Tremor is defined as a rhythmic and oscillatory movement of a body part with a relatively constant frequency and variable amplitude. It is caused by either alternating or synchronous contractions of antagonistic muscles. Tremor is the most common of all movement disorders, and essential tremor (ET) is the most common neurologic cause of postural or action tremor.
BETA BLOCKERS — Beta blockers are the most commonly used medications for the treatment of ET. The efficacy of beta blockers has been demonstrated primarily for propranolol, and most of the studies evaluated short-term therapy.
Propranolol 60 to 320 mg/day is effective for the treatment of limb tremor associated with ET. Tremor magnitude was reduced by about 50 percent as measured by accelerometry, and clinical rating scales also improved by about 50 percent. The mean dose of propranolol was 185.2 mg/day in nine of these studies.
Propranolol LA is also effective for the treatment of ET and appears to provide the same therapeutic response as conventional propranolol. One study found that propranolol LA was preferred to conventional propranolol by 87 percent of patients because of ease of administration.
Single doses of propranolol taken in anticipation of social situations that are likely to exacerbate tremor are useful in some patients.
Propranolol side effects, including lightheadedness, fatigue, impotence, and bradycardia, occurred in 12 to 66 percent of patients in clinical trials.
Other beta blockers — A selective beta-1 adrenergic blocker such as atenolol can be used instead of propranolol in patients with asthma or bronchospasm. However, beta-1 selectivity is not absolute and may diminish at higher doses (eg, >100 mg daily).
Furthermore, the data regarding efficacy of other beta blockers are not as strong as the data supporting propranolol.
While sotalol and nadolol may be effective for ET, in most instances there is no particular advantage to using these drugs compared with propranolol, and the evidence is stronger for the latter. However, nadolol may still have a role, as it is a largely peripheral acting beta blocker and may avoid adverse central effects that are sometimes induced by propranolol (eg, depression).
Although data are limited, it appears that patients who do not respond to adequate doses of one beta blocker for ET are unlikely to respond to another.
ANTICONVULSANTS — Primidone is effective for the treatment of ET, and the anticonvulsants gabapentin and topiramate probably reduce limb tremor associated with ET.
Primidone up to 750 mg/day, is effective for the treatment of limb tremor associated with ET. Tremor magnitude was reduced by about 50 percent as measured by accelerometry, and clinical rating scales also improved by about 50 percent, an effect similar to treatment with propranolol. The mean dose of primidone, available from three of these studies, was 481.7 mg/day.
Side effects from primidone were typically more severe at treatment initiation, and they included sedation, drowsiness, fatigue, depression nausea, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, and an acute toxic reaction. Primidone tolerability was not improved in a well-designed trial by use of a very low initial dose (7.5 mg/day) and slow titration (increasing by 7.5 mg/day for 20 days). Primidone may be better tolerated in patients with epilepsy in whom hepatic enzymes have been induced by the previous administration of phenobarbital or other anticonvulsant drugs.
The mechanism of action of primidone in ET is unknown; it is converted to phenylethylmalonamide and phenobarbital, but neither of these agents alone appears to have a significant effect on tremor.
Coadministration of a beta blocker and primidone may provide useful additive therapeutic benefits.
Gabapentin as monotherapy probably reduces limb tremor associated with ET. The evidence comes from one well-designed randomized controlled trial, which found that gabapentin 1200 mg/day reduced tremor compared with placebo, and reduced tremor magnitude at day 15 by 77 percent as assessed by accelerometry. Gabapentin is associated with fewer side effects than primidone.
Gabapentin as adjunct therapy has shown conflicting results for the treatment of ET.
Topiramate probably reduces limb tremor associated with ET, but its use is associated with a relatively high rate of adverse effects.
In a later review that pooled the results of three small randomized controlled crossover trials with a total of 62 patients, topiramate (400 mg/day) led to significant tremor reduction and improved functional disability compared with placebo. Adverse effects, including nausea, paresthesia, and concentration difficulty, were common in the topiramate-treated patients.
Other anticonvulsants
ADDITIONAL AGENTS
Benzodiazepines are widely used because of the usually mistaken belief that tremor is due to anxiety. On the other hand, if tremor is aggravated by anxiety, an anxiety lowering medication may partially reduce tremor. Caution is urged with use of benzodiazepines for ET because of the potential for abuse, as well as the potential for drug discontinuation to cause withdrawal symptoms and exacerbation of tremor. These problems make benzodiazepines a second-line choice for the chronic treatment of ET.
Other oral drugs
A variety of other drugs have been used to treat ET. The following levels of effectiveness were derived from the 2005 AAN guidelines on drug therapies for ET as updated in 2011, and from a separate systematic review published in 2011:
Uncertain effectiveness: Amantadine, clonidine, clozapine, glutethimide, L-tryptophan combined with pyridoxine, metoprolol, nicardipine, octanol, olanzapine, quetiapine, theophylline, tiagabine, and sodium oxybate have uncertain effectiveness for the treatment of ET; the available data for these drugs are limited or conflicting.
Ineffective: Acetazolamide, amantadine, carisbamate, 3,4-diaminopyridine, isoniazid, levetiracetam, pindolol, methazolamide, mirtazapine, nifedipine, trazodone, and verapamil are probably not effective for treating ET.
PHARMACOLOGIC TREATMENT ISSUES
In most cases, ET can be managed by primary care clinicians, beginning with exclusion of secondary causes and followed by initiation of therapy with propranolol or primidone. The decision to refer to a neurologist depends in part upon the ease or difficulty of achieving a satisfactory therapeutic response to medical treatment, as well the comfort level of the primary care clinician with use of agents such as anticonvulsants.
Several important treatment issues have been addressed by a guideline on therapies for ET published by the AAN in 2005, including:
Choice of initial therapy
Propranolol and primidone have similar effectiveness when used as initial treatment for ET.
Acute adverse reactions with primidone and chronic side effects of propranolol appear to be important limitations to the use of these drugs. (Chronic side effects of propranolol, including fatigue, impotence, and bradycardia.) (Transient acute side effects of primidone, including nausea, ataxia, dizziness, sedation, and confusion.)
Propranolol and primidone may be used in combination to treat limb tremor in ET, and the combined use of these drugs is possibly more effective than either drug alone.
Duration of benefit
Propranolol and primidone maintain effective limb tremor reduction in the majority of patients for at least one year, although increased doses of both drugs may be needed by 12 months of therapy.
SUMMARY AND RECOMMENDATIONS
The following recommendations for the treatment of essential tremor (ET) are based upon the 2005 practice parameter from the American Academy of Neurology, subsequent developments in therapeutics, and the author's clinical experience.
Propranolol 60 to 320 mg/day is effective for the treatment of limb tremor associated with ET. Tremor magnitude was reduced by about 50 percent as measured by accelerometry, and clinical rating scales also improved by about 50 percent. The mean dose of propranolol was 185.2 mg/day in nine of these studies.
Propranolol LA is also effective for the treatment of ET and appears to provide the same therapeutic response as conventional propranolol. One study found that propranolol LA was preferred to conventional propranolol by 87 percent of patients because of ease of administration.
Single doses of propranolol taken in anticipation of social situations that are likely to exacerbate tremor are useful in some patients.
Propranolol side effects, including lightheadedness, fatigue, impotence, and bradycardia, occurred in 12 to 66 percent of patients in clinical trials.
Other beta blockers — A selective beta-1 adrenergic blocker such as atenolol can be used instead of propranolol in patients with asthma or bronchospasm. However, beta-1 selectivity is not absolute and may diminish at higher doses (eg, >100 mg daily).
Furthermore, the data regarding efficacy of other beta blockers are not as strong as the data supporting propranolol.
- Atenolol, a selective beta adrenergic blocker, probably reduces limb tremor associated with ET. Two small randomized trials found that atenolol improved symptoms or accelerometer readings compared with placebo. In the first study, which only included nine patients, atenolol was less effective than propranolol; the second found that both atenolol and propranolol were similarly effective compared with placebo.
- Sotalol, a nonselective beta adrenergic receptor blocker, probably reduces limb tremor associated with ET, as demonstrated in one well-designed randomized controlled trial.
- Nadolol, a nonselective beta adrenergic receptor blocker, possibly reduces limb tremor associated with ET, as shown in a small randomized controlled trial. However, the benefit was found only for patients who previously responded to propranolol.
- Metoprolol, a selective beta adrenergic blocker, is of uncertain benefit for ET, as data regarding its effectiveness are conflicting. A randomized controlled trial found that a single dose of metoprolol 150 mg was effective for improving tremor. However, a subsequent small randomized, double-blind, crossover study found that propranolol improved outcomes compared with placebo, but metoprolol did not.
- Pindolol probably does not reduce limb tremor associated with ET, as demonstrated in a well-designed randomized controlled trial.
While sotalol and nadolol may be effective for ET, in most instances there is no particular advantage to using these drugs compared with propranolol, and the evidence is stronger for the latter. However, nadolol may still have a role, as it is a largely peripheral acting beta blocker and may avoid adverse central effects that are sometimes induced by propranolol (eg, depression).
Although data are limited, it appears that patients who do not respond to adequate doses of one beta blocker for ET are unlikely to respond to another.
ANTICONVULSANTS — Primidone is effective for the treatment of ET, and the anticonvulsants gabapentin and topiramate probably reduce limb tremor associated with ET.
Primidone up to 750 mg/day, is effective for the treatment of limb tremor associated with ET. Tremor magnitude was reduced by about 50 percent as measured by accelerometry, and clinical rating scales also improved by about 50 percent, an effect similar to treatment with propranolol. The mean dose of primidone, available from three of these studies, was 481.7 mg/day.
Side effects from primidone were typically more severe at treatment initiation, and they included sedation, drowsiness, fatigue, depression nausea, vomiting, ataxia, malaise, dizziness, unsteadiness, confusion, vertigo, and an acute toxic reaction. Primidone tolerability was not improved in a well-designed trial by use of a very low initial dose (7.5 mg/day) and slow titration (increasing by 7.5 mg/day for 20 days). Primidone may be better tolerated in patients with epilepsy in whom hepatic enzymes have been induced by the previous administration of phenobarbital or other anticonvulsant drugs.
The mechanism of action of primidone in ET is unknown; it is converted to phenylethylmalonamide and phenobarbital, but neither of these agents alone appears to have a significant effect on tremor.
Coadministration of a beta blocker and primidone may provide useful additive therapeutic benefits.
Gabapentin as monotherapy probably reduces limb tremor associated with ET. The evidence comes from one well-designed randomized controlled trial, which found that gabapentin 1200 mg/day reduced tremor compared with placebo, and reduced tremor magnitude at day 15 by 77 percent as assessed by accelerometry. Gabapentin is associated with fewer side effects than primidone.
Gabapentin as adjunct therapy has shown conflicting results for the treatment of ET.
Topiramate probably reduces limb tremor associated with ET, but its use is associated with a relatively high rate of adverse effects.
In a later review that pooled the results of three small randomized controlled crossover trials with a total of 62 patients, topiramate (400 mg/day) led to significant tremor reduction and improved functional disability compared with placebo. Adverse effects, including nausea, paresthesia, and concentration difficulty, were common in the topiramate-treated patients.
Other anticonvulsants
- Phenobarbital treatment for ET has shown conflicting outcomes in a limited number of trials.
- Levetiracetam, although not well studied for ET, appears to have no significant benefit in most reports. A 2011 systematic review of treatment for ET concluded that levetiracetam is ineffective, and the updated 2011 AAN guidelines state it probably does not reduce limb tremor in ET.
- Zonisamide treatment reduced tremor severity in two small open label studies at doses of up to 300 mg/day, but was ineffective in other small trials.
- Pregabalin treatment has shown inconsistent benefit in small trials.
ADDITIONAL AGENTS
Benzodiazepines are widely used because of the usually mistaken belief that tremor is due to anxiety. On the other hand, if tremor is aggravated by anxiety, an anxiety lowering medication may partially reduce tremor. Caution is urged with use of benzodiazepines for ET because of the potential for abuse, as well as the potential for drug discontinuation to cause withdrawal symptoms and exacerbation of tremor. These problems make benzodiazepines a second-line choice for the chronic treatment of ET.
- Alprazolam is probably effective for the treatment of limb tremor associated with ET.
- Clonazepam is possibly effective for the treatment of limb tremor associated with ET.
Other oral drugs
A variety of other drugs have been used to treat ET. The following levels of effectiveness were derived from the 2005 AAN guidelines on drug therapies for ET as updated in 2011, and from a separate systematic review published in 2011:
Uncertain effectiveness: Amantadine, clonidine, clozapine, glutethimide, L-tryptophan combined with pyridoxine, metoprolol, nicardipine, octanol, olanzapine, quetiapine, theophylline, tiagabine, and sodium oxybate have uncertain effectiveness for the treatment of ET; the available data for these drugs are limited or conflicting.
Ineffective: Acetazolamide, amantadine, carisbamate, 3,4-diaminopyridine, isoniazid, levetiracetam, pindolol, methazolamide, mirtazapine, nifedipine, trazodone, and verapamil are probably not effective for treating ET.
PHARMACOLOGIC TREATMENT ISSUES
In most cases, ET can be managed by primary care clinicians, beginning with exclusion of secondary causes and followed by initiation of therapy with propranolol or primidone. The decision to refer to a neurologist depends in part upon the ease or difficulty of achieving a satisfactory therapeutic response to medical treatment, as well the comfort level of the primary care clinician with use of agents such as anticonvulsants.
Several important treatment issues have been addressed by a guideline on therapies for ET published by the AAN in 2005, including:
- Choice of initial therapy
- Utility of combined therapy with primidone and propranolol
- Evidence of sustained benefit of pharmacologic treatment
Choice of initial therapy
Propranolol and primidone have similar effectiveness when used as initial treatment for ET.
Acute adverse reactions with primidone and chronic side effects of propranolol appear to be important limitations to the use of these drugs. (Chronic side effects of propranolol, including fatigue, impotence, and bradycardia.) (Transient acute side effects of primidone, including nausea, ataxia, dizziness, sedation, and confusion.)
Propranolol and primidone may be used in combination to treat limb tremor in ET, and the combined use of these drugs is possibly more effective than either drug alone.
Duration of benefit
Propranolol and primidone maintain effective limb tremor reduction in the majority of patients for at least one year, although increased doses of both drugs may be needed by 12 months of therapy.
SUMMARY AND RECOMMENDATIONS
The following recommendations for the treatment of essential tremor (ET) are based upon the 2005 practice parameter from the American Academy of Neurology, subsequent developments in therapeutics, and the author's clinical experience.
- Propranolol (or propranolol LA), 60 to 320 mg/day, is effective for the treatment of limb tremor associated with ET.
- Primidone, up to 750 mg/day, is effective for the treatment of limb tremor associated with ET.
- Propranolol and primidone have similar effectiveness when used as initial therapy to treat limb tremor in ET, and either drug may be used depending on concurrent medical problems and potential side effects. While both drugs are recommended by the AAN guidelines as first-line agents, we suggest that the use of primidone be reserved for patients who either do not tolerate or do not respond to propranolol.
- Propranolol can be used at doses of 60 to 320 mg/day to reduce limb tremor associated with ET; maximum tremor suppression is more likely to occur with a dose between 160 and 320 mg/day. Relative contraindications to propranolol include heart block and bronchospastic disease. Propranolol use can be limited by chronic side effects such as lightheadedness, fatigue, impotence, and bradycardia.
- Primidone treatment should begin at a dose of 12.5 to 25 mg before sleep and be titrated carefully over several weeks as tolerated and according to therapeutic response, up to 750 mg/day. Use of primidone can be limited by side effects, often acute, such as sedation, drowsiness, fatigue, nausea, vomiting, ataxia, malaise, dizziness, unsteadiness, vertigo, and confusion.
- Propranolol and primidone maintain effective limb tremor reduction in the majority of patients for at least one year. The doses of propranolol and primidone may need to be increased by 12 months of therapy when treating limb tremor.
- The combined use of propranolol and primidone is possibly more effective than either drug alone. Coadministration of propranolol and primidone is suggested if the therapeutic response to either drug alone is suboptimal for the treatment of limb tremor in ET.
- Propranolol probably reduces head tremor in ET, although the data are limited. Propranolol should be considered for treatment of head tremor in patients with ET.
- Single doses of propranolol can be used in anticipation of social situations that are likely to exacerbate tremor.
- The beta blockers atenolol and sotalol, and the anticonvulsants gabapentin (monotherapy) and topiramarate are suggested as treatment of limb tremor associated with ET for patients who do not respond to or do not tolerate propranolol or primidone.
- Alprazolam is probably effective for limb tremor with ET; its use is suggested with caution due to its abuse potential.
- Atenolol a selective beta adrenergic blocker, is suggested instead of propranolol as treatment of limb tremor in ET for patients with asthma or bronchospasm, particularly those who are unable to tolerate primidone.
- Alcohol may ameliorate ET, but regular use is discouraged because of potential long-term adverse effects and risk for rebound tremor exacerbation.
- Botulinum toxin type A (BoNT-A) injections have modest benefit for ET-related limb tremor, but they are associated with dose-dependent hand weakness. BoNT-A treatment for ET-associated limb, head, and voice tremor is suggested only for medically refractory cases.
- Surgery (unilateral thalamotomy or thalamic deep brain stimulation of the thalamic ventral intermediate nucleus) is effective treatment for contralateral limb tremor in patients with ET who fail medical therapy and are severely impaired. Surgery for ET is discussed separately.
