Chemistry:Clonazepam

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Short description: Benzodiazepine medication
Clonazepam
Clonazepam 200.svg Clonazepam ball-and-stick model.png
Clinical data
Pronunciationkləˈnazɪpam
Trade namesKlonopin, Rivotril, Paxam,[1] others[2]
AHFS/Drugs.comMonograph
MedlinePlusa682279
License data
Pregnancy
category
Dependence
liability		Physical: Very High
Addiction
liability		Moderate[4][5]
Routes of
administration		By mouth, intramuscular, intravenous, sublingual
Drug classBenzodiazepine
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability90%
Protein binding≈85%
MetabolismLiver (CYP3A)[10]
Metabolites7-aminoclonazepam
7-acetaminoclonazepam
3-hydroxy clonazepam[6][7]
Onset of actionWithin an hour[8]
Elimination half-life19–60 hours[9]
Duration of action6–12 hours[8]
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC15H10ClN3O3
Molar mass315.71 g·mol−1
3D model (JSmol)
  (verify)

Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, OCD and akathisia.[10] It is a tranquilizer of the benzodiazepine class.[10] It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken by mouth but is also used intravenously.[10][11] Effects begin within one hour and last between six and twelve hours.[8]

Common side effects may include sleepiness, poor coordination, and agitation.[10] Long-term use may result in tolerance, dependence, and life-threatening withdrawal symptoms if stopped abruptly.[10][12] Dependence occurs in one-third of people who take benzodiazepines for longer than four weeks.[9] The risk of suicide increases, particularly in people who are already depressed.[10][13] Use during pregnancy may result in harm to the fetus.[10] Clonazepam binds to GABAA receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid (GABA).[9]

Clonazepam was patented in 1960 and went on sale in 1975 in the United States from Roche.[14][15] It is available as a generic medication.[10] In 2021, it was the 46th-most commonly prescribed medication in the United States, with more than 14 million prescriptions.[16][17] In many areas of the world, it is commonly used as a recreational drug.[18][19]

Medical uses

Clonazepam is prescribed for short-term management of epilepsy, anxiety, OCD and panic disorder with or without agoraphobia.[20][21][22]

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.[23] As a result, clonazepam is sometimes used for certain rare childhood epilepsies, but it has been found to be ineffective in the control of infantile spasms.[24] Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of nonconvulsive status epilepticus; the benefits, though, tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.[25]

It is also approved for treatment of typical and atypical absences (seizures), infantile myoclonic, myoclonic, and akinetic seizures.[26] 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.[9][27]

Anxiety disorders

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.[31] Clonazepam is also effective in the management of acute mania.[32]

Muscle disorders

Restless legs syndrome can be treated using clonazepam as a third-line treatment option, as the use of clonazepam is still investigational.[33][34] Bruxism also responds to clonazepam in the short term.[35] REM sleep behavior disorder responds well to low doses of clonazepam.[36] It is also used for:

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.[40][41] 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.[41]
  • Hyperekplexia[42]
  • Many forms of parasomnia and other sleep disorders are treated with clonazepam.[43]
  • It is not effective for preventing migraines.[44]

Contraindications

  • Coma
  • Current alcohol use disorder
  • Current substance use disorder
  • Respiratory depression[45]

Adverse effects

In September 2020, the U.S. Food and Drug Administration 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.[46]

Common

Less common

  • Confusion[9]
  • Irritability and aggression[48]
  • Psychomotor agitation[49]
  • Lack of motivation[50]
  • Loss of libido
  • Impaired motor function
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Cognitive impairments[vague][51]
  • 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.[55][56][57] While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.[58] After regular use, rebound insomnia may occur when discontinuing clonazepam.[59]
  • Benzodiazepines may cause or worsen depression.[9]

Occasional

Rare

The long-term effects of clonazepam can include depression,[9] disinhibition, and sexual dysfunction.[71]

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, 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.

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[72] 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.[73] Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal.[74] 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.[75]

Tolerance and withdrawal

Main page: Medicine:Benzodiazepine withdrawal syndrome

Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator.[76][77] 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.[9]

Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.[78][79] 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.[80] In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[81] 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.[26]

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.[82][83][84] 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.[64] 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.[85]

Overdose

Main page: Medicine: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.[86] 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.[87]

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.[88]

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.[89]

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.[9]

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.[90] Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.[91]

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.[90][92]

Doses higher than 0.5–1 mg per day are associated with significant sedation.[93]

Clonazepam may aggravate hepatic porphyria.[94][95]

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.[96]

Clonazepam has similar effectiveness to other benzodiazepines at often a lower dose.[97]

Interactions

Clonazepam decreases the levels of carbamazepine,[98][99] and, likewise, clonazepam's level is reduced by carbamazepine. Azole antifungals, such as ketoconazole, may inhibit the metabolism of clonazepam.[9] Clonazepam may affect levels of phenytoin (diphenylhydantoin).[98][100][101][102] 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%.[103] Clonazepam increases the levels of primidone[101] and phenobarbital.[104]

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.[9]

Pregnancy

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 the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress.[105]

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 breastfeeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include: miscarriage, malformation, intrauterine growth retardation, functional deficits, 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 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 or breastfeeding, 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.[106]

Pharmacology

Mechanism of action

Clonazepam enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system to give its anticonvulsant, skeletal muscle relaxant, and anxiolytic effects.[107] 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 the central nervous system.[108][109]

Benzodiazepines do not have any effect on the levels of GABA in the brain.[110] 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.[111]

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 an increase in GABA's inhibitory effects and resultant central nervous system depression.[9] In addition, clonazepam decreases the utilization of 5-HT (serotonin) by neurons[112][113] and has been shown to bind tightly to central-type benzodiazepine receptors.[114] Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam),[115][116] it is said to be among the class of "highly potent" benzodiazepines.[117] The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.[118]

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[119][120] Clonazepam decreases release of acetylcholine in the feline brain[121] and decreases prolactin release in rats.[122] Benzodiazepines inhibit cold-induced thyroid-stimulating hormone (also known as TSH or thyrotropin) release.[123] Benzodiazepines act 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.[124]

Clonazepam is a 2'-chlorinated derivative of nitrazepam, which increases its potency due to electron-attracting effect of the halogen in the ortho-position.[125][8]

Pharmacokinetics

Clonazepam is lipid-soluble, rapidly crosses the blood–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.[126] Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, including CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines.[127] It has an elimination half-life of 19–60 hours.[9] 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.[128]

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[129] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[130]

Clonazepam has plasma protein binding of 85%.[131][126] Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other.[132] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[6][133] These metabolites are excreted by the kidney.[126]

It is effective for 6–8 hours in children, and 6–12 in adults.[134]

Society and culture

Recreational use

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 intentional overdose, or adverse reactions resulting from legitimate use of the medication.[135]

Formulations

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 and orally disintegrating tablets (wafers) an oral solution (drops), and as a solution for injection or intravenous infusion.[136]

Crime

In some countries, clonazepam is used by criminals to subdue their victims.[137]

Brand names

Brand name clonazepam tablets

It is marketed under the trade name Rivotril by Roche in Argentina, Australia, Austria, Bangladesh, Belgium, Brazil, Bulgaria, Canada, Colombia, Costa Rica, Croatia, the Czech Republic, Denmark, Estonia,[138] 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 trade name Klonopin by Roche in 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][136] In August 2021, Roche Australia transferred Rivotril to Pharmaco Australia Ltd.[139]

  • Klonopin 0.5 mg tablet

  • Klonopin 1 mg tablet

  • Klonopin 2 mg tablet

  • Clonazepam orally disintegrating tablet, 0.25 mg

References

  1. ↑ https://www.medsafe.govt.nz/profs/datasheet/p/Paxamtab.pdf
  2. ↑ 2.0 2.1 "Clonazepam International". Drugs.com. https://www.drugs.com/international/clonazepam.html. 
  3. ↑ "Clonazepam Use During Pregnancy". 4 May 2020. https://www.drugs.com/pregnancy/clonazepam.html. 
  4. ↑ "Addiction: Part I. Benzodiazepines--side effects, abuse risk and alternatives". American Family Physician 61 (7): 2121–2128. April 2000. PMID 10779253. https://www.aafp.org/pubs/afp/issues/2000/0401/p2121.html. 
  5. ↑ Contemporary Oral and Maxillofacial Surgery - E-Book. Elsevier Health Sciences. 2013. p. 679. ISBN 9780323226875. https://books.google.com/books?id=RcbsAwAAQBAJ&pg=PA679. 
  6. ↑ 6.0 6.1 "[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)]". Arzneimittel-Forschung 27 (2): 325–337. February 1977. PMID 577149. 
  7. ↑ "Blood concentrations of clonazepam and 7-aminoclonazepam in forensic cases in Denmark for the period 2002-2007". Forensic Science International 184 (1–3): 74–79. January 2009. doi:10.1016/j.forsciint.2008.12.004. PMID 19150586. 
  8. ↑ 8.0 8.1 8.2 8.3 Therapeutic uses of botulinum toxin. Totowa, N.J.: Humana Press. 2007. p. 214. ISBN 9781597452472. https://books.google.com/books?id=UIUhCmMtqq8C&pg=PA214. 
  9. ↑ 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 9.12 9.13 9.14 "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics". Acta Neurologica Scandinavica 118 (2): 69–86. August 2008. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 "Clonazepam". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/clonazepam.html. 
  11. ↑ "Intravenous Clonazepam in Status Epilepticus". Epilepsy Currents 16 (2): 89–90. 2016. doi:10.5698/1535-7511-16.2.89. PMID 27073337. 
  12. ↑ "Benzodiazepines: Uses, Dangers, and Clinical Considerations". Neurology International 13 (4): 594–607. November 2021. doi:10.3390/neurolint13040059. PMID 34842811. 
  13. ↑ 13.0 13.1 "Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature". The Primary Care Companion for CNS Disorders 19 (2). March 2017. doi:10.4088/PCC.16r02037. PMID 28257172. 
  14. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 535. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA535. 
  15. ↑ "B". A Historical Dictionary of Psychiatry. Oxford University Press. 2005. ISBN 9780190292010. https://books.google.com/books?id=juAJCAAAQBAJ&pg=PT66. 
  16. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  17. ↑ "Clonazepam - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Clonazepam. 
  18. ↑ Advances in the neurochemistry and neuropharmacology of Tourette Syndrome. Burlington: Elsevier Science. 2013. p. 357. ISBN 9780124115613. https://books.google.com/books?id=RYhqAAAAQBAJ&pg=PA357. "In several countries, prescription and use is now severely limited due to abusive recreational use of clonazepam." 
  19. ↑ Encyclopedia of substance abuse prevention, treatment, & recovery. Los Angeles: SAGE. 2009. p. 100. ISBN 9781412950848. https://books.google.com/books?id=CGxXIspuXVMC&pg=PT134. "frequently abused" 
  20. ↑ "Propofol treatment of refractory status epilepticus: a study of 31 episodes". Epilepsia 45 (7): 757–763. July 2004. doi:10.1111/j.0013-9580.2004.01904.x. PMID 15230698. 
  21. ↑ "Kinetics of clonazepam in relation to electroencephalographic and clinical effects". Epilepsia 24 (2): 225–231. April 1983. doi:10.1111/j.1528-1157.1983.tb04883.x. PMID 6403345. 
  22. ↑ "Clonazepam: medicine to control seizures or fits, muscle spasms and restless legs syndrome" (in en). 6 January 2020. https://www.nhs.uk/medicines/clonazepam/. 
  23. ↑ "Reduction of seizures with low-dose clonazepam in children with epilepsy". Pediatric Neurology 28 (1): 48–52. January 2003. doi:10.1016/S0887-8994(02)00468-X. PMID 12657420. 
  24. ↑ "Double-blind study of ACTH vs prednisone therapy in infantile spasms". The Journal of Pediatrics 103 (4): 641–645. October 1983. doi:10.1016/S0022-3476(83)80606-4. PMID 6312008. 
  25. ↑ "Nonconvulsive status epilepticus: high incidence of complex partial status". Epilepsia 27 (3): 276–285. May–Jun 1986. doi:10.1111/j.1528-1157.1986.tb03540.x. PMID 3698940. 
  26. ↑ 26.0 26.1 "Clonazepam. A review of a new anticonvulsant drug". Archives of Neurology 33 (5): 326–332. May 1976. doi:10.1001/archneur.1976.00500050012003. PMID 817697. 
  27. ↑ "Clonazepam add-on therapy for drug-resistant epilepsy". The Cochrane Database of Systematic Reviews 4 (4): CD012253. April 2020. doi:10.1002/14651858.CD012253.pub3. PMID 32309880. 
  28. ↑ "The treatment of panic disorder". Current Opinion in Psychiatry 18 (1): 45–50. January 2005. PMID 16639183. http://www.medscape.com/viewarticle/497207. Retrieved 25 September 2007. 
  29. ↑ "Treatment of social phobia with clonazepam and placebo". Journal of Clinical Psychopharmacology 13 (6): 423–428. December 1993. doi:10.1097/00004714-199312000-00008. PMID 8120156. 
  30. ↑ (in en) A Practitioner's Guide to Prescribing Antiepileptics and Mood Stabilizers for Adults with Intellectual Disabilities. Springer Science & Business Media. 2 March 2012. ISBN 978-1-4614-2012-5. https://books.google.com/books?id=_LOzIqD3_NoC&q=Clonazepam+panic+approved&pg=PA56. 
  31. ↑ "A randomized, naturalistic, parallel-group study for the long-term treatment of panic disorder with clonazepam or paroxetine". Journal of Clinical Psychopharmacology 32 (1): 120–126. February 2012. doi:10.1097/JCP.0b013e31823fe4bd. PMID 22198456. 
  32. ↑ "Clonazepam in the treatment of psychiatric disorders: an update". International Clinical Psychopharmacology 21 (3): 131–142. May 2006. doi:10.1097/01.yic.0000194379.65460.a6. PMID 16528135. 
  33. ↑ "[Restless legs syndrome: diagnosis and treatment. Opinion of Brazilian experts]" (in Portuguese). Arquivos de Neuro-Psiquiatria 65 (3A): 721–727. September 2007. doi:10.1590/S0004-282X2007000400035. PMID 17876423. 
  34. ↑ "Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice". Movement Disorders 23 (16): 2267–2302. December 2008. doi:10.1002/mds.22254. PMID 18925578. http://www.movementdisorders.org/publications/ebm_reviews/treatmentofrls.pdf. Retrieved 19 January 2010. 
  35. ↑ "Comparison of various treatments for sleep bruxism using determinants of number needed to treat and effect size". The International Journal of Prosthodontics 19 (5): 435–441. 2006. PMID 17323720. 
  36. ↑ "REM sleep behavior disorder". Clinical Neurophysiology 111 (Suppl 2): S136–S140. September 2000. doi:10.1016/S1388-2457(00)00414-4. PMID 10996567. 
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  68. ↑ "Urinary incontinence associated with clonazepam therapy". South African Medical Journal = Suid-Afrikaanse Tydskrif vir Geneeskunde 64 (7): 230. August 1983. PMID 6879368. 
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  91. ↑ "Sleep and aging: 2. Management of sleep disorders in older people". CMAJ 176 (10): 1449–1454. May 2007. doi:10.1503/cmaj.070335. PMID 17485699. 
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  94. ↑ "Seizure management in acute hepatic porphyria: risks of valproate and clonazepam". Neurology 30 (6): 588–592. June 1980. doi:10.1212/WNL.30.6.588. PMID 6770287. 
  95. ↑ "Safety of anticonvulsants in hepatic porphyrias". Neurology 31 (4): 480–484. April 1981. doi:10.1212/wnl.31.4.480. PMID 7194443. 
  96. ↑ "Clonazepam treatment of chronic schizophrenia: negative results in a double-blind, placebo-controlled trial". The American Journal of Psychiatry 139 (12): 1627–1628. December 1982. doi:10.1176/ajp.139.12.1627. PMID 6756174. 
  97. ↑ "Benzodiazepine Equivalency Table: Benzodiazepine Equivalency". 28 April 2017. https://emedicine.medscape.com/article/2172250-overview#a1. 
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  99. ↑ "Clinically significant carbamazepine drug interactions: an overview". Epilepsia 28 (Suppl 3): S71–S76. 1987. doi:10.1111/j.1528-1157.1987.tb05781.x. PMID 3319544. 
  100. ↑ "Phenytoin/clonazepam interaction". Therapeutic Drug Monitoring 7 (4): 481–484. August 1985. doi:10.1097/00007691-198512000-00022. PMID 4082246. 
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  105. ↑ "The effects of benzodiazepine use during pregnancy and lactation". Reproductive Toxicology 8 (6): 461–475. 1994. doi:10.1016/0890-6238(94)90029-9. PMID 7881198. 
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  107. ↑ "FDA clonazepam". https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017533s053,020813s009lbl.pdf. 
  108. ↑ "Enhancement of GABA binding by benzodiazepines and related anxiolytics". European Journal of Pharmacology 89 (3–4): 193–198. May 1983. doi:10.1016/0014-2999(83)90494-6. PMID 6135616. 
  109. ↑ "Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons". European Journal of Pharmacology 135 (2): 235–238. March 1987. doi:10.1016/0014-2999(87)90617-0. PMID 3034628. 
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  122. ↑ "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology 34 (5): 369–373. 1982. doi:10.1159/000123330. PMID 6979001. 
  123. ↑ "Inhibition of cold-induced TSH release by benzodiazepines". Brain Research 265 (2): 339–343. April 1983. doi:10.1016/0006-8993(83)90353-0. PMID 6405978. 
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  127. ↑ "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition". Clinical Pharmacokinetics 38 (1): 41–57. January 2000. doi:10.2165/00003088-200038010-00003. PMID 10668858. 
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  130. ↑ "A simple and sensitive gas chromatographic method for the determination of clonazepam in human plasma". Journal of Chromatography 116 (2): 445–450. January 1976. doi:10.1016/S0021-9673(00)89915-X. PMID 1245581. 
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  133. ↑ "Improved micromethod for determination of underivatized clonazepam in serum by gas chromatography". Clinical Chemistry 24 (10): 1774–1777. October 1978. doi:10.1093/clinchem/24.10.1774. PMID 699288. http://www.clinchem.org/cgi/reprint/24/10/1774.pdf. 
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  137. ↑ "Burundanga y Clonazepan. El cóctel de pastillas que usaba una "viuda negra" para doblegar a sus incautos pretendientes" (in Spanish). La Nacion. 8 December 2022. https://www.lanacion.com.ar/seguridad/burundanga-y-clonazepan-el-arsenal-de-pastillas-que-usaba-la-viuda-negra-de-los-polvorines-para-nid07122022/. 
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Further reading

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