Continuing Education Activity

Clonazepam is a benzodiazepine drug used for the acute treatment of panic disorder, epilepsy, and nonconvulsive status epilepticus. The drug also has many off-label indications, including restless leg syndrome, acute mania, insomnia, and tardive dyskinesia. Clonazepam is a long-acting and high-potency benzodiazepine; it behaves as a GABA-A receptor agonist. Benzodiazepines facilitate GABA-A action by increasing the frequency of chloride channel opening resulting in hyperpolarization of the neurons and reduced firing, thus producing calming effects on the brain by decreasing the excitability of neurons. Clonazepam also has serotonergic activity by increasing serotonin synthesis. This activity will highlight the indications, mechanism of action, administration, adverse event profile, contraindications, monitoring, and toxicity of clonazepam in the clinical settings pertinent for interprofessional team members in treating patients with panic and seizure disorders.

Objectives:

• Identify the indications for using clonazepam therapy.
• Select patients who will benefit from clonazepam therapy.
• Coordinate the management of a patient with clonazepam toxicity.
• Collaborate with the interprofessional team to monitor patients for clonazepam overdose and/or toxicity to improve outcomes and prevent the risk of developing severe side effects.

Indications

Clonazepam is a long-acting and high-potency benzodiazepine. It behaves as a GABA-A receptor agonist. It also has serotonergic activity by increasing serotonin synthesis.[1] Clonazepam has anticonvulsant and anxiolytic effects; it is FDA-approved for treating seizure and panic disorders.[2][3] Clonazepam also has off-label use as monotherapy or adjunctive therapy to treat mania, restless leg syndrome, insomnia, tardive dyskinesia, and REM sleep behavior disorder.[4][5][6]

Seizure Disorders

Clonazepam has a broad range of activities against different types of seizure disorders. The drug's primary indications are acute management of epilepsy and acute treatment of non-convulsive status epilepticus (complex partial seizures or absence seizures), and it is also very effective in controlling the minor motor seizures of childhood, particularly petit mal absences, Lennox-Gastaut syndrome, and infantile spasms.[7] Clonazepam is also useful in treating psychomotor, myoclonic epilepsies, grand mal, and focal motor seizures. However, it is not used as first-line therapy for these conditions. The medication can be used in patients resistant to standard treatment.  

Panic Disorder

Clonazepam causes a significant improvement in patients who have panic disorders with or without agoraphobia. Clonazepam is efficacious in the short-term management of panic disorder due to the risk of developing withdrawal symptoms and abuse. However, this drug 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.[8]

Acute Mania

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. The research found it to be significantly more effective than lithium in reducing manic symptoms; fewer patients required PRN administration of haloperidol, and the number of days on which haloperidol was needed was lower during clonazepam treatment. In this way, clonazepam reduces the need for antipsychotic drugs to treat acute mania and decreases the risk of side effects in these patients.[3] A combination of benzodiazepine and the antipsychotic haloperidol is considered the most effective treatment of acute agitation in the emergency department.[9]

Miscellaneous Uses

Clonazepam is also an option for treating akathisia, restless leg syndrome, and bruxism.[10][11][12] American Academy of Sleep Medicine (AASM) suggests using clonazepam for REM sleep behavior disorder (RBD).[13] Topical clonazepam is also being investigated for burning mouth syndrome.[14][15]

Mechanism of Action

Clonazepam is a highly potent long-acting benzodiazepine. Clonazepam exerts pharmacological effects by acting as a positive allosteric modulator of GABA-A receptors. The GABA-A receptor is a ligand-gated chloride ion selective channel whose endogenous ligand is GABA (gamma-aminobutyric acid). Benzodiazepines facilitate GABA-A action by increasing the frequency of chloride channel opening resulting in hyperpolarization of the neurons and reduced firing, thus producing calming effects on the brain by decreasing the excitability of neurons. In the absence of GABA, benzodiazepines have no effects on GABA-A receptor function.[16]

GABA is an inhibitory neurotransmitter in abundance in the cortex and limbic system. There are three 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 comprised 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.[17]

GABA receptors are also classified into various BZD receptors based on the isoforms of the alpha subunit. The benzodiazepine type-1 receptors (BZ1), which contain alpha-1 subunits, are abundant in the cortex, thalamus, and cerebellum and 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 the spinal cord, mediate the anxiolytic effects of BZDs.

Pharmacokinetics

• Absorption: Clonazepam has rapid absorption after oral administration. The maximum plasma concentration is reached within one to four hours after oral administration.

• Distribution: Clonazepam is approximately 85% bound to plasma proteins. Clonazepam has lower lipid solubility and is less likely to cause anterograde amnesia than other high-potency benzodiazepines.

• Metabolism: Clonazepam is extensively metabolized by the liver's cytochrome P-450, particularly by CYP3A, in a dose-dependent manner.

• Excretion: The elimination half-life of clonazepam is around 30 to 40 hours. Clonazepam's major metabolite, 7-amino-clonazepam, is excreted mainly in the urine.[18]

Administration

Clonazepam is available as an immediate-release tablet of 0.5 mg, 1 mg, 2 mg, and orally disintegrated tablets (ODT) of 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 2 mg strength. The medication may be administered once at bedtime to minimize somnolence. The patient should take the ODT tablet with water by swallowing it immediately after removing it from the package. 

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 daily. 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.
• Geriatric patients: The same dosage as adults. However, they require lower initial dosages as elderly patients may be more sensitive to the effects of benzodiazepines. 
• Pediatric patients (weight < 30 kg): Initially, for pediatric patients, 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.

Treatment of REM Sleep Behavior Disorder

• The recommended dose by AASM is 0.25 mg to 2 mg clonazepam 30 minutes before bedtime.[13]

Use in Specific Patient Population

Pregnancy Considerations: Clonazepam is a former FDA pregnancy class D drug. It has links with some facial and cardiac malformations of the human fetus. However, the data are equivocal. The use of clonazepam in late pregnancy can lead to either floppy infant syndrome or severe withdrawal symptoms in the neonate, including 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.[19][20]

Breastfeeding Considerations: 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 be monitored for the development of symptoms, and ideally, patients should be advised not to use clonazepam if they are breastfeeding.[19]

Liver Impairment and/or Renal Impairment: No dosage adjustment information is given in the manufacturer's labeling; use it with caution. Clonazepam is hepatically metabolized and renally excreted; its level requires monitoring in hepatic or renal impairment as it can lead to toxic drug accumulation in the body in either condition. Clonazepam is contraindicated in severe liver disease.[21][22]

Geriatric Population: According to the American Geriatric Society (AGS Beers Criteria), benzodiazepines(including clonazepam) AGS Beers Criteria are recognized as Potentially Inappropriate Medication (PIM). Benzodiazepines can cause cognitive dysfunction, delirium, falls, and fractures in older adults. However, use may be justified for seizure disorders and severe generalized anxiety disorder.[23]

Adverse Effects

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

The use of clonazepam is most commonly associated with lethargy, fatigue, sedation, drowsiness, and motor impairment (impaired coordination, impaired balance, dizziness).[17][24]

Less Common Side Effects

Clonazepam can cause blurred vision, confusion, irritability, loss of libido, lack of motivation, psychomotor agitation, hallucination, worsening of depression, short-term memory loss, and anterograde amnesia, especially with high doses.[25][26][27]

Occasional Side Effects

Occasional adverse effects of clonazepam include personality changes, behavioral disturbance, ataxia, increased frequency of seizures, thrombocytopenia, and dysphoria.[28][29][30]

Rare Side Effects

Rare but important side effects of clonazepam include paradoxical disinhibition, i.e., excitement, rage, and impulsive behavior. Older patients are especially prone to this side effect. Other side effects are suicide, psychosis, and incontinence.[31][32][33][34] Long-term use of benzodiazepine can lead to depression and sexual dysfunction.[25][35] There have been reports of Lichenoid drug eruption with the use of clonazepam.[36] Paradoxical sleep-related eating disorder (SRED) has been described, although clonazepam is used to treat SRED.[37]

Drug-Drug Interactions

• Concurrent use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and death. Avoid combination.[38]
• The use of clonazepam along with kratom may lead to increased CNS depression and death. Avoid combination.[39]
• Concurrent use of clonazepam with antidepressants, antipsychotics, hypnotics, antiepileptic drugs, and antihistamines leads to increased sedation due to pharmacodynamic synergism. Monitor the therapy.[40]
• Concurrent administration of clonazepam with CYP3A4 inducers like carbamazepine, phenobarbital, phenytoin, and primidone can reduce the concentration of clonazepam.[41]
• Concurrent administration of clonazepam with CYP3A4 inhibitors like clarithromycin, itraconazole, ketoconazole, nirmatrelvir/ritonavir, telithromycin, and voriconazole can increase the serum concentration of clonazepam.[42]

Contraindications

Narrow-angle Glaucoma

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.[43]

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 results in excessive sedation and respiratory depression.[21]

Hypersensitivity to drug or components of the formulation

Hypersensitivity to clonazepam is rare, but there are occasional reports.

Boxed Warning

• Concurrent use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and death. Avoid combination.
• The use of benzodiazepines, including clonazepam, has the potential for misuse and addiction. Misuse of benzodiazepines commonly involves concomitant use of alcohol and illicit substances, including opioids.
• The continued use of clonazepam can lead to physical dependence. Abrupt discontinuation or rapid dosage reduction of clonazepam after continued use may precipitate life-threatening acute withdrawal. A risk mitigation strategy involves a gradual dose reduction of clonazepam.[38]

Monitoring

While using clonazepam, several precautions and monitoring are necessary. Older adults and children are especially prone to the adverse effects of clonazepam due to impaired or immature liver function. 

Complete Blood Count, Renal, and Liver Function

Clonazepam is hepatically metabolized and renally excreted; its level requires hepatic or renal impairment monitoring as it can lead to toxic drug accumulation in the body in either condition. It can also rarely cause thrombocytopenia, so platelet levels should be monitored.[22]

Worsening of Seizures

Clonazepam can cause a worsening of seizures in persons having multiple types of seizure disorders. In such cases, its dosing requires adjustment or an increase in the dose.

Abrupt Discontinuation and Tolerance

Abrupt withdrawal of clonazepam should be avoided, particularly 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 developing tolerance, especially to its anticonvulsant properties, which can precipitate a seizure.

Respiratory Compromise

Patients with compromised respiratory function, such as asthma, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, etc., should exercise extreme caution when taking clonazepam. Clonazepam significantly increases the risk of respiratory depression. The medication also causes hypersalivation, which may aggravate conditions in which patients have difficulty handling secretions.

Impaired Cognitive and Motor Performance

Due to its potential effect for inducing CNS depression, clonazepam may impair judgment, thinking, and motor skills. Patients should be advised against using heavy machinery, driving, or any other activity requiring higher motor skills. It should be carefully prescribed in patients with a neuromuscular disorder such as parkinsonism or myasthenia gravis, as it can exacerbate their condition. Care is also necessary when prescribing this drug to geriatric patients as it significantly increases the risk of falls due to poor motor control.

Suicidal Behavior

Clonazepam is associated with an increased risk of depression, 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.

Alcohol Use

Patients should be strongly advised against the use of clonazepam and alcohol concomitantly since both are CNS depressants. Their cumulative effect can result in sedation, severe respiratory depression, low blood pressure, and death.

Monitoring for misuse/abuse

Clonazepam is a DEA-schedule IV drug. A prescription drug monitoring program (PDMP) can identify potential misuse.[44]

Toxicity

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.

Initial Presentation

The initial symptoms appear within a few hours with symptoms of CNS depression such as:

• Somnolence
• Diplopia
• Slurred speech
• Motor impairment

Severe Presentation

If the overdose is severe, then it may result in severe symptoms such as:

• Respiratory depression
• Hypoxemia
• Apnea
• Hypotension
• Bradycardia
• Cardiac arrest
• Pulmonary aspiration
• Coma

Severe consequences of clonazepam use alone are rare, but the toxicity increases significantly if other CNS depressants, such as opioids, ethanol, barbiturates, etc., are coadministered.[45]

Treatment of Toxicity

Supportive care and medical observation are the mainstays of the treatment. The supportive care includes monitoring vitals, IV fluids for hypotension, atropine for bradycardia, and maintaining the patency of the airway by intubation or artificial respiration if respiratory depression develops.

The 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. Flumazenil's 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.[46] 

The use of illicit benzodiazepines in combination with opioids is increasing, leading to synergistic toxicity and increased mortality. Consequently, increasing awareness among providers, patient education, and community involvement regarding hazards associated with illicit benzodiazepines is crucial.[47][48]

Enhancing Healthcare Team Outcomes

The concern lies in the healthcare community about the inappropriate long-term use of prescribed clonazepam and other BZD 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 often administer the drug. Following administration in hospital settings, its use may carry over to primary care without any indication; this is where a pharmacist performing medication reconciliation on discharge is invaluable. In primary care, patients also influence clinicians by having this conceived notion about clonazepam and BZD drugs being wonder drugs to make them feel and sleep better. These issues can result in poor patient outcomes from drug dependence, misuse, abuse, motor impairment, etc. Therefore, an interprofessional approach is required to develop ideas to reduce the use of hypnotics and develop interventions to prevent misuse in the hospital and at the primary and secondary care interface.

The prescribing clinician, nurse, and pharmacist should use controlled substance prescription monitoring program (CSPMP) databases to ensure the safe and proper use of benzodiazepines, sedative-hypnotics, opioids, and other controlled substances. A study suggests that interprofessional teamwork between primary care physicians, mid-level practitioners, nurses, and pharmacists can enhance safe medication practices involving high-risk benzodiazepines.[49] [Level 5]