HILTON HEAD—When faced with a patient with essential tremor, a neurologist may not be certain how to proceed with treatment, according to an overview presented at Vanderbilt University School of Medicine’s 38th Annual Contemporary Clinical Neurology Symposium. Various medications are available, but most are anticonvulsants, and none was developed specifically for essential tremor. The literature contains little guidance about drug dosages, and many patients do not respond to pharmacotherapy. Nevertheless, clinical judgment and the experience of colleagues may enable a neurologist to help a patient control his or her symptoms.
“The concept of having a tremor-free patient with either deep brain stimulation [DBS] or medication is not entirely valid,” said Peter Hedera, MD, Associate Professor of Neurology at Vanderbilt University School of Medicine in Nashville. Rather than focusing on eliminating tremor, neurologists should aim to improve function, he added. “I typically ask, ‘Are you able to go out? Can you eat? Do you order soup?’ That’s a perfect example …. If they say, ‘Yeah, I like it. I had soup,’ you really did great for the patient.”
The Challenges of Pharmacotherapy
More than 90% of patients with essential tremor report significant functional impairment. Tremor frequency can range from 2.5 Hz to 12 Hz. In general, higher frequencies correspond with lower amplitudes and are easier to treat. Tremor frequency among patients with essential tremor generally ranges between 5 Hz and 5.7 Hz. In some patients, however, tremor frequency decreases with time, and amplitude increases. “That means trouble for the patient and the treating neurologist because your repertoire of medications becomes much less effective,” said Dr. Hedera.
Because many therapies are available, essential tremor may seem easy to treat. Yet only one treatment, propranolol, is supported by Class I evidence. “All of the other medications are used off label, which is not unusual, of course, for neurology,” said Dr. Hedera.
Medication provides clinically meaningful benefits for about half of patients, but half do not experience improvement. Some pharmacotherapies are associated with significant side effects, including somnolence and cognitive difficulties, that limit the dose that a patient can tolerate. Many patients prefer subtherapeutic levels of their drug because its side effects are so troublesome. Overall, the data for medications used to treat essential tremor are “humbling” because they show that neurologists are unable to serve about half of patients effectively “without sometimes making treatment worse than the disease,” said Dr. Hedera.
The literature can help neurologists choose an appropriate therapy based on the presence of comorbidities, “but overall, it still remains kind of an art based on science,” said Dr. Hedera. Because of a lack of guidance about dosage, neurologists often seek the highest possible dose that does not cause side effects, he added. “Many times, I rechallenge patients on their previously failed medication unless I have good evidence that this was a good enough trial.”
Patients with essential tremor who respond to one medication tend to respond to other medications, and patients who fail to respond to one drug tend not to respond to any of the alternatives. “I like to use either both first-line or two second-line medications with a good therapeutic trial,” said Dr. Hedera.
The two first-line treatments for essential tremor are propranolol and primidone. Propranolol is a beta blocker, and this class of medications may provide improvement by blocking spindles in the muscles. Propranolol can be administered in doses of 60 mg/day to 320 mg/day. “Whenever the patient doesn’t have any contraindications for beta blocking, you can use propranolol,” said Dr. Hedera. Younger patients with fast tremor tend to respond especially well to propranolol. Neurologists may consider treating a patient with two beta blockers that target different beta receptors. Metoprolol, another beta blocker, can provide benefit, although data indicate that it is less effective than propranolol.
Gabapentin, pregabalin, and topiramate are among the second-line treatments for essential tremor, and many studies have evaluated these drugs’ effect on the disease. “I consider topiramate most effective for the secondary line,” said Dr. Hedera. “It’s my first choice … unless there is any comorbidity, especially kidney stones or glaucoma, that would conflict with the medication.” The typical dose of topiramate ranges from 150 mg/day to 300 mg/day.
Benzodiazepenes are other second-line treatments for essential tremor that may provide benefits. Clonazepam and clobazam may be good therapeutic choices because of their long half-lives, said Dr. Hedera. Research has provided evidence of clonazepam’s benefit for patients with essential tremor (in a dose of 0.5 mg/day to 6 mg/day), but clobazam has not been studied for this indication. Several trials indicate that alprazolam, in doses of 0.125 mg/day to 3 mg/day, reduces limb tremor by 25% to 34%, compared with placebo. Neurologists should be cautious, however, before initiating long-term treatment with benzodiazepenes because of their potential for dependency.