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Initial pharmacologic treatment of Parkinson disease

Initial pharmacologic treatment of Parkinson disease
Literature review current through: Jan 2024.
This topic last updated: May 19, 2023.

INTRODUCTION — 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.

Management of PD requires careful consideration of the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. A wide range of symptomatic pharmacologic, nonpharmacologic, and surgical therapies are available to maximize motor and nonmotor function and quality of life throughout the disease course.

The initial pharmacologic management of PD is reviewed here. The nonpharmacologic management of PD, including education, support, neuroprotective benefits of exercise, and nutrition, is discussed separately. (See "Nonpharmacologic management of Parkinson disease".)

Treatment of advanced PD, particularly the complications associated with long-term levodopa therapy, and management of the comorbid problems including daytime sleepiness, hallucinations, and psychosis are reviewed elsewhere. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease" and "Device-assisted and lesioning procedures for Parkinson disease" and "Management of nonmotor symptoms in Parkinson disease".)

PRETREATMENT CONSIDERATIONS

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 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.

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. 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.

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 and greater likelihood of side effects when compared with levodopa.

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 [3,23-27].

Robust 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 [28]. 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 [29].

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"'.)

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, levodopa should be taken on an empty stomach because concurrent ingestion of dietary protein may block the effect of a dose of levodopa. This risk is low in early disease, however. (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 [30,31]; 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 [32]. 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'.)

Of note, levodopa is an active ingredient in the Mucuna pruriens bean, which is available as a dietary supplement and may be contained in other substances marketed for cognitive enhancement or brain health [33]. Patients should be asked about use of supplements, particularly when side effects arise on relatively low doses of prescribed levodopa or in patients with signs of dopamine dysregulation syndrome. Data in patients with PD indicate that use of Mucuna and other supplements is common and often not reported to clinicians [34]. Nausea is relatively common with Mucuna, because the peripheral conversion of levodopa is not offset by carbidopa. Therefore, if used, it should be started in very low amounts and increased slowly. Like levodopa-carbidopa, Mucuna can be associated with dyskinesia when used at sufficiently high doses. (See "High-risk dietary supplements: Patient evaluation and counseling".)

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). Although patients often feel substantial benefit within days of starting a therapeutic dose, prospective data in drug-naïve patients with early PD suggest that the maximal symptomatic response to levodopa (300 mg per day) occurs after at least a month and possibly as long as five months after reaching 300 mg per day [35].

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. In our experience, the dose that leads to substantial clinical benefit will typically do so within days to two weeks, even if maximal benefit may be more delayed. 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 [36], 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.

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 [37-40], 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 [41-44].

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. The goal of treatment is to improve symptoms so that patients can function at a better, more acceptable level. 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.)

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, specifically, deep brain stimulation or focused ultrasound. (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 may be particularly useful in patients with prominent tremor. (See 'Amantadine' below.)

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.)

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 [23,45-52].

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 [45]. 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 [46]. 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. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'Adjunctive therapies'.)

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 [53,54] or only mild superiority of one agent over another [55,56]. 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 subcutaneously or sublingually for "rescue therapy" in patients experiencing sudden akinetic episodes, 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

PramipexolePramipexole 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.

RopiniroleRopinirole 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. (See 'Dopamine agonist withdrawal syndrome' below.)

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 including sleep attacks, 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 careful patient selection, 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 [57]. 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" [58]. 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 [59-61]. In retrospective studies, the frequency of the syndrome among patients who withdraw from DAs ranged from 8 to 19 percent [59,60,62]. Symptoms resemble those of cocaine or amphetamine 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.

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 [63,64]. 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 [65].

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. A tyramine-free diet is not necessary at the doses recommended for PD.

RasagilineRasagiline is typically started at 0.5 mg once daily and then increased to 1 mg once daily as long as it is well tolerated.

SafinamideSafinamide 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 [66]. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'Monoamine oxidase type B (MAO B) inhibitors'.)

Adverse effects – Nausea and headache are the most common side effects associated with the use of MAO B inhibitors [67]. 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 [68]. (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 [69], the results of the United Kingdom study have not been confirmed by subsequent reports, including three meta-analyses of randomized trials [70-74].

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.

Efficacy – The MAO B inhibitors have been shown to be modestly effective as early symptomatic treatment for PD [67,70,71,75-78]. 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) [70]. 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 [79]. At seven years, treatment with the combination of selegiline and levodopa was associated with significantly better symptom control than treatment with placebo and levodopa [70].

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 [80]. 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'.)

FormulationsAmantadine 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, avoiding evening dosing as it may cause insomnia; 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 [81]. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for bradykinesia and rigidity [82]. 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 [83]. 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.

DosingTrihexyphenidyl 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 [83-85].

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), 25 mg with each dose of carbidopa-levodopa.

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 can usually taper off antiemetics or supplemental carbidopa 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'.)

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 at each clinical visit [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 [86-90].

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 [86,91-96], subsequent prospective longitudinal studies estimate a five-year cumulative incidence of nearly 50 percent [87,97]. The annual incidence is estimated to be 10 to 12 per 100 patient-years among DA users [87,97,98].

Risk factors for an ICD include DA dose and duration of treatment, younger age, male sex, and comorbid anxiety and depression [99,100]. 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 [101]. 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 [87,97].

Limited data suggest that ICDs improve with discontinuation of DAs in most but not all patients [86-88]. 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 [61], 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 [102]. 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 [103].

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 [104]. 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 [105].

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) [106].

DDS typically involves male patients with early-onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-related dyskinesia [106-108]. 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 [106]. (See 'Impulse control disorders' above.)

A form of complex, prolonged, purposeless, and stereotyped behavior called punding also may be associated with DDS [109].

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) [110]. DDS may occur more frequently with DAs than with levodopa [110], 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 [111].

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 [111]. Treatment of psychosis in patients with PD is discussed in detail elsewhere. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Psychosis'.)

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 [112]. For patients with dysphagia, orally disintegrating carbidopa-levodopa is a potential treatment option. (See 'Formulations' above.)

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 [113,114].

Management of parkinsonism-hyperpyrexia syndrome involves replacing antiparkinson medications at the dose that was used prior to the onset of the syndrome [114]. 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. (See "Neuroleptic malignant syndrome", section on 'Specific treatments'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parkinson disease" and "Society guideline links: COVID-19 – Index of guideline topics" and "Society guideline links: COVID-19 – Neurologic care".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Parkinson disease (The Basics)" and "Patient education: Medicines for Parkinson disease (The Basics)")

Beyond the Basics topics (see "Patient education: Parkinson disease treatment options — medications (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Parkinson disease".)

SUMMARY AND RECOMMENDATIONS

When to initiate therapy – All pharmacologic therapies for Parkinson disease (PD) are symptomatic. Treatment should generally begin when motor symptoms are affecting function and quality of life. Fear of starting levodopa is common and should be discussed early on to help avoid unnecessary delays in treatment. (See 'When should drug therapy be started?' above.)

Preferred therapy for most patients – In most patients with early PD seeking control of motor symptoms, we suggest levodopa as initial therapy (Grade 2A). Among dopaminergic therapies, levodopa has superior effects on motor function, activities of daily life, and quality of life and is often the best tolerated, especially in older adults. (See 'Levodopa monotherapy (most patients)' above.)

Levodopa-related motor complications may arise in many patients within several years of starting levodopa; however, accumulating evidence suggests that the disease itself, rather than the choice and timing of initial dopaminergic therapy, determines the onset and severity of motor complications. (See 'What is the natural history of motor complications?' above.)

Alternatives in select patients – In select cases, initial treatment with a dopamine agonist (DA), monoamine oxidase type B (MAO B) inhibitor, or amantadine is a reasonable alternative to early levodopa. Examples include younger patients at high risk for dyskinesia, in whom a DA may be considered, and patients with mild symptoms and a preference for once-daily medication, in whom an MAO B inhibitor may be preferred. Most such patients progress to require levodopa within a few years. (See 'Alternatives in select patients' above.)

Some patients with significant tremor despite levodopa may benefit from add-on therapy with amantadine or an anticholinergic such as trihexyphenidyl. (See 'Amantadine' above and 'Anticholinergics' above.)

Administration of levodopa – Levodopa should be administered at the minimum effective dose to control symptoms, and patients should be counseled regarding risk of motor complications. (See 'General principles' above.)

Starting dose – Our usual starting dose of levodopa is carbidopa-levodopa (Sinemet) 25 mg/100 mg (immediate-release [IR]), one-half tablet two to three times daily with meals. Some patients will feel adequate symptom relief initially with just one-half of a tablet per dose; others may need as high as two tablets per dose, three times daily. Titration is individualized based on clinical response and side effects. (See 'Initial dosing and titration' above and 'Follow-up and monitoring' above.)

Adverse effects – Nausea, somnolence, dizziness, and headache are the most common early side effects of levodopa; effects are usually mild and minimized by starting with low doses and titrating slowly. More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, psychosis, and orthostatic hypotension. (See 'Adverse effects' above and 'Approach to dopaminergic side effects' above.)

Follow-up and monitoring – The clinical course of PD is variable among individual patients, and longitudinal assessments and regular clinical follow-up are essential to optimize motor function with symptomatic medications. (See 'Follow-up and monitoring' above.)

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. (See 'Impulse control disorders' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel Tarsy, MD, who contributed to earlier versions of this topic review.

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Topic 4896 Version 66.0

References

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