Continuing Education Activity
Clonazepam is a benzodiazepine drug used for the acute management of panic disorder, epilepsy, and non-convulsive status epilepticus. It also has many off label indications for its use like restless leg syndrome, acute mania, insomnia, and tardive dyskinesia. This activity will highlight the indications, mechanism of action, administration, adverse event profile, contraindications, monitoring, and toxicity of the clonazepam in the clinical settings pertinent for members of the interprofessional team in the treatment of patients with panic and seizure disorders.
- Identify the mechanism of action and administration of clonazepam.
- Outline the typical presentation of a patient with clonazepam withdrawal.
- Summarize the signs and symptoms of a patient with clonazepam toxicity.
- Review the importance of improving care coordination amongst interprofessional team members to reduce appropriate long term use of prescribed clonazepam for the prevention of risk of developing severe side effects.
Clonazepam is a long-acting and high potency benzodiazepine. It behaves both as a GABA-A receptor agonist. It also has serotonergic activity by increasing serotonin synthesis. Clonazepam has anticonvulsant and anxiolytic effects. It is FDA-approved for the treatment of seizure disorders and panic disorders. It also has off label use as monotherapy or adjunctive therapy for the treatment of mania, restless leg syndrome, insomnia, tardive dyskinesia, and REM sleep behavior disorder.
Clonazepam has a broad range of activity against different types of seizure disorders. Its primary indications are for acute management of epilepsy and acute treatment of non-convulsive status epilepticus (complex partial seizures or absence seizures). It is also very effective in controlling the minor motor seizures of childhood, particularly petit mal absences, Lennox-Gastaut syndrome, and infantile spasm. Clonazepam is also useful in the treatment of psychomotor, myoclonic epilepsies, grand mal, and focal motor seizures. However, it is not used as first-line therapy for these conditions. It can be used in patients resistant to standard treatment.
Clonazepam causes a significant improvement in patients who have panic disorders with or without agoraphobia. It is efficacious in the short-term management of panic disorder due to the risk of developing withdrawal symptoms and abuse. However, it is also less likely to cause rebound anxiety upon cessation than other benzodiazepines because of its longer half-life. Clinicians also use it for the acute treatment of panic attacks.
Clonazepam has anticonvulsant and serotonin agonist activity, both of which are associated with its antimanic effect. Therefore, it is sometimes helpful for the treatment of acute mania. Research found it to be significantly more effective than lithium in reducing manic symptoms, and fewer patients required PRN administration of haloperidol, as well as the number of days on which haloperidol was needed, was lower during clonazepam treatment. This way, the clonazepam not only reduces the need for antipsychotic drugs in the treatment of acute mania but also decreases the risk of side effects in these patients.. Nowadays, a combination of a benzodiazepine and antipsychotic haloperidol is considered the most effective treatment of acute agitation in the emergency department.
Clonazepam is also a side option for the treatment of akathisia, restless leg syndrome, rapid eye movement behavior disorder, and bruxism.
Mechanism of Action
Clonazepam is highly potent and a long-acting benzodiazepine. It exerts its pharmacological effects by acting as a positive allosteric modulator on GABA-A receptors. The GABA-A receptor is a ligand-gated chloride ion-selective channel whose endogenous ligand is GABA (gamma-aminobutyric acid). Benzodiazepines (BZDs) facilitate GABA-A action by increasing the frequency of chloride channel opening resulting in hyperpolarization of the neurons and decreased firing, thus producing calming effects on the brain by reducing the excitability of the neurons.
GABA is an inhibitory neurotransmitter that is present in abundance in the cortex and limbic system. There are three types of GABA receptors A, B, and C. However, BZDs act only on GABA-A receptors. Each receptor complex has 2 GABA-binding sites and 1 BZD-binding site and is made of five subunits two alpha, two beta, and one gamma. BZDs do not bind to the same receptor site on the receptor complex as the endogenous ligand GABA but bind to distinct BZD-binding sites situated at the interface between the alpha and gamma subunits. The binding results in a conformational change in the GABA-A receptor's chloride channel that results in the hyperpolarization of the cell and accounts for GABA's inhibitory effect throughout the central nervous system.
GABA receptors also classify into various BZDs receptors based on the isoforms of the alpha subunit. The benzodiazepine type-1 receptors (BZ1), which contain alpha-1 subunits, are present in abundance in the cortex, thalamus, and cerebellum are responsible for their anticonvulsant and sedative effects. Whereas benzodiazepine type-2 receptors containing alpha-2 subunits, mostly concentrated in the limbic system, motor neurons and dorsal horn of spinal cord, mediate the anxiolytic effects of BZDs.
Clonazepam is available as a tablet may be administered once at bedtime to minimize somnolence. The patient should take the drug with water by swallowing the whole tablet and must be immediately used after removing from package. Clonazepam has rapid absorption after oral administration. The maximum plasma concentration is reached within one to four hours after oral administration, and it is approximately 85% bound to plasma proteins. Clonazepam is highly metabolized by the liver's cytochrome P-450 in particular by CYP3A in a dose-dependent manner. The elimination half-life of clonazepam is around 30 to 40 hours.
Treatment of Absence Seizures, Petit Mal Variant (Lennox-Gastaut syndrome), and Akinetic and Myoclonic Seizures (myoclonia)
- Adults and adolescents (weight > 30 kg)
Therapy should start with 0.5 mg tablets taken orally three times per day. The dosage may be increased by 0.5 to 1 mg every three days until seizures are under control. The maximum daily dose should not exceed 20 mg.
The same dosage as adults. However, they require lower initial dosages as the elderly may be more sensitive to the effects of benzodiazepines.
- Pediatric patients (weight < 30 kg)
For the pediatric patients initially, 0.01 to 0.03 mg/kg/day orally (not to exceed 0.05 mg/kg/day) divided into two or three doses is recommended. The maximum dose in this population should not exceed 0.1 to 0.2 mg/kg in 3 doses.
Treatment of Panic Disorder
Treatment should start at a dose of 0.25 mg tablets, taken twice a day orally for three days, after which the dose should be increased to 0.5 mg tablets twice daily. The maximum daily dose should not exceed 1 to 4 mg.
The adverse effects of clonazepam derive from its property to act as a central nervous system depressant like all the other BZD drugs.
Common Side Effects
Most commonly, the use of clonazepam is associated with lethargy, fatigue, sedation, drowsiness, and motor impairment (impaired coordination, impaired balance, dizziness).
Less Common Side Effects
Less commonly, it also causes blurred vision, confusion, irritability, loss of libido, lack of motivation, psychomotor agitation, hallucination, worsening of depression, short term memory loss, and anterograde amnesia with high doses.
Occasional Side Effects
Occasional adverse effects if clonazepam includes personality changes, behavioral disturbance, ataxia, increased frequency of seizures, thrombocytopenia, and dysphoria.
Rare Side Effects
Some of the rare but important side effects of the clonazepam include paradoxical disinhibition, i.e., is excitement, rage, and impulsive behavior. The Elderly are especially prone to this side effect. Other side effects are suicide, psychosis, and incontinence.
Long-term use of benzodiazepine can lead to depression and sexual dysfunction.
Clonazepam is a class D drug. It has links with some facial and cardiac malformations of the human fetus. However, the data is equivocal. Use of clonazepam in the late pregnancy can lead to either floppy infant syndrome or severe withdrawal symptoms in the neonate, which may include hypotonia, cyanosis, apneic spells, and impaired metabolic responses to cold stress. Clonazepam should only be used during pregnancy if the clinical benefits outweigh the clinical risks to the fetus.
Clonazepam is excreted into the breastmilk, although not in a significant amount. But for the premature neonate or those exposed during the pregnancy, it may cause problems because the pathway by which it undergoes metabolism is usually impaired in newborns. Therefore, such neonates should have monitoring for the development of symptoms, and ideally, patients should be advised not to use clonazepam if they are breastfeeding.
Clonazepam being a BZD drug, is generally contraindicated in acute closed-angle glaucoma. Theoretically, these agents can induce relaxation of the iris and also have a mild anticholinergic activity, which can precipitate an acute attack of closed-angle glaucoma.
Significant Liver Disease
The liver extensively metabolizes clonazepam. In the case of liver disease, benzodiazepine oxidation decreases, which leads to the accumulation of the drug and result in excessive sedation and respiratory depression.
Hypersensitivity to Drug or Components of the Formulation
Hypersensitivity to clonazepam is rare, but there are occasional reports.
While using clonazepam, several precautions for the patients and monitoring are necessary. Elderly and children are especially prone to the adverse effects of clonazepam due to impaired and immature liver function, respectively. And for symptoms of depression or suicidal thoughts in patients taking clonazepam.
Monitor Complete Blood Count, Renal, and Liver Function
Clonazepam is hepatically metabolized and renally excreted; its level should be particularly monitored in the case of hepatic or renal impairment as it can lead to toxic accumulation of the drug in the body in either condition. It can also rarely cause thrombocytopenia, so platelet levels should also be monitored.
Worsening of Seizures
Clonazepam can cause a worsening of seizures in persons having multiple types of seizure disorder. In that case, its dosing requires adjustment.
Abrupt Discontinuation and Tolerance
Abrupt withdrawal of clonazepam should be avoided in particular in those patients on long-term, high-dose therapy for a seizure disorder or other conditions. As it may result in status epilepticus and withdrawal symptoms. Withdrawal symptoms include anxiety, irritability, insomnia, tremors, headache, depression, sweating, confusion, hallucinations, and seizures. Long term use also leads to the development of tolerance, especially to its anticonvulsant properties, which can precipitate a seizure.
Patients with a compromised respiratory function such as cases of asthma, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, etc. should take clonazepam with extreme caution. It significantly increases the risk of respiratory depression. It also causes hypersalivation, so it may aggravate conditions in which patients have difficulty handling secretions.
Impaired Cognitive and Motor Performance
Due to its potential effect of CNS depression, clonazepam may impair judgment, thinking, and motor skills. Patients should be advised against the use of heavy machinery, driving, or any other activity that requires higher motor skills. It should be carefully prescribed in patients with a neuromuscular disorder such as parkinsonism, myasthenia gravis as it can exacerbate their condition and also in the elderly as it greatly increases the risk of falls due to poor motor control.
Clonazepam is associated with an increased risk of suicidal behavior and thinking. So the patients and their caregivers should be cautioned to look for any symptoms of worsening of depression, changes in mood or behavior, or suicidal ideation.
Patients should be strongly advised against the use of clonazepam and alcohol concomitantly since both of these are CNS depressants, and their cumulative effect can result in sedation, severe respiratory depression, low blood pressure, and death.
The therapeutic range of clonazepam is from 0.02 to 0.08 mcg/mL. Any level over 0.08 mcg/mL is considered toxic. The symptoms of overdose develop rapidly.
The initial symptoms appear within a few hours with symptoms of CNS depression such as
- Slurred speech
- Motor impairment
- If the overdose is severe, then it may result in severe symptoms such as
- Respiratory depression
- Cardiac arrest
- Pulmonary aspiration
Severe consequences with clonazepam use alone are rare, but the toxicity increase significantly if other CNS depressants such are opioid, ethanol, barbiturates, etc. are coadministered.
Treatment of Toxicity
Supportive care and medical observation are the mainstays of the treatment. The supportive care includes monitoring of vitals, IV fluids for the hypotension, atropine for bradycardia, and maintaining the patency of the airway by intubation or artificial respiration if respiratory depression develops. Use of flumazenil, a competitive benzodiazepine receptor antagonist, as the antidote is controversial as its use correlates with lowered seizure threshold and widened QRS complex resulting in adverse effects. Its side effects do not outweigh the potential benefits. It has no role in multidrug toxicity and should only be used following a consultation with a medical toxicologist.
Enhancing Healthcare Team Outcomes
The concern lies in the healthcare community about the inappropriate long term use of prescribed clonazepam and other BZDs drugs despite their serious adverse effects profile like the risk of falls, cognitive impairment, and addiction. Interventions to decrease the inappropriate use of clonazepam involve an interprofessional team that includes clinicians, nurses, pharmacists, and primary care providers. Clonazepam is usually started after an acute event or during the hospital stay by the clinicians. Once ordered by the clinicians, nurses usually administer the drug. Following administration in hospital settings, its use may carry over to the primary care without any indication for it; this is where a pharmacist performing medication reconciliation on discharge is invaluable. In primary care, patients also influence the clinicians by having this conceived notion about clonazepam and BZDs drugs being a wonder drug to make them feel and sleep better. These issues can result in severe outcomes in the form of dependence, motor impairment, etc. Therefore, an interprofessional approach is required to come up with the ideas to reduce the use of hypnotics and develop interventions to prevent misuse not only in the hospital but also at the primary and secondary care interface.