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Not to be confused with clozapine, clorazolam, or clobazam.
Clonazepam structure.svg
Clonazepam 3D animated.gif
Systematic (IUPAC) name
Clinical data
Trade names Klonopin, Rivotril, Clonotril
AHFS/ monograph
MedlinePlus a682279
Licence data US FDA:link
  • AU: C
  • US: D
Oral, I.M., I.V, sublingual
Pharmacokinetic data
Bioavailability 90%
Protein binding ~85%
Metabolism Hepatic CYP3A4
Half-life 18–50 hours
Excretion Renal
1622-61-3 YesY
PubChem CID 2802
DrugBank DB01068 YesY
ChemSpider 2700 YesY
KEGG D00280 YesY
Chemical data
Formula C15H10ClN3O3
 YesY (what is this?)  (verify)

Clonazepam[2] is a benzodiazepine drug having anxiolytic, anticonvulsant,[3] muscle relaxant, amnestic, sedative, and hypnotic properties.[4] It is marketed under the trade name Rivotril by Roche in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Germany, Hungary, Ireland, Italy, Mexico, Norway, Portugal, Peru, South Africa, the United States, and Spain; Linotril and Clonotril in India, South Korea, and other parts of Europe; and under the trade name Klonopin by Roche in the United States. Other names, such as Ravotril, Rivatril, Iktorivil, Clonex, Paxam, Petril, Naze and Kriadex, are known throughout the world.[citation needed] Clonazepam has an elimination half-life of 18–50 hours to 19–60 hours,[5] and is generally considered to be an intermediate-acting benzodiazepine. Clonazepam has no active metabolites.[5] Clonazepam is a chlorinated derivative of nitrazepam[6] and therefore a chloro-nitrobenzodiazepine.[7]

Clonazepam has an intermediate onset of action, with a peak blood level occurring one to four hours after oral administration. Long-term effects of benzodiazepines include tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome, which occurs in one third of patients treated with clonazepam for longer than four weeks.[8]

Benzodiazepines such as clonazepam have a fast onset of action, high effectivity rate, and low toxicity in overdose; however, as with most medications, it may have drawbacks due to adverse or paradoxical effects. The benzodiazepine clorazepate may be an alternative to clonazepam due to a slow onset of tolerance and its availability in a slow-release formula to counter fluctuations in blood levels. The pharmacological property of clonazepam, as with other benzodiazepines, is the enhancement of the neurotransmitter GABA via modulation of the GABAA receptor.[8]

Medical uses[edit]

Clonazepam may be prescribed for epilepsy.[9][10] Clonazepam is approved by the Food and Drug Administration for treatment of epilepsy and panic disorder. It is also approved for treatment of typical and atypical absences, infantile myoclonic, myoclonic and akinetic seizures[11] and also as a second line agent. 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. The benzodiazepine clorazepate may be preferred over clonazepam due to a slower onset of tolerance and availability in slow-release formulation to counter fluctuations in blood levels, although there is not a manufacturer of this slow-release formulation in the United States as of January 2014. The pharmacological property of clonazepam as with other benzodiazepines is the enhancement of the neurotransmitter GABA via modulation of the GABAA receptor.[8] 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.[8]

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.[12] 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.[13] Clonazepam is less effective and less potent as an anticonvulsant in controlling infantile seizure compared to nitrazepam in the treatment of West syndrome, an age-dependent epilepsy affecting the very young.

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 of the patients, and the addition of phenytoin for lasting control was required in these patients.[14]

Clonazepam has also been found effective in treating:

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.[30]

Clonazepam may help reduce the severity of tinnitus symptoms.[31]


Klonopin 0.5 mg.
Klonopin 1 mg.

Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available as tablets (0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg) and orally disintegrating tablets (wafers) (0.25 mg, 0.5 mg), an oral solution (drops), and as a solution for injection or intravenous infusion.[citation needed]

Adverse effects[edit]


Less common[edit]

  • Confusion[8]
  • Irritability and aggression[33]
  • Psychomotor agitation[34]
  • Lack of motivation[35]
  • Loss of libido
  • Impaired motor function[vague]
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Cognitive impairments[vague][36]
  • 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.[citation needed]
  • The "hangover effect" some experience not only results from clonazepam's considerably long half-life, but also, like many other benzodiazepines, when taken as a sleep aid, clonazepam's disruption or interference with the brain's delta waves. Delta waves signify the brain's slowest waves (~4 Hz) and occur during Stage 4 sleep, which designates humans' deepest sleep state (when the muscles are the most relaxed; breathing slows and becomes shallow), and the stage right before R.E.M. sleep and dreaming (Stage 5). Therefore, upon waking, this disruption of Stage 4 delta wave sleep causes a deficit in adequate brain/body rest or "recharge".[citation needed]

[40][41] While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.[42] After regular use, rebound insomnia may occur when discontinuing clonazepam.[43]



Long-term effects[edit]

The long-term effects of clonazepam can include depression,[8] disinhibition, and sexual dysfunction.[57]


  • Anxiety, irritability, insomnia, tremors
  • Potential to exacerbate existing panic disorder upon discontinuation
  • Seizures[58] 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.[59] Many individuals treated on a long-term basis develop a form of dependence known as "low-dose dependence,"[according to whom?] as was shown in one double-blind, placebo-controlled study of 34 therapeutic low-dose benzodiazepine users. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal.[60] Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side-effects) of the drug.

Tolerance and withdrawal[edit]

Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist.[61][62] 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 increases 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. 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 desensitisation, down regulation, receptor decoupling, and alterations in subunit composition and in gene transcription coding.[8]


Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.[63][64] 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.[65] In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[66] 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.[67]


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.[68][69][70] 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.[49] Carbamazepine has been tested in the treatment of clonazepam withdrawal and was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring.[71]


An individual who has exceeded their recommended dosage of clonazepam may display one or more of the following symptoms:

  • Somnolence (difficulty staying awake)
  • Mental confusion
  • Nausea
  • Impaired motor functions
    • Impaired reflexes
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Respiratory depression
  • Hypotension
  • Coma

Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a 4-year-old boy who suffered an overdose of clonazepam.[72] The combination of clonazepam and certain barbiturates, e.g. amobarbital, at prescribed doses has resulted in a synergistic potentiation of the effects of each drug, leading to serious respiratory depression.[73]

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.[74]

Although an overdose of clonazepam is a serious medical concern, there have been no known instances of death from such an overdose. The LD50 for both mice and rats is greater than 2,000 mg per kilogram of body weight.[75]

Detection in biological fluids[edit]

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.[76]

Special precautions[edit]

The elderly metabolise benzodiazepines more slowly than younger individuals 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 2 weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due the risk of drug accumulation.[8]

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.[77] Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.[78]

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.[77][79]

Doses higher than 0.5–1 mg per day are associated with significant sedation.[80]

Clonazepam may aggravate hepatic porphyria.[81][82]

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.[83]


Clonazepam decreases the levels of carbamazepine,[84][85] and, likewise, clonazepam's level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam.[8] Clonazepam may affect levels of phenytoin (diphenylhydantoin).[84][86][87][88] 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%.[89] Clonazepam increases the levels of primidone[87] and phenobarbital.[90]

Combined use of clonazepam with certain antidepressants, antiepileptics, such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics, nonbenzodiazepine hypnotics like zolpidem and alcohol may result in enhanced sedative effects.[8]


Clonazepam, like other benzodiazepines, will impair one'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 both psychological and physical dependence. Patients physically 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.


There is some medical evidence of various malformations, e.g., 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 the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis and impaired metabolic responses to cold stress.[91]

The safety profile of clonazepam during pregnancy is less clear than that of other benzodiazepines, and if benzodiazepines are indicated during pregnancy, chlordiazepoxide and diazepam may 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 the fetus. Caution is also required if clonazepam is used during breast feeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, floppy infant syndrome, carcinogenesis and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds, diarrhea and vomiting, and growth retardation. This syndrome can develop between 3 days to 3 weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolised is usually impaired in newborns. If clonazepam is used during pregnancy or breast feeding, it is recommended that serum levels of clonazepam are monitored and that signs of central nervous system depression and apnea are also checked for. In many cases, non-pharmacological treatments, such as relaxation therapy, psychotherapy and avoidance of caffeine, can be an effective and safer alternative to the use of benzodiazepines for anxiety in pregnant women.[92]


Clonazepam's primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABAA receptors, 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 GABAA receptor by increasing the opening frequency of chloride ion channels, which leads to increased inhibitory effects with resultant central nervous system depression.[8] In addition, clonazepam decreases the utilization of 5-HT (serotonin) by neurons[93][94] and has been shown to bind tightly to central-type benzodiazepine receptors.[95] Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam),[96] it is said to be among the class of "highly potent" benzodiazepines.[97] The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.[98]

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[99][100] Clonazepam decreases release of acetylcholine in the feline brain[101] and decreases prolactin release in rats.[102] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[103] Benzodiazepines acted via micromolar benzodiazepine binding sites as Ca2+ channel blockers and 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.[104]

Mechanism of action[edit]

Clonazepam 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 the central nervous system.[105][106]

Benzodiazepines do not have any effect on the levels of GABA in the brain.[107] Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.[108]


Clonazepam is lipid soluble, rapidly crosses the blood–brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites. Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, particularly CYP2C19 and to a lesser extent CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines.[109] It has an elimination half-life of 19–60 hours.[8] 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.[110]

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[111] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[112]

Clonazepam is largely bound to plasma proteins.[113] Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other.[114] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[115][116]

Recreational use[edit]

A 2006 US government study of nationwide emergency department (ED) visits conducted by SAMHSA found that sedative-hypnotics in the US were the most frequently implicated pharmaceutical drug in ED visits, with benzodiazepines accounting for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits in the study, however it should be noted that alcohol alone was responsible for over twice as many ED visits than clonazepam in the same study. The study examined the number of times non-medical use of certain drugs were implicated in ED visit. The criteria for non-medical use in this study were purposefully broad, and include, for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.[117]


  1. ^ Saunders Nursing Drug Handbook 2014
  2. ^ US Patent 3123529
  3. ^ Anticonvulsants can also being used for the treatment of neuropathic pain.
  4. ^ Cowen PJ; Green AR; Nutt DJ (March 1981). "Ethyl beta-carboline carboxylate lowers seizure threshold and antagonizes flurazepam-induced sedation in rats". Nature 290 (5801): 54–5. doi:10.1038/290054a0. PMID 6259533. 
  5. ^ a b "Benzodiazepine Names". Retrieved 2008-12-29. 
  6. ^ Dreifuss FE; Penry JK; Rose SW; Kupferberg HJ; Dyken P; Sato S (March 1975). "Serum clonazepam concentrations in children with absence seizures". Neurology 25 (3): 255–8. doi:10.1212/WNL.25.3.255. PMID 1089913. 
  7. ^ Robertson MD; Drummer OH (May 1995). "Postmortem drug metabolism by bacteria". J Forensic Sci 40 (3): 382–6. PMID 7782744. 
  8. ^ a b c d e f g h i j k l m n o Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics." (PDF). Acta Neurol Scand 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456. 
  9. ^ Rossetti AO; Reichhart MD; Schaller MD; Despland PA; Bogousslavsky J (July 2004). "Propofol treatment of refractory status epilepticus: a study of 31 episodes". Epilepsia 45 (7): 757–63. doi:10.1111/j.0013-9580.2004.01904.x. PMID 15230698. 
  10. ^ Ståhl Y, Persson A, Petters I, Rane A, Theorell K, Walson P; Persson; Petters; Rane; Theorell; Walson (April 1983). "Kinetics of clonazepam in relation to electroencephalographic and clinical effects". Epilepsia 24 (2): 225–31. doi:10.1111/j.1528-1157.1983.tb04883.x. PMID 6403345. 
  11. ^ Browne TR (May 1976). "Clonazepam. A review of a new anticonvulsant drug". Arch. Neurol. 33 (5): 326–32. doi:10.1001/archneur.1976.00500050012003. PMID 817697. 
  12. ^ Dahlin MG, Amark PE, Nergårdh AR; Amark; Nergårdh (January 2003). "Reduction of seizures with low-dose clonazepam in children with epilepsy". Pediatr. Neurol. 28 (1): 48–52. doi:10.1016/S0887-8994(02)00468-X. PMID 12657420. 
  13. ^ Hrachovy RA, Frost JD Jr, Kellaway P, Zion TE; Frost Jr; Kellaway; Zion (October 1983). "Double-blind study of ACTH vs prednisone therapy in infantile spasms". J Pediatr 103 (4): 641–5. doi:10.1016/S0022-3476(83)80606-4. PMID 6312008. 
  14. ^ Tomson T; Svanborg E, Wedlund JE (May–Jun 1986). "Nonconvulsive status epilepticus: high incidence of complex partial status". Epilepsia 27 (3): 276–85. doi:10.1111/j.1528-1157.1986.tb03540.x. PMID 3698940. 
  15. ^ Davidson, Jonathan et al. (1993). "Treatment of Social Phobia With Clonazepam and Placebo". Journal of Clinical Psychopharmacology. doi:10.1097/00004714-199312000-00008. 
  16. ^ Bisdorff, A. R. (2011). "Management of vestibular migraine". Therapeutic Advances in Neurological Disorders 4 (3): 183–191. doi:10.1177/1756285611401647. PMC 3105632. PMID 21694818.  edit
  17. ^ Cloos, Jean-Marc (2005). "The Treatment of Panic Disorder". Curr Opin Psychiatry 18 (1): 45–50. PMID 16639183. Retrieved 2007-09-25. 
  18. ^ Curtin F, Schulz P; Schulz (2004). "Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis". J Affect Disord 78 (3): 201–8. doi:10.1016/S0165-0327(02)00317-8. PMID 15013244. 
  19. ^ Gillies D, Beck A, McCloud A, Rathbone J, Gillies D; Beck; McCloud; Rathbone; Gillies (2005). Gillies, Donna, ed. "Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis". Cochrane Database Syst Rev (4): CD003079. doi:10.1002/14651858.CD003079.pub2. PMID 16235313. 
  20. ^ Lerner AG, Skladman I, Kodesh A, Sigal M, Shufman E; Skladman; Kodesh; Sigal; Shufman (2001). "LSD-induced Hallucinogen Persisting Perception Disorder treated with clonazepam: two case reports". Isr J Psychiatry Relat Sci 38 (2): 133–6. PMID 11475916. 
  21. ^ Zhou, L.; Chillag, KL.; Nigro, MA. (Oct 2002). "Hyperekplexia: a treatable neurogenetic disease". Brain Dev 24 (7): 669–74. doi:10.1016/S0387-7604(02)00095-5. PMID 12427512. 
  22. ^ Schenck, CH.; Arnulf, I.; Mahowald, MW. (Jun 2007). "Sleep and Sex: What Can Go Wrong? A Review of the Literature on Sleep Related Disorders and Abnormal Sexual Behaviors and Experiences". Sleep 30 (6): 683–702. PMC 1978350. PMID 17580590. 
  23. ^ "[Restless legs syndrome: diagnosis and treatment. Opinion of Brazilian experts]". Arq Neuropsiquiatr 65 (3A): 721–7. Sep 2007. doi:10.1590/S0004-282X2007000400035. PMID 17876423. 
  24. ^ Trenkwalder, C.; Hening, WA.; Montagna, P.; Oertel, WH.; Allen, RP.; Walters, AS.; Costa, J.; Stiasny-Kolster, K.; Sampaio, C. (Dec 2008). "Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice" (PDF). Mov Disord 23 (16): 2267–302. doi:10.1002/mds.22254. PMID 18925578. 
  25. ^ Huynh, NT.; Rompré, PH.; Montplaisir, JY.; Manzini, C.; Okura, K.; Lavigne, GJ. (2006). "Comparison of various treatments for sleep sex bruxism using determinants of number needed to treat and effect size". Int J Prosthodont 19 (5): 435–41. PMID 17323720. 
  26. ^ Ferini-Strambi, L.; Zucconi, M. (Sep 2000). "REM sleep behavior disorder". Clin Neurophysiol. 111 Suppl 2: S136–40. doi:10.1016/S1388-2457(00)00414-4. PMID 10996567. 
  27. ^
  28. ^
  29. ^ Lipton, S.A.; Rosenberg, P.A.; Rosenberg, Paul A. (1994). "Excitatory amino acids as a final common pathway for neurological disorders". New Engl. J. Med. 330 (9): 613–22. doi:10.1056/NEJM199403033300907. PMID 7905600. 
  30. ^ Nardi, AE.; Perna, G. (May 2006). "Clonazepam in the treatment of psychiatric disorders: an update". Int Clin Psychopharmacol 21 (3): 131–42. doi:10.1097/01.yic.0000194379.65460.a6. PMID 16528135. 
  31. ^ Han SS, Nam EC, Won JY, Lee KU, Chun W, Choi HK, Levine R (2012). "Clonazepam quiets tinnitus: a randomised crossover study with Ginkgo biloba.". J Neurol Neurosurg Psychiatry 83 (8): 821–7. doi:10.1136/jnnp-2012-302273. 
  32. ^ Stacy, M. (2002). "Sleep disorders in Parkinson's disease: epidemiology and management". Drugs Aging 19 (10): 733–9. doi:10.2165/00002512-200219100-00002. PMID 12390050. 
  33. ^ Lander CM; Donnan GA; Bladin PF; Vajda FJ (1979). "Some aspects of the clinical use of clonazepam in refractory epilepsy". Clin Exp Neurol 16: 325–32. PMID 121707. 
  34. ^ Sorel L; Mechler L; Harmant J (1981). "Comparative trial of intravenous lorazepam and clonazepam im status epilepticus". Clin Ther 4 (4): 326–36. PMID 6120763. 
  35. ^ Wollman M; Lavie P; Peled R (1985). "A hypernychthemeral sleep-wake syndrome: a treatment attempt". Chronobiol Int 2 (4): 277–80. doi:10.3109/07420528509055890. PMID 3870855. 
  36. ^ Aronson, Jeffrey Kenneth (20 Nov 2008). Meyler's Side Effects of Psychiatric Drugs (Meylers Side Effects). Elsevier Science. p. 403. ISBN 978-0-444-53266-4. 
  37. ^ "Clonazepam Side Effects". 2010. 
  38. ^ The interface of neurology internal medicine. Philadelphia: Wolters Kluwer Health/Lippincott Wiliams Wilkins. 1 September 2007. p. 963. ISBN 978-0-7817-7906-7. 
  39. ^ The American Psychiatric Publishing Textbook of Psychopharmacology (Schatzberg, American Psychiatric Publishing Textbook of Psychopharmacology). USA: American Psychiatric Publishing, Inc. 31 July 2009. p. 471. ISBN 978-1-58562-309-9. 
  40. ^ Goswami, Meeta; R. Pandi-Perumal, S.; Thorpy, Michael J. (24 Mar 2010). Narcolepsy:: A Clinical Guide. Springer. p. 73. ISBN 978-1-4419-0853-7. 
  41. ^ Kelsey, Jeffrey E.; Newport, D. Jeffrey; Nemeroff, Charles B. (2006). Principles of psychopharmacology for mental health professionals. Hoboken, N.J.: Wiley-Liss. p. 269. ISBN 978-0-471-25401-0. 
  42. ^ Lee-chiong, Teofilo (24 April 2008). Sleep Medicine: Essentials and Review. Oxford University Press, USA. pp. 463–465. ISBN 978-0-19-530659-0. 
  43. ^ Trevor, Anthony J.; Katzung, Bertram G.; Masters, Susan B. (1 January 2008). Katzung Trevor's pharmacology: examination board review. New York: McGraw Hill Medical. p. 191. ISBN 978-0-07-148869-3. 
  44. ^ Sjö O; Hvidberg EF; Naestoft J; Lund M (4 April 1975). "Pharmacokinetics and side-effects of clonazepam and its 7-amino-metabolite in man". Eur J Clin Pharmacol 8 (3–4): 249–54. doi:10.1007/BF00567123. PMID 1233220. 
  45. ^ Veall RM; Hogarth HC (22 November 1975). "Letter: Thrombocytopenia during treatment with clonazepam". Br Med J 4 (5994): 462. doi:10.1136/bmj.4.5994.462. PMC 1675341. PMID 1192127. 
  46. ^ Alvarez N; Hartford E; Doubt C (April 1981). "Epileptic seizures induced by clonazepam". Clin Electroencephalogr 12 (2): 57–65. PMID 7237847. 
  47. ^ Ishizu T, Chikazawa S, Ikeda T, Suenaga E; Chikazawa; Ikeda; Suenaga (July 1988). "[Multiple types of seizure induced by clonazepam in an epileptic patient]". No to Hattatsu (in Japanese) 20 (4): 337–9. PMID 3214607. 
  48. ^ Bang F; Birket-Smith E; Mikkelsen B (September 1976). "Clonazepam in the treatment of epilepsy. A clinical long-term follow-up study". Epilepsia 17 (3): 321–4. doi:10.1111/j.1528-1157.1976.tb03410.x. PMID 824124. 
  49. ^ a b Bruni J (7 April 1979). "Recent advances in drug therapy for epilepsy". Can Med Assoc J (PDF) 120 (7): 817–24. PMC 1818965. PMID 371777. 
  50. ^ Rosenfeld WE, Beniak TE, Lippmann SM, Loewenson RB; Beniak; Lippmann; Loewenson (1987). "Adverse behavioral response to clonazepam as a function of Verbal IQ-Performance IQ discrepancy". Epilepsy Res. 1 (6): 347–56. doi:10.1016/0920-1211(87)90059-3. PMID 3504409. 
  51. ^ White MC; Silverman JJ; Harbison JW (February 1982). "Psychosis associated with clonazepam therapy for blepharospasm". J Nerv Ment Dis 170 (2): 117–9. doi:10.1097/00005053-198202000-00010. PMID 7057171. 
  52. ^ Williams A; Gillespie M (July 1979). "Clonazepam-induced incontinence". Ann Neurol 6 (1): 86. doi:10.1002/ana.410060127. PMID 507767. 
  53. ^ Sandyk R (August 13, 1983). "Urinary incontinence associated with clonazepam therapy". S Afr Med J 64 (7): 230. PMID 6879368. 
  54. ^ Anders RJ; Wang E; Radhakrishnan J; Sharifi R; Lee M (October 1985). "Overflow urinary incontinence due to carbamazepine". J Urol 134 (4): 758–9. PMID 4032590. 
  55. ^ Olsson R, Zettergren L; Zettergren (May 1988). "Anticonvulsant-induced liver damage". Am. J. Gastroenterol. 83 (5): 576–7. PMID 3364416. 
  56. ^ van der Bijl P, Roelofse JA; Roelofse (1991). "Disinhibitory reactions to benzodiazepines: a review". J. Oral Maxillofac. Surg. 49 (5): 519–23. doi:10.1016/0278-2391(91)90180-T. PMID 2019899. 
  57. ^ Cohen LS, Rosenbaum JF; Rosenbaum (October 1987). "Clonazepam: new uses and potential problems". J Clin Psychiatry. 48 Suppl: 50–6. PMID 2889724. 
  58. ^ Lockard JS; Levy RH; Congdon WC; DuCharme LL; Salonen LD (December 1979). "Clonazepam in a focal-motor monkey model: efficacy, tolerance, toxicity, withdrawal, and management". Epilepsia 20 (6): 683–95. doi:10.1111/j.1528-1157.1979.tb04852.x. PMID 115680. 
  59. ^ Vining EP (August 1986). "Use of barbiturates and benzodiazepines in treatment of epilepsy". Neurol Clin 4 (3): 617–32. PMID 3528811. 
  60. ^ Bernik MA; Gorenstein C; Vieira Filho AH (1998). "Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users". Journal of psychopharmacology (Oxford, England) 12 (2): 146–50. doi:10.1177/026988119801200205. PMID 9694026. 
  61. ^ Adjeroud, S; Tonon, Mc; Leneveu, E; Lamacz, M; Danger, Jm; Gouteux, L; Cazin, L; Vaudry, H (May 1987). "The benzodiazepine agonist clonazepam potentiates the effects of gamma-aminobutyric acid on alpha-MSH release from neurointermediate lobes in vitro". Life Sciences 40 (19): 1881–7. doi:10.1016/0024-3205(87)90046-4. PMID 3033417. 
  62. ^ Yokota, K; Tatebayashi, H; Matsuo, T; Shoge, T; Motomura, H; Matsuno, T; Fukuda, A; Tashiro, N (March 2002). "The effects of neuroleptics on the GABA-induced Cl− current in rat dorsal root ganglion neurons: differences between some neuroleptics" (PDF). British Journal of Pharmacology 135 (6): 1547–55. doi:10.1038/sj.bjp.0704608. PMC 1573270. PMID 11906969. 
  63. ^ Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". Encephale 9 (4 Suppl 2): 287B–292B. PMID 6373234. 
  64. ^ Scherkl R, Scheuler W, Frey HH; Scheuler; Frey (December 1985). "Anticonvulsant effect of clonazepam in the dog: development of tolerance and physical dependence". Arch Int Pharmacodyn Ther 278 (2): 249–60. PMID 4096613. 
  65. ^ Crawley JN; Marangos PJ; Stivers J; Goodwin FK (January 1982). "Chronic clonazepam administration induces benzodiazepine receptor subsensitivity". Neuropharmacology 21 (1): 85–9. doi:10.1016/0028-3908(82)90216-7. PMID 6278355. 
  66. ^ Bacia T; Purska-Rowińska E; Okuszko S (1980). "Clonazepam in the treatment of drug-resistant epilepsy: a clinical short- and long-term follow-up study". Monogr Neural Sci 5: 153–9. PMID 7033770. 
  67. ^ Browne TR (May 1976). "Clonazepam. A review of a new anticonvulsant drug". Arch Neurol 33 (5): 326–32. doi:10.1001/archneur.1976.00500050012003. PMID 817697. 
  68. ^ Sironi VA; Miserocchi G; De Riu PL (April 1984). "Clonazepam withdrawal syndrome". Acta Neurol (Napoli) 6 (2): 134–9. PMID 6741654. 
  69. ^ Sironi VA; Franzini A; Ravagnati L; Marossero F (August 1979). "Interictal acute psychoses in temporal lobe epilepsy during withdrawal of anticonvulsant therapy". J Neurol Neurosurg Psychiatry 42 (8): 724–30. doi:10.1136/jnnp.42.8.724. PMC 490305. PMID 490178. 
  70. ^ Jaffe R; Gibson E (June 1986). "Clonazepam withdrawal psychosis". J Clin Psychopharmacol 6 (3): 193. doi:10.1097/00004714-198606000-00021. PMID 3711371. 
  71. ^ Sechi GP; Zoroddu G; Rosati G (September 1984). "Failure of carbamazepine to prevent clonazepam withdrawal statusepilepticus". Ital J Neurol Sci 5 (3): 285–7. doi:10.1007/BF02043959. PMID 6500901. 
  72. ^ Welch TR; Rumack BH; Hammond K (1977). "Clonazepam overdose resulting in cyclic coma". Clin Toxicol 10 (4): 433–6. doi:10.3109/15563657709046280. PMID 862377. 
  73. ^ Honer WG; Rosenberg RG; Turey M; Fisher WA (November 1986). "Respiratory failure after clonazepam and amobarbital". Am J Psychiatry 143 (11): 1495. PMID 3777263. 
  74. ^ "Clonazepam, Prescription Marketed Drugs,". 
  75. ^ Jeffrey K Aronson (18 November 2011). Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Elsevier. p. 73. ISBN 978-0-444-53742-3. 
  76. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 335-337.
  77. ^ a b Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  78. ^ Wolkove, N.; Elkholy, O.; Baltzan, M.; Palayew, M. (May 2007). "Sleep and aging: 2. Management of sleep disorders in older people". CMAJ 176 (10): 1449–54. doi:10.1503/cmaj.070335. PMC 1863539. PMID 17485699. 
  79. ^ Trimble MR; Cull C (1988). "Children of school age: the influence of antiepileptic drugs on behavior and intellect". Epilepsia. 29 Suppl 3: S15–9. doi:10.1111/j.1528-1157.1988.tb05805.x. PMID 3066616. 
  80. ^ Hollister LE (1975). "Dose-ranging studies of clonazepam in man". Psychopharmacol Commun 1 (1): 89–92. PMID 1223993. 
  81. ^ Bonkowsky HL; Sinclair PR; Emery S; Sinclair JF (June 1980). "Seizure management in acute hepatic porphyria: risks of valproate and clonazepam". Neurology 30 (6): 588–92. doi:10.1212/WNL.30.6.588. PMID 6770287. 
  82. ^ Reynolds NC Jr; Miska RM (April 1981). "Safety of anticonvulsants in hepatic porphyrias". Neurology 31 (4): 480–4. doi:10.1212/wnl.31.4.480. PMID 7194443. 
  83. ^ Karson CN; Weinberger DR; Bigelow L; Wyatt RJ (December 1982). "Clonazepam treatment of chronic schizophrenia: negative results in a double-blind, placebo-controlled trial". Am J Psychiatry 139 (12): 1627–8. PMID 6756174. 
  84. ^ a b Lander CM; Eadie MJ; Tyrer JH (1975). "Interactions between anticonvulsants". Proc Aust Assoc Neurol 12: 111–6. PMID 2912. 
  85. ^ Pippenger CE (1987). "Clinically significant carbamazepine drug interactions: an overview". Epilepsia 28 (Suppl 3): S71–6. doi:10.1111/j.1528-1157.1987.tb05781.x. PMID 3319544. 
  86. ^ Saavedra IN; Aguilera LI; Faure E; Galdames DG (August 1985). "Phenytoin/clonazepam interaction". Ther Drug Monit 7 (4): 481–4. doi:10.1097/00007691-198512000-00022. PMID 4082246. 
  87. ^ a b Windorfer A Jr; Sauer W (1977). "Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepin and dipropylacetate". Neuropadiatrie 8 (1): 29–41. doi:10.1055/s-0028-1091502. PMID 321985. 
  88. ^ Windorfer A; Weinmann HM; Stünkel S (March 1977). "[Laboratory controls in long-term treatment with anticonvulsive drugs (author's transl)]". Monatsschr Kinderheilkd 125 (3): 122–8. PMID 323695. 
  89. ^ Khoo KC; Mendels J; Rothbart M; Garland WA; Colburn WA; Min BH; Lucek R; Carbone JJ; Boxenbaum HG; Kaplan SA (September 1980). "Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam". Clin Pharmacol Ther 28 (3): 368–75. doi:10.1038/clpt.1980.175. PMID 7408397. 
  90. ^ Bendarzewska-Nawrocka B; Pietruszewska E; Stepień L; Bidziński J; Bacia T (January–Feb 1980). "[Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy]". Neurol Neurochir Pol 14 (1): 39–45. PMID 7374896.  Check date values in: |date= (help)
  91. ^ McElhatton PR (November–Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198.  Check date values in: |date= (help)
  92. ^ Iqbal, MM.; Sobhan, T.; Ryals, T. (Jan 2002). "Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant". Psychiatr Serv 53 (1): 39–49. doi:10.1176/ PMID 11773648. 
  93. ^ Meldrum BS (1986). "Drugs acting on amino acid neurotransmitters". Adv Neurol 43: 687–706. PMID 2868623. 
  94. ^ Jenner P; Pratt JA; Marsden CD (1986). "Mechanism of action of clonazepam in myoclonus in relation to effects on GABA and 5-HT". Adv Neurol 43: 629–43. PMID 2418652. 
  95. ^ Gavish M; Fares F (November 1985). "Solubilization of peripheral benzodiazepine-binding sites from rat kidney" (PDF). J Neurosci 5 (11): 2889–93. PMID 2997409. 
  96. ^ "Benzodiazepine Equivalency Table" based on NRHA Drug Newsletter, April 1985 and Benzodiazepines: How they Work & How to Withdraw (The Ashton Manual), 2002.[1]
  97. ^ Chouinard G (2004). "Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound". J Clin Psychiatry. 65 Suppl 5: 7–12. PMID 15078112. 
  98. ^ Macdonald RL; McLean MJ (1986). "Anticonvulsant drugs: mechanisms of action". Adv Neurol 44: 713–36. PMID 2871724. 
  99. ^ Tardy M; Costa MF; Rolland B; Fages C; Gonnard P. (April 1981). "Benzodiazepine receptors on primary cultures of mouse astrocytes". J Neurochem 36 (4): 1587–9. doi:10.1111/j.1471-4159.1981.tb00603.x. PMID 6267195. 
  100. ^ Gallager DW; Mallorga P; Oertel W; Henneberry R; Tallman J (February 1981). "{3H}Diazepam binding in mammalian central nervous system: a pharmacological characterization". J Neurosci (PDF) 1 (2): 218–25. PMID 6267221. 
  101. ^ Petkov V; Georgiev VP; Getova D; Petkov VV (1982). "Effects of some benzodiazepines on the acetylcholine release in the anterior horn of the lateral cerebral ventricle of the cat". Acta Physiol Pharmacol Bulg 8 (3): 59–66. PMID 6133407. 
  102. ^ Grandison L (1982). "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology 34 (5): 369–73. doi:10.1159/000123330. PMID 6979001. 
  103. ^ Camoratto AM; Grandison L (18 April 1983). "Inhibition of cold-induced TSH release by benzodiazepines". Brain Res 265 (2): 339–43. doi:10.1016/0006-8993(83)90353-0. PMID 6405978. 
  104. ^ Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations" (PDF). Proc Natl Acad Sci USA (PDF) 81 (10): 3118–22. doi:10.1073/pnas.81.10.3118. PMC 345232. PMID 6328498. 
  105. ^ Skerritt JH; Johnston GA (May 6, 1983). "Enhancement of GABA binding by benzodiazepines and related anxiolytics". Eur J Pharmacol 89 (3–4): 193–8. doi:10.1016/0014-2999(83)90494-6. PMID 6135616. 
  106. ^ Lehoullier PF, Ticku MK; Ticku (March 1987). "Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons". Eur. J. Pharmacol. 135 (2): 235–8. doi:10.1016/0014-2999(87)90617-0. PMID 3034628. 
  107. ^ Varotto M; Roman G; Battistin L (30 April 1981). "[Pharmacological influences on the brain level and transport of GABA. I) Effect of various antipileptic drugs on brain levels of GABA]". Boll Soc Ital Biol Sper 57 (8): 904–8. PMID 7272065. 
  108. ^ Battistin L, Varotto M, Berlese G, Roman G; Varotto; Berlese; Roman (February 1984). "Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities". Neurochem Res 9 (2): 225–31. doi:10.1007/BF00964170. PMID 6429560. 
  109. ^ Dresser, G.K.; Spence, J.D.; Bailey, D.G. (2000). "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition". Clin. Pharmacokinet. 38 (1): 41–57. doi:10.2165/00003088-200038010-00003. PMID 10668858. 
  110. ^ "Monograph - Clonazepam -- Pharmacokinetics". Medscape. January 2006. Retrieved 2007-12-30. 
  111. ^ Parry GJ (1976). "An animal model for the study of drugs in the central nervous system". Proc Aust Assoc Neurol 13: 83–8. PMID 1029011. 
  112. ^ Gerna M; Morselli PL (January 21, 1976). "A simple and sensitive gas chromatographic method for the determination of clonazepam in human plasma". J Chromatogr 116 (2): 445–50. doi:10.1016/S0021-9673(00)89915-X. PMID 1245581. 
  113. ^ Tokola RA; Neuvonen PJ (1983). "Pharmacokinetics of antiepileptic drugs". Acta neurologica Scandinavica. Supplementum 97: 17–27. doi:10.1111/j.1600-0404.1983.tb01532.x. PMID 6143468. 
  114. ^ Greenblatt DJ, Miller LG, Shader RI; Miller; Shader (October 1987). "Clonazepam pharmacokinetics, brain uptake, and receptor interactions". J Clin Psychiatry. 48 Suppl: 4–11. PMID 2822672. 
  115. ^ Ebel S; Schütz H (February 27, 1977). "[Studies on the detection of clonazepam and its main metabolites considering in particular thin-layer chromatography discrimination of nitrazepam and its major metabolic products (author's transl)]". Arzneimittelforschung 27 (2): 325–37. PMID 577149. 
  116. ^ Edelbroek PM; De Wolff FA (October 1978). "Improved micromethod for determination of underivatized clonazepam in serum by gas chromatography" (PDF). Clinical chemistry (PDF) 24 (10): 1774–7. PMID 699288. 
  117. ^ United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2006). "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. Retrieved 9 February 2009. 


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