Clonazepam


Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder, and akathisia. It is a long-acting benzodiazepine. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.
Common side effects may include sleepiness, weakness, poor coordination, difficulty concentrating, and agitation. Clonazepam may also decrease memory formation. Long-term use may result in tolerance, dependence, and life-threatening withdrawal symptoms if stopped abruptly. Dependence occurs in one-third of people who take benzodiazepines for longer than four weeks. The risk of suicide increases, particularly in people who are already depressed. Use during pregnancy may result in harm to the fetus. Clonazepam binds to GABAA receptors, thus increasing the effect of the chief inhibitory neurotransmitter γ-aminobutyric acid.
Clonazepam was patented in 1960, marketed in 1964, and went on sale in 1975 in the United States from Roche. It is available as a generic medication. In 2023, it was the 62nd most commonly prescribed medication in the United States, with more than 10million 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, obsessive–compulsive disorder, 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, but it is ineffective in the control of infantile spasms. Clonazepam is mainly prescribed for the acute management of epilepsy. Clonazepam is effective in the acute control of non-convulsive 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.
It is also approved for the treatment of typical and atypical absences and infantile 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

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. Clonazepam is also effective in the management of acute mania.

Muscle disorders

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. REM sleep behavior disorder responds well to low doses of clonazepam. It is also used for:
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.

Common

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, 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 similar to delirium tremens
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, including side effects, of the drug.
A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.

Tolerance and withdrawal

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.