INTRODUCTION — The array of pharmacologic and surgical treatments available for the treatment of idiopathic Parkinson disease (PD) is broader than for any other degenerative disease of the central nervous system. Management of individual patients requires careful consideration of a number of factors, including the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. Treatment can be divided into pharmacologic, nonpharmacologic, and surgical therapy.

The initial medical 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".)

Correct diagnosis is fundamental to the appropriate therapy of PD, although the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes. The diagnosis of PD is reviewed in detail separately. (See "Diagnosis and differential diagnosis of Parkinson disease".)

WHEN TO START DRUG THERAPY

Shared decision-making — 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 [1-4]:

●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

In some patients, an additional influence is the fear of starting levodopa due to reports of its association with motor fluctuations and dyskinesias, 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. (See 'Discussing concerns about motor complications' below.)

Discussing concerns about motor complications — A substantial number of patients with PD develop levodopa-related complications within several years of starting levodopa. These include motor fluctuations (the "wearing off" phenomenon) and a variety of complex fluctuations in motor function [5,6]. It is estimated that such motor complications occur in at least 50 percent of patients after 5 to 10 years of treatment [2]. The risk of motor complications increases with a younger age of PD onset [7-9]. (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 [2].

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 [10,11]. This viewpoint was reinforced by data from several trials establishing that higher levodopa dose is a risk factor for motor complications [9,12-14]. As a result, it is commonly proposed that the initiation of levodopa be delayed until symptoms significantly interfere with function.

However, there is increasing evidence that the choice and timing of initial therapy for PD, whether levodopa, dopamine agonist (DA), or monoamine oxidase type B (MAO B) inhibitor, has little impact on the long-term outcome of PD in terms of motor fluctuations and dyskinesia [15-17]. Delaying treatment unnecessarily deprives patients of therapeutic benefit early in the disease, when the potential for sustained improvement is greatest [18]. In a delayed-start trial of levodopa in which half of patients were randomly assigned to levodopa for 80 weeks and 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 [19]. 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 [20].

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 his or her individual needs. In addition, patients should be reassured that the onset of motor fluctuations likely depends on the 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.

HOW TO CHOOSE INITIAL THERAPY — Like the decision of when to start pharmacotherapy in patients with PD, the choice of which pharmacotherapy to use initially is individualized based on characteristics of the patient, the disease, and the drugs. There is no single preferred therapy, and trade-offs are common. Optimal care requires a flexible trial-and-error approach.

The four main drugs or classes of drugs that have antiparkinson activity are monoamine oxidase type B (MAO B) inhibitors, amantadine, dopamine agonists (DAs), and levodopa. Anticholinergic drugs also have some activity, mainly for tremor. They differ with respect to potency, dosing frequency, and side effects. All are considered to be symptomatic therapies, and none have been firmly established as disease modifying or neuroprotective [21].

The most important patient-related factors are age, which has important implications for tolerability of certain drug classes, and severity of symptoms, as the antiparkinson potency of different classes of drugs varies. Categorization of symptom severity should be based on holistic assessment of the patient, including neurologic examination findings and a detailed assessment of how symptoms affect daily function and quality of life.

Guiding principles include the following:

●MAO B inhibitors and amantadine have modest antiparkinson effects overall but are convenient and usually well tolerated. Their primary use is therefore in patients with mild symptoms that have not yet begun to have a major impact on daily function and quality of life.

●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.

●DAs have intermediate potency for improving motor symptoms and have a lower risk of motor complications than levodopa; however, they carry a higher risk of somnolence, hallucinations, and impulse control disorders (ICDs), and they are not well tolerated in older adults and those with cognitive dysfunction.

MILD SYMPTOMS, MINIMAL IMPACT ON DAILY LIFE — 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 (algorithm 1).

For those who desire medication at this stage, a monoamine oxidase type B (MAO B) inhibitor is a reasonable choice among the low-potency dopaminergic options. Amantadine monotherapy is an alternative antiparkinson drug preferred by some clinicians in this setting. Levodopa can be a good option as well, particularly among older adults. (See 'Levodopa' below.)

Monoamine oxidase type B inhibitors — Patients at any age with very early PD and minimal signs and symptoms who are looking for a small amount of benefit are good candidates for an MAO B inhibitor as initial therapy. 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.

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'.)

The MAO B inhibitors have been shown to be modestly effective as early symptomatic treatment for PD [22-28]. 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 (odds ratio [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) [22]. 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 [29]. At seven years, treatment with the combination of selegiline and levodopa was associated with significantly better symptom control than treatment with placebo and levodopa [22].

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 [30,31]. Morning and mid-day dosing is advised to avoid insomnia. Some clinicians use a lower dose (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 [32].

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 [33]. (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 [25]. 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 impulse control disorders (ICDs) [34]. (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 [35], the results of the United Kingdom study have not been confirmed by subsequent reports, including three meta-analyses of randomized trials [22,23,36-38].

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.

Amantadine monotherapy as an alternative — Amantadine monotherapy is an alternative to an MAO B inhibitor as a low-potency antiparkinson therapy for younger patients with PD (eg, age <70 years) and mild symptoms, particularly when tremor is prominent. The two have not been directly compared as monotherapy in this setting. Some clinicians perceive that amantadine is less effective than an MAO B inhibitor, while others feel that the dopaminergic effects are similar, and amantadine is well tolerated, particularly in younger patients. The benefit induced by amantadine is transient in some patients and often limited to a year or two.

In early uncontrolled clinical trials, two-thirds of patients receiving amantadine monotherapy for early PD showed an improvement in tremor, bradykinesia, and rigidity [39]. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for bradykinesia and rigidity [40].

●Formulations – Amantadine is available in an immediate-release (IR) formulation, in 100 mg tablets or capsules, as well as extended-release (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.

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 [41]. 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 dyskinesias 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'.)

Tremor-dominant disease — Occasional patients with PD have a relatively isolated and symptomatic tremor without significant bradykinesia or gait impairment. Although these patients may be considered similarly to others for initiation of a dopamine agonist (DA) or levodopa as discussed below (see 'Mild to moderate symptoms affecting daily life' below), some younger patients may benefit from initial therapy with an anticholinergic (eg, trihexyphenidyl) alone.

Amantadine monotherapy is also sometimes preferred in older adults with mild, tremor-predominant symptoms. (See 'Amantadine monotherapy as an alternative' above.)

Role of anticholinergics — Anticholinergic drugs are sometimes useful as monotherapy for patients with PD who are ≤65 years of age and have disturbing tremor but do not have significant bradykinesia or gait disturbance. They can also be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or DAs.

We avoid anticholinergics 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.

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 [42,43].

The centrally acting anticholinergic drugs trihexyphenidyl and benztropine have been used for many years in PD and continue to have a useful role [44]. 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.

●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.

MILD TO MODERATE SYMPTOMS AFFECTING DAILY LIFE — When motor symptoms of PD begin to interfere with daily function and quality of life, symptomatic therapy with a dopamine agonist (DA) or levodopa is indicated. The major factors that influence choice of therapy in such patients are age and severity of symptoms (algorithm 1).

Age ≤65 years: dopamine agonist versus levodopa — Neurologists have debated for years whether to select levodopa or a DA as initial therapy in relatively younger patients with PD. Since opinions vary widely and conclusive data do not exist, the consensus is that decisions should be individualized. The definition of a "younger" patient has also been debated. For practical purposes we use 65 years as a young age cutoff; some would consider 60 years or even 50 years as a more appropriate cutoff for this decision.

As demonstrated in the clinical trials discussed below, levodopa is more effective than DAs for reduction of motor symptoms but more frequently produces dyskinesia than DAs, especially in younger patients. When given alone, DAs rarely cause dyskinesia, and they have the advantage of being available in once-daily formulations. However, DAs produce more frequent nonmotor side effects (eg, somnolence, peripheral edema, nausea, dizziness, and impulse control disorders [ICDs]) than levodopa. Neurologic side effects (eg, hallucinations and confusion) are also more frequent with DAs, although these are much less common in younger patients in general.

Therefore, either a DA or levodopa may be reasonable as initial therapy in patients ≤65 years of age whose symptoms have begun to impact daily function and quality of life. The advantages and disadvantages of each should be weighed carefully by the clinician and patient together, with treatment ultimately customized to the patient's specific needs and priorities. While some patients may choose to start with a DA for convenience, especially if symptoms are mild, others may reasonably choose levodopa for its greater antiparkinson potency and better tolerability.

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 [45]. 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 variability in outcomes used. 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 2.1-3.0).

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 [46]. 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 (figure 1) [47]. 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, and both treatments resulted in similar quality of life.

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'.)

Age >65 years: levodopa — For patients older than 65 years of age with mild to moderate disease in whom a low-potency agent such as a monoamine oxidase type B (MAO B) inhibitor was inadequate or is thought likely to be inadequate for symptoms, we suggest therapy with levodopa rather than a DA. DAs are not well tolerated in older adults and those with cognitive dysfunction, and levodopa is more effective for improving motor function and quality of life. (See 'Levodopa' below.)

As noted above, 65 years as an age cutoff is somewhat arbitrary, and the presence of cognitive dysfunction at baseline also influences sensitivity to the neurologic side effects of DAs. If used in patients aged 65 to 70 years or in those with cognitive dysfunction, DAs should be approached with caution, as side effects of orthostasis, confusion, hallucinations, and sleepiness are common. DAs should be avoided in patients over the age of 70 years due to poor tolerability.

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 [45-53].

Formulations — The few studies that have compared the efficacy of various DAs with each other have found either no significant difference [54,55] or only mild superiority of one agent over another [56,57]. The choice among them is therefore based primarily on issues of formulation, dosing frequency, 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

●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. (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, constipation, dizziness, hallucinations, and nausea and more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08-2.98) [45].

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.

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 [58]. Thus, there is a potential for decreased milk production in postpartum women taking these agents, which are contraindicated in women 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" [59]. 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. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Daytime sleepiness'.)

Dopamine agonist withdrawal syndrome — The DA withdrawal syndrome is described in some patients with PD who abruptly stop taking a DA [60-62]. In retrospective studies, the frequency of the syndrome among patients who withdraw from DAs ranged from 8 to 19 percent [60,61,63]. 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.

Limited role of ergot dopamine agonists — Of note, the ergot-derived DAs (eg, bromocriptine, pergolide, and cabergoline) also have antiparkinson activity and were once used in patients with PD. However, they have been largely replaced by nonergot DAs in PD due to rare but potentially severe complications associated with long-term use of ergot derivatives.

●Pergolide and cabergoline – Pergolide and cabergoline have been associated with risks of cardiac, pulmonary, and peritoneal fibrosis and valvular heart disease with chronic use [64-73]. Pergolide was withdrawn from the United States market in 2007, and neither drug should be used to treat PD.

●Bromocriptine – A European Medicines Agency (EMA) review found insufficient evidence to determine whether there is an increased risk of valvular heart disease in patients taking bromocriptine [73]. However, the EMA concluded that a risk of fibrosis could not be excluded for bromocriptine and added warnings to limit daily doses to less than 30 mg and avoid use in patients with preexisting valve problems. Since the introduction of the nonergot DAs, bromocriptine is rarely used in PD.

MODERATE TO SEVERE SYMPTOMS, ANY AGE

Levodopa — Levodopa is our preferred therapy in patients at any age with moderate or severe symptoms (algorithm 1). It is also very reasonable to use for milder symptoms in older adults and in younger adults who prefer it as initial therapy or who are intolerant of dopamine agonist (DA) monotherapy or are no longer deriving sufficient benefit from it.

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 [1,45,74-76]. 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 40 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 for levodopa 150, 300, and 600 mg daily, respectively) [14]. A subsequent open-label randomized trial in early PD demonstrated a small benefit of levodopa over DAs and monoamine oxidase type B (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) [15].

Although levodopa is associated with a higher risk of dyskinesia than the DAs, there is increasing evidence that the choice of initial therapy for PD, whether levodopa, DA, or MAO B inhibitor, has little impact on the long-term outcome of PD in terms of motor fluctuations and dyskinesia. (See 'Discussing concerns about motor complications' above.)

Formulations — Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension. In the United States, the decarboxylase inhibitor is carbidopa. The combination drug carbidopa-levodopa (immediate-release [IR] Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg, with the numerator referring to carbidopa and the denominator referring to the levodopa dose. An IR formulation of carbidopa-levodopa (Parcopa) is available that dissolves on the tongue and can be taken without water [77,78]; 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 12.5/50, 25/100, and 50/200 mg formulations. In many countries, both carbidopa-levodopa (eg, Sinemet) and benserazide-levodopa (eg, Prolopa) are marketed.

Controlled-release (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 [79]. 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'.)

Dosing — Treatment should begin with small doses of an IR levodopa formulation, such as carbidopa-levodopa (Sinemet) 25/100 mg, one-half tablet two to three times daily with meals. Tolerance for the appropriate starting dose must be assessed individually. Once initiated without side effects, the total daily dose of carbidopa-levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily (spaced every four to six hours during waking hours, starting with the morning dose) as tolerated. A dose before sleep is usually not necessary early in levodopa therapy. Older adults or those with dementia should begin with smaller doses and slower titration because of their increased susceptibility to psychiatric side effects.

The usual practice is to titrate to the lowest levodopa dose that produces a useful clinical response. This varies from patient to patient, but at the start it is typically in the vicinity of 300 to 600 mg of levodopa daily. The vast majority of patients with idiopathic PD will enjoy a significant initial therapeutic response to moderate doses of levodopa (300 to 600 mg daily). Complete absence of response to a levodopa dose of 1000 to 1500 mg/day suggests that the original diagnosis of PD may be incorrect and that one of the other parkinsonian syndromes, such as multiple system atrophy, progressive supranuclear palsy, or vascular parkinsonism, should be considered. One exception is tremor-predominant PD, as large-amplitude tremors may be resistant to levodopa. (See "Diagnosis and differential diagnosis of Parkinson disease".)

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 purposes (although the difference between twice-daily and three-times-daily dosing may not be seen as an important advantage by many patients).

Both the immediate- and the controlled-release tablet formulations appear to maintain a similar level of symptom control after several years of use [80], 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.

Patients taking levodopa for the first time should take each dose with a meal or snack to avoid nausea, a common early side effect. Patients with more advanced disease, especially those with motor fluctuations, often notice that a dose of levodopa is more effective if taken on an empty stomach 30 minutes before or one hour after meals due to reduced competition with other amino acids for gastrointestinal absorption. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease", section on 'Dietary adjustments'.)

Small starting doses of levodopa of less than 25/100 mg three times daily combined with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to cause nausea because of inadequate amounts of carbidopa; this can be managed by administering supplemental doses of carbidopa or by use of antiemetics such as trimethobenzamide or domperidone (not available in the United States) taken prior to Sinemet. Phenothiazine antiemetics such as prochlorperazine and metoclopramide should be avoided because they are dopamine receptor blockers that can aggravate parkinsonian symptoms.

Adverse effects — Nausea, somnolence, dizziness, and headache are among the more common early side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients. More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, psychosis, and orthostatic hypotension.

Levodopa may also induce a mild to moderate elevation in serum homocysteine levels [81-84], 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 [85-88].

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.)

No benefit of early COMT inhibitors — 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 levodopa-carbidopa alone or combined with entacapone [89]. 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 [90].

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"'.)

APPROACH TO DOPAMINERGIC SIDE EFFECTS

Nausea — Nausea is a common adverse effect of dopamine agonists (DAs) and levodopa. In patients on low doses, additional carbidopa may be adequate to relieve nausea. If additional carbidopa is ineffective or unaffordable, domperidone, if available, can be very helpful, as can standing or as-needed doses of ondansetron or trimethobenzamide. Patients often can come off of the domperidone or antiemetics after several months without emergence of nausea.

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 minimum necessary dose prior to 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 [4]. 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 [91-95].

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 [91,96-101], subsequent prospective longitudinal studies estimate a five-year cumulative incidence of nearly 50 percent [92,102]. The annual incidence is estimated to be 10 to 12 per 100 patient-years among DA users [92,102,103].

Risk factors include DA dose and duration of treatment, younger age, male sex, and comorbid anxiety and depression [104,105]. 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 [106]. 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 [92,102].

Limited data suggest that ICDs improve with discontinuation of DAs in most but not all patients [91-93]. 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 [62], which may also interfere with assessing the response to adding levodopa. (See 'Dopamine agonist withdrawal syndrome' above.)

For patients with persistent ICD despite discontinuation of DA therapy, there are limited data to suggest that cognitive behavioral therapy (CBT) might be useful [107]. 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 [108].

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 [109]. 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 [110].

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) [111].

DDS typically involves male patients with early-onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-related dyskinesia [111-113]. 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 [111]. (See 'Impulse control disorders' above.)

A form of complex, prolonged, purposeless, and stereotyped behavior called punding also may be associated with DDS [114].

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) [115]. DDS may occur more frequently with DAs than with levodopa [115], 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 [116].

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 [116]. 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

Motor fluctuations and dyskinesias — A substantial number of patients with PD develop levodopa-related complications within several years of starting levodopa, including motor fluctuations ("wearing off"), failed doses, involuntary movements known as dyskinesia, abnormal cramps and postures of the extremities and trunk known as dystonia, and a variety of complex fluctuations in motor function [5,6]. Management is reviewed in detail separately. (See "Medical management of motor fluctuations and dyskinesia in Parkinson disease".)

Persistent tremor despite dopaminergic therapy — Patients ≤65 years with significant tremor despite levodopa may benefit from add-on therapy with amantadine or an anticholinergic such as trihexyphenidyl. Patients should be counseled thoroughly and monitored closely for cognitive impairment on these drugs as well as other anticholinergic side effects on trihexyphenidyl (constipation, urinary retention). (See 'Role of anticholinergics' above.)

If tremor persists despite maximal medical therapy, patients should be referred for deep brain stimulation. (See "Device-assisted and lesioning procedures for Parkinson disease".)

Inpatient considerations — Given the high prevalence of motor fluctuations in PD, and the disabling nature of both off periods and severe dyskinesias, 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 (see 'Age ≤65 years: dopamine agonist versus levodopa' above). 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 [117]. 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 [118,119].

Management of parkinsonism-hyperpyrexia syndrome involves replacing antiparkinson medications at the dose that was used prior to the onset of the syndrome [119]. Levodopa and DAs can be given orally or via nasogastric tube. Non-oral 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 5^th to 6^th 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 10^th to 12^th 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

●The decision to initiate symptomatic medical therapy in patients with Parkinson disease (PD) is influenced by the degree to which symptoms interfere with function or impair quality of life and patient preferences regarding use of medications. Fear of starting levodopa is common and should be discussed early on to help avoid unnecessary delays in treatment. (See 'When to start drug therapy' above.)

●The four main drugs or classes of drugs that have symptomatic antiparkinson activity as monotherapy are monoamine oxidase type B (MAO B) inhibitors (rasagiline, safinamide, and selegiline), amantadine, dopamine agonists (DAs; bromocriptine, pramipexole, ropinirole, and rotigotine), and levodopa. Anticholinergic drugs also have some activity, mainly for tremor. They differ with respect to potency, dosing frequency, and side effects. (See 'How to choose initial therapy' above.)

●The choice of which pharmacotherapy to use initially is individualized. The most important patient-related factors are age, which has important implications for tolerability of certain drug classes, and severity of symptoms, which influences the likelihood of symptomatic benefit (algorithm 1). Amantadine and MAO B inhibitors have relatively modest antiparkinson effects, whereas levodopa is the most potent antiparkinson therapy.

●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. For most patients who desire medication at this stage, we suggest an MAO B inhibitor over other antiparkinson therapies (Grade 2C). While MAO B inhibitors may not produce a functionally significant benefit in some patients, they are generally well tolerated and are given once daily. Amantadine monotherapy is an alternative, particularly for younger adults with predominant tremor. (See 'Monoamine oxidase type B inhibitors' above and 'Amantadine monotherapy as an alternative' above.)

●When motor symptoms of PD begin to interfere with daily function and quality of life, symptomatic therapy with a DA or levodopa is indicated (algorithm 1).

•For patients 65 years of age and younger, we suggest either a DA or levodopa as initial therapy (Grade 2A). The advantages and disadvantages of each should be weighed carefully by the clinician and patient together, with treatment ultimately customized to the patient's specific needs and priorities. While some patients may choose to start with a DA for convenience, especially if symptoms are mild, others may reasonably choose levodopa for its greater antiparkinson potency and better tolerability. (See 'Age ≤65 years: dopamine agonist versus levodopa' above.)

•For older patients (>65 years) with symptoms of PD that affect daily life, we suggest initiation of levodopa (Grade 2A). DAs are less well tolerated in older adults and those with cognitive dysfunction, and levodopa is more effective for improving motor function and quality of life. (See 'Age >65 years: levodopa' above and 'Moderate to severe symptoms, any age' above.)

●There is no clear benefit of initiating treatment with controlled-release (CR) levodopa compared with the immediate-release (IR) preparation, and the former may limit the ability to follow the initial response to therapy. As a result, we always initiate therapy with an IR preparation and switch to CR tablets only in patients who desire fewer daytime doses, or as a trial in those who have refractory nausea or confusion with IR tablets. (See 'Levodopa' above.)

●Anticholinergic drugs should be reserved for younger patients in whom tremor is the predominant problem. Their use in older patients, those with dementia, and those without tremor is strongly discouraged. (See 'Role of anticholinergics' above.)