Parkinson's Disease Management

See Also

Management
General Measures

Consult neurology
1. Especially for all patients with onset under age 60 years
Adjunctive services
1. Group support
2. Disease specific education
3. Nutrition guidance (Healthy Diet)
  1. Maintain adequate hydration
  2. Adequate Protein and calorie intake
  3. Levodopa timing at least 30-45 minutes before a high Protein meal
  4. Vitamin D Supplementation
  5. Calcium Supplementation
4. Avoid Herbals and supplements to treat Parkinsonism
  1. No evidence of benefit (including Vitamin E)
Exercise guidance (consider physical therapy Consultation)
1. Stretching
2. Strengthening
3. Balance training
4. Voice training
Medications
1. See Levodopa
2. See Dopamine Agonist
3. See treatment algorithm below
4. See adjunctive managament below
Surgical management
1. See Thalamic Stimulation (Deep Brain Stimulation)

Management
Treatment Algorithm

See medication details below for dosing and adverse effects
Precautions
1. Medications do not slow Parkinsonism progression
  1. Focus on symptom management that maintains function, yet limits medication adverse effects
  2. Start medications at low dose, and slowly advance to the lowest effective dose
2. Levodopa is the most effective agent, but has serious Extrapyramidal Side Effects
3. Longterm Levodopa causes Dyskinesias (e.g. Choreiform movement) that may be permanent
  1. Dyskinesia is higher risk at younger ages
  2. Onset in up to 50% within 4-6 years (and in 100% by 20 years)
4. Delay starting Levodopa until it is indicated (see protocol below)
  1. However, start when there is any impact on activity
No functional deficit (normal ADLs, quality of life)
1. No medications needed
2. See General Measures above
Age <65 years
1. Significant Motor Symptoms
  1. Carbidopa/Levodopa (Sinemet)
2. Mild Motor Symptoms
  1. Monoamine oxidase Type B inhibitor (MAOB Inhibitor, e.g. Selegilene)
  2. Consider agents to reduce Tremor (e.g. Anticholinergics, Amantadine)
  3. If progression, add Non-ergot Dopamine Agonist (e.g. Pramipexole)
  4. If progression, add Carbidopa/Levodopa (Sinemet)
Age >65 years or Cognitive Impairment
1. Significant Motor Symptoms
  1. Carbidopa/Levodopa (Sinemet)
2. Mild Motor Symptoms
  1. Monoamine oxidase Type B inhibitor (MAOB Inhibitor, e.g. Selegilene)
  2. If progression, add Carbidopa/Levodopa (Sinemet)
Adjuncts to Carbidopa/Levodopa for refractory symptoms and Late-Stage Parkinsonism
1. Decrease Carbidopa/Levodopa doses up to 30% when adding a second agent (decrease adverse effects)
2. Freezing Movement
  1. Intranasal Levodopa (Inbrija)
  2. Immediate-Release Levodopa (low dose)
  3. Apomorphine (Apokyn)
3. Motor functuations (on-off fluctuations in motor activity, and off-time management)
  1. Modify Carbidopa/Levodopa (Sinemet) doses and intervals
  2. Add second agent
    1. Monoamine oxidase Type B inhibitor (MAOB Inhibitor, e.g. Selegilene)
    2. Non-ergot Dopamine Agonist (e.g. Pramipexole)
    3. Catechol O-methyltransferase Inhibitors (COMT Inhibitors, Entacapone)
4. Dyskinesias (involuntary Choreiform movements)
  1. Decrease medication dosing (Carbidopa/Levodopa, Non-ergot Dopamine Agonist)
  2. Amantadine
Additional Refractory Measures
1. Intrajejunal Levodopa
2. Deep Brain Stimulation

Management
Medication Details

Carbidopa/Levodopa (Sinemet, Rytary)
1. See Carbidopa/Levodopa (Sinemet)
2. Immediate release (Sinemet or the more rapid onset Rytary) start at 25/100 orally three times daily
  1. May titrate up by one tablet every 1-2 days as needed up to 3 tabs three times daily
  2. Longterm, frequency may need to increase to 4-6 times daily (early wearing off)
3. Preparations
  1. Immediate release is preferred over the sustained release product (other than Rytary)
  2. Carbidopa/Levodopa Enteral Suspension (Duopa) is infused over 16 hours per day
  3. Inbrija (inhaled Levodopa) is indicated for prn "off-time"
Monoamine oxidase Type B inhibitor (MAOB Inhibitor)
1. General
  1. Indicated in early mild motor symptoms
  2. Less effective than Sinemet or Dopamine Agonists
    1. However, fewer adverse effects including less Dyskinesia
    2. May cause Dizziness, hallucinayions, Nausea, vivid dreams and Headaches
2. Preparations
  1. Selegiline HCL (Eldepryl) 5 mg at breakfast and lunch
    1. Available generically for $90/month
    2. Contrast with Rasagaline for $430, Safinamide for $670
  2. Rasagiline (Azilect) 0.5 mg orally daily (may be increased to 1 mg orally daily)
  3. Safinamide (Xadago) 50 mg orally daily (may be increased to 100 mg orally daily after 2 weeks)
Anticholinergic Medications
1. Indicated in early treatment of predominant Tremors
  1. Not effective in Bradykinesia or Dyskinesia
2. Preparations
  1. BenztropineMesylate (Cogentin)
    1. Dose: Start at 0.5 mg at bedtime
    2. May titrate dose by 0.5 mg weekly up to 6 mg/day divided 2-4 times daily
  2. Trihexyphenidyl HCl (Artane)
    1. Dose: Start at 1 mg daily
    2. May titrate dose by 2 mg weekly up to 15 mg/day divided 3-4 times daily
3. Adverse effects (limit use of Anticholinergics to under age 70 years, see Beers Criteria)
Non-ergot Dopamine Agonists
1. Effective control of motor symptoms with reduced of-time (esp. age <60 years old)
  1. However, less effective than Levodopa
2. Adverse effects include Somnolence, hallucations, decreased impulse control (e.g. Gambling Addiction)
  1. However have lower risk of Dyskinesia than than Levodopa
  2. Avoid in patients with Psychosis or addictions
3. Dosing
  1. Start at low dose and may titrate to symptom control every 5-7 days
  2. When stopping agents, taper off over 2-3 weeks
4. Pramipexole (Mirapex)
  1. Immediate Release start 0.125 mg three times daily (may increase by 0.125-0.25 mg/week up to 4.5 mg/day)
  2. Extended Release start 0.375 mg daily (may increase by 0.75 mg/week up to 4.5 mg/day)
5. Ropinirole (Requip)
  1. Immediate Release start 0.25 mg three times daily (may increase by 0.25 mg/week up to 24 mg/day)
  2. Extended Release start 2 mg daily (may increase by 2 mg/week up to 24 mg/day)
6. Rotigotine (Neupro) transdermal patch
  1. Apply once daily (available in 1, 2, 3, 4, 6 and 8 mg)
7. Apomorphine
  1. Dopamine Agonist prn for off-time and severe motor freezing episodes
  2. Start at low dose with first dose in office with Blood Pressure and pulse monitoring
  3. Give with Antiemetic (NOT Zofran due to interaction causing Hypotension, Syncope)
  4. Titrate to effective dose every few days
  5. Preparations
    1. Apomorphine SQ Injection (Apokyn) (30 mg/3 ml) pen in marked in ml (not mg)
    2. Apomorphine Sublingual Film (Kynmobi)
Amantadine HCL (Gocovri, Osmolex, Symadine, Symmetrel)
1. Decreases Levodopa induced motor disorder (only agent to reduce Dyskinesias)
  1. Dyskinesia reducing effect may be only modest and may last for less than 8 months
2. Continue long-term and taper off over 2 weeks when discontinuing
3. Dosing (start low dose)
  1. Immediate-Release 100 mg orally once to twice daily
  2. Extended-Release (Gocovri, Osmolex) orally daily
4. Metman (1999) Arch Neurol 56:1383-6 [PubMed]
Catechol O-methyltransferase Inhibitors (COMT Inhibitors)
1. Indications
  1. Late-stage Parkinson's Disease to minimize off periods
  2. Extends Levodopa Half-Life to reduce off-time (not indicated as monotherapy)
2. Adverse Effects
  1. Orthostatic Hypotension
  2. Carbidopa/Levodopa related Dyskinesias may worsen
  3. Urine Discoloration (dark orange-brown)
  4. Constipation
3. Agents
  1. Entacapone (Comtan) 200 mg with each dose of Carbidopa/Levodopa up to 8 doses (1600 mg/day)
    1. Available as a combination with Carbidopa/Levodopa (Stalevo)
  2. Opicapone (Ongentys) 50 mg once nightly
    1. Decrease dose to 25 mg daily if moderate hepatic dysfunction
  3. Tolcapone (Tasmar) - avoid
    1. Rare lethal hepatotoxicity (closely watch Liver Function Tests)
Inbrija (inhaled Levodopa)
1. Indicated in off-time motor rigidity or Tremor
2. Rapid onset (10 min after inhalation) and duration of 1 hour used for prn "off time" rigidity or Tremor
3. Less expensive ($30/dose) than Apokyn ($200/dose), an injectable option for off-time
4. Requires dexterity to replace capsule in Inhaler
5. Avoid in underlying lung disease (e.g. Asthma, COPD) due to bronchospasm risk
6. (2019) Presc Lett 26(5)
Adenosine A2A Antagonist
1. Istradefylline (Nourianz)
  1. Marketed as non-Dopaminergic adjunct for off-time symptoms (e.g. Tremor)
  2. Dose 20 mg orally daily
  3. However, efficacy is low, cost is high ($1500/month) and has adverse effects (e.g. Dyskinesias, Hallucinations)
  4. (2020) presc lett 27(2): 10-1

Management
Miscellaneous Non-motor Conditions

Constipation
1. Increase fluid and fiber intake
2. Wean Anticholinergics
3. Consider Probiotics
4. Consider polyethylene gylcol (Miralax), and add additional bowel regimen agents as needed
5. Consider Lubriprostone (Amitiza) in refractory cases
Major Depression
1. Cognitive Behavioral Therapy
2. Serotonin-Norepinephrine reuptake inhibitors (e.g. Venlafaxine) are preferred first-line agents
3. Selective Serotonin Reuptake Inhibitor (SSRI)
4. Motor agents may have Antidepressant effects (MAOB Inhibitor, Non-ergot Dopamine Agonists)
Cognitive Impairment (Dementia)
1. Present in 60% of Parkinsonism patients by 12 years from Parkinsonism onset
2. Wean any Anticholinergics
3. Consider Cholinesterase Inhibitors (e.g. Rivastigmine)
Dysphagia
1. Swallowing evaluation
2. Use adjuncts to extend medication active time
3. Eat during "on" time and stick to soft foods
Drooling
1. Non-pharmacologic Interventions with speech therapy referral are first-line
2. Glycopyrrolate
3. Onabotulinum Toxin A (Botox)
Urine urgency and Urinary Incontinence
1. Solifenacin (Vesicare)
2. Mirabegron (Myrbetriq)
3. Oxybutynin (Ditropan)
Psychosis or Hallucinations
1. Wean Anticholinergics, Dopamine Agonists (e.g. Amantadine, Benztropine, selegeline)
2. Decrease Levodopa dosing
3. Consider low dose Antipsychotics
  1. Clozapine (Clozaril)
  2. Quetiapine (Seroquel) 12.5 mg daily
4. Avoid harmful agents
  1. Avoid Nuplazid (Pimavanserin, Serotonin-selective agent) until further study
    1. Expensive with potential for serious adverse effects
    2. http://www.fiercebiotech.com/regulatory/updated-fda-s-internal-review-of-acadia-s-parkinson-s-drug-raises-safety-benefit
  2. Avoid Zyprexa
    1. Ineffective for Psychosis in Parkinsonism
    2. Exacerbates motor symptoms
  3. Avoid Haloperidol
    1. Exacerbates motor symptoms, and adverse effects may be severe
Fatigue (one-third of Parkinsonism patients)
1. Carbidopa-Levodopa is associated with less Fatigue
2. Methylphenidate (Ritalin) may improve Fatigue
Orthostatic Hypotension
1. Educate on nonpharmacologic measures and lifestyle
2. Reduce Antihypertensives
3. Reduce dosing of Anticholinergic Medications and Dopamine Agonists
4. Consider Midodrine, Fludrocortisone in refractory cases
Sleep disturbance
1. Daytime Somnolence (>50% of Parkinsonism patients)
  1. Stop Dopamine Agonists
  2. Modafinil (Provigil)
    1. Do not use to prevent sleep attacks
2. Insomnia
  1. Melatonin
  2. Ramelteon (Rozerem)
3. Sleep attacks
  1. Do not perform hazardous duties
  2. Do not drive
  3. Do not operate machinery
4. Awakens from Bradykinesia
  1. Sinemet before bed or
  2. COMT Inhibitor or
  3. Dopamine Agonist
5. REM Sleep Behavior Disorder
  1. Presents with dramatic and sometimes violent activity during sleep (yelling, kicking, jumping)
  2. Decrease nighttime anti-parkinson drug dose
  3. Consider Melatonin
  4. Consider Clonazepam (Klonopin), starting at low dose
6. Restless Leg Syndrome
  1. See Restless Leg Syndrome for management

References

(2022) Presc Lett 29(5): 29-30
Ahlskog (2011) Mayo Internal Medicine Review Lecture
Schim (2001) CMEA Medicine Lecture, San Diego
Clarke (2003) Clin Evid 10:1582-98 [PubMed]
Clarke (2004) Lancet Neurol 3:466-74 [PubMed]
Gazewood (2013) Am Fam Physician 87(4): 267-73 [PubMed]
Halli-Tierney (2020) Amf fam Physician 102(11):679-91 [PubMed]
Nutt (2005) N Engl J Med 353:1021-7 [PubMed]
Olanow (2001) Neurology 56:S1-88 [PubMed]
Rao (2006) Am Fam Physician 74:2046-56 [PubMed]
Young (1999) Am Fam Physician 59(8):2155-67 [PubMed]