.[76]Many individuals treated on a long-term basis develop a dependence.Physiologicaldependence was demonstrated byflumazenil-precipitated withdrawal.[77]Use of alcohol or otherCNSdepressants while taking clonazepam greatly intensifies the effects, including side effects, of the drug.

A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.[78]

Tolerance and withdrawal

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Main article:Benzodiazepine withdrawal syndrome

Like all benzodiazepines, clonazepam is a GABA-positiveallosteric modulator.[79][80]One-third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long-term use increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A gradual reduction in dosage reduces the severity of thebenzodiazepine withdrawal syndrome.Due to the risks of tolerance and withdrawal seizures, clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance, but tolerance to the higher dose may occur and adverse effects may intensify. The mechanism of tolerance includes receptor desensitization, down regulation, receptor decoupling, and alterations in subunit composition and ingene transcriptioncoding.[10]

Toleranceto the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.[81][82]Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than withchlordiazepoxide.[83]In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[84]Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long-term effectiveness as an anticonvulsant.[28]

Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised bydysphoricmanifestations, irritability, aggressiveness, anxiety, and hallucinations.[85][86][87]Sudden withdrawal may also induce the potentially life-threatening condition,status epilepticus.Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects.[67]Carbamazepinehas been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-inducedstatus epilepticusfrom occurring.[88]

Overdose

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Main article:Benzodiazepine overdose

Excess doses may result in:

Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a four-year-old boy who overdosed on clonazepam.[89]The combination of clonazepam and certain barbiturates (for example,amobarbital), at prescribed doses has resulted in asynergisticpotentiation of the effects of each drug, leading to serious respiratory depression.[90]

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.[91]

Detection in biological fluids

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Clonazepam and 7-aminoclonazepam may be quantified inplasma,serum,orwhole bloodin order to monitor compliance in those receiving the drug therapeutically. Results from such tests can be used to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses.[92]

Special precautions

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The elderly metabolize benzodiazepines more slowly than younger people and are also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and are to be administered for no longer than two weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due to the risk of drug accumulation.[10]

The elderly are especially susceptible to increased risk of harm from motor impairments and drug accumulation side effects. Benzodiazepines also require special precaution if used by individuals that may be pregnant, alcohol- or drug-dependent, or may havecomorbidpsychiatric disorders.[93]Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.[94]

Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs, behavioural disturbances occur most frequently with clonazepam andphenobarbital.[93][95]

Doses higher than 0.5–1 mg per day are associated with significant sedation.[96]

Clonazepam may aggravatehepatic porphyria.[97][98]

Clonazepam is not recommended for patients with chronicschizophrenia.A 1982 double-blinded, placebo-controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.[99]

Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.[100]

Interactions

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Clonazepam decreases the levels ofcarbamazepine,[101][102]and, likewise, clonazepam's level is reduced by carbamazepine. Azole antifungals, such asketoconazole,may inhibit the metabolism of clonazepam.[10]Clonazepam may affect levels ofphenytoin(diphenylhydantoin).[101][103][104][105]In turn, Phenytoin may lower clonazepam plasma levels by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%.[106] Clonazepam increases the levels ofprimidone[104]andphenobarbital.[107]

Combined use of clonazepam with certainantidepressants,anticonvulsants(such asphenobarbital,phenytoin,andcarbamazepine), sedativeantihistamines,opiates,andantipsychotics,nonbenzodiazepines(such aszolpidem), and alcohol may result in enhanced sedative effects.[10]

Pregnancy

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See also:Long-term effects of benzodiazepines § Neonatal effects

There is some medical evidence of various malformations (for example, cardiac or facial deformations when used in early pregnancy); however, the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam, when used late in pregnancy, may result in the development of a severe benzodiazepine withdrawal syndrome in theneonate.Withdrawal symptoms from benzodiazepines in theneonatemay includehypotonia,apnoeicspells,cyanosis,and impairedmetabolicresponses to cold stress.[108]

The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy,chlordiazepoxideanddiazepammay be a safer choice. The use of clonazepam during pregnancy should only occur if the clinical benefits are believed to outweigh the clinical risks to thefetus.Caution is also required if clonazepam is used during breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include:miscarriage,malformation,intrauterine growth retardation,functional deficits,carcinogenesis,andmutagenesis.Neonatal withdrawal syndrome associated with benzodiazepines includehypertonia,hyperreflexia,restlessness,irritability,abnormal sleep patterns, inconsolable crying,tremors,or jerking of the extremities,bradycardia,cyanosis,sucklingdifficulties,apnea,risk of aspiration of feeds,diarrheaand vomiting, andgrowth retardation.This syndrome can develop between three days to three weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolized is usually impaired in newborns. If clonazepam is used during pregnancy orbreastfeeding,it is recommended that serum levels of clonazepam are monitored and that signs ofcentral nervous systemdepression andapneaare also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy, and avoidance ofcaffeine,can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.[109]

Pharmacology

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Mechanism of action

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Clonazepam enhances the activity of the inhibitory neurotransmittergamma-aminobutyric acid(GABA) in the central nervous system to give itsanticonvulsant,skeletal muscle relaxant,andanxiolyticeffects.[110]It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across thecentral nervous system.[111][112]

Benzodiazepines do not have any effect on the levels of GABA in the brain.[113]Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affectglutamate decarboxylaseactivity. It differs from other anticonvulsant drugs it was compared to in a study.[114]

Clonazepam's primarymechanism of actionis the modulation ofGABAfunction in the brain, by the benzodiazepine receptor, located onGABAAreceptors,which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAAreceptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA's inhibitory effects and resultantcentral nervous system depression.[10]In addition, clonazepam decreases the utilization of5-HT (serotonin)by neurons[115][116]and has been shown to bind tightly to central-type benzodiazepine receptors.[117]Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam),[118][119]it is said to be among the class of "highly potent"benzodiazepines.[120]The anticonvulsant properties of benzodiazepines are due to the enhancement ofsynapticGABA responses, and the inhibition of sustained, high-frequency repetitive firing.[121]

Benzodiazepines, including clonazepam, bind to mouseglial cellmembranes with high affinity.[122][123]Clonazepam decreases release ofacetylcholinein the feline brain[124]and decreasesprolactinrelease in rats.[125]Benzodiazepines inhibit cold-inducedthyroid-stimulating hormone(also known as TSH or thyrotropin) release.[126]Benzodiazepines act viamicromolarbenzodiazepine binding sites asCa2+channel blockersand significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study.[127]

Clonazepam is a2'-chlorinatedderivative ofnitrazepam,which increases its potency due to electron-attracting effect of the halogen in theortho-position.[128][9]

Pharmacokinetics

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Clonazepam is lipid-soluble, rapidly crosses theblood–brain barrier,and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine.[129]Clonazepam is metabolized extensively via nitroreduction bycytochrome P450enzymes, includingCYP3A4.Erythromycin,clarithromycin,ritonavir,itraconazole,ketoconazole,nefazodone,cimetidine,and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines.[130]It has anelimination half-lifeof 19–60 hours.[10]Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.[131]

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[132]Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[133]

Clonazepam has plasma protein binding of 85%.[134][129]Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other.[135]The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[7][136]These metabolites are excreted by the kidney.[129]

It is effective for 6–8 hours in children, and 8–12 in adults.[137][1]

Society and culture

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Recreational use

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See also:Benzodiazepine misuse

A 2006 US government study of hospital emergency department (ED) visits found that sedative-hypnotics were the most frequently implicated pharmaceutical drug in visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits. Alcohol alone was responsible for over twice as many ED visits as clonazepam in the same study. The study examined the number of times the non-medical use of certain drugs was implicated in an ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example,drug abuse,accidental or intentionaloverdose,or adverse reactions resulting from legitimate use of the medication.[138]

Formulations

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Clonazepam was approved in the United States as ageneric drugin 1997 and is now manufactured and marketed by several companies.

Clonazepam is available as tablets and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.[139]

Crime

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In some countries, clonazepam is used by criminals to subdue their victims.[140]

Brand names

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Brand name clonazepam tablets

It is marketed under the brand name Rivotril byRochein Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia,[141]Germany, Hungary, Iceland, Ireland, Italy, China, Mexico, the Netherlands, Norway, Portugal, Peru, Pakistan, Romania, Serbia, South Africa, South Korea, Spain, Turkey, and the United States; Emcloz, Linotril, Lonazep, Clotrin and Clonotril in India and other parts of Europe; under the name Riklona in Indonesia and Malaysia; and under the brand name Klonopin byRochein the United States. Other names, such as Antelepsin, Clonoten, Ravotril, Rivotril, Iktorivil, Clonex (Israel), Paxam, Petril, Naze, Zilepam and Kriadex, are used throughout the world.[2][139]In August 2021, Roche Australia transferred Rivotril to Pharmaco Australia Ltd.[142]

  • Klonopin 0.5 mg tablet
  • Klonopin 1 mg tablet
  • Klonopin 2 mg tablet
  • Clonazepam orally disintegrating tablet, 0.25 mg

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