Parkinson's Disease: A Healthcare Professional's Guide
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Mar 8, 2020.
Parkinson's Disease: Etiology
Parkinson's disease (PD) is a progressive, chronic neurological condition, and affects more than 10 million people worldwide. In the US, approximately 60,000 Americans are diagnosed each year and roughly one million are living with PD. It occurs mainly in those over the age of 60, although older and much younger people may be diagnosed, as well. Four percent of people with PD are diagnosed before age 50, and men are 1.5 times more likely to have Parkinson's disease than women.
The cause of PD is still not fully known, but research is ongoing to identify biomarkers.
- It is known that neurons in the substantia nigra die and dopamine production declines, leading to progressive disease.
- Most research suggests that Parkinson's disease is due to a complicated mix of genetics and one's environment; however, only about 15% of those with PD also have a first-degree relative with PD.
Typical Signs and Symptoms of PD
Resting tremor, bradykinesia, and rigidity are the cardinal movement symptoms of PD.
- Tremor, often seen in the hands, arms, legs, jaw, lips and face, tends to occur at rest (when relaxed) instead of during purposeful movement.
- Unilateral tremor in the hand may often be the first noticed symptom.
- Bradykinesia is seen in most patients but may not be a presenting sign.
- Rigidity may be present in the trunk and limbs.
- Feet shuffling, gait freezing, quick walking pace, loss of manual dexterity, and micrographia (small handwriting) may appear.
- Postural instability and lack of coordination, both added risk factors for falling, often occurs later in the course of the disease.
Diagnosis of PD
Parkinson's disease is almost always diagnosed with a clinical evaluation, not a neurodiagnostic test.
- Bradykinesia, plus either tremor or rigidity, should be present for a diagnosis of idiopathic PD.
- Symptoms that first occur on one side (unilateral) and a resting tremor are other diagnostic clues.
- If a patient's symptoms improve after taking dopaminergic medication, such as levodopa or a dopamine agonist, this supports the diagnosis.
Differential Diagnosis in Parkinson's Disease
The differential diagnosis list for Parkinson's disease is long. An evaluation by a qualified neurologist is important in Parkinson's disease, as many other syndromes can mimic its symptoms.
Other conditions that may be mistaken for PD include:
Risk Factors with Parkinson's Disease
Proposed Risk Factors
- Older Age
- Family history
- Industrial/toxin/occupational exposures (e.g., manganese)
- Head Trauma (e.g., concussions)
- Certain genetic traits
- Being male
Pharmacotherapy of Parkinson's Disease
Ironically, medications used to treat the motor symptoms of PD can lead to dyskinesias (movement disorders). Knowing when to initiate treatment, add or discontinue agents, and adjust dosing can help to modify adverse events.
Agents used in PD treatment include:
Carbidopa/Levodopa: The Standard for Decades
- Carbidopa/levodopa (brands include: Parcopa, Sinemet, Sinemet CR, Rytary, and generic options) has been a mainstay of PD since the 1960's.
Levodopa/carbidopa provides exogenous dopamine levels to the CNS and is considered the most effective therapy for symptoms. Carbidopa is included to prevent the peripheral conversion of levodopa to dopamine, lowering levodopa side effects such as nausea, vomiting and tachycardia.
Levodopa/carbidopa is most effective for the treatment of bradykinesia and rigidity, but less effective for tremor, freezing, and postural instability. There have been concerns of worsening involuntary movements with early use of levodopa. But a recent study suggests that concern is unfounded.
Nonetheless, treatments should be individualized and other early therapies, such as the MAO-B inhibitor rasagiline (Azilect) or dopamine agonists such as pramipexole (Mirapex) may be preferred for initial and/or combined therapy.
A prospective, placebo-controlled, randomized study published in the New England Journal of Medicine in 2019 looked at early versus delayed start of levodopa is 445 patients. A group of 445 early Parkinson's patients in the Netherlands were randomly assigned to either start levodopa therapy right away, or wait 40 weeks and then start taking the drug. Results demonstrated early use of levodopa did not lead to development of significantly different rates of involuntary movement, such as dyskinesias and "off" episodes. Researchers state it can be used more confidentally, but judiciously, in early disease when symptoms first appear. However, levodopa doesn't appear to provide any protection against progression of Parkinson's in the brain or have a disease-modifying effect.
Movement disorders like dyskinesias with carbidopa/levodopa can still be an issue with this drug. The timing of initial treatment with a neurologist is important, and symptoms should be present before initiation.
A wide range of other side effects may occur:
- nausea, vomiting
- postural hypotension
- low blood pressure
- dry mouth
- behavioral disturbances
- 'wearing off' phenomenon.
Levodopa-carbidopa can lose effectiveness completely over time or only at certain times during the day. Wearing-off is partly due to the short half-life of levodopa, which leads to swings in plasma levodopa levels. Older patients may experience hallucinations, and dyskinesias may be more common with levodopa doses over 300 mg per day. Transient GI side effects may be tempered by taking in divided doses with meals.
Options for carbidopa/levodopa forms:
- Immediate-release tablets (Sinemet)
- orally-disintegrating tablets (Parcopa, brand discontinued)
- Enteral suspension (Duopa)
- Controlled-release tablets (Sinemet CR)
- Rytary capsules, extended-release
See the individual monographs for the most recent dosing specifics.
Dosing is started at the low end to lessen acute GI effects. Give in divided daily doses with meals.
Dose may be titrated every 3 to 4 days based on tolerance. Taper doses gradually when discontinuing to lessen withdrawal effects.
End-of-Dose Wearing "Off"
The addition of entacapone to carbidopa/levodopa (brand: Stalevo) has been shown to lead to a greater degree of improvement in some Parkinson's disease symptoms than use of carbidopa/levodopa alone. Entacapone is a catechol-O-methyltransferase (COMT) inhibitor that boosts the effectiveness of levodopa by allowing a greater CNS penetration. Stalevo may be an option when patients experience end-of-dose "wearing-off" and when the patient's total daily doses of levodopa are 600 mg or less without experiencing dyskinesias.
In December 2018, the FDA cleared Acorda Therapeutics’ Inbrija (levodopa), an oral, dry powder inhalation for the treatment of "off" episodes in people with Parkinson’s disease already taking a carbidopa/levodopa regimen. In Phase 3 studies, a significant improvement in motor function was seen at week 12 compared to a placebo. Onset of action was seen as early as 10 minutes. Common side effects include cough, upper respiratory tract infection, nausea, and discolored sputum.
Dopamine Agonists: Another Tool
Dopamine agonists such as pramipexole (Mirapex, Mirapex ER), ropinirole (Requip, Requip XL), and transdermal rotigotine (Neupro) stimulate the post-synaptic dopamine receptors directly. This class causes less frequent dyskinesias than carbidopa/levodopa and can improve tremor, bradykinesia and rigidity.
- Dopamine agonists may be used first-line, especially in younger patients, to delay levodopa therapy and dyskinesias, and in combination with carbidopa/levodopa or MAOBIs.
- Dopamine agonists can provide good control of motor symptoms for several years before levodopa therapy is required. However, these drugs may not be as effective as carbidopa/levodopa for more advanced disease.
- Dopamine agonists are ineffective in patients who do not respond to levodopa.
Dopamine Agonists: ADRs
Dopamine agonists can result in numerous CNS dose-related side effects: nausea, orthostatic hypotension, hallucinations, confusion, edema, psychosis, sedation, sudden sleep attacks, and impulse control disorders such as gambling and sexual obsessions. Patients over 70 years may be especially prone to hallucinations with DAs.
- Initial treatment with dopamine agonists in early disease may delay treatment and dyskinesias associated with carbidopa/levodopa.
- However, dopamine agonist monotherapy many not be effective in advanced disease.
- Taking doses after meals may help to relieve nausea, and patients should be monitored closely.
- Dopamine agonists may be combined with MAOBIs in early disease to delay levodopa.
Dopamine Agonists: Formulations & Dosing
Available dopamine agonists for treatment of Parkinson's disease include:
- Bromocriptine (Parlodel) - rarely used clinically
- Pramipexole (Mirapex, Mirapex ER)
- Ropinirole (Requip, Requip XL)
- Rotigotine (Neupro Patch)
- Apomorphine (Apokyn)
The manufacturers of pergolide (Permax) drug products, also dopamine agonists, voluntarily removed these drugs from the U.S. market in 2007 because of the risk of serious damage to patients’ heart valves (valvulopathy). Two studies were published in 2007 in the NEJM warning of this risk.
Dopamine Agonists: Impulse Control Disorders
Parkinson's disease patients taking dopamine agonists may exhibit unusual behaviors, like compulsive shopping, gambling, or hypersexuality. In fact, impulse control disorders are found in roughly 10 percent of patients taking dopamine agonists.
A study published in JAMA Internal Medicine looked at over 10 years of safety data for these drugs and researchers reported that pramipexole (Mirapex) and ropinirole (Requip) were most frequently associated with this disorder. The compulsive behaviors usually improve or disappear when the dose is reduced or the drug is discontinued.
Place in Therapy: MAO-B Inhibitors
Monoamine oxidase functions in the CNS to metabolize dopamine to norepinephrine and 5-HT. MAO-B inhibitors block the metabolism and increase the availability of dopamine.
As monotherapy, MAO-B inhibitors only modestly reduce motor fluctuations and treat early, mild symptoms. They may be added to dopamine agonists or levodopa in more advanced disease and to help to reduce "off" time.
Rasagiline studies have established efficacy for both monotherapy and as an adjunct. However, selegiline studies are conflicting for adjunct treatment in later disease, although the use of selegiline monotherapy for mild symptoms has been shown to be effective.
In March 2017, a new MAO-B inhibitor Xadago (safinamide) was approved as an add-on treatment for patients with Parkinson’s disease who are currently taking levodopa/carbidopa and experiencing “off” episodes.
MAO-B Inhibitors: Dosing and Side Effects
In general, the side effect profile with MAO-B inhibitors is good. Commercially available MAO-B inhibitors include:
- selegiline, 5 mg tablets (Eldepryl) and 1.25 mg ODT (Zelapar)
- rasagiline (Azilect)
- safinamide (Xadago)
Selegiline is dosed once or twice a day with breakfast and lunch while rasagiline is given once a day. Zelapar is an orally-disintegrating tablet given once daily before breakfast without water. Xadago is given once daily as a tablet; it has not been shown to be effective as monotherapy for the treatment of Parkinson's disease; it is used only in combination with levodopa/carbidopa.
ADRs with MAO-B inhibitors can include stimulation, confusion (selegiline); arthralgia, dyspepsia, depression, flu-like syndrome, and constipation (rasagiline); dyskinesia, fall, nausea, and insomnia (safinamide). Dizziness, headaches and worsening of levodopa side effects can also occur.
Any MAO-B inhibitor should be slowly discontinued to lessen withdrawal side effects.
COMT Inhibitors: Entacapone, Tolcapone
COMTIs on the market include:
COMTIs, or catechol-O-methyltransferase inhibitors, are a useful adjunct to help manage motor fluctuations that do not respond to levodopa dose adjustments and help manage end-of-dose "wearing off". COMTIs block the peripheral metabolism of levodopa to 3-O-methyldopa, lengthening the dopamine half-life and boosting brain dopamine availability.
- Tolcapone is associated with liver toxicity, requires regular LFTs, and should be used only if other options to control motor fluctuation are inadequate.
- Entacapone (Comtan) does not require LFTs, and this drug is also available as a combo agent with levopdopa/carbidopa (Stalevo). Fixed dose combo agents often make dose titration difficult in Parkinson's disease, however.
COMTIs: Formulations and Dosing
- entacapone (Comtan): Available as a 200 mg tablet. Give 200 mg with each dose of levodopa up to a max of 1600 mg/day of entacapone (8 daily doses).
- carbidopa/levodopa/entacapone (Stalevo): Available in 6 strengths (12.5/50/200; 18.75/75/200; 25/100/200; 31.25/125/200; 37.5/150/200; 50/200/200). Stalevo dosing is available here.
- tolcapone (Tasmar): Available as 100 mg tablet. Give dose with carbidopa/levodopa up to 600 mg/day. Stop tolcapone therapy if no benefit after 3 weeks at the maximum dose.
- Taper COMTIs slowly to discontinue.
COMTIs: Adverse Effect Profile
COMTIs can lead to levodopa toxicity, including dyskinesias, hallucinations, and confusion, due to the fact that they boost levodopa availability in the CNS.
Patients should be warned that entacapone (Comtan), as well as the triple combo agent carbidopa/levodopa/entacapone (Stalevo) can cause the urine to turn orange.
There have only been very rare reports of liver toxicity with entacapone and LFTs are not required.
However, tolcapone can lead to hepatoxicity, including acute hepatic failure.
- AST/ALT should be followed at baseline, and then every 2 to 4 weeks for 6 months after initiation of treatment or any dose increase; then periodically.
- Tolcapone should only be used to control motor fluctuations in patients taking levodopa that can't be controlled with other medications.
Dyskinesias, hallucinations, and confusion are possible effects. Other common COMTI side effects include nausea/vomiting, diarrhea, orthostatic hypotension, and dizziness. Do not abruptly discontinue COMTIs, as it may lead to a syndrome of hyperpyrexia and confusion, a symptom complex resembling NMS.
Amantadine: An Antiviral for PD
Amantadine is an antiviral that has mild antiparkinsonian activity and may offer benefits to patients with bradykinesia, rigidity, or tremor.
Amantadine may provide short-term relief in mild, early-stage PD. It may also be given with carbidopa-levodopa in later stages to help control dyskinesias induced by carbidopa-levodopa. Immediate-release amantadine is available in 100 mg tablets or capsules and a 50 mg/5 mL syrup.
While its mechanism of action is unclear, amantadine appears to have positive dopaminergic effects.
A new formulation of amantadine, Osmolex ER, an extended-release option for treatment of Parkinson’s Disease and drug-Induced movement disorder, was FDA-approved in Feb. 2018. The once-daily tablet is a unique formulation of immediate-release and extended-release amantadine. The effectiveness of Osmolex ER is based upon bioavailability studies that compared Osmolex ER to immediate-release amantadine.
Amantadine: Dosing and Side Effects
Immediate-release amantadine is usually started at 100 mg/day and slowly titrated to an initial maintenance dose of 100 mg given 2 or 3 times daily; the maximum dose is 300 mg/day. Start at lower doses if combined with other PD meds, and taper slowly to stop treatment.
Osmolex ER comes as extended-release tablets containing 129 mg, 193 mg, or 258 milligrams (mg) of amantadine. The initial dosage is 129 mg once daily in the morning. The dosage may be increased in weekly intervals to a maximum daily dose of 322 mg once daily in the morning. Due to the ER formulation, patients should swallow the tablets whole, and not chew, crush, or divide. In patients with kidney disease, dosing adjustments are required.
Confusion and hallucinations may be the most concerning and troublesome side effect for patients and caregivers; other common side effects of amantadine include nausea, headache, dizziness, lightheadedness and insomnia. Less common side effects include livedo reticularis and peripheral edema.
Anticholinergics: Used for Tremor, But Problematic in the Elderly
- Anticholinergics can be used as monotherapy in patients younger than 60 to 65 whose main symptom is tremor.
- However, due to troublesome neuropsychiatric side effects like memory impairment, confusion, hallucinations, and delirium, especially in the elderly over 65 to 70 years, anticholinergics should be avoided in this age group.
- The Beers Guideline warns against use of anticholinergic drugs in the elderly when possible.
- Other typical side effects of anticholinergics include dry mouth, blurred vision, urinary retention, and constipation.
Anticholinergics: Dosing Considerations
Trihexyphenidyl is available as a 2 mg and 5 mg tablet, and as a 2 mg per 5mL elixir (see images here).
- Trihexyphenidyl dosing usually initiates at 1 mg once daily and is titrated up slowly; the typical maintenance dose is 2 mg given 3 times a day. Give with food. Taper slowly to stop treatment.
- Maximum dose of trihexyphenidyl is 15 mg/day in 4 divided doses.
- Benztropine doses are typically started at 0.5 to 1 mg once daily at bedtime, then are titrated slowly to a usual dose of 1 to 2 mg three times a day. Taper slowly to stop treatment.
- Maximum dose of benztropine is 4 to 6 mg; use lower doses in the elderly. Doses may be given 2 to 4 times daily.
Nuplazid Approved for Parkinson’s Disease Psychosis
Treatment of psychosis in PD patients can be tricky as antipsychotic drugs often alter dopamine levels that can adversely affect PD symptoms.
However, in May 2016 FDA approved Acadia’s once-daily Nuplazid (pimavanserin) tablets, the first atypical antipsychotic to treat hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Nuplazid exhibits inverse agonist and antagonist activity at serotonin 5-HT2A receptors and to a lesser extent at serotonin 5-HT2C receptors, but has no measurable activity at dopaminergic receptors.
In a six-week study, Nuplazid was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms of Parkinson’s disease.
The recommended dose of Nuplazid is 34 mg taken orally once daily (without titration). For patients taking strong CYP3A4 inhibitors reduce the Nuplazid dose to 10 mg once daily. Can be taken with or without food. Nuplazid comes as a 34-mg capsule and a 10-mg tablet.
Common side effects include: swelling (peripheral edema), nausea, and confusion. Nuplazid can also lead to QT interval prolongation.
In September 2018, the FDA finalized a post-marketing analysis that found no new or unexpected safety risks associated with Nuplazid.
Other Unique Agents
Although a Parkinson's disease cure does not yet exist, unique agents help to expand treatment options.
Duopa, approved in 2015, is a levodopa/carbidopa enteral suspension given via the small intestine using a surgically placed pump. Duopa, given over a 16 hour period, may help to lessen the “off times” as it can offer more stable plasma concentrations.
In 2014, droxidopa (Northera) was approved to help PD patients who have symptomatic neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure. NOH can lead to a fall in blood pressure when a Parkinson's patient stands, leading to dizziness or dangerous falls. Northera works by constricting (narrowing) the blood vessels and increasing blood pressure.
Long-Acting Gocovril Approved for Dyskinesias
In the U.S., roughly 150,000 to 200,000 people with Parkinson's disease are impacted by dyskinesia with limited treatment options. Dyskinesias are involuntary movements that occur due to levodopa-based Parkinson's disease treatment and can impact activities of daily living.
In August 2017, the FDA approved Gocovri (amantadine) extended-release capsules for treatment of dyskinesia in patients with Parkinson's disease receiving levodopa-based therapy, with or without dopaminergic medications.
- Gocovri is the first Parkinson's disease medicine proven in controlled trials to reduce both dyskinesia and off time in patients receiving levodopa.
- Gocovri is a high dose 274 mg amantadine (equivalent to 340 mg amantadine HCl) taken once-daily at bedtime.
- In studies, a statistically significant reduction in the Unified Dyskinesia Rating Scale was seen compared to placebo in two studies: 37% vs. 12%, respectively, in study 1, and 46% vs. 16% in study 2, both at 12 weeks.
The most commonly observed adverse reactions (>10% and greater than placebo) with Gocovri were hallucinations, dizziness, dry mouth, peripheral edema, constipation, fall and orthostatic hypotension.
Nourianz Approved to Treat "Off" Episodes in PD
During "off" episodes, medications are not working well and PD symptoms increase, which may include tremor and difficulty walking.
In 2019 the FDA approved Kyowa Kirin’s Nourianz (istradefylline), classified as an adenosine A2A receptor antagonist. Nourianz is used in conjunction with levodopa and carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes. It is a once-a-day oral treatment.
- Effectiveness of Nourianz was shown in four 12-week, placebo-controlled studies with over 1,100 participants already being treated with levodopa and carbidopa (Sinemet).
- Nourianz led to a statistically significant decrease from baseline in daily “off” time compared to patients receiving a placebo in all 4 studies.
- Common side effects include: involuntary muscle movement (dyskinesia), dizziness, constipation, nausea, hallucinations and difficulty sleeping (insomnia).
Advances: What About Neuroprotection?
Neuroprotective therapies could help to protect further loss of neurons in the brain and slow disease progression, but no such drugs have been approved for Parkinson's disease -- yet.
Agents in research for preventing, slowing or halting the progression of Parkinson's disease include:
- inosine - antioxidant that may have a protective effect or slow progression of PD; in Phase III studies.
- neurotrophic factors - GDNF may protect dopamine cells.
- BIIB054, NPT088, PD01A, and RO7046015 that target alpha-synuclein
- exenatide - an approved diabetes drug that has protected brain cells in pre-clinical Parkinson’s models.
These compounds, many funded and researched by the Michael J Fox Foundation, target proteins and pathways known to play a role in the disease.
Researchers have reported from Phase II studies that a cancer drug for leukemia, nilotinib (Tasigna) seemed to improve PD symptoms, possibly due to a dopamine boost. Further research with nilotinib is ongoing.
Lifestyles Changes to Augment Drug Therapy
While drug therapy is the cornerstone of treatment for most PD patients, lifestyle adjustments can have a major impact, too.
Eating habits, such as a healthy diet high in fiber and plenty of water can help to prevent constipation. Exercise, possibly with a physical therapist, can help to keep muscles stronger and improve flexibility and balance. Learning to avoid falls and maintaining activities of daily living can boost confidence and lengthen independence.
- Some patients and caregivers might find strength in joining the Drugs.com Support Group or Parkinson's disease news blog to voice concerns, share experiences, and keep up with the latest research.
- In addition, patients and families who may have an interest in joining a clinical trial should speak to their physician and can find additional information on the Michael J. Fox Foundation's Fox Trial Finder.
Finished: Parkinson's Disease: A Healthcare Professional's Guide
Alzheimer's disease is a top 10 cause of death in the U.S. Behavioral issues, caregiver concerns, failed drug trials, and a modest effect with drug treatment add to the pitfalls…
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- FDA Approves Inbrija (levodopa inhalation powder) for Intermittent Treatment of OFF Episodes in People with Parkinson’s Disease. New Drugs. Drugs.com. December 21, 2018. Accessed March 8, 2020 at https://www.drugs.com/newdrugs/fda-approves-inbrija-levodopa-inhalation-powder-intermittent-off-episodes-parkinson-s-4893.html
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