Parkinson's Disease: A Healthcare Professional's Guide
Parkinson's Disease: Etiology
Parkinson's disease (PD), a progressive, chronic neurological condition, occurs in roughly 1 in 100 people over the age of 60, although older and much younger people may be diagnosed, as well. One million people in the U.S. and 5 million worldwide are estimated to be living with PD.
The prevalence of PD rises with age, and by 2030 further projections suggest that over 9 million people may be diagnosed.
The cause of PD is still not fully known and no biomarkers have been identified yet, but research is ongoing. 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 percent 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.
What Else Could It Be? Differential Diagnosis
The differential diagnosis list for Parkinson's disease is long. An evaluation by a qualified neurologist is important in PD, as many other syndromes can mimic its symptoms. Other conditions that may be mistaken for PD include:
Risk Factors and Protective Factors Linked With PD
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 (Parcopa, Sinemet, Sinemet CR, generics) 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 in PD. Carbidopa prevents the peripheral conversion of levodopa to dopamine, lowering levodopa side effects such as nausea/vomiting and tachycardia.
However, it may be preferred to use other treatments first, such as a MAOBI, especially in mild disease, as prolonged treatment with dopamine agonists or carbidopa/levodopa is associated with dyskinesias and "off" episodes. Levodopa/carbidopa is most effective for the treatment of bradykinesia and rigidity, but less effective for tremor, freezing, and postural instability.
Movement disorders like dyskinesias with carbidopa/levodopa can be problematic and irreversible; that is why the timing of initial treatment with a neurologist is important. A wide range of other side effects may occur: nausea, vomiting, postural hypotension, hallucination, psychosis, low blood pressure, tachycardia, confusion, dry mouth, dizziness, headaches, hallucinations, behavioral disturbances, and the 'wearing off' phenomenon. Older patients may experience hallucinations, and dyskinesias may be more common with levodopa doses over 300 mg/day. Transient GI side effects may be tempered by taking in divided doses with meals.
Options for carbidopa/levodopa dose forms:
- Immediate-release tablets (Sinemet); orally-disintegrating tablets (Parcopa)
- Enteral suspension (Duopa)
- Controlled-release tablets (Sinemet CR):
- Rytary capsules
See monographs for 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.
Dopamine Agonists (DAs)
DAs such as pramipexole, 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. DAs can provide good control of motor symptoms for several years before levodopa therapy is required. However, DAs may not be as effective as carbidopa/levodopa for more advanced disease. DAs are ineffective in patients who do not respond to levodopa.
Dopamine Agonists: ADRs
Dopamine agonists (DA) 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, DA monotherapy many not be effective in advanced disease. Taking doses after meals may help to relieve nausea, and patients should be monitored closely. DAs may be combined with MAOBIs in early disease to delay levodopa.
Dopamine Agonists: Formulations & Dosing
Available dopamine (dopa) agonists for treatment of PD include:
- Bromocriptine (Parodel) - rarely used clinically
- Pramipexole (Mirapex, Mirapex ER)
- Ropinirole (Requip, Requip XL)
- Rotigotine (Neupro Patch)
- Apomorphine (Apokyn)
Dopa Agonists: Impulse Control Disorders
PD 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 onky modestly reduce motor fluctuations and treat early, mild symptoms. They may be added to dopa 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, 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.
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 entacapone (Comtan) and tolcapone (Tasmar). 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 does not require LFTs, and this drug is available as a combo agent with levopdopa/carbidopa (Stalevo). Fixed dose combo agents often make dose titration difficult in PD, however.
COMTIs: Formulations and Dosing
- Entacapone (Comtan): Available as a 200 mg tablet. Give 200 mg with each dose of levodopa up to 1600 mg/day.
- 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 maimum 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 urine to turn orange. As mentioned, 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.
There have only been very rare reports of liver toxicity with entacapone and LFTs are not required. Other common COMTI side effects include nausea/vomiting, diarrhea, orthostatic hypotension, and dizziness. Do not abruptly discontinue COMTIs.
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. Amantadine is available in 100 mg tablets or capsules and a 50 mg/5 mL syrup. While its mechanism of action is unclear, it appears to have positive dopaminergic effects.
Amantadine: Dosing and ADRs
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.
Confusion and hallucinations may be the most concerning and troublesome side effect for patients and caregivers; other common ADRs include nausea, headache, dizziness and insomnia. Less common side effects include livedo reticularis and peripheral edema.
Anticholinergics: Used for Tremor, But Problematic in the Elderly
Anticholinergic drugs, such as trihexyphenidyl or benztropine are effective for tremor in about half of the patients that do not respond to other treatments. 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, anticholinergics should be avoided in this age group.
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/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. Common side effects include: swelling (peripheral edema), nausea, and confusion. Nuplazid can also lead to QT interval prolongation.
The Latest Research: Parkinson's Disease
Although a Parkinson's disease cure does not yet exist, new approvals are expanding 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” in PD as it can offer more stable plasma concentrations.
An investigational drug also under research for "wearing off" syndrome is called tozadenant. Tozadenant is a selective inhibitor of the adenosine 2a (A2a) receptor.
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.
Long-Acting Gocovril Approved for Dyskinesias
In the U.S., there are roughly 150,000- 200,000 people with Parkinson's disease whose daily life is 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. 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.
Gocovri is a high dose 274 mg amantadine (equivalent to 340 mg amantadine HCl) taken once-daily at bedtime. The most commonly observed adverse reactions (> 10 percent and greater than placebo) with Gocovri were hallucinations, dizziness, dry mouth, peripheral edema, constipation, fall and orthostatic hypotension.
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, pioglitazone, neurotrophic factors, alpha-synuclein, and isradipine. These compounds target proteins and pathways known to play a role in the disease.
In July 2016, researchers reported from a very small, early stage study that a cancer drug for leukemia, nilotinib (Tasigna) seemed to improve PD symptoms, possibly due to a dopamine boost. But further research with nilotinib is needed and ongoing. Studies have also looked at the use of approved therapies, such as rasagiline, selegiline or levodopa, especially in early disease; however, definitive neuroprotective results have not been proven.
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 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
- FDA Approves Gocovri (amantadine) for the Treatment of Dyskinesia in Parkinson's Disease Patients. Drugs.com August 24, 2017. Accessed August 28, 2017 at https://www.drugs.com/newdrugs/fda-approves-gocovri-amantadine-dyskinesia-parkinson-s-patients-4581.html
- Connolly B, Lang A. Pharmacologic Treatment of Parkinson's Disease: A Review. JAMA. 2014;311(16):1670-1683. doi:10.1001/jama.2014.3654.
- Caslake R, Macleod A, Ives N, et al. Monoamine oxidase B inhibitors versus other dopaminergic agents in early Parkinson's disease. Cochrane Database Syst Rev. 2009 (4): CD006661.
- Gazewood JD, Richards DR, Clebak K. Parkinson Disease: An Update. Am Fam Physician. 2013 Feb 15;87(4):267-273. Accessed 8/22/2016 at http://www.aafp.org/afp/2013/0215/p267.html#
- Parkinson's disease causes. Michael J. Fox Foundation. Accessed 8/22/2016 at https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?causes&navid=causes
- Drugs.com. New Clues to Easing Side Effects From Parkinson's Disease. News Nov 18, 2015. Accessed 8/22/2016 at https://www.drugs.com/news/new-clues-easing-parkinson-s-59085.html
- Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006;66(7):968–75.
- Institute for Safe Medication Practices. ISMP Safety Alert. Delayed administration and contraindicated drugs place hospitalized Parkinson's disease patients at risk. March 12, 2015. Accessed 8/22/2016 at https://www.ismp.org/newsletters/acutecare/showarticle.aspx?id=103
- Akhtar de la Fuente, A. Parkinson's Disease: An Update in Drug Therapy. December 2015. ACPE No. 0798000014156L01. FreeCE.com. Accessed 8/22/2016.
- Drugs.com. Epilepsy. Overview. Content from Mayo Clinic. November 2015. Accessed 8/22/2016 at https://www.drugs.com/mcd/epilepsy
- Parkinson's disease medications. Michael J. Fox Foundation. Accessed 8/22/2016 at https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?medication&navid=medication
- Grimes DA, Lang AE. Treatment of early Parkinson's disease. Can J Neurol Sci. 1999. Suppl 2:S39-44.