What are the first‑line pharmacologic treatment options for focal (partial) seizures?

First-Line Pharmacologic Treatment Options for Focal Seizures

For adults and children with newly diagnosed focal (partial) seizures, carbamazepine and lamotrigine are the recommended first-line monotherapy options, with levetiracetam emerging as an equally effective alternative that may be preferred in certain clinical situations. 1

Primary First-Line Agents

Carbamazepine

• Carbamazepine remains a cornerstone first-line treatment for focal onset seizures, demonstrating high efficacy in achieving seizure control and long-term remission 1, 2
• Particularly well-suited for men and patients without concerns about drug interactions 3
• Shows superior performance compared to gabapentin for 12-month remission outcomes 1
• Requires monitoring for potential adverse effects including drowsiness, dizziness, and rash 1

Lamotrigine

• Lamotrigine demonstrates the best overall treatment profile among all antiepileptic drugs for focal seizures, with significantly lower treatment failure rates compared to most other agents 1
• Performs better than carbamazepine in terms of treatment failure for any reason (HR 1.26,95% CI 1.10-1.44) and treatment failure due to adverse events 1
• Particularly preferred for women of childbearing potential due to lower teratogenic risk compared to valproate 1, 3
• Demonstrates high-certainty evidence for superior tolerability while maintaining equivalent seizure control efficacy 1

Levetiracetam

• Levetiracetam shows equivalent efficacy to lamotrigine with no significant difference in treatment failure outcomes (HR 1.01,95% CI 0.88-1.20) 1
• Offers the advantage of minimal cardiovascular effects and no requirement for cardiac monitoring 4
• Demonstrates 68-73% efficacy in controlling seizures with favorable tolerability profile 4, 1
• Represents an excellent alternative first-line option, particularly in elderly patients or those with cardiac comorbidities 4

Alternative First-Line Considerations

Oxcarbazepine

• Approved for monotherapy in many countries and demonstrates good efficacy for focal seizures 5, 2
• May be considered when carbamazepine is not tolerated, though shows slightly higher treatment failure rates compared to lamotrigine (HR 1.30,95% CI 1.02-1.66) 1

Zonisamide

• Shows comparable performance to lamotrigine with no significant difference in treatment failure (HR 1.18,95% CI 0.96-1.44) 1
• Supported by high-certainty evidence as an effective first-line option 1

Agents to Avoid as First-Line Treatment

Phenytoin

• Should not be used as first-line therapy due to significantly higher treatment failure rates compared to lamotrigine (HR 1.44,95% CI 1.11-1.85) 1
• Associated with 12% hypotension risk and requires continuous cardiac monitoring 4
• Generally considered a last-choice drug due to adverse effect profile 5

Phenobarbital

• Performs significantly worse than all other options for treatment withdrawal in focal seizures 6
• Shows the highest treatment failure rate compared to lamotrigine (HR 1.97,95% CI 1.45-2.67) 1
• Should be reserved as a last-resort option due to adverse effects including sedation and cognitive impairment 5

Valproate

• While effective, valproate is not recommended as first-line for focal seizures and shows higher treatment failure rates than lamotrigine (HR 1.35,95% CI 1.09-1.69) 1
• Absolutely contraindicated in women of childbearing potential without explicit discussion of teratogenic risks 6, 1

Clinical Decision Algorithm

Step 1: Assess patient characteristics

• Gender and reproductive potential: If female of childbearing age → lamotrigine or levetiracetam preferred 1, 3
• Age: If elderly → levetiracetam or lamotrigine preferred due to better tolerability 4, 3
• Cardiac comorbidities: If present → levetiracetam preferred (no cardiac monitoring required) 4

Step 2: Select initial agent

• Default choice: Lamotrigine (best overall profile for treatment failure and tolerability) 1
• Alternative: Levetiracetam (equivalent efficacy, simpler monitoring) 1
• Traditional option: Carbamazepine (particularly for men, established efficacy) 1, 3

Step 3: Initiate monotherapy

• Start with a single agent at appropriate dose 6
• Titrate to maximum tolerated dose before considering treatment failure 4
• Monitor for common adverse effects: drowsiness, headache, gastrointestinal disturbances, dizziness, rash 1

Critical Pitfalls to Avoid

• Never use phenobarbital as first-line treatment due to significantly inferior outcomes 6, 1
• Do not prescribe valproate to women of childbearing potential without contraceptive measures and explicit teratogenic risk discussion 6, 1
• Avoid combination therapy initially—monotherapy is preferred to minimize adverse effects and drug interactions 6
• Do not routinely prescribe antiepileptic drugs after a single unprovoked seizure—wait for a second seizure unless specific high-risk features are present 7, 6