From the Guidelines
Refractory Parkinson's disease management should prioritize adjusting medication regimens and considering advanced therapies, with a focus on improving motor symptoms and quality of life, as evidenced by recent guidelines 1.
Medication Adjustments
When managing refractory Parkinson's disease, medication adjustments are crucial. Options include:
- Increasing levodopa doses (up to 1500-2000mg daily in divided doses)
- Adding COMT inhibitors like entacapone (200mg with each levodopa dose) or opicapone (50mg once daily)
- Using MAO-B inhibitors such as rasagiline (1mg daily) or safinamide (50-100mg daily)
- Adding dopamine agonists like pramipexole (up to 4.5mg daily) or rotigotine patches (up to 16mg/24hr) These adjustments aim to optimize dopaminergic stimulation and reduce motor fluctuations.
Advanced Therapies
When medications fail to provide adequate control, advanced therapies should be considered, including:
- Deep brain stimulation (DBS) targeting the subthalamic nucleus or globus pallidus
- Continuous levodopa-carbidopa intestinal gel infusion (Duopa/Duodopa)
- Subcutaneous apomorphine infusion (2-6mg/hr during waking hours) These approaches work by either modulating abnormal brain circuitry (DBS) or providing more continuous dopaminergic stimulation to reduce motor fluctuations.
Non-Motor Symptoms
Non-motor symptoms like depression, cognitive impairment, and autonomic dysfunction should also be addressed with appropriate medications and therapies. Regular physical therapy, occupational therapy, and speech therapy are essential components of comprehensive management to maintain function and quality of life in refractory Parkinson's disease.
REM Sleep Behavior Disorder (RBD)
In patients with refractory Parkinson's disease and secondary RBD, treatment options include:
- Clonazepam (starting at 0.25 mg) 1
- Immediate-release melatonin (starting at 3 mg and increasing by 3-mg increments to 15 mg) 1
- Rivastigmine, an acetylcholinesterase inhibitor, may be considered for patients with RBD and cognitive impairment refractory to other treatments 1 The use of deep brain stimulation (DBS) is not recommended for the treatment of secondary RBD due to medical condition in adults, as it has not demonstrated improved control of dream enactment among patients with PD with RBD 1.
From the FDA Drug Label
The primary efficacy endpoint for Study 1 was the change in total daily OFF time assessed from baseline to the end of the 12-week treatment period based on patient diaries. There was a statistically significant reduction in the amount of daily OFF time in patients treated with ONAPGO compared to placebo (p=0.0114; see Table 2). There was also a statistically significant increase in daily ON time without troublesome dyskinesia in patients treated with ONAPGO compared to placebo (p=0. 0188; see Table 3).
Apomorphine (SQ) is effective in reducing daily OFF time and increasing daily ON time without troublesome dyskinesia in patients with refractory Parkinson's disease who have motor fluctuations while receiving carbidopa/levodopa and other concomitant medications to treat PD, as shown in Study 1 2.
- The study demonstrated a statistically significant reduction in daily OFF time and a statistically significant increase in daily ON time without troublesome dyskinesia in patients treated with apomorphine (SQ) compared to placebo.
- The results suggest that apomorphine (SQ) may be a useful treatment option for patients with refractory Parkinson's disease who experience motor fluctuations.
From the Research
Definition and Treatment of Refractory Parkinson's Disease
- Refractory Parkinson's disease refers to a progressive neurodegenerative condition characterized by bradykinesia, tremor, rigidity, and postural instability, which becomes challenging to treat with medications alone 3.
- The treatment of refractory Parkinson's disease often involves deep brain stimulation (DBS), which has become a crucial player in treating patients with disabling motor complications from medical treatment 3.
- DBS targets include the subthalamic nucleus (STN), the globus pallidus pars interna (GPi), and the ventral intermediate nucleus (VIM) of the thalamus, with ongoing studies exploring alternative targets for refractory axial motor symptoms and other motor and nonmotor symptoms 3.
Medication Management and "Wearing Off" Phenomenon
- Medications such as carbidopa/levodopa, rasagiline, and entacapone are commonly used to treat Parkinson's disease, but require careful titration and monitoring due to potential side effects and the "wearing off" phenomenon 4.
- The "wearing off" phenomenon refers to the gradual decrease in medication efficacy over time, leading to a resurgence of symptoms, and highlights the need for individualized treatment approaches and vigilant supervision 4.
Treatment Approaches for Early and Advanced Parkinson's Disease
- Early Parkinson's disease treatment should focus on patient education, counseling, and pharmacologic intervention when functional disability appears, with dopamine agonists and levodopa being common initial treatments 5, 6.
- Advanced Parkinson's disease treatment may involve the use of catechol-O-methyl-transferase inhibitors, neurosurgery, and other therapies to manage motor fluctuations and nonmotor symptoms 5, 7.
- The choice of treatment should be tailored to the individual patient's needs, taking into account factors such as age, symptoms, and comorbidities 5, 6.
Pharmacological Treatment of Tremor in Parkinson's Disease
- Levodopa is the most efficacious drug for controlling troublesome tremor in Parkinson's disease, with oral dopamine agonists and anticholinergics also being effective in some cases 7.
- Propranolol and clozapine may be considered as adjunctive treatments for patients with insufficient tremor response to levodopa, and deep brain stimulation and focused ultrasound are first-line considerations for patients with drug-refractory tremor 7.