A 58-year-old woman with Parkinson's disease on levodopa + carbidopa for 5 years now experiences motor fluctuations ('on–off' phenomena) and involuntary movements during 'on' periods. Which drug is the preferred choice to manage her levodopa-induced dyskinesias?

Explanation

## Management of Levodopa-Induced Dyskinesias (LID) **Key Point:** Amantadine is the only FDA-approved and most effective drug specifically for reducing levodopa-induced dyskinesias in advanced Parkinson's disease. It works via NMDA receptor antagonism and is the preferred agent when dyskinesias become troublesome. ### Mechanism of Amantadine in LID 1. **NMDA antagonism**: Blocks excitatory glutamatergic transmission in the striatum 2. **Dopamine release**: Enhances dopamine release from remaining neurons 3. **Receptor sensitization**: Reduces abnormal sensitization of dopamine receptors that develops with chronic levodopa exposure 4. **Efficacy**: Reduces dyskinesia severity by 20–50% in responders ### Comparison of Options in Advanced PD | Drug | Class | Primary Role | Effect on Dyskinesias | Effect on Motor Symptoms | |------|-------|--------------|----------------------|------------------------| | **Amantadine** | NMDA antagonist | Dyskinesia reduction | ↓↓ Reduces dyskinesias | Mild improvement | | Entacapone | COMT inhibitor | Extend levodopa effect | No direct effect; may worsen if dose not adjusted | ↑ Prolongs 'on' time | | Pramipexole | Dopamine agonist | Adjunctive motor control | No direct effect; may worsen | ↑ Improves motor symptoms | | Trihexyphenidyl | Anticholinergic | Tremor control | No effect on dyskinesias | ↑ Mild tremor benefit only | **High-Yield:** Amantadine is the **only agent with proven efficacy specifically for reducing dyskinesias**. It is distinct from agents that extend levodopa effect (COMT inhibitors, MAO-B inhibitors) or improve motor symptoms (dopamine agonists). When dyskinesias are the primary problem in advanced PD, amantadine is the answer. **Clinical Pearl:** Amantadine typically requires 2–4 weeks to show benefit and is often combined with other agents. Doses are typically 100 mg BD to TDS. Renal function must be monitored (renally excreted). **Warning:** Do not confuse dyskinesia management with motor symptom management. Entacapone and pramipexole improve motor symptoms but do not reduce dyskinesias; they may even worsen them if levodopa dose is not reduced. Anticholinergics like trihexyphenidyl are ineffective for dyskinesias. ### Algorithm for Advanced PD with Dyskinesias ```mermaid flowchart TD A[Advanced PD on levodopa with dyskinesias]:::outcome --> B{Primary problem?}:::decision B -->|Dyskinesias| C[Add amantadine]:::action B -->|Motor fluctuations + dyskinesias| D[Reduce levodopa dose + add amantadine]:::action B -->|Motor fluctuations only| E[Add COMT inhibitor or MAO-B inhibitor]:::action C --> F[Reassess in 2–4 weeks]:::outcome D --> F E --> F ```