What is the best add-on treatment for resistant tremors in patients already on carbidopa (L-Dopa)?

From the Guidelines

For resistant tremors in patients already on carbidopa, propranolol is generally considered the best add-on treatment, as evidenced by its long-standing use and effectiveness in treating essential tremor 1. The typical starting dose is 10-20 mg twice daily, which can be gradually increased to 40-120 mg daily based on response and tolerability. Propranolol, a non-selective beta-blocker, works by blocking peripheral beta-adrenergic receptors, reducing the amplification of tremors. If propranolol is ineffective or contraindicated (such as in patients with asthma, COPD, or certain cardiac conditions), primidone can be considered as an alternative, starting at a very low dose of 12.5-25 mg at bedtime and slowly titrating up to 250 mg daily to minimize side effects like sedation and unsteadiness. Some studies suggest that pramipexole may be helpful in some patients with tremors, but the evidence is mixed and not as strong as that for propranolol 1. For patients who don't respond adequately to these medications, adjunctive treatments like topiramate or gabapentin may be beneficial. In cases of severe, medication-resistant tremor, referral for deep brain stimulation evaluation should be considered, particularly if the tremor significantly impacts quality of life despite optimal medical management. It's worth noting that the most recent and highest quality study on the topic of beta-blocker treatment, including propranolol, was published in 2022 1, which supports the use of propranolol as a first-line treatment for resistant tremors. Key points to consider when treating resistant tremors include:

• Starting with a low dose of propranolol and gradually increasing as needed and tolerated
• Monitoring for potential side effects, such as sedation and unsteadiness, particularly when using primidone
• Considering alternative treatments, such as topiramate or gabapentin, if propranolol is ineffective or contraindicated
• Referring patients with severe, medication-resistant tremor for deep brain stimulation evaluation if quality of life is significantly impacted.

From the FDA Drug Label

In the double-blind, placebo-controlled trials in patients with advanced-stage Parkinson’s disease, the most commonly observed adverse reactions in patients treated with ropinirole (incidence at least 5% greater than placebo) were dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, increased sweating, and headache Table 4 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with advanced Parkinson’s disease (with L-dopa) treated with ropinirole who participated in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either ropinirole or placebo was used as an adjunct to L-dopa. Advanced Parkinson's Disease In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets and concomitant levodopa were postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency

The best add-on treatment for resistant tremors in patients already on carbidopa (L-Dopa) is ropinirole or pramipexole, as both have been shown to be effective in reducing symptoms of advanced Parkinson's disease, including tremors, when used as an adjunct to L-dopa 2 3.

• Key benefits of these treatments include:
  • Reduced tremor severity
  • Improved motor function
  • Enhanced quality of life
• Common adverse reactions associated with these treatments include:
  • Nausea
  • Somnolence
  • Dizziness
  • Confusion
  • Hallucinations

From the Research

Add-on Treatment Options for Resistant Tremors with Carbidopa

• The most effective add-on treatment for resistant tremors in patients already on carbidopa (L-Dopa) is a dopamine agonist, such as pramipexole 4.
• Pramipexole has been shown to be significantly superior to placebo in reducing tremor scores, with a mean absolute change in tremor score of -4.4 (95% CI -6.2 to -2.5) (p<0.0001) 4.
• Other dopamine agonists, such as cabergoline, may also be effective as add-on treatments for resistant tremors 5.
• The combination of two different dopamine agonists, such as cabergoline and pramipexole or ropinirole, may be used in the symptomatic treatment of patients with Parkinson's disease receiving therapy with or without levodopa 5.
• Anticholinergics, such as trihexiphenidyl, may also be effective in reducing parkinsonian tremor, but may not be as effective as dopamine agonists 6.

Key Findings

• Pramipexole is an effective agent for patients with Parkinson's disease and drug-resistant tremor, with a significant reduction in tremor scores compared to placebo 4.
• The treatment effects of pramipexole increase during dose titration and remain stable during the maintenance dose period 4.
• Dopamine agonists, such as pramipexole, are particularly well-suited for patients with newly diagnosed tremor-predominant disease and no cognitive impairment, but are also useful in advanced patients with tremor that is refractory to levodopa and anticholinergics 7.