clonazepam clonazepam clonazepam, sold under the brand names klonopin and rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. it is a tranquilizer of the benzodiazepine class. it possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. it is typically taken by mouth. effects begin within one hour and last between six and twelve hours. not to be confused with clozapine, clonazolam, or clorazolam. clonazepam clinical datapronunciationkləˈnazɪpam trade namesklonopin, rivotril, othersahfs/drugs.commonographmedlineplusa682279license data us dailymed: clonazepam us fda: clonazepam pregnancycategory au: b3 dependenceliabilityphysical: moderatepsychological: moderate to highaddictionliabilitymoderateroutes ofadministrationby mouth, intramuscular, intravenous, sublingualdrug classbenzodiazepineatc coden03ae01 (who) legal statuslegal status au: s4 (prescription only) br: class b1 (psychoactive drugs) ca: schedule iv de: prescription only (anlage iii for higher doses) nz: class c uk: class c us: schedule iv un: psychotropic schedule iv in general: ℞ (prescription only) pharmacokinetic databioavailability90%protein binding≈85%metabolismliver (cyp3a)metabolites7-aminoclonazepam 7-acetaminoclonazepam3-hydroxy clonazepamonset of actionwithin an hourelimination half-life19–60 hoursduration of action6–12 hoursexcretionkidneyidentifiers iupac name 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one cas number1622-61-3 ypubchem cid2802iuphar/bps6963drugbankdb01068 ychemspider2700 yunii5pe9fde8gbkeggd00280 ychebichebi:3756 ychemblchembl452 ycomptox dashboard (epa)dtxsid1022845 echa infocard100.015.088 chemical and physical dataformulac15h10cln3o3molar mass315.71 g·mol−13d model (jsmol)interactive image smiles o=c1cn=c(c2ccccc2cl)c2cc((=o))ccc2n1 inchi 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) ykey:dgbigwxxngsact-uhfffaoysa-n y (verify) common side effects include sleepiness, poor coordination, and agitation. long-term use may result in tolerance, dependence, and withdrawal symptoms if stopped abruptly. dependence occurs in one-third of people who take benzodiazepines for longer than four weeks. there is an increased risk of suicide, particularly in people who are already depressed. if used during pregnancy it may result in harm to the fetus. clonazepam binds to gabaa receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid (gaba). clonazepam was patented in 1960 and went on sale in 1975 in the united states from roche. it is available as a generic medication. in 2020, it was the 44th most commonly prescribed medication in the united states, with more than 14 million prescriptions. in many areas of the world it is commonly used as a recreational drug. medical uses clonazepam is prescribed for short term management of epilepsy, anxiety, and panic disorder with or without agoraphobia. seizures 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. as a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms. clonazepam is mainly prescribed for the acute management of epilepsies. clonazepam has been found to be effective in the acute control of non-convulsive status epilepticus; however, the benefits tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients. it is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures. a subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance. anxiety disorders panic disorder with or without agoraphobia. clonazepam has also been found effective in treating other anxiety disorders, such as social phobia, but this is an off-label use. the effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo-controlled. clonazepam is also effective in the management of acute mania. muscle disorders restless legs syndrome can be treated using clonazepam as a third-line treatment option as the use of clonazepam is still investigational. bruxism also responds to clonazepam in the short-term. rapid eye movement sleep behavior disorder responds well to low doses of clonazepam. the treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics. spasticity related to amyotrophic lateral sclerosis. other benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. in this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol or risperidone. the effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required. hyperekplexia many forms of parasomnia and other sleep disorders are treated with clonazepam. it is not effective for preventing migraines. contraindications coma current alcohol use disorder current substance use disorder respiratory depression. adverse effects in september 2020, the u.s. food and drug administration (fda) required the boxed warning be 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. common sedation euphoria motor impairment less common confusion irritability and aggression psychomotor agitation lack of motivation loss of libido impaired motor function impaired coordination impaired balance dizziness cognitive impairments hallucinations. short-term memory loss anterograde amnesia (common with higher doses) some users report hangover-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. while benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting rem sleep. after regular use, rebound insomnia may occur when discontinuing clonazepam. benzodiazepines may cause or worsen depression. occasional dysphoria induction of seizures or increased frequency of seizures personality changes behavioural disturbances ataxia rare suicide through disinhibition psychosis incontinence liver damage paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities) rage excitement impulsivity the long-term effects of clonazepam can include depression, disinhibition, and sexual dysfunction. drowsiness 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 by alcohol consumption, and therefore 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. withdrawal-related 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 similar to delirium tremens (with long-term use of excessive doses) benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behavior. many individuals treated on a long-term basis develop a dependence. physiological dependence was demonstrated by flumazenil-precipitated withdrawal. use of alcohol or other cns depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug. a recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms. tolerance and withdrawal main article: benzodiazepine withdrawal syndrome like all benzodiazepines, clonazepam is a gaba-positive allosteric modulator. 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 the benzodiazepine 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 in gene transcription coding. tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. in humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently. 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 with chlordiazepoxide. in general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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. abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. 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. carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring. overdose main article: benzodiazepine overdose excess doses may result in: difficulty staying awake mental confusion impaired motor functions impaired reflexes impaired coordination impaired balance dizziness respiratory depression low blood pressure coma 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. the combination of clonazepam and certain barbiturates (for example, amobarbital), at prescribed doses has resulted in a synergistic potentiation of the effects of each drug, leading to serious respiratory depression. overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting. detection in biological fluids clonazepam and 7-aminoclonazepam may be quantified in plasma, serum, or whole blood in 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. special precautions 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. 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 have comorbid psychiatric disorders. clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines. 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 and phenobarbital. doses higher than 0.5–1 mg per day are associated with significant sedation. clonazepam may aggravate hepatic porphyria. clonazepam is not recommended for patients with chronic schizophrenia. a 1982 double-blinded, placebo-controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia. clonazepam has similar effectiveness to other benzodiazepines at often a lower dose. interactions clonazepam decreases the levels of carbamazepine, and, likewise, clonazepam's level is reduced by carbamazepine. azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam. clonazepam may affect levels of phenytoin (diphenylhydantoin). 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%. clonazepam increases the levels of primidone and phenobarbital. combined use of clonazepam with certain antidepressants, anticonvulsants (such as phenobarbital, phenytoin, and carbamazepine), sedative antihistamines, opiates, and antipsychotics, nonbenzodiazepines (such as zolpidem), and alcohol may result in enhanced sedative effects. pregnancy