Clonazepam is used in the prophylactic management of Lennox-Gastaut syndrome (petit mal variant epilepsy) and akinetic and myoclonic seizures. The drug also may be used in the management of absence (petit mal) seizures in patients who have not responded to succinimides. In some patients, use of clonazepam may permit reduction in dosage or discontinuance of other anticonvulsants; however, paradoxical increases in seizure activity also have occurred.
(See Cautions: Precautions and Contraindications.)A decreased response to the drug may occur after several months or years of clonazepam therapy; however, seizures may be less severe than those before clonazepam therapy. In some patients, dosage adjustment may restore efficacy.
Most studies to date on the use of clonazepam have been uncontrolled and have involved patients with seizures refractory to other anticonvulsants. In addition, clonazepam has been used mainly as an adjunct to other drugs. For these reasons, determination of the precise role of clonazepam in the management of seizure disorders must await the results of well-controlled comparative studies.
Clonazepam has been used with some success in other refractory seizures, including partial seizures with complex symptomatology (psychomotor seizures) and other partial (focal) seizures and some cases of infantile spasms. Clonazepam also has been useful in some patients with tonic-clonic (grand mal) seizures; however, when used in patients with multiple types of seizure disorders, the drug may increase the frequency of or precipitate tonic-clonic seizures in some patients. If this occurs, addition of another anticonvulsant and/or increase in dosage may be required.
IV clonazepam has been used with good results in the management of status epilepticus; however, a parenteral dosage form of the drug is not currently commercially available in the US.
Panic Attacks and Disorder
Clonazepam is used in the treatment of panic disorder with or without agoraphobia. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a clinically important change in behavior related to the attacks.
According to DSM-IV, panic disorder is characterized by recurrent unexpected panic attacks, which consist of a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, lightheaded, or faint; derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; fear of dying; paresthesias (numbness or tingling sensations); and chills or hot flushes.
The efficacy of clonazepam for the management of panic disorder has been established by 2 multicenter, double-blind, placebo-controlled studies of 6-9 weeks' duration in adult outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without agoraphobia. In these studies, clonazepam was found to be superior to placebo on the following measures of efficacy: change from baseline in panic attack frequency, the Clinician's Global Impression Severity of Illness Score, and the Clinician's Global Impression Improvement Score.
The first study was a fixed-dose study of 9 weeks' duration involving clonazepam dosages of 0.5, 1, 2, 3, or 4 mg daily. This study was conducted in 4 phases: a 1-week placebo run-in phase, a 3-week phase of upward titration of the dosage, a 6-week fixed-dosage maintenance phase, and a 7-week discontinuance phase. A substantial difference from placebo was observed consistently only in the group receiving 1 mg of clonazepam daily; the difference between the reduction from baseline in the number of full panic attacks was approximately 1 per week in patients receiving clonazepam 1 mg daily compared with placebo. At the study end point (the end of the fixed-dosage maintenance phase), 74% of patients receiving clonazepam 1 mg daily were free of panic attacks compared to 56% of patients receiving placebo. Daily dosages exceeding 1 mg were less effective and more commonly associated with adverse effects (e.g., somnolence and ataxia) in this study.
The second study was of 6 weeks' duration and used a flexible dosing schedule involving clonazepam dosages ranging from 0.5-4 mg daily. The study was conducted in 3 phases: a 1-week placebo run-in phase, a 6-week optimal dose-finding phase, and a 6-week discontinuance phase. The mean clonazepam dosage during the optimal dosing period was 2.3 mg daily. The difference between the reduction from baseline in the number of full panic attacks was approximately 1 per week in patients receiving clonazepam compared with placebo. At the study end point, 62% of patients receiving clonazepam were free of panic attacks compared with 37% of patients receiving placebo.
Subgroup analysis from these 2 controlled studies for possible race- or gender-related effects on treatment outcome did not suggest any difference in efficacy based on either the race or gender of the patient.
The manufacturer states that the efficacy of clonazepam for long-term use (i.e., longer than 9 weeks) has not been systematically evaluated in controlled studies. However, limited information from follow-up studies of patients with panic disorder who responded favorably to benzodiazepine therapy indicates that the benefits observed during short-term therapy are usually maintained for longer periods (e.g., up to several years) without increases in dosage. In an open study in which patients with panic disorder were treated with clonazepam over a 2-year period, clonazepam produced and maintained a therapeutic benefit without evidence of tolerance development (as manifested by dosage escalation or worsening of clinical status). The manufacturer states that there is insufficient experience concerning how long patients with panic disorder who are treated with clonazepam should remain on the drug. However, some clinicians state that panic disorder is a chronic condition; therefore, it may be reasonable to continue therapy in responding patients. If clonazepam is used for extended periods, the need for continued therapy with the drug should be reassessed periodically.
(See Dosage and Administration: Dosage.)
Panic disorder can be treated with cognitive behavioral psychotherapy and/or pharmacologic therapy. Currently, there are several classes of drugs that appear to be effective in the pharmacologic management of panic disorder, including tricyclic antidepressants (e.g., imipramine, clomipramine), monoamine oxidase inhibitors (e.g., phenelzine), selective serotonin-reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), selective serotonin- and norepinephrine-reuptake inhibitors (e.g., venlafaxine), and benzodiazepines (e.g., alprazolam, clonazepam). When choosing among the available drugs in the treatment of panic disorder, clinicians should consider their acceptance and tolerability by patients; their ability to reduce or eliminate panic attacks, reduce clinically important anxiety and disability secondary to phobic avoidance, and ameliorate other common comorbid conditions (such as depression); their cost; and their ability to prevent relapse during long-term therapy.
Because of their better tolerability when compared with other agents (such as the tricyclic antidepressants, monoamine oxidase inhibitors, and benzodiazepines) and the lack of physical dependence problems commonly associated with benzodiazepines, some clinicians currently prefer selective serotonin-reuptake inhibitors as first-line therapy in the management of panic disorder. However, benzodiazepines such as clonazepam have a more rapid onset of action often with immediate reduction of panic symptoms, whereas antidepressants may require several weeks or more for therapeutic effect. Therefore, benzodiazepines can be used for early symptom control (usually in combination with another form of treatment such as cognitive behavioral therapy or antidepressant therapy) and are useful in relieving anticipatory anxiety. Benzodiazepines also can be used to treat surges of anxiety or panic, although some experts state that this as-needed use of benzodiazepines should not replace the use of adequate daily dosages when clinically necessary. In addition, some clinicians consider the anxiolytic effect of benzodiazepines advantageous in reducing anxiety between panic attacks. The most serious risk factor associated with benzodiazepines in panic disorder is physical dependence; withdrawal symptoms or a recurrence of panic symptoms may occur during drug tapering or following abrupt discontinuance of therapy. Therefore, gradual discontinuance of clonazepam therapy is advised. (See
Chronic Toxicityand see also Dosage and Administration.) In addition, as with other benzodiazepines, clonazepam can produce sedation and psychomotor impairment and potentially may interact with alcohol if it is not restricted. (See Cautions: Precautions and Contraindications.)
Clonazepam also has been used in patients who experience akathisia while receiving antipsychotic drugs (e.g., for management of schizophrenia) and for the treatment of acute catatonic reactions, whether associated with schizophrenia or other conditions.
The efficacy of clonazepam as a hypnotic has not been fully evaluated.