WE MOVE March 25, 2004. Benzodiazepines act upon the hypothalamic, thalamic, and limbic regions, causing varying levels of depressed CNS activity. This action is thought to be mediated through GABA receptors (i.e., increasing GABA's affinity for its receptors) or through serotonergic mechanisms.
Benzodiazepine therapy may improve sleep and reduce arousals due to PLMS, yet may be less effective in eliminating movement and sensory abnormalities associated with RLS. However, in some patients with severe RLS, such therapy significantly decreases the total number of abnormal leg movements during rest. Overall, long-term nightly benzodiazepine therapy has been shown to remain effective with a low risk of adverse effects, tolerance, or abuse. Patients with mild or intermittent symptoms, particularly young individuals, may receive the most benefit from such therapy. If combined with carbidopa/levodopa or dopamine agonists, benzodiazepines may assist in the management of severe RLS symptoms.
Clonazepam was approved by the FDA in 1975 and is primarily used in the treatment of refractory myoclonic seizures. Several clinical studies have documented the efficacy of clonazepam in alleviating RLS symptoms. Other benzodiazepines that may be effective alternatives include temazepam, diazepam, and triazolam. Temazepam was approved by the FDA in 1981 and triazolam was approved in 1982, both for the short-term management of insomnia. Diazepam was originally approved in 1963 and is used primarily as a skeletal muscle relaxant, such as in the treatment of spasticity; as an adjunct to other pharmacologic therapies in the prophylaxis of seizures; for acute alcohol withdrawal; and for the short-term treatment of anxiety disorders. Such benzodiazepine agents are schedule C-IV controlled substances. Typical dosages for the treatment of RLS are 0.5 to 2.0 mg/day clonazepam, 7.5 to 30.0 mg/day temazepam, 5.0 to 15.0 mg/day diazepam, or 0.125 to 0.5 mg/day triazolam. Such medications are usually administered orally shortly before or at bedtime.
The elimination half-life of clonazepam is approximately 18 to 40 hours, whereas triazolam has an elimination half-life ranging from 1.5 to 5.5 hours. Although diazepam is the most rapidly absorbed of the benzodiazepines following oral administration, it and its major active metabolite desmethyldiazepam have long half-lives of 30 to 60 hours and 30 to 100 hours, respectively. The parent compound of temazepam has a half-life of 8 to 15 hours.
Potential adverse effects associated with benzodiazepine therapy for RLS include somnolence, especially with the use of long-acting medications (e.g., clonazepam); decreased libido; a risk of falls during the night, particularly in elderly patients; and exacerbation of comorbid obstructive sleep apnea. Depending upon dosage levels, therapy with such agents may result in tolerance and dependency; in addition, if therapy is discontinued abruptly rather than through gradually tapered dosages, there may be precipitation of withdrawal. However, in patients receiving long-term therapy for RLS, there is usually a low risk of such phenomena. Patients should be advised not to take such medications in combination with alcohol nor with other CNS depressants. In addition, physicians should carefully monitor benzodiazepine therapy in those patients who are currently receiving additional pharmacologic agents that may potentiate the effects of benzodiazepines, further depressing CNS activities.
Other benzodiazepines may be considered as possible alternatives in the treatment of RLS. Such agents include alprazolam (Xanax®), lorazepam (Ativan®), chlordiazepoxide (Librium®), or flurazepam (Dalmane®), all of which are schedule C-IV controlled substances.
• Alprazolam, which is primarily used in the treatment of anxiety or the management of panic disorder, has a relatively short half-life (i.e., 11 to 16 hours) and does not have active metabolites. Because its efficacy for long-term therapy (e.g., over 4 months) has not been assessed, its ongoing use should only be considered upon further evaluation.
• Lorazepam, primarily used in the treatment of anxiety and status epilepticus, does not have active metabolites and has a half-life of approximately 13 hours in adults. Although its elimination half-life is shorter than that of diazepam, lorazepam remains active in the CNS longer than diazepam.
• Chlordiazepoxide is a long-acting benzodiazepine and primarily used to manage anxiety disorders. Its half-life is approximately 5 to 30 hours, whereas the half-lives of its active metabolites range from 14 to 100 hours.
• Flurazepam is primarily used as a hypnotic in the short-term management of insomnia. Although this agent has a plasma half-life of approximately 2.3 hours, the half-lives of its active metabolites (i.e., desalkylflurazepam and N-1-hydroxyethylflurazepam) range from 30 to 100 and 2 to 4 hours, respectively. Its prolonged use is usually not indicated and therefore should only be considered upon further evaluation.
