What is the next step for a patient with persistent tremors despite being on primidone (oral anticonvulsant) 50 milligrams (mg) per oral (po) daily?

Management of Persistent Tremors on Primidone 50 mg Daily

Increase the primidone dose to 250 mg three times daily (750 mg/day total), as the current 50 mg daily dose is substantially below the therapeutic range established by FDA labeling and clinical evidence. 1

Dose Titration Strategy

The patient is currently on a subtherapeutic dose. The FDA-approved dosing schedule for primidone should be followed:

• Days 1-3: 100-125 mg at bedtime
• Days 4-6: 100-125 mg twice daily
• Days 7-9: 100-125 mg three times daily
• Day 10 onward: 250 mg three times daily (maintenance dose) 1

Since the patient is already on 50 mg daily, you can accelerate this titration by starting at 100 mg at bedtime and advancing more quickly through the schedule, reaching the target maintenance dose of 250 mg three times daily within 10-14 days. 1

Target Therapeutic Dose

• Standard maintenance dose: 250 mg three to four times daily (750-1000 mg/day total) 1
• Therapeutic serum level: 5-12 mcg/mL of primidone 1
• Maximum dose if needed: Up to 500 mg four times daily (2000 mg/day), though this is rarely necessary 1

Research demonstrates that while low doses (250 mg/day) can be effective for essential tremor, they are not more effective than higher doses (750 mg/day), and the current 50 mg dose is far below even the low-dose threshold studied. 2

Evidence Supporting Dose Escalation

Primidone and propranolol are first-line agents for essential tremor, with approximately 50% of patients achieving adequate tremor control. 3 The medication works through both primidone itself and its metabolite phenobarbital, which requires adequate dosing to reach therapeutic levels. 4, 5

Clinical trials show that:

• Both 250 mg/day and 750 mg/day doses provide significant tremor reduction compared to baseline 2
• Higher doses (750 mg/day) do not necessarily provide better tremor control but may cause more side effects 2
• The therapeutic effect is maintained over 12 months at appropriate doses 2

Managing Side Effects During Titration

Common early side effects occur in the first 48-72 hours and include:

• Acute sedation, vertigo, nausea, and ataxia 6, 5
• These effects typically resolve with continued use as tolerance develops 3, 6
• Approximately 15-30% of patients may not tolerate primidone due to these early effects 3, 6, 5

Key strategies to minimize side effects:

• Use gradual dose escalation as outlined above 1
• Take initial doses at bedtime to sleep through peak side effects 1
• Reassure patients that early side effects typically resolve within days 6
• Very slow titration using suspension formulations does not appear to improve tolerability compared to standard tablet titration 6

Alternative Approaches if Dose Escalation Fails

If the patient cannot tolerate higher primidone doses or tremor persists despite reaching 750-1000 mg/day:

1. Add propranolol (if no contraindications like asthma or heart block): Start 40 mg twice daily, increase to 120-320 mg/day in divided doses 3

2. Combine primidone with propranolol: The two medications can be used together for additive effect 3

3. Consider alternative medications:

   • Gabapentin or topiramate as second-line agents 3
   • Benzodiazepines (clonazepam) for intermittent use 3

4. Surgical options if medication-refractory: Deep brain stimulation or thalamotomy provide tremor control in approximately 90% of patients with medication-resistant essential tremor 3

Monitoring Parameters

• Assess tremor severity using standardized scales at each follow-up visit 2
• Check serum primidone levels if response is inadequate at appropriate doses (target 5-12 mcg/mL) 1
• Monitor for drug interactions: Primidone induces CYP3A4 and may affect other medications 4
• Avoid concurrent use with strong CYP450 inducers (rifampin, carbamazepine, phenytoin) which decrease primidone efficacy 4

Critical Pitfall to Avoid

Do not continue the current 50 mg daily dose expecting therapeutic benefit. This dose is approximately 5-15 times lower than the established therapeutic range and will not provide adequate tremor control. 1, 2 The patient requires systematic dose escalation to the standard maintenance range of 750-1000 mg/day to achieve meaningful tremor reduction. 1, 3