Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, and akathisia, with some evidence supporting use in treatment of mania due to bipolar disorder. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally (swallowed by mouth) 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 (GABA).
Clonazepam was patented in 1960 and approved 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, 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 (seizures) 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 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.
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. REM sleep behavior disorder responds well to low doses of clonazepam. It is also used for: The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics Spasticity related to amyotrophic lateral sclerosis (ALS)
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. Studies vary in confidence as to whether current evidence supports the use of clonazepam for treatment of acute mania. The effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, as is whether 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. Clonazepam is also used topically to treat burning mouth syndrome via its action on the ion channel TRPM8.
Contraindications Coma Current alcohol use disorder Current substance use disorder Respiratory depression
Adverse effects In September 2020, the US 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 Increased libido 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 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, 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 (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, 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.
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 Death
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.R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 335-337.
Special precautions