Essential Tremor Medication
- Author: Deborah A Burke, MD; Chief Editor: Selim R Benbadis, MD more...
Beta-adrenergic blockers (principally propranolol) and primidone are the first-line treatment for essential tremor. Each provides good benefit in 50-70% of cases and neither has been demonstrated to be unequivocally superior to the other. Adverse effects are more prominent early in treatment with primidone but are more prominent later in treatment with propranolol. Starting with propranolol is preferable in younger individuals, and primidone is started first in older patients.
Patients are usually started on one of these medications. The drug is introduced at a low dose that is increased slowly until complete response, tolerance, or usual maximum dose is attained. If some benefit is achieved but is incomplete, the other medication may be introduced and increased in an effort to achieve maximum benefit. Treatment with both drugs has been shown to be effective in patients who have had an insufficient response to one. Patients should not expect complete resolution of symptoms.
More evidence exists to support effectiveness in upper extremity tremor than in head or lower extremity tremor. A decrease in tremor amplitude rather than in frequency is the usual response, although some evidence indicates that primidone may decrease tremor frequency as well.
For patients who do not achieve an adequate response with primidone and propranolol, the authors try topiramate. Clozapine, an atypical neuroleptic, has been shown to be effective in a randomized, double-blind, crossover study of patients who had definite or probable essential tremor and poor response to propranolol or primidone. Thirteen of 15 patients demonstrated greater than 50% improvement of upper extremity tremor with 12.5 mg of clozapine.
The mechanism of action in the reduction of essential tremor is not known. The action is hypothesized to be mediated primarily by peripheral beta2 adrenoreceptors, but some evidence indicates that beta1-receptor antagonists such as metoprolol also have some efficacy. Peripheral beta2 adrenoreceptors are located in the extrafusal muscle fibers and on the intrafusal fibers of the muscle spindles.
Propranolol, 1 of 2 medications of choice for essential tremor, has been shown to be effective in double-blind, placebo-controlled trials. It is a nonselective beta-adrenergic blocker with negative inotropic, chronotropic, and dromotropic properties. Propranolol is lipophilic with central nervous system (CNS) effects. Its mechanism of action is probably related to peripheral beta2 antagonism. The drug's long-acting formulation has efficacy similar to that of the standard formulation and may allow fewer daily doses.
In general, beta1-receptor antagonists are more effective than placebo but are not as effective as beta2-receptor antagonists. Metoprolol, a relatively selective beta1-receptor antagonist, may be useful in patients with asthma and other pulmonary conditions.
Primidone and, to a lesser extent, phenobarbital have demonstrated tremor-suppressing effects. Their mechanism of action is unknown, but it presumably involves the CNS.
Primidone is metabolized to phenobarbital and PEMA. It has tremor-suppressing activity independent of plasma concentrations of phenobarbital and is thought to be superior to phenobarbital. PEMA is not tremorolytic. Primidone is believed to have an independent mechanism for its effect on tremor.
It is strongly recommended that treatment with primidone be initiated with low doses because adverse effects at initiation of treatment are common. Start with one quarter or one half of a 50-mg tablet at bedtime and increase the dose slowly every week. Alternatively, introduce primidone using a 250 mg/5 mL suspension. Start with 1 drop at bedtime and increase the dose by 1 drop each night for 20 nights. Then convert the patient to a 50-mg tablet and increase the dose slowly every week.
For patients who initially respond to primidone but later develop a tolerance to it, increasing the dose to as high as 1000 mg/day in an effort to regain benefit is advisable.
Topiramate's mechanism of action is unknown, but the blockage of voltage-dependent sodium channels and the augmentation of GABA are thought to play a role. Topiramate is not extensively metabolized and is excreted unchanged in the urine.
Antipsychotics, 2nd Generation
In a randomized, double-blind, crossover study of 15 patients who had definite or probable essential tremor and poor response to propranolol or primidone, 13 showed greater than 50% improvement of upper extremity tremor with 12.5 mg of clozapine.
Clozapine's mechanism of effect in essential tremor is unknown. The long-term effects of clozapine in essential tremor have not been studied. The drug may be tried before resorting to surgery when other methods have failed. Clozapine is weakly antidopaminergic, antiadrenergic (alpha1 and alpha2 receptors), anticholinergic, antihistaminergic (H1, H3), and antiserotonergic (5-HT1c, 5-HT2, 5-HT3).
In a case series report, 4 patients (3 with Parkinson disease and 1 with essential tremor) who responded initially to propranolol had improvement of tremor with mirtazapine.
Mirtazapine is a potent 5-HT2, 5-HT3, and H1 antagonist. It is a moderate peripheral alpha1-adrenergic antagonist and a moderate antagonist of muscarinic receptors. The drug's half-life is 20-40 hours.
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