Can primidone (anticonvulsant) cause restlessness at night, especially in patients with a history of sleep disorders or anxiety?

Can Primidone Cause Restlessness at Night?

Yes, primidone can cause restlessness at night, along with other neuropsychiatric side effects including insomnia, agitation, and anxiety, particularly when first starting the medication or in patients with pre-existing sleep or anxiety disorders. 1

FDA-Documented Neuropsychiatric Effects

The FDA label for primidone explicitly warns about several relevant side effects that can manifest as nighttime restlessness:

• Trouble sleeping (insomnia) is listed as a specific warning symptom that requires immediate medical attention 1
• New or worsening anxiety and feeling agitated or restless are documented adverse effects 1
• New or worsening irritability can occur, which may manifest as nighttime restlessness 1
• Sleepiness that can be severe is paradoxically also reported, particularly when first starting treatment 1

Acute Intolerance Syndrome

The most critical consideration is primidone's well-documented acute intolerance reaction after initial doses:

• 82% of patients experience acute neurotoxic symptoms when starting primidone without phenobarbital pre-treatment, including sedation, ataxia/unsteadiness, confusion, dizziness, and nausea 2
• Acute toxic side effects occur maximally after just 2 doses in the majority of patients (10 of 13 in one study), producing sedation and giddiness that could manifest as restlessness 3
• These acute effects are related to primidone itself rather than its metabolites (phenobarbital and phenylethylmalonamide) 3

Clinical Context and Risk Factors

Patients with pre-existing sleep disorders or anxiety are at particular risk for experiencing restlessness with primidone:

• The medication can cause both sedation and paradoxical activation/agitation 1
• Primidone is metabolized to phenobarbital, and the conversion rate is highly variable between individuals 4
• The therapeutic drug monitoring shows primidone levels of 5-10 mg/L are therapeutic, but individual responses vary significantly 4

Practical Management Strategies

If restlessness at night occurs with primidone:

• Consider phenobarbital pre-treatment (10 mg/day for 2-3 weeks) before starting primidone, which reduces acute intolerance from 82% to 17% 2
• Start with very low doses (62.5 mg) and titrate slowly to minimize acute neurotoxic effects 2, 3
• Monitor for the full spectrum of neuropsychiatric symptoms including anxiety, agitation, and mood changes that the FDA requires reporting 1
• Assess timing of administration - if restlessness occurs at night, consider whether it's related to peak drug levels or withdrawal/rebound effects 3

Important Caveats

• Do not abruptly discontinue primidone if restlessness occurs, as sudden cessation can cause serious problems including status epilepticus in epilepsy patients 1
• Rare psychiatric complications have been reported, including one case of catatonic schizophrenia with supratherapeutic levels 5
• The medication requires close monitoring especially in the first weeks of treatment when acute intolerance is most likely 2, 3