MANAGEMENT OF PARKINSONS DISEASE

1. PARKINSONS MX

2. • Parkinson disease (PD) is the most common neurodegenerative movement
disorder, affecting millions of adults worldwide. Progressive degeneration of
dopamine-producing neurons in the substantia nigra of the midbrain accounts
for the emergence of the classic clinical triad of tremor, rigidity, and bradykinesia
as well as a wide range of nonmotor and neuropsychiatric manifestations that
affect function and quality of life. It has become clear that PD is not just a
disorder of dopamine depletion. Other regions of the brain, inside and outside
the basal ganglia, are affected by cell loss and biochemical derangement

3. • Spectrum of dopaminergic therapies — Dopaminergic therapy is the mainstay
of pharmacologic treatment for PD. Dopaminergic therapies that have been
studied in early PD as monotherapy include the following agents or classes of
agents, listed in descending order of dopaminergic potency:
• ●Levodopa, most commonly in the form of carbidopa-levodopa (Sinemet)
• ●Nonergot dopamine agonists (DAs; pramipexole, ropinirole, and rotigotine)
• ●Monoamine oxidase type B (MAO B) inhibitors (rasagiline, safinamide,
and selegiline)
• ●Amantadine, a dopamine promoter with anticholinergic effects
• All are considered to be symptomatic therapies, and none have been firmly
established as disease modifying or neuroprotective [1,2]. Selection is based on
patient characteristics (age, comorbidities), disease severity, and drug efficacy
and side effects.
• In addition to the dopaminergic therapies, anticholinergic drugs are also used for
tremor management in select patients with early PD.

4. • When should drug therapy be started? — The decision to initiate symptomatic medical
therapy in patients with PD is determined by the degree to which symptoms interfere with
functioning or impair quality of life. The timing of this decision varies greatly among patients
but is influenced by a number of factors, including [3-6]:
• ●The effect of disease on the dominant hand
• ●The degree to which the disease interferes with work, activities of daily living, or social and
leisure function
• ●The presence of significant bradykinesia or gait disturbance
• ●Patient values and preferences regarding the use of medications
• Patients with very mild signs and symptoms of PD do not necessarily need
any antiparkinson therapy if symptoms are not interfering with quality of life and they prefer
to avoid medication side effects. Patients in this situation can be referred for clinical trials of
neuroprotective therapies, which often enroll patients who have not yet
initiated dopaminergic therapies.
• In some patients, an additional influence is the fear of starting levodopa due to reports of its
association with motor fluctuations and dyskinesia, and an unproven belief that the long-
term duration of a given patient's responsiveness to levodopa is finite and that the drug, like
money in a savings or retirement account, should be rationed. In such a patient, the current
understanding of motor fluctuations should be discussed at the time of initiating therapy to
avoid unnecessary disability or reduced quality of life.

5. • What is the natural history of motor complications? — A substantial number of patients with PD develop levodopa-related
motor complications within 5 to 10 years of starting levodopa. These include motor fluctuations (the "wearing off"
phenomenon) and a variety of complex fluctuations in motor function [7,8]. It is estimated that such motor complications
occur in at least 50 percent of patients after 5 to 10 years of treatment [4]. The risk of motor complications increases with a
younger age of PD onset [9-11]. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease".)
• The development of motor fluctuations over time is most likely due to progressive degeneration of nigrostriatal dopamine
terminals, which increasingly limits the normal physiologic uptake and release of dopamine, thereby leading to reduced
buffering of the natural fluctuations in plasma levodopa levels that occur due to its 90-minute pharmacologic half-life [4].
• There has been longstanding concern among some clinicians that levodopa causes motor fluctuations and dyskinesia by its
potential to promote oxidative stress and accelerated neurodegeneration, rather than by the change in levodopa
pharmacodynamics that occurs with natural progression of the underlying disease [12,13]. This viewpoint was reinforced by
data from several trials establishing that higher levodopa dose is a risk factor for motor complications [11,14-16]. As a result,
it is commonly proposed that the initiation of levodopa be delayed until symptoms significantly interfere with function, as
determined by careful discussion and decision-making between patient and clinician.
• However, there is increasing evidence that the choice and timing of initial therapy for PD, whether levodopa, DA, or MAO B
inhibitor, have little impact on the long-term outcome of PD in terms of motor fluctuations and dyskinesia [17-19]. Delaying
treatment unnecessarily deprives patients of therapeutic benefit early in the disease, when the potential for sustained
improvement is greatest [20]. In a delayed-start trial of levodopa in which one-half of patients were randomly assigned to
levodopa for 80 weeks and one-half were assigned to placebo for the first 40 weeks followed by 40 weeks of levodopa, 39
percent of the placebo group required symptomatic therapy with levodopa before reaching the 40-week mark [21]. In
addition, the groups had similar rates of motor complications at 80 weeks, suggesting that the early-start group was not
negatively affected by longer exposure to levodopa [22].
• Given these data, clinicians should always try to find the lowest dose of dopaminergic medication, either singly or in
combination, that adequately manages the patient's symptoms according to their individual needs. In addition, patients
should be reassured that the timing of the onset of motor fluctuations is variable and likely depends on an unpredictable
rate of progression of underlying disease, rather than choice of initial therapy, and that any delay in onset of motor
fluctuations using DAs occurs at the expense of reduced efficacy when compared with levodopa.

6. • LEVODOPA MONOTHERAPY (MOST PATIENTS)In most patients with early PD seeking control of motor
symptoms, we suggest levodopa as initial therapy [2]. In select cases, initial treatment with monoamine oxidase
type B (MAO B) inhibitors, dopamine agonists (DAs), or amantadine may be offered as an alternative to early
levodopa. (See 'Alternatives in select patients' below.)
• Efficacy and rationale — Levodopa (L-dopa) is the main precursor in dopamine synthesis and is well established
as the most effective drug for the symptomatic treatment of idiopathic PD. It has superior effects on motor
function, activities of daily life, and quality of life compared with other drugs and classes, including DAs [3,23-
26].
• Evidence supports the benefit of levodopa compared with placebo as well as other dopaminergic therapies. In a
randomized trial of levodopa versus placebo in 361 patients with untreated PD, the mean change in Unified
Parkinson Disease Rating Scale (UPDRS) scores from baseline to 42 weeks was greater for placebo (reflecting
more decline) than for all levodopa doses studied (7.8 points for placebo versus 1.9, 1.9, and 1.4 points for
levodopa 150, 300, and 600 mg daily, respectively) [16]. A subsequent open-label randomized trial in early PD
demonstrated a small benefit of levodopa over DAs and MAO B inhibitors on patient-rated quality of life over
seven years of follow-up, and the levodopa group was the least likely to need add-on therapy at two years (20
percent) compared with the DA and MAO B inhibitor groups (40 and 64 percent, respectively) [17]. Additional
comparative data between levodopa and DAs are reviewed below. (See 'Nonergot dopamine agonists' below.)
• There appears to be no advantage for using levodopa combined with a catechol-O-methyl transferase (COMT)
inhibitor as initial therapy for PD compared with levodopa alone. The STRIDE-PD trial randomly assigned 747
patients with early PD to carbidopa-levodopa alone or combined with entacapone [27]. Patients assigned to
combined therapy with entacapone had a shorter time to onset of dyskinesia and increased frequency of
dyskinesia. In a trial of 750 levodopa-treated patients without motor fluctuations, adjunct entacapone did not
improve motor scores [28].
• The use of COMT inhibitors for management of motor fluctuations associated with levodopa is reviewed
separately. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on
'Approach to "wearing off"'.)

7. • General principles — Guiding principles with regard to initiating levodopa therapy include the following:
• ●Levodopa is the most effective agent for control of motor symptoms of PD but also requires the most frequent dosing and is associated with the
highest risk of dopaminergic motor complications, such as "wearing off" and dyskinesia.
• ●Levodopa is more likely to cause dyskinesia than other options within the first five years, and thus the minimum effective dose should be used and
patients should be counseled regarding this risk. Patients should be monitored for development of dyskinesia, for which the dose can be reduced.
• ●Patients should be advised to take levodopa with meals to minimize nausea and improve adherence. In later disease, concurrent ingestion of
dietary protein may block the effect of a dose of levodopa, but risk of this is low in early disease. (See "Medical management of motor fluctuations
and dyskinesia in Parkinson disease", section on 'Dietary adjustments'.)
• ●Dopaminergic motor complications should be discussed with patients who are fearful of initiating levodopa early. (See 'What is the natural history
of motor complications?' above.)
• ●Controlled-release (CR) formulations of levodopa and carbidopa-levodopa-entacapone have not been shown to be superior for motor benefit in
early PD. Immediate-release (IR) carbidopa-levodopa is the preferred initial formulation [2].
• Formulations — Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and
liver in order to prevent nausea, vomiting, and orthostatic hypotension. By preventing peripheral conversion to dopamine, which does not cross the
blood-brain barrier, carbidopa allows a smaller amount of levodopa to be administered systemically to produce the desired therapeutic
effect centrally.
• In the United States, the decarboxylase inhibitor is carbidopa. The combination drug carbidopa-levodopa (IR Sinemet) is available in tablets of 10
mg/100 mg, 25 mg/100 mg, and 25 mg/250 mg, with the numerator referring to carbidopa and the denominator referring to levodopa dose. An IR
formulation of carbidopa-levodopa (Parcopa) is available that dissolves on the tongue and can be taken without water [29,30]; its time of onset of
action is not different from Sinemet.
• In some countries, benserazide is the peripheral decarboxylase inhibitor. The combination drug benserazide-levodopa (eg, Madopar or Prolopa) is
available in 12.5 mg/50 mg, 25 mg/100 mg, and 50 mg/200 mg formulations. In many countries, both carbidopa-levodopa (eg, Sinemet)
and benserazide-levodopa (eg, Prolopa) are marketed.
• CR tablet formulations of carbidopa-levodopa and benserazide-levodopa are available as Sinemet CR and Madopar HBS, respectively. Compared with
IR levodopa, the absorption of CR tablets is approximately 70 percent. An extended-release (ER) capsule formulation (Rytary in the United
States; Numient in Europe) contains IR and ER beads of carbidopa-levodopa that are absorbed in the gastrointestinal tract at different rates [31]. The
role of ER capsules in the management of motor fluctuations is discussed separately. (See "Medical management of motor fluctuations and
dyskinesia in Parkinson disease", section on 'Role of longer-acting oral levodopa formulations'.)

8. • Initial dosing and titration — Levodopa should be initiated using an IR formulation. For carbidopa-levodopa, we use the 25
mg/100 mg IR tablet for initial titration, starting at one-half tablet two to three times daily with meals. We establish
tolerability at this dose for several days to a week before making further adjustments.
• Clinicians should always aim for the lowest levodopa dose that produces a useful clinical response (see 'Response
assessment' below). Some patients will feel adequate symptom relief with just one-half of a tablet per dose, two to three
times daily; others may need as high as two tablets per dose, three times daily (spaced every four to six hours, starting with
the morning dose; a dose before sleep is usually not necessary early in the disease). For the initial titration, we typically
adjust each dose in one-half tablet increments and observe for several days to weeks in between dose adjustments. Slower
titrations may be appropriate in some older adults and those with dementia due to increased susceptibility to side effects.
• The majority of patients with idiopathic PD will enjoy a significant initial therapeutic response to total daily doses of
levodopa in the range of 300 to 600 mg. Complete absence of response should prompt consideration of the diagnosis of
other parkinsonian syndromes, such as progressive supranuclear palsy and multiple system atrophy, except in cases of
unresponsive typical Parkinson tremor. (See 'Inadequate early response to levodopa' below.)
• Levodopa should not be stopped abruptly in patients with PD, because sudden withdrawal has been associated (rarely) with
a syndrome resembling neuroleptic malignant syndrome or akinetic crisis. (See 'Parkinsonism-hyperpyrexia
syndrome' below.)
• CR tablet levodopa preparations are available but not recommended as initial therapy. CR tablets are less completely
absorbed and require a dose up to 30 percent higher to achieve an equivalent clinical effect. The peak clinical effect of each
CR tablet is typically less than for IR preparations, since CR formulations reach the brain more slowly over time. This presents
a disadvantage in assessing the response of patients just initiating therapy. As a result, we always start with an IR preparation
and subsequently switch to CR tablets only if patients desire twice-per-day dosing for convenience (although the difference
between twice-daily and three-times-daily dosing may not be seen as an important advantage by many patients).
• Both the IR and the CR tablet formulations appear to maintain a similar level of symptom control after several years of use
[32], and use of CR tablets does not offer any long-term advantage in terms of motor fluctuations. CR tablets are sometimes
better tolerated in patients with nausea or confusion on IR tablets.

9. • Adverse effects — Nausea, somnolence, dizziness, and headache are among the more common early side effects that may
accompany treatment with levodopa. They are less likely to occur when slow starting doses and slow titration are used and
tend to resolve over time or with dose adjustment and supportive measures. More serious adverse reactions to levodopa
(mainly in older patients) may include confusion, hallucinations, delusions, agitation, psychosis, and orthostatic hypotension.
(See 'Approach to dopaminergic side effects' below.)
• Levodopa may also induce a mild to moderate elevation in serum homocysteine levels [33-36], which in turn may be
associated with an increased risk of hip fractures in older adults. (See "Osteoporotic fracture risk assessment", section on
'Possible risk factors'.)
• In addition, there is accumulating evidence suggesting that levodopa exposure in patients with idiopathic PD is associated
with low serum levels of vitamin B12, elevated methylmalonic acid levels, and a higher than expected incidence of
sensorimotor peripheral neuropathy [37-40].
• Compulsive dopaminergic drug use has been reported in patients taking DAs, typically in conjunction with levodopa therapy.
However, it is unclear that these behavioral issues arise with any frequency with levodopa monotherapy. (See 'Dopamine
dysregulation syndrome' below.)
• Follow-up and monitoring
• Response assessment — Levodopa should be titrated to subjective symptom response. Clinical examination is important but
is a single time point, at an interval from levodopa administration that may vary from visit to visit. The patient's and care
partner's overall impression of response over the interval since levodopa was initiated or adjusted is often much
more informative.
• We advise patients to observe for improvements in their original bothersome symptoms, such as tremor, slowed general
mobility, loss of finger dexterity, and gait impairment, as well as for side effects. Some but not all patients also experience
benefits in nonmotor symptoms.
• Over time, patients should also be monitored for motor complications of levodopa therapy, including motor fluctuations
("wearing off"), failed doses, involuntary movements (dyskinesia), and abnormal cramps and postures of the extremities and
trunk (dystonia). (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on
'Symptom spectrum'.)
• Patients should also be monitored for emergent or worsening impulse control disorders (ICDs) due to dopaminergic
therapies, especially DAs. (See 'Impulse control disorders' below and 'Dopamine dysregulation syndrome' below.)

10. • Inadequate early response to levodopa — The majority of patients with PD will experience significant benefit from initiation of levodopa at low to
moderate doses (eg, 300 to 600 mg per day). (See 'Initial dosing and titration' above.)
• The occasional exception to this is tremor-predominant PD, which can require high doses of levodopa to control tremor. Sometimes, high levodopa
doses are precluded by side effects, and thus patients never experience adequate control of tremor. The addition of amantadine and/or
anticholinergic medications may be helpful in this setting, but at the risk of adverse effects, especially in older adults. If satisfactory control of tremor
cannot be reached with these medications, such patients should be considered for surgical therapies. (See 'Amantadine' below
and 'Anticholinergics' below and "Device-assisted and lesioning procedures for Parkinson disease".)
• In all other cases, when patients do not experience benefit from two tablets of carbidopa-levodopa three times daily, either subjectively or objectively,
or experience very short-lived or modest benefit, an alternative parkinsonian syndrome should be considered (eg, multiple system atrophy,
progressive supranuclear palsy, or vascular parkinsonism) (see "Diagnosis and differential diagnosis of Parkinson disease"). In such cases, levodopa can
be further titrated, as high as 300 mg three to four times per day, to more definitively rule out PD. However, if there is no benefit from 300 mg of
levodopa three to four times daily, the diagnosis is unlikely to be idiopathic PD. In such patients, a trial of dopaminergic therapy with a DA
or amantadine is very unlikely to be helpful.
• Waning response to levodopa — Patients with idiopathic PD often experience adequate control of symptoms for prolonged periods on an initial
therapeutic dose of levodopa, some for several years. Eventually, however, the benefit of levodopa begins to wane.
• In some patients, the duration of benefit from each levodopa dose begins to shorten, and symptoms return before the next dose is due ("wearing
off"). Management of this phenomenon and other motor fluctuations includes closer spacing of doses to bridge the gaps and adding drugs that extend
the benefit of levodopa. These strategies are reviewed in detail separately. (see "Medical management of motor fluctuations and dyskinesia in
Parkinson disease")
• Other patients do not report "wearing off" but nonetheless feel that their function is not optimized with carbidopa-levodopa monotherapy, even at
1.5 or 2 tablets three times daily. In such patients, we typically add additional dopaminergic therapy to levodopa, choosing from among the same
drugs discussed below as alternative monotherapies. Selection is individualized based on the following considerations:
• ●MAO B inhibitors offer a convenient once-daily option to augment overall benefit of levodopa, although the result is usually modest. (See 'MAO B
inhibitors' below.)
• ●DAs provide more potent augmentation of dopaminergic benefits in appropriate patients. When used as adjunctive therapy, DAs can be beneficial at
lower doses than those used as monotherapy, thus reducing the risk of side effects. They can also be used to keep the total levodopa dose a bit lower,
reducing the risk of dyskinesia from levodopa. (See 'Nonergot dopamine agonists' below.)
• ●The addition of amantadine can be particularly useful in patients with prominent tremor. (See 'Amantadine' below.)

11. • Waning response to levodopa — Patients with idiopathic PD often experience adequate control of
symptoms for prolonged periods on an initial therapeutic dose of levodopa, some for several years.
Eventually, however, the benefit of levodopa begins to wane.
• In some patients, the duration of benefit from each levodopa dose begins to shorten, and symptoms
return before the next dose is due ("wearing off"). Management of this phenomenon and other motor
fluctuations includes closer spacing of doses to bridge the gaps and adding drugs that extend the
benefit of levodopa. These strategies are reviewed in detail separately. (see "Medical management of
motor fluctuations and dyskinesia in Parkinson disease")
• Other patients do not report "wearing off" but nonetheless feel that their function is not optimized
with carbidopa-levodopa monotherapy, even at 1.5 or 2 tablets three times daily. In such patients, we
typically add additional dopaminergic therapy to levodopa, choosing from among the same drugs
discussed below as alternative monotherapies. Selection is individualized based on the following
considerations:
• ●MAO B inhibitors offer a convenient once-daily option to augment overall benefit of levodopa,
although the result is usually modest. (See 'MAO B inhibitors' below.)
• ●DAs provide more potent augmentation of dopaminergic benefits in appropriate patients. When
used as adjunctive therapy, DAs can be beneficial at lower doses than those used as monotherapy,
thus reducing the risk of side effects. They can also be used to keep the total levodopa dose a bit
lower, reducing the risk of dyskinesia from levodopa. (See 'Nonergot dopamine agonists' below.)
• ●The addition of amantadine can be particularly useful in patients with prominent tremor.
(See 'Amantadine' below.)
•

12. • ALTERNATIVES IN SELECT PATIENTS
• While levodopa is an appropriate first-line symptomatic therapy in all patients with early PD, there is a role for
alternative therapies in select patients, depending on patient and disease characteristics and patient
preference.
• Our approach — Examples of when an alternative treatment is reasonable to offer as first-line monotherapy
include the following:
• ●Mild symptoms, preference for once-daily medication – In patients of any age preferring once-daily
medication and only requiring modest benefit, monoamine oxidase type B (MAO B) inhibitors are a reasonable
alternative to levodopa. Guiding principles are discussed below. (See 'MAO B inhibitors' below.)
• ●Younger patients at high risk for dyskinesia – In patients under 50 years of age who are at high risk of
dyskinesia, initial monotherapy with a dopamine agonist (DA) can be considered. Risk factors for dyskinesia
include younger age at disease onset, lower body weight, and female sex [2]. (See 'Nonergot dopamine
agonists' below.)
• Amantadine monotherapy can also be considered, particularly when tremor is prominent.
(See 'Amantadine' below.)
• ●Patients with tremor-predominant disease – Occasional patients with PD have a relatively isolated and
symptomatic tremor without significant bradykinesia or gait impairment. While levodopa remains the initial
agent of choice, often higher doses of levodopa are required for high-amplitude
tremor. Amantadine monotherapy can be considered in patients with milder tremor. (See 'Amantadine' below.)
• Anticholinergic drugs are sometimes useful as monotherapy in patients with bothersome tremor but are less
well tolerated in older patients because of the risk of cognitive impairment, constipation, and prostatism.
(See 'Anticholinergics' below.)
• For patients who do not respond adequately to a lower-potency dopaminergic agent or who progress despite
optimal titration, levodopa should be initiated. (See 'General principles' above.)

13. • Nonergot dopamine agonists — Three nonergot DAs (pramipexole, ropinirole, and transdermal rotigotine) are in widespread use for PD and have all
been shown to be effective as monotherapy in patients with early disease [23,41-48].
• A systematic review identified 29 trials in 5247 patients with early PD in which a DA with or without levodopa was compared with placebo, levodopa,
or both [23]. Treatment with a DA reduced motor symptoms of PD, although symptomatic control of PD was better with levodopa in most trials that
compared them directly; meta-analysis was not possible due to variable outcome methodologies across studies. Patients assigned to a DA were less
likely to develop dyskinesia (odds ratio [OR] 0.51, 95% CI 0.43-0.59), dystonia (OR 0.64, 95% CI 0.51-0.81), and motor fluctuations (OR 0.75, 95% CI
0.63-0.9) but more likely to develop nonmotor side effects, including edema (OR 3.7, 95% CI 2.6-5.2), somnolence (OR 1.5, 95% CI 1.1-2.0),
constipation (OR 1.6, 95% CI 1.1-2.3), dizziness (OR 1.5, 95% CI 1.1-1.9), hallucinations (OR 1.7, 95% CI 1.1-2.5), and nausea (OR 1.3, 95% CI 1.1-1.7).
• In one of the larger individual trials, the cumulative incidence of dyskinesia over five years was 20 percent in patients assigned to ropinirole (with or
without supplementation with levodopa) and 45 percent in patients assigned to levodopa [41]. The degree of dyskinesia was generally mild and
nondisabling in both groups. Another trial found a similar 22 percent absolute reduction in the development of dyskinesia and a 16 percent reduction
in "wearing off" in patients assigned to pramipexole compared with those assigned to levodopa [42]. However, patients assigned to levodopa had
lower incidences of freezing, somnolence, and leg edema (the last two attributable to side effects of pramipexole) and had better symptomatic
control than those assigned to pramipexole; both treatments resulted in similar improvement in quality of life.
• Patient selection and precautions — In patients under 50 years of age who are at high risk of dyskinesia (eg, younger age at disease onset, lower body
weight, female sex), initial monotherapy with a DA is an alternative to early levodopa [2]. DAs have intermediate potency for improving motor
symptoms and have a lower risk of motor complications than levodopa. When given alone, DAs rarely cause dyskinesia, and they have the advantage
of being available in once-daily formulations.
• Important precautions include the following:
• ●DAs should be avoided in patients with a history of impulse control disorders (ICDs), cognitive impairment, excessive daytime sleepiness, or
hallucinations. Consider avoiding DAs in patients whose occupations involve driving or using heavy machinery, given the risk of sleep attacks.
• ●Risk factors for development of ICDs from DAs include male sex, younger age, history of ICDs, history of mood disorders, and family history of ICDs
and addiction [2]. (See 'Impulse control disorders' below.)
• ●DAs should be avoided in older adults due to increased risk of adverse effects, especially cognitive impairment.
• DAs are ineffective in patients who have shown no therapeutic response to levodopa, but they do have a role in patients with advanced PD as a
treatment for motor complications of levodopa. The use of DAs in advanced PD is discussed separately.

14. • Agent selection and formulations — The few studies that have conducted head-to-head comparisons of the efficacy of
various DAs have found either no significant difference [49,50] or only mild superiority of one agent over another [51,52].
Therefore, the choice of which DA to use is based on formulation (oral versus transdermal), dosing frequency (immediate
versus extended release), and cost.
• Pramipexole and ropinirole are oral DAs available in both immediate-release (IR; at least three times daily) and extended-
release (ER) once-daily formulations. Rotigotine is a once-daily transdermal patch. ER or transdermal formulations are
generally preferred for convenience when not prohibited by issues such as renal impairment (for pramipexole ER), inability to
swallow whole pills (for oral ER formulations), or cost.
• Apomorphine is an additional DA that can be administered parenterally for "rescue therapy" in patients experiencing sudden
akinetic episodes, either subcutaneously by intermittent injection or by continuous infusion for management of motor
fluctuations. (See "Device-assisted and lesioning procedures for Parkinson disease", section on 'Continuous subcutaneous
apomorphine' and "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'Dopamine
agonists'.)
• Dosing and titration
• ●Pramipexole – Pramipexole IR is usually started at 0.125 mg three times a day. The dose should be increased gradually by
0.125 mg per dose every five to seven days. Pramipexole ER is usually started at 0.375 mg daily at bedtime and titrated by
0.375 mg increments every five to seven days. Most patients can be managed on total daily doses of 1.5 to 4.5 mg. Dose
adjustments are required for renal insufficiency, and the ER formulation is not recommended in patients with a creatinine
clearance <30 mL/minute.
• ●Ropinirole – Ropinirole IR is usually started at 0.25 mg three times a day. The dose should be increased gradually by 0.25
mg per dose each week for four weeks to a total daily dose of 3 mg. After week 4, the ropinirole dose may be increased
weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Ropinirole ER is usually started at 2 mg daily at bedtime
and titrated by 2 mg increments every five to seven days, up to a maximum of 24 mg. Benefit most commonly occurs in the
dose range of 12 to 16 mg per day.
• ●Rotigotine – Transdermal rotigotine is a once-daily patch that is usually started at 2 mg/24 hours and titrated weekly by
increasing the patch size in 2 mg/24 hour increments to a dose of 6 mg/24 hours.
• DAs should not be stopped abruptly, because sudden withdrawal of DAs has been very rarely associated with a syndrome
resembling neuroleptic malignant syndrome or akinetic crisis (see 'Parkinsonism-hyperpyrexia syndrome' below) and with a
stereotyped withdrawal syndrome.

15. • Adverse effects — Adverse effects caused by DAs are similar to those of levodopa, including nausea, vomiting, sleepiness,
orthostatic hypotension, confusion, and hallucinations. Peripheral edema is common with the chronic use of DAs but does
not occur in patients using levodopa alone. In randomized trials comparing DAs with levodopa, patients assigned to DAs are
more likely to report edema, somnolence, constipation, dizziness, hallucinations, and nausea and more likely to discontinue
treatment due to adverse events (OR 2.49, 95% CI 2.08-2.98) [23].
• Most adverse effects of DAs can be avoided by initiating treatment with very small doses and titrating to therapeutic levels
slowly over several weeks. Patients intolerant of one DA may tolerate another. As with all of the antiparkinsonian drugs,
older adults and patients with dementia are much more susceptible to side effects of hallucinations and mental confusion.
(See 'Approach to dopaminergic side effects' below.)
• DAs as a class are associated with the development of ICDs such as pathologic gambling, compulsive sexual behavior, or
compulsive buying in up to 50 percent of patients with long-term use. Compulsive use of dopaminergic drugs is a less
common adverse effect. (See 'Impulse control disorders' below and 'Dopamine dysregulation syndrome' below.)
• The use of transdermal rotigotine is associated with skin site reactions, which are typically transient and mild to moderate in
severity, but occasionally severe enough to result in discontinuation.
• Ergot-related side effects such as Raynaud phenomenon, erythromelalgia, and retroperitoneal or pulmonary fibrosis are
uncommon with bromocriptine, and they do not occur at all with the nonergot agonists ropinirole, pramipexole,
and rotigotine.
• Dopamine receptor agonists decrease prolactin concentration [53]. Thus, there is a potential for decreased milk production
in postpartum patients taking these agents, which are contraindicated in patients who are breastfeeding.
• The manufacturer of pramipexole has issued a warning regarding somnolence that can occur abruptly and without
premonition, particularly at a dose above 1.5 mg/day. Patients with PD who drive are at particular risk of developing these
"sleep attacks" [54]. Patients should be warned of this potential side effect and asked about factors that may increase the
risk of drowsiness, such as concomitant sedating medications, sleep disorders, and medications that increase pramipexole
levels (eg, cimetidine). While this may be more common with pramipexole, it can happen with any of the DAs.
• Dopamine agonist withdrawal syndrome — The DA withdrawal syndrome is described in some patients with PD who
abruptly stop taking a DA [55-57]. In retrospective studies, the frequency of the syndrome among patients who withdraw
from DAs ranged from 8 to 19 percent [55,56,58]. Symptoms resemble those of cocaine withdrawal and include anxiety,
panic attacks, depression, sweating, nausea, pain, fatigue, dizziness, and drug craving. These symptoms were refractory to
other antiparkinson medications, including levodopa, and only responded to resuming the DA.

16. • MAO B inhibitors — In patients of any age preferring once-daily medication and only requiring modest benefit, MAO B
inhibitors are a reasonable alternative to levodopa as first-line therapy. Guiding principles are as follows:
• ●While MAO B inhibitors are relatively low potency in terms of their dopaminergic effects and may not produce a functionally
significant benefit in some patients, they are given once or twice daily and are generally well tolerated.
• ●Levodopa confers greater improvement in mobility than an MAO B inhibitor, and there is a higher rate of discontinuation
due to adverse effects with MAO B inhibitors [2].
• ●Sixty percent of those randomized to MAO B inhibitors will require additional dopaminergic therapy within two to three
years [2].
• Three MAO B inhibitors are available for use in patients with PD: selegiline, rasagiline, and safinamide. They have not been
directly compared with each other, and the choice among the three is based on clinician and patient preference. Safinamide,
as the most recently approved of the three, may be more costly than the older MAO B inhibitors and is more often used as
adjunctive therapy with levodopa in advanced PD. (See "Medical management of motor fluctuations and dyskinesia in
Parkinson disease", section on 'Adjunctive therapies'.)
• ●Dosing
• •Selegiline – The most commonly used dose of selegiline in patients with PD is 5 mg twice daily, which is the dose used in
most clinical trials of selegiline and the approved dose in the package insert [59,60]. Morning and midday dosing is advised to
avoid insomnia. Some clinicians use a lower dose (eg, 5 mg daily) based on the rationale that selegiline binds irreversibly to
MAO B, and a single dose is sufficient to achieve enzymatic inhibition for longer than 24 hours [61].
• Doses of selegiline higher than 10 mg daily should not be used in patients with PD as they may result in nonselective MAO
inhibition and place the patient at risk of hypertensive crisis due to dietary interactions with tyramine-containing foods.
• •Rasagiline – Rasagiline is typically started at 0.5 mg once daily and then increased to 1 mg once daily as long as it is well
tolerated.
• •Safinamide – Safinamide is usually given as adjunctive therapy with levodopa to help with motor fluctuations; whether as
monotherapy or adjunctive therapy, safinamide is started at 50 mg once daily and can be increased to 100 mg daily after 14
days based upon tolerability and benefit [62]. (See "Medical management of motor fluctuations and dyskinesia in Parkinson
disease", section on 'Monoamine oxidase type B (MAO B) inhibitors'.)

17. • ●Adverse effects – Nausea and headache are the most common side effects associated with the use
of MAO B inhibitors [63]. Other possible adverse effects of MAO B inhibitors include confusion
and hallucinations. Falls, insomnia, and dyskinesia also may occur, but these may be manifestations
of advanced PD rather than adverse effects of MAO B inhibitors.
• Selegiline may cause confusion in older adults, more so than the other MAO B inhibitors, thereby
limiting its use in patients with late-onset disease. Selegiline enhances the effect of levodopa by
slowing its oxidative metabolism. In a few case reports, rasagiline use was associated with ICDs [64].
(See 'Impulse control disorders' below.)
• Serious adverse reactions have rarely occurred following the concomitant use of selegiline with
tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs). In practice, the vast
majority of patients on these combinations are able to tolerate them for years without problems.
However, the package insert warns not to use selegiline with either tricyclics or SSRIs. The possible
interaction of SSRIs and MAO B inhibitors in patients with PD is discussed in greater detail separately.
(See "Management of nonmotor symptoms in Parkinson disease", section on 'Safety considerations
with SSRI use'.)
• Although one observational study from the United Kingdom showed increased mortality in patients
using selegiline [65], the results of the United Kingdom study have not been confirmed by
subsequent reports, including three meta-analyses of randomized trials [66-70].
• Recommended time intervals to avoid drug interactions when switching or discontinuing
antidepressants and MAO inhibitors are reviewed separately. (See "Switching antidepressant
medications in adults", section on 'Switching to or from MAOIs'.)
• Unlike nonselective MAO inhibitors, selegiline does not precipitate a hypertensive crisis in patients
who concomitantly ingest tyramine-containing foods at a daily dose of 10 mg or lower.

18. • ●Efficacy – The MAO B inhibitors have been shown to be modestly effective as early
symptomatic treatment for PD [63,66,67,71-74]. A meta-analysis of 12 randomized
trials of 2514 patients comparing MAO B inhibitors versus placebo in early PD (11
of 12 trials used selegiline) found that treatment with MAO B inhibitors led to small
but statistically significant improvements in Unified Parkinson Disease Rating Scale
(UPDRS) motor scores at one year (mean difference 3.8 points, 95% CI 2.3-5.3,
six trials), a reduction in the need for levodopa at one year (OR 0.48, 95% CI 0.37-
0.62, four trials), and a reduction in the development of motor fluctuations (OR 0.73,
95% CI 0.58-0.91, six trials) [66]. There was a higher risk of nausea (OR 1.8) and
a nonsignificant trend towards more treatment withdrawals with MAO B inhibitors
than placebo (13 versus 9 percent, OR 1.7, 95% CI 0.98-3.0).
• Additional evidence supporting the long-term symptomatic benefit of selegiline for
PD comes from the continuation phase of a randomized controlled trial involving 157
patients with PD, in which patients who were initially assigned to selegiline in
the earlier phase of the study were treated with combined selegiline and levodopa,
while those initially assigned to placebo were treated with combined placebo and
levodopa [75]. At seven years, treatment with the combination of selegiline and
levodopa was associated with significantly better symptom control than treatment
with placebo and levodopa

19. • Amantadine — Amantadine monotherapy is an alternative to early levodopa in younger patients who are at risk for dyskinesia, particularly when
tremor is prominent.
• The mechanism of action of amantadine in PD is uncertain; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine
receptors, and possibly exert central anticholinergic effects [76]. It also has N-methyl-D-aspartate (NMDA) receptor antagonist properties that may
account for its therapeutic effect by interfering with excessive glutamate neurotransmission in the basal ganglia.
• Aside from use as monotherapy, amantadine can be useful for managing levodopa-induced dyskinesia and "off" time in patients with more advanced
PD. This indication is reviewed separately. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on
'Amantadine for dyskinesia'.)
• ●Formulations – Amantadine is available in an IR formulation, in 100 mg tablets or capsules, as well as ER once-daily formulations (capsules or
tablets). Absent comparative studies, IR and ER formulations appear to be similarly effective and tolerated, and ER amantadine tends to be more
expensive.
• ●Dosing – The dose of IR amantadine used in early PD is 100 mg two to three times daily; there is no evidence that larger doses are of additional
benefit. The ER formulations are dosed once daily. Amantadine is excreted unchanged in the urine and should be used with caution in the presence of
renal failure; both IR and ER formulations require dose modifications according to estimated creatinine clearance. If patients experience insomnia or
nightmares, switching to morning dosing is often advised.
• ●Adverse effects – Peripheral side effects include livedo reticularis and ankle edema, which are rarely severe enough to limit treatment. Confusion,
hallucinations, and nightmares occur infrequently but are more common in older patients, even after long periods of use without side effects. These
effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients.
• ●Efficacy – In early uncontrolled clinical trials, two-thirds of patients receiving amantadine monotherapy for early PD showed an improvement in
tremor, bradykinesia, and rigidity [77]. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for
bradykinesia and rigidity [78]. Amantadine has not been directly compared with MAO B inhibitors as monotherapy. The benefit induced by
amantadine is transient in some patients and often limited to a year or two.
• Anticholinergics — Anticholinergic drugs are sometimes useful as monotherapy for younger patients with PD who have disturbing tremor but do not
have significant bradykinesia or gait disturbance. Importantly, anticholinergics should be avoided in older adults with PD and those with significant
cognitive impairment due to increased risk of adverse effects. All patients should be counseled thoroughly and monitored closely for side effects,
including cognitive impairment, constipation, and urinary retention.
• The centrally acting anticholinergic drugs trihexyphenidyl and benztropine have been used for many years in PD [79]. Other anticholinergic agents
such as biperiden, orphenadrine, and procyclidine produce similar effects and are more commonly used in Europe than the United States.
Benztropine also may increase the effect of dopamine by inhibiting its presynaptic reuptake, but it is not known whether this contributes to its
mechanism of action.

20. • ●Dosing – Trihexyphenidyl is the most widely prescribed anticholinergic agent, although there is little
evidence to suggest that one drug in this class is superior to another. The starting dose
of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three times daily. Younger
patients may tolerate higher doses if needed for tremor but should be vigilant for the development
of side effects. Benztropine traditionally is more commonly used by psychiatrists for the management
of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg twice daily.
• ●Adverse effects – Adverse effects of anticholinergic drugs are common and often limit their use.
Older adults and cognitively impaired patients are particularly susceptible to memory
impairment, confusion, and hallucinations and should not receive these drugs. When an
anticholinergic drug is used to treat sialorrhea or urinary frequency, peripherally acting agents such
as propantheline should be used, although confusion and hallucinations are not infrequent adverse
effects with these drugs as well. Younger patients usually tolerate these agents better than older
adults, although some experience dysphoric symptoms, sedation, or memory impairment.
• Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary
retention, impaired sweating, and tachycardia. Caution is advised in patients with known
prostatic hypertrophy or closed-angle glaucoma. Discontinuation of anticholinergic drugs should be
performed gradually to avoid withdrawal symptoms that may manifest as an acute exacerbation of
parkinsonism, even in those in whom the clinical response has not seemed significant.
• ●Efficacy – Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal
ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs
exacerbate and anticholinergic drugs improve parkinsonian symptoms [79-81].

21. • APPROACH TO DOPAMINERGIC SIDE EFFECTS
• Nausea — Nausea is a common adverse effect of levodopa and dopamine agonists (DAs). It is usually most
apparent early in treatment and lessens over time.
• Patients taking levodopa for the first time should take each dose with a meal or snack to reduce the risk of
nausea. For some patients, small starting doses of levodopa (eg, one-half of a 25 mg/100 mg tablet
of carbidopa-levodopa) produce nausea due to inadequate doses of carbidopa. This can be managed
by administering supplemental doses of carbidopa (or benserazide, where available).
• For nausea due to either levodopa or DAs, an antiemetic such as trimethobenzamide or domperidone (not
available in the United States) can be taken 30 to 60 minutes prior to each dose. Phenothiazine antiemetics
such as prochlorperazine and metoclopramide should be avoided because they are dopamine receptor blockers
that can aggravate parkinsonian symptoms.
• Patients often can taper off antiemetics after several months without reemergence of nausea. For patients with
persistent nausea, long-acting formulations of levodopa and DAs are sometimes better tolerated than
immediate-release (IR) formulations.
• Orthostasis — Orthostasis can be caused or worsened by dopaminergic therapy and may develop later in the
course of the disease rather than upon initiation of dopaminergic therapy. Patients with a history of
hypertension may require a reduction or even discontinuation of their antihypertensive medications. Given the
lower relative efficacy of amantadine, monoamine oxidase type B (MAO B) inhibitors, and DAs versus levodopa,
these are usually tapered and withdrawn if necessary prior to lowering levodopa for orthostasis. If orthostasis
persists on a minimum necessary dose of levodopa monotherapy, symptomatic medications for orthostatic
hypotension may be needed. (See "Treatment of orthostatic and postprandial hypotension".)
• Confusion and hallucinations — Confusion and hallucinations can be caused or worsened by dopaminergic
therapy and typically develop later in the course of the disease rather than upon initiation of dopaminergic
therapy. Given the lower relative efficacy of amantadine, MAO B inhibitors, and DAs versus levodopa, these are
usually tapered and withdrawn if necessary prior to lowering levodopa. If confusion and hallucinations persist
on levodopa monotherapy, levodopa should be tapered to the minimum necessary dose prior to the addition of
antipsychotics. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Psychosis'.)

22. • Impulse control disorders — Impulse control disorders (ICDs) can develop in any patient on dopaminergic therapy at any stage of PD but are most
commonly associated with DA therapy. Patients and caregivers should be educated about ICDs when dopaminergic therapy is initiated and monitored
closely for their development [6]. If a bothersome or destructive ICD is present, DA therapy should be reduced until the ICD resolves. This is a
potentially serious iatrogenic disorder that was not well recognized when DAs were first being used in PD. With greater awareness of its various
manifestations, it has become recognized to be quite common [82-86].
• ICDs can range from nonbothersome (compulsive solitaire-playing, compulsive cleaning) to very intrusive and destructive (gambling leading to loss of
house and savings; hypersexuality leading to infidelity and divorce). While early, mostly short-term or cross-sectional studies identified ICDs in
approximately 5 to 15 percent of patients with PD treated with DAs [82,87-92], subsequent prospective longitudinal studies estimate a five-year
cumulative incidence of nearly 50 percent [83,93]. The annual incidence is estimated to be 10 to 12 per 100 patient-years among DA users
[83,93,94].
• Risk factors include DA dose and duration of treatment, younger age, male sex, and comorbid anxiety and depression [95,96]. The risk appears to be
similar across different DAs and different formulations. Untreated PD itself has not been associated with ICDs compared with healthy controls [97].
Longitudinal studies have not found a strong association between levodopa and ICDs, although there is some evidence that higher doses may be
associated with a small increase in risk [83,93].
• Limited data suggest that ICDs improve with discontinuation of DAs in most but not all patients [82-84]. We typically taper the DA gradually and
follow the patient closely to determine if they need additional levodopa for motor symptoms, rather than making an abrupt or simultaneous
conversion. Most patients will ultimately need to start or increase levodopa, and this can be titrated according to symptoms. Abrupt discontinuation
of a DA can result in dopamine withdrawal syndrome [57], which may also interfere with assessing the response to adding levodopa.
• For patients with persistent ICD despite discontinuation of DA therapy, there are limited data to suggest that cognitive behavioral therapy (CBT) might
be useful [98]. A small trial found no clear benefit of naltrexone compared with placebo in 50 patients with PD, although confidence intervals were
wide and some measures favored active treatment [99].
• Data are mixed with regard to amantadine and ICDs. One randomized crossover trial of 17 patients found that amantadine (target dose 100 mg twice
daily), administered as add-on to baseline antiparkinsonian medications, reduced or abolished pathologic gambling in all treated patients [100].
However, five patients dropped out of the trial due to side effects that included confusion, orthostatic hypotension, insomnia, and visual
hallucinations. The high dropout rate is consistent with the notion that amantadine may be poorly tolerated in patients with PD taking other
antiparkinsonian medications. By contrast, analysis of a large observational dataset found a positive association between amantadine use and risk of
ICDs, independent of DA use, levodopa dose, and other potential confounders [101].

23. • Dopamine dysregulation syndrome — Compulsive use of dopaminergic drugs develops in a
small number of patients with PD and has been termed the "dopaminergic dysregulation
syndrome" (DDS) [102].
• DDS typically involves male patients with early-onset PD who take increasing quantities of
dopaminergic drugs despite increasingly severe drug-related dyskinesia [102-104]. DDS can
be associated with a cyclical mood disorder characterized by hypomania or manic psychosis.
Tolerance (or frank dysphoria) to the mood-elevating effects of dopaminergic therapy
develops, and a withdrawal state occurs with dose reduction or withdrawal. ICDs including
hypersexuality and pathologic gambling may accompany DDS [102]. (See 'Impulse control
disorders' above.)
• A form of complex, prolonged, purposeless, and stereotyped behavior called punding also
may be associated with DDS [105].
• DDS appears to be uncommon but not rare. In a series of 202 patients with PD, criteria for
DDS were fulfilled in seven (3.4 percent) [106]. DDS may occur more frequently with DAs
than with levodopa [106], but data are scarce. A small case-control study found that
susceptibility factors for DDS included younger age at disease onset, higher novelty-seeking
personality traits, depressive symptoms, and alcohol intake [107].
• Management of DDS is not well studied. Practitioners should limit dopaminergic dose
increases when possible, particularly in patients who may have increased susceptibility to
DDS. Continuous subcutaneous apomorphine infusions may be useful to suppress "off"
period dysphoria, and low doses of clozapine or quetiapine may be helpful for some patients
[107]. Treatment of psychosis in patients with PD is discussed in detail elsewhere.
(See "Management of nonmotor symptoms in Parkinson disease", section on 'Psychosis'.)

24. • OTHER MANAGEMENT ISSUES
• Inpatient considerations — Given the high prevalence of motor fluctuations in PD, and the disabling
nature of both "off" periods and severe dyskinesia, care should be taken in the inpatient setting to
administer all PD medications at the appropriate dose and the correct time. Patients should be
advised to bring a medication list (including when doses are taken) and the medications themselves,
in case some are not quickly available on the hospital formulary.
• Failure to conform to the patient's individualized regimen can result in either complications of
untreated parkinsonism, such as falls, aspiration, or rigidity, or adverse effects of medications,
including orthostasis, confusion, and hallucinations. Dopamine-blocking agents, including
antipsychotics and antiemetics, must be avoided.
• Swallowing restrictions — Most patients with PD can go without antiparkinson medications for a
brief period (ie, <24 hours) when oral intake is temporarily restricted (eg, when perioperative or
periprocedural) or when seriously ill. In patients who are critically ill and bedbound, the parkinsonian
symptoms are typically overshadowed by the burden of other medical problems, and antiparkinson
medications may not provide any clear benefit. However, sudden withdrawal or dose reduction of
antiparkinson medications can rarely precipitate the parkinsonism-hyperpyrexia syndrome.
(See 'Parkinsonism-hyperpyrexia syndrome' below.)
• When treatment is still desired for patients who are restricted to take nothing by mouth (nil per os
[NPO]), options include transdermal rotigotine and apomorphine by injection or continuous infusion.
The use of apomorphine requires a test dose prior to ongoing treatment. Initiation of transdermal
rotigotine or apomorphine in the inpatient setting requires a thorough review of historical reactions
to dopamine agonists (DAs) and careful weight of benefits versus risks, which include orthostasis,
confusion, and hallucinations. For patients with a nasogastric feeding tube, levodopa tablets can be
crushed and given through the tube [108]. For patients with dysphagia, orally
disintegrating carbidopa-levodopa is a potential treatment option. (See 'Formulations' above.)

25. • Parkinsonism-hyperpyrexia syndrome — There have been reports of patients with PD who
developed neuroleptic malignant syndrome in the context of sudden withdrawal or dose
reductions of levodopa or DAs, and rarely amantadine, as well as with switching from one
agent to another. In this context, the condition has been termed the "parkinsonism-
hyperpyrexia syndrome." (See "Neuroleptic malignant syndrome", section on 'Antiparkinson
medication withdrawal'.)
• Prompt recognition and treatment are important, as severe cases and even fatalities have
been reported [109,110].
• Management of parkinsonism-hyperpyrexia syndrome involves
replacing antiparkinson medications at the dose that was used prior to the onset of the
syndrome [110]. Levodopa and DAs can be given orally or via nasogastric tube. Nonoral
options for DAs include transdermal rotigotine and apomorphine by injection or continuous
infusion. The use of apomorphine requires a test dose prior to ongoing treatment.
(See "Device-assisted and lesioning procedures for Parkinson disease", section on
'Continuous subcutaneous apomorphine'.)
• In addition to replacing antiparkinson medications, patients with significant hyperthermia
and rigidity should be admitted to an intensive care unit setting and undergo aggressive
supportive care as well as monitoring for potential dysautonomia and other complications.
(See "Neuroleptic malignant syndrome", section on 'Supportive care'.)
• For patients with severe symptoms who do not respond to
restarting antiparkinson medications and supportive care within the first day or
two, additional though unproven measures to consider include the use
of dantrolene, bromocriptine, and/or amantadine.

26. • Drug-induced parkinsonism is likely the most common drug-induced movement disorder and one of the most common nondegenerative causes of
parkinsonism. Any medication that interferes with dopamine transmission may cause parkinsonism. The prototypical drugs are dopamine receptor
blocking agents, specifically those that block D2.
• Drug-induced parkinsonism and idiopathic Parkinson disease (PD) may be clinically indistinguishable, and dopamine transporter imaging such as
single-photon emission computed tomography (SPECT) and positron emission tomography (PET) can help differentiate them. The diagnosis of drug-
induced parkinsonism is important to recognize, as the syndrome is reversible when the offending medication is removed.
• This topic reviews the causes, clinical features, diagnosis, and treatment of drug-induced parkinsonism. Other drug-induced movement disorders, such
as tardive dyskinesia, are reviewed separately. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis" and "Tardive dyskinesia:
Prevention, treatment, and prognosis".)
• EPIDEMIOLOGYThe exact prevalence of drug-induced parkinsonism is unclear because the symptoms are often under-recognized and misdiagnosed,
even by neurologists [1-5]. Several large, population-based studies in Europe estimated a prevalence of drug-induced parkinsonism ranging from 0.09
to 1.7 percent [6-12]. In these same populations, idiopathic Parkinson disease (PD) occurred with only a slightly higher prevalence (0.37 to 1.9
percent).
• The percentage of patients with drug-induced parkinsonism increases with age, with the highest incidence in those between 60 and 80 years. This is
likely because dopamine cells and dopamine transport decrease with age, and less dopamine receptor blockade is required to reach the threshold for
parkinsonism [13-15]. Other smaller studies challenge this assertion, however [16].
• Additional at-risk populations include patients with parkinsonism before antipsychotic drug exposure, especially those with subclinical PD who would
eventually become symptomatic as a matter of course, but in whom the drug triggers an earlier onset. There is conflicting evidence about whether
drug-induced parkinsonism is more common in males or females [17-21].
• PATHOPHYSIOLOGYAn interruption in dopaminergic transmission underlies the pathophysiology of drug-induced parkinsonism. The most common
mechanism is a structural or functional blockade of the dopamine D2 receptor in the striatum by dopamine D2 receptor blocking drugs. This changes
the output of the indirect pathway of the basal ganglia-thalamocortical motor loop, similar to changes seen in idiopathic Parkinson disease (PD) (figure
1). (See "Epidemiology, pathogenesis, and genetics of Parkinson disease".)
• Alteration in dopamine function can also occur with drugs like tetrabenazine and reserpine, which inhibit monoamine (including dopamine) storage
into presynaptic vesicles by interfering with vesicular monoamine transporter type 2 (VMAT2) [22].
• There are likely additional mechanisms that are not yet understood, as suggested by the wide array of medications that can cause parkinsonism
without clear striatal dopamine effects.

27. • CAUSATIVE DRUGSPrototypical dopamine D2 receptor blocking agents include not only the first- and second-
generation antipsychotics, but also certain antiemetic and prokinetic agents, most
notably metoclopramide and prochlorperazine (table 1). Other less commonly implicated classes of drugs
include dopamine-depleting agents (eg, tetrabenazine and reserpine), certain mood stabilizers (eg, valproate),
antidepressants, and calcium channel blockers.
• First-generation antipsychotics — Drug-induced parkinsonism was first seen with the first-generation (typical)
antipsychotic drugs, which are potent antagonists of the dopamine D2 receptor. (See "First-generation
antipsychotic medications: Pharmacology, administration, and comparative side effects".)
• Potency, route, and dose of these agents all influence the risk of developing drug-induced parkinsonism. In
general, the more potent the antipsychotic, the more frequently patients will develop parkinsonism [17,23].
Patients receiving intramuscular (IM) or suppository forms develop parkinsonism more quickly and at lower
doses than those receiving them parenterally [17,24]. For any given drug and formulation, higher doses lead to
more D2 receptor blockade, which increases the risk of parkinsonism [15,16].
• Across a range of drugs and potencies, parkinsonism has been reported in 32 to 50 percent of older adult
patients exposed to first-generation antipsychotics [23,25]. Risk for younger patients is likely less, although
exact estimates are unavailable [17].
• Second-generation antipsychotics — Second-generation (atypical) antipsychotics are thought to cause
parkinsonism less frequently than first-generation antipsychotics because they have lower affinity for D2
receptors and higher affinity for other targets, including serotonergic, histaminergic, and muscarinic receptors
[22]. However, they do have the potential to cause parkinsonism, and risk is not uniform across all drugs.
• Among the second-generation antipsychotics, risperidone, olanzapine, ziprasidone, lurasidone,
and paliperidone are associated with a higher risk of parkinsonism, while quetiapine and clozapine have a
lower risk [21,26-28]. High doses of risperidone and olanzapine have approximately the same risk of
parkinsonism as first-generation antipsychotic drugs [23,29]. In the authors' clinical experience, these two
agents are the most likely of the second-generation antipsychotics to cause drug-induced parkinsonism,
followed closely by ziprasidone, lurasidone, and paliperidone. More evidence is needed to determine the risk
of drug-induced parkinsonism in newer antipsychotic drugs, including asenapine and iloperidone.

28. • Aripiprazole and brexpiprazole have a slightly different mechanism of action and are considered
"dopamine stabilizers," as they act as a D2 receptor antagonist in dopamine-rich sites of the brain and
a D2 agonist in dopamine-poor sites [30]. While this different mechanism of action suggests that these
drugs may carry a lower risk of parkinsonism, aripiprazole was reported to cause drug-induced
parkinsonism more frequently than olanzapine in the World Health Organization
(WHO) pharmacovigilance database [21]. Older adults may be more susceptible. In a 12-week
randomized trial of aripiprazole versus placebo in older adults with depression (median age 66 years),
parkinsonism was reported in 17 percent of patients exposed to aripiprazole, at a median daily dose of
7 mg [30]. There has been one reported case of brexpiprazole causing severe parkinsonism in an older
woman [31].
• Pimavanserin is a newer atypical antipsychotic without affinity for D2 receptors. It is an inverse agonist
at the 5-HT2A receptor, meaning it binds to this receptor and decreases its activity. Based on its
pharmacologic profile, pimavanserin should theoretically have no risk of drug-induced parkinsonism. It
has been approved by the US Food and Drug Administration for the treatment of Parkinson disease
(PD) psychosis and is an alternative to clozapine or quetiapine in patients with PD
[32,33]. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Psychosis'.)
• Antiemetic and prokinetic medications — Several commonly used antiemetics and prokinetic agents
are derivatives of benzamide or phenothiazine antipsychotics and cause both central and peripheral
blockade of dopamine D2 receptors. These drugs, notably prochlorperazine and metoclopramide, have
a well-established association with a spectrum of involuntary movements, including acute dystonic
reactions, drug-induced parkinsonism, and tardive dyskinesia [24,34-36]. The exact risk of drug-
induced parkinsonism in patients taking these medications chronically is not known but could
potentially be as high as that of first-generation antipsychotics.
• Domperidone is considered to have low risk of drug-induced parkinsonism because it acts mainly on
peripheral dopamine receptors [37]; however, reversible parkinsonism has been reported [38,39].

29. • Dopamine-depleting agents — Reserpine, tetrabenazine, deutetrabenazine, and valbenazine cause
parkinsonism through the depletion of dopamine. Tetrabenazine, deutetrabenazine,
and valbenazine are reversible inhibitors of vesicular monoamine transporter type 2 (VMAT2), which
is responsible for uptake of monoamines (including dopamine) into presynaptic vesicles. Reserpine is
an irreversible VMAT2 inhibitor and is 10 to 20 times more potent than tetrabenazine [40].
• Tetrabenazine is used for chorea in Huntington disease (HD) and other hyperkinetic movement
disorders. In a placebo-controlled trial for HD chorea, 15 percent of patients developed parkinsonism
[41]. This number was consistent with another larger cohort of patients with varied hyperkinetic
movement disorders [42].
• Deutetrabenazine and valbenazine are newer VMAT2 inhibitors, and therefore evidence is more
limited. In short-term trials of deutetrabenazine in patients with HD [43] and tardive dyskinesia [44],
no worsening of parkinsonism was noted compared with placebo. Similarly, no increase in
parkinsonism was reported in a trial of valbenazine versus placebo in patients with tardive dyskinesia
with up to one year of follow-up, although attrition was high in the extension study (36 percent)
[45,46]. However, valbenazine-induced parkinsonism has been reported in a subsequent case series
[47]. Like tetrabenazine, these medications should be used with caution in patients who are at risk
for parkinsonism until more experience is available.
• Valproic acid — Valproic acid can cause drug-induced parkinsonism; however, this side effect is
relatively rare compared with the risk of drug-induced parkinsonism with antipsychotic agents.
• There are more than 100 cases of valproic acid-induced parkinsonism reported in the literature [48].
Gamma-aminobutyric acid (GABA)-induced inhibition of dopamine transport in the basal ganglia is a
suspected mechanism.

30. • Other drugs
• ●Lithium – Lithium has been implicated in case reports to cause a parkinsonian syndrome [39,49,50]. In a
Canadian administrative database study, patients over 65 years of age who were on lithium monotherapy for a
year or longer were more likely to be prescribed antiparkinson medication than a control group of patients on
monotherapy with other antidepressants, suggesting that lithium by itself has the potential to produce
parkinsonian symptoms [51].
• ●Selective serotonin reuptake inhibitors (SSRIs) – Multiple SSRIs have been reported to cause de novo
parkinsonism or worsen motor symptoms in patients with PD [39]. These
include citalopram, fluoxetine, sertraline, fluvoxamine, and paroxetine [52-55]. However, many of the reported
patients were also treated concurrently or recently with antipsychotic medications. It is not well understood why
SSRIs by themselves would cause parkinsonism, and the risk is likely low.
• ●Calcium channel blockers – Cinnarizine and flunarizine are weak calcium channel blockers with additional
antihistamine effects, serotonin receptor blockade, and dopamine D2 receptor blocking activity. They are
structurally similar to phenothiazine antipsychotics, which may explain their extrapyramidal effects. They are not
approved or available in the United States but are used in other regions for varied indications including
treatment of vertigo, migraine prophylaxis, and peripheral vascular disease.
• Drug-induced parkinsonism caused by cinnarizine and flunarizine is well described in regions where these drugs
are in use. The clinical presentation is similar to that in patients with antipsychotic-induced parkinsonism [56-59].
Animal studies suggest that the mechanism may be reduced dopaminergic neurotransmission, although this has
not been confirmed in human studies [60].
• There are a handful of case reports of other calcium channel blocking agents causing parkinsonism,
including amlodipine [61,62], diltiazem [39,63], and verapamil [39,64]. This is extremely rare, and because these
drugs do not resemble phenothiazines, it is not clear how they lead to parkinsonism. There is insufficient
evidence to support stopping these medications prior to making the diagnosis of PD.
• ●Others – Many other medications have been reported to cause drug-induced parkinsonism, often as single case
reports (table 2) [22,39,60,65-69].

31. • CLINICAL FEATURES
• Patients with drug-induced parkinsonism present with a motor syndrome of bradykinesia, rigidity, and/or resting tremor that
is clinically indistinguishable from idiopathic Parkinson disease (PD). These motor features are described in detail elsewhere.
(See "Clinical manifestations of Parkinson disease".)
• Onset of the symptoms typically occurs within a few weeks to months of the initiation of the offending agent [70]. In a large
survey study published in the era of first-generation antipsychotics, 90 percent of patients who developed parkinsonism while
being treated with an antipsychotic drug did so within the first 72 days of exposure to the medication [17]. However,
parkinsonism may also occur after many years of exposure to a medication [71,72]. In such cases, it can be difficult to exclude
emerging symptoms of idiopathic PD.
• Rigidity is the most common finding on examination, reported to occur 65 to 100 percent of the time [17,71,73-75].
Bradykinesia and resting tremor are more variable and found in 25 to 80 percent [73,75,76] and 35 to 88 percent [17,71,73-
76] of patients, respectively.
• In clinical practice, drug-induced parkinsonism is often thought to be symmetric, but studies show that asymmetric symptoms
occur 30 to 54 percent of the time [71,75,76].
• DIAGNOSIS
• Drug-induced parkinsonism is a clinical diagnosis that should be considered when a patient develops motor symptoms of
parkinsonism after starting or increasing the dose of an antipsychotic drug or other potentially offending agent (table
2 and table 1), or when a patient exhibits parkinsonism within a year of exposure to an offending drug. In the majority of
cases, parkinsonian symptoms emerge over the first two to three months, although they may also develop years after initial
exposure (algorithm 1) and take months to resolve after discontinuation [17,71,72]. A good drug history of both current and
recently discontinued medications is key to the diagnosis.
• Response to drug discontinuation — Drug-induced parkinsonism can be definitively diagnosed if the parkinsonism resolves
within six months after stopping the offending agent.
• Symptoms associated with drug-induced parkinsonism typically resolve after the reduction or removal of the offending agent
over the course of weeks to months [17,72,77]. In a group of 48 patients with drug-induced parkinsonism, it took an average
of seven weeks for symptom resolution; 11 percent of patients had symptoms persisting beyond 18 months [73]. Although
prolonged drug-induced parkinsonism has been described, it is difficult to exclude an underlying neurodegenerative cause in
such cases, and further testing is often indicated. (See 'Ancillary testing' below.)

32. • Patients with ongoing drug exposure — Because drug-induced parkinsonism
may be clinically indistinguishable from idiopathic Parkinson disease (PD) and
can even present asymmetrically with rest tremor [78], it cannot be diagnosed
by examination alone in the setting of ongoing drug exposure. Below we
describe clinical clues or tests that may help to separate drug-induced
parkinsonism from idiopathic PD for cases in which the offending drug cannot
be stopped.
• Clinical clues — The presence of concurrent movement disorders such as
akathisia, orofacial dyskinesia, or any other tardive syndrome suggests
that parkinsonism is more likely to be caused by a medication than by PD
[41,75,79]. (See "Tardive dyskinesia: Etiology, risk factors, clinical features,
and diagnosis", section on 'Clinical spectrum'.)
• By contrast, hyposmia on olfactory testing suggests the presence of an
underlying neurodegenerative parkinsonism (such as idiopathic PD) as
opposed to drug-induced parkinsonism [80-82]. (See "Diagnosis and differential
diagnosis of Parkinson disease", section on 'Olfactory testing'.)

33. • Ancillary testing — It is reasonable to obtain single-photon emission computed tomography (SPECT; 123I-FP-CIT also known as DaTscan) in cases of
suspected drug-induced parkinsonism where the causative agent cannot be stopped, or when parkinsonism persists several months after stopping the
drug (algorithm 1).
• Other nuclear imaging modalities such as positron emission tomography (PET) imaging or cardiac 123I-metaiodobenzylguanidine (MIBG, iobenguane I-
123) scintigraphy may distinguish drug-induced parkinsonism from an unmasked neurodegenerative process such as PD but are not widely available in
clinical practice. Available evidence suggests that transcranial ultrasound of the substantia nigra does not help to differentiate drug-induced
parkinsonism from idiopathic PD [83,84].
• ●Striatal dopamine transporter imaging – Striatal dopamine transporter imaging with SPECT (123I-FP-CIT [DaTscan]) or PET (18F-FP-CIT) demonstrates
reduced uptake of the radioligand in the striatum of patients with PD compared with normal uptake in patients with drug-induced parkinsonism [79,85-
89]. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'DaTscan' and "Diagnosis and differential diagnosis of Parkinson
disease", section on 'PET'.)
• In a meta-analysis of five studies, DaTscans had a sensitivity and specificity of 85 and 80 percent in differentiating idiopathic PD from vascular
parkinsonism or drug-induced parkinsonism [83]. DaTscan is widely available, while dopamine transporter PET imaging is generally restricted to tertiary
care centers. Referral to neurology is generally appropriate before ordering a DaTscan, as interpretation can be difficult.
• ●Cardiac scintigraphy – Cardiac 123I-MIBG scintigraphy measures cardiac postganglionic sympathetic innervation. Cardiac uptake of MIBG is significantly
reduced in PD and is normal in patients with drug-induced parkinsonism.
• Small studies have shown that abnormal cardiac 123I-MIBG scintigraphy reliably predicts which patients will have persistent parkinsonism and response
to levodopa after drug withdrawal [80,83,85]. The combined use of 123I-MIGB scintigraphy and DaTscan further improves predictive power [85].
However, MIBG scans for PD are not readily available for clinical use.
• Patients with recurrent or irreversible symptoms — There are descriptions in the literature of drug-induced parkinsonism that resolves initially after
removing the offending agent, only to recur and progress months to years later. There are also reports of patients with drug-induced parkinsonism who
do not improve with removal of the offending medication, but instead continue to have worsening parkinsonism.
• In most cases, such irreversible or temporarily reversible symptoms are felt to represent patients with early PD pathology that is too mild to manifest
motor symptoms, and the dopamine receptor blockade "unmasks" their preclinical PD.
• This hypothesis was initially based upon the findings of autopsy studies that demonstrated Lewy body pathology in a group of patients with reversible
drug-induced parkinsonism [70,90]. Subsequent longitudinal studies using dopamine transporter imaging have also found that evidence of
dopaminergic denervation on imaging is predictive of continued worsening of parkinsonism after medication discontinuation, while normal dopamine
imaging correlates with full recovery [85,91].

34. • DIFFERENTIAL DIAGNOSISThere are numerous other causes of primary and secondary parkinsonism. In
addition to idiopathic Parkinson disease (PD), other primary neurodegenerative disorders with
prominent parkinsonism include dementia with Lewy bodies, corticobasal degeneration, multiple
system atrophy, and progressive supranuclear palsy (table 3). Other secondary causes of parkinsonism
include cerebrovascular disease, toxins, head trauma, and infections. These and other disorders are
reviewed in detail separately. (See "Diagnosis and differential diagnosis of Parkinson disease".)
• MANAGEMENTThere are two approaches to managing drug-induced parkinsonism: avoidance or
discontinuation of known causative medications and symptomatic treatment of the parkinsonism.
• Avoidance or discontinuation of causative drugs — The best way to treat drug-induced parkinsonism
is to avoid using causative agents, especially in high-risk populations such as older adults.
Unfortunately, this is not always possible, as some patients with psychosis need to be treated with
antipsychotic agents. Mild drug-induced parkinsonism that is not bothersome to the patient does not
always need to be treated, especially if the patient is otherwise stable and deriving benefit from the
offending drug.
• If a patient develops bothersome parkinsonism on a medication known to cause parkinsonism, the first
step is to stop the offending medication and follow the patient clinically to see if the parkinsonism
resolves. When this is not an option, as is often the case when antipsychotics are given for severe
psychiatric conditions, we recommend working with the clinician prescribing the antipsychotic to
determine if it is reasonable to either decrease the dose of the medication or switch to a less potent
agent.
• For patients with idiopathic Parkinson disease (PD) who have psychosis, preferred agents
include quetiapine, clozapine, or pimavanserin if an antipsychotic is necessary [32,75,92-95].
(See "Management of nonmotor symptoms in Parkinson disease", section on 'Psychosis'.)

35. • Symptomatic treatment — When the causative agent cannot be discontinued, lowered, or switched to
an alternative drug, symptomatic treatment of parkinsonism may be considered. Because the
supporting evidence and the effectiveness of these agents are limited, clinicians should delay using
them until the parkinsonism is severe enough to interfere with motor function or quality of life.
• Use of these therapies should be discussed with the treating psychiatrist prior to initiation. Given the
limited evidence and balancing the likelihood of motor improvement versus severity of side effects and
availability, we suggest trying levodopa first in most patients. If this fails to improve symptoms, other
options (in order of preference) include amantadine, anticholinergics, and electroconvulsive therapy
(ECT), if available.
• ●Levodopa – Observational studies, including an open-label pilot study of levodopa in 16 patients with
disabling drug-induced parkinsonism, suggest that levodopa provides minimal benefit [75]. However,
levodopa may improve motor symptoms in the subgroup of patients with drug-induced parkinsonism
who have abnormal dopamine transporter scans and thus are more likely to have primary
neurodegenerative parkinsonism. In such patients, it is even more important to stop the offending
medication, if at all possible. (See 'Patients with recurrent or irreversible symptoms' above.)
• In the authors' experience, a levodopa trial is a reasonable first step in treating drug-induced
parkinsonism and may lessen motor symptoms, especially in patients with abnormal ancillary testing.
A main concern of prescribing levodopa to psychiatric patients is worsening of psychosis. While
levodopa tends to be well tolerated in most psychiatric patients in general, there are reports of
aggravated psychosis with high doses (>1000 mg/day), and discussion with the patient's psychiatrist
about the risks and benefits of levodopa therapy should occur prior to initiation [96,97]. Practice
varies, and some psychiatrists advise against levodopa in patients with psychosis.

36. • The typical starting dose of carbidopa-levodopa is 25/100 mg three times daily. If there is no
improvement in motor symptoms, the dose can be increased gradually every couple of weeks
as tolerated, up to 75/300 mg three times daily. Adverse effects and monitoring of levodopa
are reviewed separately. (See "Initial pharmacologic treatment of Parkinson disease", section
on 'Adverse effects'.)
• ●Amantadine – Amantadine has been suggested for the treatment of drug-induced
parkinsonism as an alternative to anticholinergics. However, the evidence is mixed [98,99],
and worsening of psychotic symptoms has been reported with amantadine in patients with
schizophrenia [100,101]. The dose of amantadine is 100 mg two to three times daily. Livedo
reticularis and ankle edema are common side effects.
• ●Anticholinergics – Anticholinergics such as benztropine have long been used by psychiatrists
to prevent and treat extrapyramidal symptoms like parkinsonism. However, there is little high-
quality evidence to suggest that they are effective [24,75,102,103]. Side effects, including
memory impairment, delirium, and urinary retention, may be problematic, especially in older
adults. Benztropine may be started at 1 to 2 mg/day in divided doses. If necessary, the dose
may be increased gradually every three to four days to 6 to 8 mg/day as tolerated.
• ●Electroconvulsive therapy – There are numerous case reports of ECT improving motor
symptoms in PD, with the proposed mechanism being upregulation of dopamine D1 receptors
[104]. Anecdotal evidence suggests that ECT can improve drug-induced parkinsonism as well
[104-106]. ECT may therefore be an option for patients with drug-induced parkinsonism who
also have a psychiatric indication for ECT, such as refractory depression.