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Essential Tremor
Drugs Used to Treat ET Primidone (Mysoline®) Primidone is metabolized to phenobarbital, with a plasma half-life of about 10 days, and phenylethylmalonamide (PEMA), which has a plasma half-life of approximately 30 hours. Both metabolites accumulate with chronic therapy. The major metabolite, PEMA, may potentiate the anticonvulsant effects of phenobarbital. However, the specific mechanism of action of primidone's tremorolytic effect is unknown. Because PEMA and phenobarbital appear to have no or little antitremor action, investigators suggest that primidone or an unknown metabolite is the effective component in alleviating tremor. Primidone is currently available as scored 50 mg and 250 mg tablets. Another way to initiate therapy is through the use of a liquid suspension containing primidone. It is also available as a pediatric oral suspension at a concentration of 250 mg/5 mL. Primidone therapy is typically prescribed on a constant-use basis. The usual starting dose is low—e.g., 12.5 or 25 mg (i.e., 1/4 or 1/2 of a 50 mg tablet) at bedtime—to help minimize the possibility of developing an acute reaction (see below). Optimal clinical response and dose regulation are achieved with slow upward titration over the course of several months. Dosage level is then adjusted to identify the lowest, most efficacious dose with a minimum of adverse effects. This dose is generally at <250 mg/day. Although doses have been titrated as high as 500 to 750 mg/day for some ET patients, doses over 250 mg/day typically confer little additional benefit. Primidone is typically well tolerated with ongoing therapy. In addition, in many patients, once daily dosing at bedtime may result in tremor attenuation of long duration. Due to the potential benefits associated with such administration, it is appropriate to attempt a single evening dose equal to the total daily dosage for responders who have achieved optimal tremor reduction with divided doses. Please refer to table 6 for a typical dosing schedule.
Serious adverse reactions to primidone are rare; however, mild side effects are frequent. In addition, about 20% or less of patients may develop an acute idiosyncratic toxic response when primidone therapy is initiated. Associated, usually transient symptoms may include nausea, vomiting, sedation, vertigo, ataxia, and additional flu-like complaints. Adverse effects typically subside in about 1 to 4 days with continued therapy. Therefore, if possible, patients should not discontinue primidone but continue to take a low dose of the drug. As mentioned above, the possibility of developing an acute response to primidone may be minimized or prevented if therapy is initiated at low doses. In addition, patient compliance may be increased if clinicians inform patients about the possibility of developing such a response, stress that symptoms usually subside, and recommend that the initial dose be taken at bedtime. Administration before retiring in the evening may increase the possibility that patients may sleep through feelings of sedation and other possible adverse effects and wake to the tremor-reducing benefits of the drug. In several placebo-controlled trials, primidone has been shown to be efficacious in attenuating ET. In addition, near complete suppression of tremor is more commonly achieved with primidone than with a beta-blocker. A single dose of primidone may result in a 60% to 66% reduction in upper limb tremor amplitude. However, tremors of the head, voice, and other regions appear to be improved less consistently. Even in the same patient, primidone therapy may attenuate hand tremor yet have no beneficial effect on head tremor. Although the beta-blocker propranolol may initially be better tolerated than primidone, chronic use of propranolol may continue to be associated with adverse effects. In contrast, side effects of chronic primidone therapy are typically minimal and infrequent, resulting in better long-term tolerability. It has been suggested that some ET patients may develop tolerance to chronic pharmacologic therapy. For example, tolerance has been observed with primidone in up to 13% of ET patients at 12 months. However, a number of studies analyzing the long-term effects of therapy have demonstrated that primidone retains its anti-tremor effect for at least 1 year. Caution should be used when prescribing primidone for debilitated patients and those with impaired hepatic or renal function. In addition, the medication should not be prescribed for patients with porphyria, those with severe respiratory depression, or for women who are pregnant or breast-feeding. Before primidone therapy is initiated, a complete blood count should be ordered and subsequently performed every 6 to 12 months to detect blood dyscrasias. Although rare, red cell hypoplasia or aplasia, granulocytopenia, agranulocytosis, and megaloblastic anemia have been reported in association with primidone administration. Anemia may respond to folic acid therapy without discontinuation of primidone. Propranolol (Inderal®) Propranolol is currently available in 10, 20, 40, 60, and 80 mg tablets for oral administration. (It is also available as Inderal LA® in 60, 80, 120, and 160 mg extended-release capsules.) Propranolol may be administered on an occasional-use (PRN) or constant-use basis.
FDA-approved uses of propranolol are primarily for the management of cardiovascular disease, including hypertension, angina, cardiac arrhythmia, and myocardial infarction. However, researchers have found it to be beneficial in providing symptomatic relief of ET in approximately 50% to 70% of patients. Although complete tremor suppression usually is not achieved and tremor frequency remains unaffected, propranolol has been shown to reduce tremor amplitude by 50% to 60%. Accordingly, propranolol appears to be most efficacious in managing high-amplitude, low frequency tremor. It also appears to be most effective for tremor of the upper limbs, with some efficacy shown for head, voice, or tongue tremor. A number of investigations have reported that, in a majority of patients, propranolol retains its anti-tremor effect after 1 year of chronic therapy. However, to maintain efficacy, dosage increases may be required for some patients. Propranolol is generally well tolerated. Relative contraindications may include heart failure, cardiac conduction disorders, asthma or bronchoasthmatic conditions, or diabetes. Adverse effects are usually mild and temporary, typically diminishing with time and rarely requiring cessation of therapy. These effects may include diminished exercise tolerance, fatigue, bradycardia, peripheral vasoconstriction, bronchospasm, and GI disturbances. With higher doses, side effects may include weakness, depression, insomnia, lassitude, and impotence. The pulse rate will decline in most patients, requiring monitoring of blood pressure and pulse rate. Caution should be used when prescribing propranolol for elderly patients and nursing mothers. In addition, such therapy should be avoided in late pregnancy due to risks of intrauterine growth retardation, bradycardia, or neonatal hypoglycemia. Propranolol therapy should not be discontinued abruptly due to possible rebound hypertension. Other beta-blockers Combination therapy In addition, when appropriate, primidone and propranolol may be administered in combination with benzodiazepines, such as lorazepam or clonazepam. For example, clonazepam may be initiated at 0.25 mg/day and slowly increased over several weeks to a range of 1.0 to 2.0 mg/day in divided doses. As is the case with propranolol, benzodiazepines may be used at small doses on a PRN basis about 30 minutes to 1 hour before an important event. In such cases, clonazepam or lorazepam may be taken at 0.25 or 0.5 mg. Calcium channel blockers Carbonic anhydrase inhibitors Other agents
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