Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

mild parkinsonism

1st line – carbidopa/levodopa, dopamine agonist, MAO-B inhibitor, amantadine, or trihexyphenidyl

Back
ONGOING
|
mild parkinsonism
1st line – 

carbidopa/levodopa, dopamine agonist, MAO-B inhibitor, amantadine, or trihexyphenidyl

Patients with mild disease may elect to postpone treatment until disability occurs.[99]

When symptoms begin to interfere with the patient's quality of life or activities of daily living, treatment is initiated with a dopaminergic agent. An attempt is made to improve symptoms without causing unwanted adverse effects. Adverse effects are typically dose-dependent and differ slightly between agents. However, overall, these medications are well tolerated and safe.[136]

Options for initial therapy for motor symptoms include levodopa, a dopamine agonist, or a monoamine oxidase-B (MAO-B) inhibitor. There is no evidence of disease modification by any of these agents as initial therapy.[99][136]

Levodopa, in the form of carbidopa/levodopa, is the preferred initial dopaminergic therapy to improve motor symptoms for patients with early PD.[99] Studies demonstrate that levodopa provides greater benefit for motor symptoms than dopamine agonists or MAO-B inhibitors, and a lower risk of discontinuation due to adverse effects than MAO-B inhibitors.[99][Evidence C] There is no evidence to support superiority of one formulation of levodopa over another in patients with early PD; however, guidelines recommend immediate-release in preference to controlled-release levodopa, due to higher bioavailability and more predictable symptom relief.[99] Levodopa is combined with carbidopa to reduce nausea (and vomiting if present).

Although treatment with levodopa provides superior motor benefits, it is associated with a higher risk of dyskinesia compared with dopamine agonists. Risk factors for levodopa-induced dyskinesia include younger age at disease onset, lower body weight, female sex, and greater disease severity. Levodopa should be prescribed at the lowest effective dose to minimize the risk of dyskinesia and other adverse effects, and patients should be monitored for response to treatment and adverse effects.[99]

A dopamine agonist (e.g., pramipexole, ropinirole, rotigotine) may be considered as initial dopaminergic therapy to improve motor symptoms instead of levodopa in younger patients (ages <60 years) with early PD who are at higher risk for developing dyskinesia.[99][136][138][139][140] Dopamine agonists are not suitable for patients with early PD who have a higher risk of medication-related adverse effects, including patients ages >60 years, or with a history of impulse control disorders, preexisting cognitive impairment, excessive daytime sleepiness, or hallucinations.[99] There is no strong evidence supporting any particular drug, mode of administration, or drug formulation when using dopamine agonists to treat early PD. Patients should be regularly monitored for adverse effects such as lower extremity swelling, excessive daytime sleepiness, hallucinations, and worsening of postural hypotension and impulse control disorders. Dopamine agonists should be tapered and discontinued if adverse effects become disabling.[99]

A trial of an MAO-B inhibitor (e.g., selegiline, rasagiline, safinamide) is reasonable if levodopa is not suitable. MAO-B inhibitors may confer modest symptomatic benefit and are well tolerated, but additional therapy is required earlier with MAO-B inhibitors than with levodopa or dopamine agonists.[99][136][140][141] Early treatment with rasagiline does not confer long-term benefits.[142] Selegiline is only approved for adjunctive use, but may be substituted for rasagiline if rasagiline is not available.

Anticholinergic agents (e.g., trihexyphenidyl) may be considered for treatment of PD with tremor-predominant symptomatology. Possible adverse effects, including worsening of cognitive decline and constipation, should be carefully monitored. Amantadine is often considered for treatment of levodopa-induced dyskinesia and resistant tremor, However, amantadine use is often limited in older patients due to concerns about potentiating cognitive impairment, and it is not suitable for patients with hallucinations.[136]

Choice of initial therapy is based on the individual patient’s needs, preferences, and risk for adverse effects.[136]

Initiate therapy with a low dose and increase gradually according to response and tolerability.

Primary options

carbidopa/levodopa: 100 mg orally (immediate-release) three times daily initially, increase gradually according to response, maximum 800 mg/day

More

Secondary options

pramipexole: 0.125 to 1.5 mg orally (immediate-release) three times daily; 0.375 to 4.5 mg orally (extended-release) once daily

OR

ropinirole: 0.25 to 8 mg orally (immediate-release) three times daily; 2-24 mg orally (extended-release) once daily

OR

rotigotine transdermal: apply 2 mg/24 hour patch to 8 mg/24 hour patch once daily

Tertiary options

selegiline: 5 mg orally twice daily at breakfast and lunchtime

OR

rasagiline: 1 mg orally once daily

OR

safinamide: 50-100 mg orally once daily

OR

trihexyphenidyl: 1-15 mg/day orally given in 3-4 divided doses

OR

amantadine: 100-200 mg orally (immediate-release) twice daily; 129-322 mg orally (extended-release) once daily in the morning

More

Plus – physical and nonpharmacologic therapies

Back
ONGOING
|
mild parkinsonism
Plus – 

physical and nonpharmacologic therapies

Treatment recommended for ALL patients in selected patient group

Exercise should always be encouraged; it has been shown to improve functional performance on motor tasks at any stage of disease, and may have beneficial effects on cognition.[101][102][131] [ Cochrane Clinical Answers logo ]

Physical therapy, occupational therapy, and speech therapy are important in the evaluation and management of specific symptoms, and in maintaining function.[103][104][105][106]

Progressive resistance exercise, aerobic exercise, and balance training have been shown to reduce motor symptoms and improve functional status.[101][107][108][109] Activities such as Tai Chi, dance, and music therapy have also been shown to be safe and beneficial for patients with PD, and may improve quality of life and reduce falls.[110][111][112][113][114] Water-based therapy has shown benefits in improving balance, mobility, and quality of life in people with PD, and may be preferred to land-based therapy by patients with fear of falling.[108][115][116]

Gait-specific training, rather than generic exercise programs, should be employed if improved gait performance is the specific outcome of interest.[108][117] Specific physical therapy programs aimed at improving freezing of gait in PD, such as Lee Silverman Voice Treatment-BIG therapy (LSVT-BIG), have been shown to be effective in reducing motor impairments.[118][119]

External cueing (external temporal or spatial stimuli, including rhythmic auditory cues, visual cues,verbal cues, or attentional cues) during physical therapy reduces motor disease severity and improves gait outcomes.[108][120]

Community-based exercise programs, which may include a home exercise component, are recommended. These reduce motor disease severity and improve nonmotor symptoms, functional outcomes, and quality of life.[108]

Virtual reality interventions may be effective for improving balance, motor function, gait, quality of life, and ability to perform activities of daily living in patients with PD, although the evidence is mostly of low quality.[121][122][123]

Individually tailored and standard cognitive training may improve memory, executive function, and attention in people with PD.[129] Similarly, cognitive rehabilitation has been reported to lead to improvements in one or more cognitive domains.[124][130]

Plus – additional carbidopa or antiemetic

Back
ONGOING
|
mild parkinsonism
|
with nausea on carbidopa/levodopa or dopamine agonist
Plus – 

additional carbidopa or antiemetic

Treatment recommended for ALL patients in selected patient group

For patients taking carbidopa/levodopa, nausea (and vomiting if present) can be treated with additional doses of carbidopa.

Ondansetron may be considered for treating nausea in patients taking either carbidopa/levodopa or a dopamine agonist. Domperidone is an effective alternative but it is not available in the US.

Primary options

carbidopa: 25 mg orally with each dose of carbidopa/levodopa

Secondary options

ondansetron: 4-8 mg orally every 8-12 hours when required, maximum 24 mg/day

moderate parkinsonism

1st line – carbidopa/levodopa, dopamine agonist, MAO-B inhibitor, amantadine, or trihexyphenidyl

Back
ONGOING
|
moderate parkinsonism
1st line – 

carbidopa/levodopa, dopamine agonist, MAO-B inhibitor, amantadine, or trihexyphenidyl

The moderate stage of parkinsonism is arbitrarily defined by increased severity in symptoms, as well as evolution of complications of disease treatment.

Management is similar to that of mild parkinsonism. Symptoms may become more severe and higher doses of medication are needed. Using carbidopa/levodopa and a dopamine agonist or an MAO-B inhibitor together is more common.

Dopamine agonists are not suitable for patients ages >60 years or with hallucinations. Trihexyphenidyl should be used with caution in patients with any cognitive impairment or severe constipation, and patients should be monitored for adverse effects. Amantadine use is often limited in older patients due to concerns about potentiating cognitive impairment, and it is not suitable for patients with hallucinations.[136]

An extended-release capsule formulation of carbidopa/levodopa that combines immediate- and sustained-release pellets has been shown to reduce daily off-time compared with immediate-release formulations and the combination of carbidopa/levodopa and entacapone.[152][153][154]

Initiate therapy with a low dose and increase gradually according to response and tolerability.

Primary options

carbidopa/levodopa: 100 mg orally (immediate-release) three times daily initially, increase gradually according to response, maximum 800 mg/day

More

Secondary options

pramipexole: 0.125 to 1.5 mg orally (immediate-release) three times daily; 0.375 to 4.5 mg orally (extended-release) once daily

OR

ropinirole: 0.25 to 8 mg orally (immediate-release) three times daily; 2-24 mg orally (extended-release) once daily

OR

rotigotine transdermal: apply 2 mg/24 hour patch to 8 mg/24 hour patch once daily

OR

selegiline: 5 mg orally twice daily at breakfast and lunchtime

OR

rasagiline: 0.5 to 1 mg orally once daily

OR

safinamide: 50-100 mg orally once daily

OR

trihexyphenidyl: 1-15 mg/day orally given in 3-4 divided doses

OR

amantadine: 100-200 mg orally (immediate-release) twice daily; 129-322 mg orally (extended-release) once daily in the morning

More

Plus – physical and nonpharmacologic therapies

Back
ONGOING
|
moderate parkinsonism
Plus – 

physical and nonpharmacologic therapies

Treatment recommended for ALL patients in selected patient group

Exercise should always be encouraged; it has been shown to improve functional performance on motor tasks at any stage of disease, and may have beneficial effects on cognition.[101][102][131] [ Cochrane Clinical Answers logo ]

Physical therapy, occupational therapy, and speech therapy are important in the evaluation and management of specific symptoms, and in maintaining function.[103][104][105][106]

Progressive resistance exercise, aerobic exercise, and balance training have been shown to reduce motor symptoms and improve functional status.[101][107][108][109] Activities such as Tai Chi, dance, and music therapy have also been shown to be safe and beneficial for patients with PD, and may improve quality of life and reduce falls.[110][111][112][113][114] Water-based therapy has shown benefits in improving balance, mobility, and quality of life in people with PD, and may be preferred to land-based therapy by patients with fear of falling.[108][115][116]

Gait-specific training, rather than generic exercise programs, should be employed if improved gait performance is the specific outcome of interest.[108][117] Specific physical therapy programs aimed at improving freezing of gait in PD, such as Lee Silverman Voice Treatment-BIG therapy (LSVT-BIG), have been shown to be effective in reducing motor impairments.[118][119]

External cueing (external temporal or spatial stimuli, including rhythmic auditory cues, visual cues,verbal cues, or attentional cues) during physical therapy reduces motor disease severity and improves gait outcomes.[108][120]

Community-based exercise programs, which may include a home exercise component, are recommended. These reduce motor disease severity and improve nonmotor symptoms, functional outcomes, and quality of life.[108]

Virtual reality interventions may be effective for improving balance, motor function, gait, quality of life, and ability to perform activities of daily living in patients with PD, although the evidence is mostly of low quality.[121][122][123]

Individually tailored and standard cognitive training may improve memory, executive function, and attention in people with PD.[129] Similarly, cognitive rehabilitation has been reported to lead to improvements in one or more cognitive domains.[124][130]

Plus – carbidopa/levodopa

Back
ONGOING
|
moderate parkinsonism
|
with wearing off (motor fluctuations) on dopamine agonist, not taking carbidopa/levodopa
Plus – 

carbidopa/levodopa

Treatment recommended for ALL patients in selected patient group

Carbidopa/levodopa can be added to a dopamine agonist. Taking medications more frequently may improve symptoms in patients who experience wearing off (motor fluctuations).

Primary options

carbidopa/levodopa: 100 mg orally (immediate-release) three times daily initially, increase gradually according to response, maximum 800 mg/day

More

Plus – COMT inhibitor, dopamine agonist, MAO-B inhibitor, istradefylline, or switch to extended-release carbidopa/levodopa

Back
ONGOING
|
moderate parkinsonism
|
with wearing off (motor fluctuations), taking carbidopa/levodopa
Plus – 

COMT inhibitor, dopamine agonist, MAO-B inhibitor, istradefylline, or switch to extended-release carbidopa/levodopa

Treatment recommended for ALL patients in selected patient group

The addition of a catechol-O-methyltransferase (COMT) inhibitor (e.g., entacapone, opicapone, tolcapone) may extend carbidopa/levodopa therapeutic benefit.[143][144][145][146][147] Entacapone is available as a proprietary formulation with carbidopa/levodopa to ease administration and improve patient compliance. Due to the risk of serious hepatotoxicity, tolcapone is restricted to when other adjunctive therapy is ineffective or contraindicated.

If after adding a COMT inhibitor patients still experience motor fluctuations, a dopamine agonist or monoamine oxidase-B (MAO-B) inhibitor can also be added to reduce off-time, with or without reducing the requisite levodopa dose.[143][148][149][150][151]

Istradefylline is an adenosine A2A receptor antagonist that may be considered as an add-on therapy to carbidopa/levodopa.[155] It can reduce off-time, improve motor function, and reduce tremor during off-time in patients with PD. Possible adverse effects, including emergence or worsening of dyskinesia, should be carefully monitored.[155][156][157][158] Istradefylline is approved for use in PD in the US and some other countries; however, the European Medicines Agency refused a marketing authorization for istradefylline as it concluded that the benefits of treatment did not outweigh the risks.

An extended-release capsule formulation of carbidopa/levodopa that combines immediate- and sustained-release pellets has been shown to reduce daily off-time compared with immediate-release formulations and the combination of carbidopa/levodopa and entacapone.[152][153][154]

Initiate therapy with a low dose and increase gradually according to response and tolerability.

Primary options

entacapone: 200 mg orally two to four times daily with each dose of carbidopa/levodopa, maximum 1600 mg/day

OR

opicapone: 50 mg orally once daily at bedtime

Secondary options

pramipexole: 0.125 to 1.5 mg orally (immediate-release) three times daily; 0.375 to 4.5 mg orally (extended-release) once daily

OR

ropinirole: 0.25 to 8 mg orally (immediate-release) three times daily; 2-24 mg orally (extended-release) once daily

OR

rotigotine transdermal: apply 2 mg/24 hour patch to 8 mg/24 hour patch once daily

OR

selegiline: 5 mg orally twice daily at breakfast and lunchtime

OR

rasagiline: 0.5 to 1 mg orally once daily

OR

safinamide: 50-100 mg orally once daily

OR

carbidopa/levodopa: dose of extended-release tablet or capsule depends on previous dose of carbidopa/levodopa

OR

istradefylline: 20-40 mg orally once daily

More

Tertiary options

tolcapone: 100 mg orally three times daily initially, with the first dose of the day given with the first daily dose of carbidopa/levodopa, maximum 600 mg/day

Plus – reduce dopaminergic medications (if tolerated) or add amantadine

Back
ONGOING
|
moderate parkinsonism
|
with dyskinesias
Plus – 

reduce dopaminergic medications (if tolerated) or add amantadine

Treatment recommended for ALL patients in selected patient group

Dyskinesias are an adverse effect of carbidopa/levodopa therapy, characterized by involuntary excessive movements, that can develop as disease progresses.

If mild and not bothersome, dyskinesias can be observed. However, they often lead to discomfort and, in some cases, undesired weight loss and balance dysfunction due to excessive body sway.

The first approach should be to consider dose reduction and increase in frequency of carbidopa/levodopa treatment and decreasing the dose of other dopaminergic medications, if this can be done without loss of therapeutic efficacy.

If this cannot be achieved, amantadine is usually added (if the patient is not already on this drug) to reduce these symptoms. An extended-release formulation of amantadine is available for the treatment of dyskinesias in people with PD receiving levodopa-based therapy, with or without concomitant dopaminergic medications. The immediate-release formulation is also commonly used off-label for treating dyskinesias in people with PD. Amantadine use is often limited in older patients due to concerns about potentiating cognitive impairment, and it is not suitable for patients with hallucinations.[136]

Primary options

amantadine: 137-274 mg orally (extended-release) once daily at night; 100-200 mg orally (immediate-release) twice daily

More

Consider – deep brain stimulation

Back
ONGOING
|
moderate parkinsonism
|
with dyskinesias
Consider – 

deep brain stimulation

Treatment recommended for SOME patients in selected patient group

Deep brain stimulation is used for patients who previously responded well to medication, but have developed intolerable side effects or no longer receive benefit from medication.

In general, the goal of surgery is to provide a constant "best medicine" state, and no additional improvement beyond what is achieved with dopaminergic agents is expected.

The globus pallidus interna (GPi) and the subthalamic nucleus are the two primary targets of DBS.[160][162][169][170][171] The Congress of Neurological Surgeons recommends targeting the GPi if reduction of medication is not anticipated and a goal is to reduce the severity of "on" medication dyskinesias.[167]

Plus – pharmacotherapy or deep brain stimulation

Back
ONGOING
|
moderate parkinsonism
|
with refractory tremor
Plus – 

pharmacotherapy or deep brain stimulation

Treatment recommended for ALL patients in selected patient group

If the patient has a tremor that shows insufficient response to dopaminergic agents, adding an anticholinergic agent (e.g., trihexyphenidyl) or amantadine (if the patient is not already on this) may be considered. Anticholinergics should be used with caution in patients with any cognitive impairment or severe constipation, and patients should be monitored for adverse effects. Amantadine use is often limited in older patients due to concerns about potentiating cognitive impairment, and it is not suitable for patients with hallucinations.[136]

Second-line options include medications used to treat essential tremor, such as propranolol and primidone.

If a patient has disabling tremor that is refractory to all medical therapy, deep brain stimulation (DBS) of the subthalamic nucleus, globus pallidus, or ventral intermediate nucleus of the thalamus should be considered.[160][162] In general, the goal of DBS in patients with PD is to provide a constant "best medicine" state; no additional improvement beyond what is achieved with dopaminergic agents is expected, but drug-refractory tremor often responds to DBS.[159]

Primary options

trihexyphenidyl: 1-15 mg/day orally given in 3-4 divided doses

OR

amantadine: 100-200 mg orally (immediate-release) twice daily; 129-322 mg orally (extended-release) once daily in the morning

More

Secondary options

propranolol hydrochloride: 40 mg (immediate-release) orally twice daily, increase gradually according to response, maximum 160 mg/day given in 2-3 divided doses

OR

primidone: 25 mg orally once daily initially, increase gradually according to response, maximum 750 mg/day given in 3 divided doses

Plus – additional carbidopa or antiemetic

Back
ONGOING
|
moderate parkinsonism
|
with nausea on carbidopa/levodopa or dopamine agonist
Plus – 

additional carbidopa or antiemetic

Treatment recommended for ALL patients in selected patient group

For patients taking carbidopa/levodopa or dopamine agonists, nausea (and vomiting if present) can be treated with additional doses of carbidopa.

Ondansetron may be considered for treating nausea in patients taking either carbidopa/levodopa or a dopamine agonist. Domperidone is an effective alternative but it is not available in the US.

Primary options

carbidopa: 25 mg orally with each dose of carbidopa/levodopa

Secondary options

ondansetron: 4-8 mg orally every 8-12 hours when required, maximum 24 mg/day

advanced parkinsonism

1st line – carbidopa/levodopa

Back
ONGOING
|
advanced parkinsonism
1st line – 

carbidopa/levodopa

This stage of disease is often complicated by changes in response to carbidopa/levodopa and sudden and unpredictable off-periods. Progression of the disease often leads to motor and nonmotor fluctuations, dyskinesia, freezing of gait, and worsening of gastrointestinal symptoms such as dysphagia, gastric emptying delay, and constipation. Commonly patients have cognitive impairment and may have hallucinations.

Patients with advanced PD are likely to be taking several medications concurrently. Most patients take carbidopa/levodopa.

An extended-release capsule formulation of carbidopa/levodopa that combines immediate- and sustained-release pellets has been shown to reduce daily off-time compared with immediate-release formulations and the combination of carbidopa/levodopa and entacapone.[152][153][154]

Primary options

carbidopa/levodopa: 100 mg orally (immediate-release) three times daily initially, increase gradually according to response, maximum 800 mg/day

More

Plus – physical and nonpharmacologic therapies

Back
ONGOING
|
advanced parkinsonism
Plus – 

physical and nonpharmacologic therapies

Treatment recommended for ALL patients in selected patient group

Exercise should always be encouraged; it has been shown to improve functional performance on motor tasks at any stage of disease, and may have beneficial effects on cognition.[101][102][131] [ Cochrane Clinical Answers logo ]

Physical therapy, occupational therapy, and speech therapy are important in the evaluation and management of specific symptoms, and in maintaining function.[103][104][105][106]

Progressive resistance exercise, aerobic exercise, and balance training have been shown to reduce motor symptoms and improve functional status.[101][107][108][109] Activities such as Tai Chi, dance, and music therapy have also been shown to be safe and beneficial for patients with PD, and may improve quality of life and reduce falls.[110][111][112][113][114] Water-based therapy has shown benefits in improving balance, mobility, and quality of life in people with PD, and may be preferred to land-based therapy by patients with fear of falling.[108][115][116]

Gait-specific training, rather than generic exercise programs, should be employed if improved gait performance is the specific outcome of interest.[108][117] Specific physical therapy programs aimed at improving freezing of gait in PD, such as Lee Silverman Voice Treatment-BIG therapy (LSVT-BIG), have been shown to be effective in reducing motor impairments.[118][119]

External cueing (external temporal or spatial stimuli, including rhythmic auditory cues, visual cues,verbal cues, or attentional cues) during physical therapy reduces motor disease severity and improves gait outcomes.[108][120]

Community-based exercise programs, which may include a home exercise component, are recommended. These reduce motor disease severity and improve nonmotor symptoms, functional outcomes, and quality of life.[108]

Virtual reality interventions may be effective for improving balance, motor function, gait, quality of life, and ability to perform activities of daily living in patients with PD, although the evidence is mostly of low quality.[121][122][123]

Individually tailored and standard cognitive training may improve memory, executive function, and attention in people with PD.[129] Similarly, cognitive rehabilitation has been reported to lead to improvements in one or more cognitive domains.[124][130]

This patient group should exercise with supervision and fall precautions in place.

Consider – dopamine agonist

Back
ONGOING
|
advanced parkinsonism
Consider – 

dopamine agonist

Treatment recommended for SOME patients in selected patient group

Patients with advanced PD are likely to be taking several medications concurrently.

Dopamine agonists are not suitable for patients ages >60 years or with hallucinations.

Initiate therapy with a low dose and increase gradually according to response and tolerability.

Primary options

pramipexole: 0.125 to 1.5 mg orally (immediate-release) three times daily; 0.375 to 4.5 mg orally (extended-release) once daily

OR

ropinirole: 0.25 to 8 mg orally (immediate-release) three times daily; 2-24 mg orally (extended-release) once daily

OR

rotigotine transdermal: apply 2 mg/24 hour patch to 8 mg/24 hour patch once daily

Consider – MAO-B inhibitor

Back
ONGOING
|
advanced parkinsonism
Consider – 

MAO-B inhibitor

Treatment recommended for SOME patients in selected patient group

Patients with advanced PD are likely to be taking several medications concurrently.

Primary options

selegiline: 5 mg orally twice daily at breakfast and lunchtime

OR

rasagiline: 0.5 to 1 mg orally once daily

OR

safinamide: 50-100 mg orally once daily

Consider – COMT inhibitor

Back
ONGOING
|
advanced parkinsonism
Consider – 

COMT inhibitor

Treatment recommended for SOME patients in selected patient group

Patients with advanced PD are likely to be taking several medications concurrently.

Entacapone is available as a proprietary formulation with carbidopa/levodopa to ease administration and improve patient compliance.

Due to the risk of serious hepatotoxicity, tolcapone is restricted to when other adjunctive therapy is ineffective or contraindicated.

Primary options

entacapone: 200 mg orally two to four times daily with each dose of carbidopa/levodopa, maximum 1600 mg/day

OR

opicapone: 50 mg orally once daily at bedtime

Secondary options

tolcapone: 100 mg orally three times daily initially, with the first dose of the day given with the first daily dose of carbidopa/levodopa, maximum 600 mg/day

Consider – istradefylline

Back
ONGOING
|
advanced parkinsonism
Consider – 

istradefylline

Treatment recommended for SOME patients in selected patient group

Patients with advanced PD are likely to be taking several medications concurrently.

Possible adverse effects of istradefylline, including emergence or worsening of dyskinesia, should be carefully monitored.[155][156][157][158]

Istradefylline is approved for use in PD in the US and some other countries; however, the European Medicines Agency refused a marketing authorization for istradefylline as it concluded that the benefits of treatment did not outweigh the risks.

Primary options

istradefylline: 20-40 mg orally once daily

More

Plus – apomorphine or as-needed doses of carbidopa/levodopa

Back
ONGOING
|
advanced parkinsonism
|
with unpredictable off-times
Plus – 

apomorphine or as-needed doses of carbidopa/levodopa

Treatment recommended for ALL patients in selected patient group

The later stage of disease is often complicated by changes in response to carbidopa/levodopa and sudden and unpredictable off-periods.

Apomorphine (a nonselective dopamine agonist available as subcutaneous injection or sublingual formulation) can be used under specialist guidance as rescue therapy for sudden wearing off. Apomorphine is often helpful for patients who have dysphagia in the off-state, or first thing in the morning, when symptoms are severe.

Similarly, as-needed doses of carbidopa/levodopa can be used as rescue therapy. Dissolvable carbidopa/levodopa and/or levodopa inhalation powder may be considered if dysphagia is problematic.[166]

Primary options

apomorphine: consult specialist for guidance on subcutaneous or sublingual dose

OR

carbidopa/levodopa: 50 mg orally as needed for sudden unpredictable off periods; increase by 50 mg/dose according to response

More

OR

levodopa inhaled: 84 mg (2 capsules) inhaled once to five times daily when required

Plus – deep brain stimulation and/or switch to enteral carbidopa/levodopa

Back
ONGOING
|
advanced parkinsonism
|
with severe refractory motor fluctuations
Plus – 

deep brain stimulation and/or switch to enteral carbidopa/levodopa

Treatment recommended for ALL patients in selected patient group

Deep brain stimulation (DBS) is only used in patients who are refractory to medication. In patients with motor fluctuations, DBS can be beneficial to reduce off-time. In general, the goal of DBS is to provide a constant "best medicine" state; no additional improvement beyond what is achieved with dopaminergic agents is expected. The globus pallidus interna and the subthalamic nucleus are two possible primary targets in DBS; one or other may be preferred depending on circumstances.[162][167][170][171]

Patients with severe fluctuations who experience delayed onset of on-time after taking each dose of levodopa and sudden off-times, and who require very frequent dosing of levodopa, may be ideal candidates for carbidopa/levodopa enteral suspension (also known as levodopa/carbidopa intestinal gel, or LCIG). This provides a continuous intrajejunal infusion of levodopa/carbidopa enteral suspension that reduces plasma concentration variability, and is an effective therapy for reducing motor fluctuations and improving quality of life.[161][162] As use requires titration/programming to determine the appropriate dose, it should be used only by a specialist.

Intrajejunal infusion may be supplemented with oral carbidopa/levodopa, particularly for sudden off-times if these continue to occur despite continuous infusion.

Primary options

carbidopa/levodopa: consult specialist for guidance on dose of enteral suspension

Plus – reduce dopaminergic medications (if tolerated) or add amantadine

Back
ONGOING
|
advanced parkinsonism
|
with refractory dyskinesias
Plus – 

reduce dopaminergic medications (if tolerated) or add amantadine

Treatment recommended for ALL patients in selected patient group

Dyskinesias are an adverse effect of carbidopa/levodopa therapy, characterized by involuntary excessive movements, that can develop as disease progresses.If mild and not bothersome, dyskinesias can be observed. However, they often lead to discomfort and, in some cases, undesired weight loss and balance dysfunction due to excessive body sway.

The first approach should be to consider dose reduction and increase in frequency of carbidopa/levodopa treatment and decreasing the dose of other dopaminergic medications, if this can be done without loss of therapeutic efficacy.

If this cannot be achieved, amantadine is usually added (if the patient is not already on this drug) to reduce these symptoms. An extended-release formulation of amantadine is available for the treatment of dyskinesias in people with PD receiving levodopa-based therapy, with or without concomitant dopaminergic medications. The immediate-release formulation is also commonly used off-label for treating dyskinesias in people with PD. Amantadine use is often limited in older patients due to concerns about potentiating cognitive impairment, and it is not suitable for patients with hallucinations.[136]

Primary options

amantadine: 137-274 mg orally (extended-release) once daily at night; 100-200 mg orally (immediate-release) twice daily

More

Consider – deep brain stimulation

Back
ONGOING
|
advanced parkinsonism
|
with refractory dyskinesias
Consider – 

deep brain stimulation

Treatment recommended for SOME patients in selected patient group

Deep brain stimulation is used for patients who previously responded well to medication, but have developed intolerable side effects or no longer receive benefit from medication.[162][167]

In general, the goal of surgery is to provide a constant "best medicine" state, and no additional improvement beyond what is achieved with dopaminergic agents is expected.

The globus pallidus interna and the subthalamic nucleus are the two primary targets.[160] The Congress of Neurological Surgeons recommends targeting the GPi if reduction of medication is not anticipated and a goal is to reduce the severity of "on" medication dyskinesias.[167]

Plus – deep brain stimulation

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ONGOING
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advanced parkinsonism
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with refractory tremor
Plus – 

deep brain stimulation

Treatment recommended for ALL patients in selected patient group

If a patient has disabling tremor that is refractory to all suitable medical therapy, they should be referred for consideration of deep brain stimulation (DBS) of the subthalamic nucleus, globus pallidus, or ventral intermediate nucleus of the thalamus.[160][162][167]

In general, the goal of DBS in patients with PD is to provide a constant "best medicine" state; no additional improvement beyond what is achieved with dopaminergic agents is expected, but drug-refractory tremor often responds to DBS.[159]

Plus – additional carbidopa or antiemetic

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ONGOING
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advanced parkinsonism
|
with nausea on carbidopa/levodopa or dopamine agonist
Plus – 

additional carbidopa or antiemetic

Treatment recommended for ALL patients in selected patient group

For patients taking carbidopa/levodopa or dopamine agonists, nausea (and vomiting if present) can be treated with additional doses of carbidopa.

Ondansetron may be considered for treating nausea in patients taking either carbidopa/levodopa or a dopamine agonist. Domperidone is an effective alternative but it is not available in the US.

Primary options

carbidopa: 25 mg orally with each dose of carbidopa/levodopa

Secondary options

ondansetron: 4-8 mg orally every 8-12 hours when required, maximum 24 mg/day

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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