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Medical management of motor fluctuations and dyskinesia in Parkinson disease

Medical management of motor fluctuations and dyskinesia in Parkinson disease
Authors:
Tsao-Wei Liang, MD
Daniel Tarsy, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Sep 30, 2021.

INTRODUCTION — Motor fluctuations and dyskinesia are important complications of levodopa therapy that affect many patients with advancing Parkinson disease (PD). Depending on the most prominent symptom and the baseline medication regimen, a variety of pharmacologic strategies can be used to manage motor complications.

Device-assisted and surgical treatments are additional therapeutic options that improve motor function in selected patients with advanced typical PD and motor fluctuations, whose condition cannot be further improved by medical therapy. These treatments (deep brain stimulation [DBS], continuous levodopa-carbidopa intestinal gel [LCIG] infusion, and continuous subcutaneous apomorphine infusion [CSAI]) are reviewed separately. (See "Device-assisted and lesioning procedures for Parkinson disease".)

Initial pharmacologic treatment of PD, management of nonmotor symptoms, and other aspects of advanced PD are reviewed separately. (See "Initial pharmacologic treatment of Parkinson disease" and "Management of nonmotor symptoms in Parkinson disease" and "Nonpharmacologic management of Parkinson disease" and "Palliative approach to Parkinson disease and parkinsonian disorders".)

PATHOPHYSIOLOGY — The etiology of motor fluctuations is multifactorial. As PD progresses and nigrostriatal dopaminergic neurons continue to degenerate, presynaptic neurons lose their ability to store and release levodopa after enzymatic conversion to dopamine. As a result, the response to exogenous levodopa begins to mirror its short half-life (90 minutes). It is also believed that the rapid cycling kinetics and pulsatile stimulation of dopamine receptors by dopamine may contribute to the narrowing of the therapeutic window over time. An additional factor is that levodopa absorption in the small intestine is highly dependent on proper intestinal absorption, which can be impaired by a number of factors including poor gastric emptying, slow intestinal transit times, competing dietary protein, and small intestinal bacterial overgrowth (SIBO).

Dyskinesia is caused by overstimulation of dopamine receptors, primarily by the use of levodopa, but also by agents that either stimulate or enhance the effect of dopamine at the receptor (eg, dopamine agonists, monoamine oxidase type B [MAO B] inhibitors, and catechol-O-methyl transferase [COMT] inhibitors). While associated with a relative excess of dopamine, dyskinesia can occur at even low therapeutic levodopa doses, depending on a patient's highly individual sensitivity. Dyskinesia is especially common in patients with young-onset PD (ie, before the age of 50 years) and can occur early or later in the course of the illness.

Of note, levodopa was given in relatively high doses when it was first used as therapy for PD in the late 1960s and early 1970s. As a result, dyskinesia was often seen early in treatment, especially in individuals with advanced PD who were being treated for the first time. Once levodopa was combined with carbidopa, the amount of levodopa required to produce a clinical benefit was drastically reduced. Consequently, dyskinesia became much less common in the early stages of treatment.

SYMPTOM SPECTRUM — When levodopa therapy is first instituted, patients with PD typically experience a smooth and prolonged response. However, as the disease advances, the effect of levodopa begins to wear off three to four hours after a dose. Motor complications of levodopa, in the form of motor fluctuations and dyskinesia, occur in 30 to 40 percent of patients during the first five years of use and nearly 60 percent or more by 10 years [1-4].

Motor fluctuations – Motor fluctuations are alterations between periods marked by a positive response to levodopa ("on"), and periods marked by reemergence of parkinsonian symptoms ("off") as the response to levodopa wears off. Types of motor fluctuations include the following:

"Wearing off," characterized by the reemergence of parkinsonian symptoms as the effect of levodopa diminishes near the end of the dose interval, usually three to four hours after a dose. "Wearing off" is often the first and most commonly encountered fluctuation in patients with PD. (See 'Approach to "wearing off"' below.)

Unpredictable "off" periods, with no obvious relationship between the time of levodopa administration and the appearance of "off" episodes. (See 'Unpredictable "off" periods' below.)

Freezing of gait (FOG), in which forward progression halts or is markedly reduced despite the intention to walk. This is one of the most debilitating motor symptoms in patients with PD and can lead to falls and loss of independence. (See 'Freezing of gait' below.)

Failure of the "on" response, with lack of an "on" response or no response following a dose of levodopa. (See 'Failure of "on" response' below.)

Acute akinesia, manifesting as a sudden severe exacerbation of PD including an akinetic state that lasts for several days and does not respond to treatment with antiparkinson medication. (See 'Acute akinesia' below.)

Nonmotor features of PD have the potential to fluctuate concurrently, especially feelings of panic or confusion, and may be even more disabling than the motor features. Management of nonmotor features of PD is reviewed separately. (See "Management of nonmotor symptoms in Parkinson disease".)

Dyskinesia – Levodopa-related dyskinesia refers to abnormal, involuntary movements brought on by use of levodopa. Other dopaminergic medications are less likely to lead to dyskinesia and motor fluctuations, but some, such as the dopamine agonists, may exacerbate preexisting dyskinesia. Levodopa-related dyskinesia encompasses a variety of involuntary movements or postures, including chorea, dystonia, ballism, and myoclonus [5], which emerge at various times in relation to levodopa dosing:

Peak-dose dyskinesia appears when the patient is "on" and is often choreiform in nature. Peak-dose dyskinesia usually starts 30 to 90 minutes after a dose of levodopa. (See 'Approach to peak-dose dyskinesia' below.)

Diphasic dyskinesia is a rare form of dyskinesia leading to two separate periods of involuntary movement after a levodopa dose, the first occurring when patients turn "on" and the second when they begin to wear "off." ”Wearing off” dyskinesia are less common and are sometimes characterized by large-amplitude leg movements. (See 'Diphasic dyskinesia' below.)

"Wearing off" dystonia manifests as dystonia, usually involving the limbs but sometimes involving the face, neck, or trunk, which emerges during "off" periods. These are particularly common first thing in the morning, before a dose of levodopa. (See 'Dystonia' below.)

EVALUATION — Patients should be evaluated for levodopa response and adverse effects at each visit in an effort to optimize response and quality of life. Visits also provide an opportunity to review terminology and improve the ability of patients to recognize and report motor complications.

History and observation Patients should be asked at each visit whether and when they sense jerky movements during a dosing cycle or a "wearing off" of the benefit between doses. Because some patients may confuse dyskinesia and tremor and the distinction cannot always be resolved by interview, direct observation or home video may be necessary. Direct observation during an extended (one- to four-hour) outpatient visit or by home video recording can also be useful to observe for dyskinesia and "off" or "on" responses after doses of levodopa.

Clinicians should inquire whether the patient takes a dose of levodopa on a fixed schedule (by the clock) or when experiencing "wearing off." Since consumption of dietary protein during a meal can interfere with the uptake of levodopa in the gut, thereby causing an erratic response to levodopa, clinicians should pay close attention to when and what the patient eats in relation to the response to levodopa dosing [6].

Symptom diaries – Symptom diaries may be helpful but are sometimes unreliable, especially if the patient is unfamiliar with definitions of dyskinesia (often confusing it with tremor and vice versa), dystonia, or "off" episodes. It is essential to carefully establish definitions for these terms with the patient and caregivers before beginning to use diaries or video recordings so that they are as accurate and informative as possible [7].

Reasons for subspecialty referral – In general, referral to a movement disorder specialist is warranted for medically refractory patients who experience troublesome motor fluctuations and dyskinesia in order to optimize medical therapy or to discuss invasive therapies [8].

APPROACH TO "WEARING OFF" — A variety of strategies can help to mitigate "wearing off," and management requires an individualized, trial-and-error approach. Although the majority of patients begin to experience "wearing off" after five years of levodopa treatment, a minority may note this phenomenon even earlier.

Dietary adjustments — The absorption of levodopa in the duodenum and its transport across the blood-brain barrier are facilitated by a large neutral amino acid transporter protein. Ingested protein has the potential to compete with levodopa transport in the gut and brain, thereby reducing levodopa's clinical benefit [9].

Patients should be made aware of these potential interactions, and effects of the diet should be examined in patients who begin to have motor fluctuations. Patients who report that protein-rich meals impair the levodopa benefit or "on" response should avoid protein at the time of drug administration and/or take the medication on an empty stomach, 30 to 60 minutes before or 60 to 90 minutes after a meal.

Further efforts to reduce or redistribute the amount of consumed protein are sometimes essential, particularly in patients with complex fluctuations, including dose failures and unpredictable "off" periods. A protein redistribution diet in which most dietary protein intake is reserved for the evening has demonstrated some benefit in small studies [10,11], but the quality of the studies was generally low [12], and many patients find this type of diet impractical. Nonetheless, a protein redistribution diet is worth trying in selected patients (see 'Unpredictable "off" periods' below and 'Failure of "on" response' below). Consultation with a nutritionist is recommended when there are concerns about adequate caloric intake or nutritional needs.

Beyond dietary adjustments, additional strategies to improve gastrointestinal absorption remain exploratory and await further confirmation in larger clinical trials [13]. For example, preliminary studies suggest that eradication of Helicobacter colonization, which is present in approximately half of the population, may be a useful method for improving levodopa absorption and reducing motor fluctuations in patients with PD [14,15]. In addition, limited data suggest that the prevalence of small intestinal bacterial overgrowth (SIBO) is higher among patients with PD compared with controls, and that SIBO may interfere with levodopa absorption and contribute to motor fluctuations [16,17].

Levodopa dose and interval adjustment — For patients who are on a low dose of levodopa and are not experiencing side effects, "wearing off" can be managed initially by increasing the dose of levodopa [18]. However, this strategy can be counterproductive when the individual levodopa dose is high (ie, >200 mg) and may amplify dyskinesia and "off" dystonia.

For more advanced PD when peak-dose dyskinesia becomes problematic, shortening the dosing interval while administering lower doses (ie, smaller but more frequent doses, sometimes called levodopa dose fractionation [19]) is a common strategy. This strategy may require additional levodopa doses at the end of the day, especially if the patient is planning activities later in the evening. Sometimes lower doses fail to reach a therapeutic threshold necessary to turn the patient "on," resulting in more dose failures and an increase in "off" time.

Dose fractionation can usually be accomplished with standard tablet doses of levodopa. Liquifying carbidopa-levodopa may be considered for patients who have difficulty titrating tablet doses. However, this approach is not practical since carbidopa-levodopa is insoluble in water and no commercial preparation of liquid carbidopa-levodopa is available. Instructions for preparation of a daily supply of liquid carbidopa-levodopa are available, but use of this method is generally not recommended unless supervised by a clinical pharmacologist and movement disorder neurologist familiar with this technique [20].

As PD progresses, a subset of patients occasionally exhibits a "brittle" response pattern or an "all or none" response. In this situation, an individual dose may produce no evident clinical response, and slightly higher doses trigger an exaggerated response with dyskinesia. While the precise mechanism for this "all or none" response is uncertain, one hypothesis is that the pharmacologic response threshold becomes higher as PD advances, reducing the therapeutic window between a response and dyskinesia. However, this explanation was challenged by findings from a longitudinal study that monitored the response to levodopa infusions in 20 subjects with PD. The investigators found that once dyskinesia first emerged, the onset and offset of the antiparkinsonian response and dyskinesia were similar, suggesting a therapeutic window no longer exists once dyskinesia emerges [21].

Role of longer-acting oral levodopa formulations — Two longer-acting oral levodopa formulations exist: an older, controlled-release (CR) tablet and a newer, extended-release (ER) capsule. Each has unique characteristics and limitations that inform use in selected patients in various stages of PD.

CR tablets – In general, CR tablets are primarily used as a form of levodopa in early PD, when patients are typically free of motor complications and experience a smooth and prolonged response to levodopa. Patients who desire twice-per-day dosing for convenience purposes can be switched from immediate-release (IR) to CR tablets, although the difference between twice-daily and three-times-daily dosing may not be seen as an important advantage by many patients. Their use in this context does not offer any long-term advantage in terms of motor fluctuations. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Levodopa'.)

The role of the CR tablet in managing motor fluctuations is more limited and is generally reserved for bedtime use to reduce middle-of-the-night or early morning "wearing off." Daytime use is complicated by the unpredictable onset of levodopa action and sometimes delayed responses, which can exacerbate motor fluctuations and promote onset of delayed dyskinesia. Although an early study suggested that CR carbidopa-levodopa tablets were useful in the early stages of the "wearing off" phenomenon and could add up to 90 additional minutes throughout the day to levodopa's duration of effect [22], the overall evidence is inconsistent [22-25], and two systematic reviews have concluded that CR tablets do not reliably decrease "off" time compared with IR levodopa formulations [18,26]. In addition, the CR tablet is less well absorbed than the IR tablet and takes longer to "kick in"; thus, an individual dose increase of approximately 30 percent may be required to achieve the same clinical response.

ER capsules – The ER capsule formulation of carbidopa-levodopa (Rytary in the United States, Numient in Europe) may be helpful for patients experiencing motor fluctuations with standard tablet forms of levodopa despite dose/interval adjustments and use of adjunctive dopaminergic medications. In this setting, ER capsules can be used to replace daytime IR and CR tablets. Converting IR/CR tablets to ER capsules is sometimes difficult and should be accomplished gradually, using the conversion table provided by the manufacturer. In practice, ER capsules can lead to a reduced number of daily doses and potential reduction in motor fluctuations, but at a higher cost, with a similar pill burden and twofold higher daily mg dose of levodopa. Bedtime use of ER capsules to replace CR tablets is also an option to reduce middle-of-the-night or early morning "wearing off."

The ER capsule contains IR and ER beads of carbidopa-levodopa that are absorbed in the gastrointestinal tract at different rates. Unlike CR tablets, ER capsules can be opened and the beads sprinkled on a small amount of applesauce to ease administration for patients who have difficulty swallowing pills. Pharmacokinetic studies indicate that ER capsules reach an initial peak of one hour, very similar to IR tablets, and that the peak is sustained for four to five hours, followed by a gradual "wearing off" over six or more hours. In addition, the peak concentration (Cmax) of ER capsules is notably lower than an equivalent dose of IR tablets, making it necessary to increase the dose of ER capsules by at least twofold to achieve an "on" response [27]. Therefore, ER capsules have the potential to reduce Cmax-related side effects such as peak-dose dyskinesia, in addition to alleviating "wearing off" effects and "off" time.

Supporting evidence for the ER capsule formulation includes a randomized controlled trial in which ER carbidopa-levodopa capsules reduced "off" time by approximately 70 minutes a day compared with IR carbidopa-levodopa tablets, though the final total daily levodopa dose of the ER formulation was on average approximately twice that of the IR formulation [28]. Another trial demonstrated that the ER capsules reduced "off" time compared with IR carbidopa-levodopa tablets combined with entacapone [29].

One of the major limitations of ER capsules is the cost of the drug, which can amount to over USD $3 per capsule without drug plan coverage. ER capsules are not included on the formulary of many drug plans in the United States, so formulary exemptions, prior authorizations, and letters of medical necessity are often necessary to obtain coverage for the drug.

Adjunctive therapies — If levodopa adjustments for "wearing off" are not adequate or tolerated, the addition of an adjunctive therapy (eg, dopamine agonist, catechol-O-methyl transferase [COMT] inhibitor, monoamine oxidase type B [MAO B] inhibitor, istradefylline) to the levodopa regimen can help to reduce "off" time. Adding one adjunct medication at a time and using the lowest effective dose of each medication can help to reduce dopaminergic side effects. The main limiting factor to all adjunctive medications is that they may cause or worsen dyskinesia as well as nonmotor dopaminergic side effects (eg, orthostasis, impulse control disorders). All have similar effects on "wearing off," and selection of a specific drug should be individualized based on characteristics of the patient, the disease, and the drugs.

Dopamine agonists — Adding a nonergot dopamine agonist, such as pramipexole or ropinirole (available in short- and long-acting formulations), or rotigotine, a dopamine agonist in a skin patch formulation, may help to reduce "off" periods [30-37]. However, due to the possibility of excessive dopaminergic stimulation and dyskinesia, the dose of concomitant levodopa should be lowered or adjusted accordingly. Visual hallucinations, edema, excessive daytime somnolence, hypotension, and impulse control disorders are other potential side effects of dopamine agonists. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Adverse effects'.)

Because older patients and those with cognitive dysfunction may be more prone to dopaminergic side effects, dopamine agonists should be combined with levodopa judiciously in patients older than 65 years of age. In addition, when used as an adjunct, dopamine agonists should be started at the lowest dose possible and titrated carefully.

Studies comparing the efficacy of various dopamine agonists generally have found minimal differences between agents, so that the choice of agonist depends on indication, tolerability, and preferred delivery method (ie, oral versus patch) [37-40]. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Nonergot dopamine agonists'.)

Catechol-O-methyl transferase (COMT) inhibitors — Adding a COMT inhibitor (entacapone, opicapone, or tolcapone) can prolong and potentiate the levodopa effect and thereby reduce "off" time when used as adjunctive therapy with levodopa [18,26]. The net result is an increased levodopa effect in fluctuating patients. Entacapone and opicapone are the safer COMT inhibitors and should be tried first; tolcapone, which is generally more potent than entacapone, has been associated with transaminitis and rare cases of fulminant hepatotoxicity. Opicapone, a once-daily drug, was first available in Europe and subsequently approved by the US Food and Drug Administration (FDA) in 2020 [41-44].

When adding a COMT inhibitor to a regimen of levodopa, particularly in patients with preexisting dyskinesia, the levodopa dose should be reduced by 10 to 30 percent to avoid exacerbating peak-dose dyskinesia and other dopaminergic side effects. While use of a COMT inhibitor is associated with lower total daily levodopa dose requirements (by as much as 30 percent), improvement in motor fluctuations rather than levodopa dose reduction should be the goal of this therapy.

The dose of entacapone is one 200 mg tablet taken along with each dose of levodopa, up to a maximum of eight doses per day. The combination tablet of carbidopa, levodopa, and entacapone is also available, although sometimes cost is prohibitive. The dose of opicapone is 50 mg once daily except in patients with moderate liver impairment, in whom the dose is 25 mg daily. The starting dose of tolcapone is 100 mg three times daily; the clinical effect may be evident immediately, but dose titration is required for optimal benefit.

The most common side effects of COMT inhibitors are due to increased dopaminergic stimulation and include dyskinesia, psychiatric effects (such as visual hallucinations), nausea, orthostatic hypotension, and somnolence. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of the COMT inhibitor. Entacapone and tolcapone lead to a harmless orange urine discoloration usually not requiring drug withdrawal, but may occasionally also cause diarrhea, often severe enough to necessitate drug discontinuation. Opicapone does not cause urine discoloration and appears to cause less diarrhea than entacapone [42,43].

In clinical trials, tolcapone was associated with transient, asymptomatic elevations of transaminases (aspartate transaminase [AST] and alanine transaminase [ALT]) in 1 to 3 percent of subjects exposed to the drug [45]. Three reported deaths from hepatotoxicity in patients using tolcapone prompted its removal from the market in Canada and Europe [45]. It is still available in the United States with the recommendation that it be used for treatment of motor fluctuations only after other methods have been exhausted and with monitoring of ALT and AST levels at baseline and every two to four weeks for the first six months of therapy.

Increasing the dose of carbidopa given with levodopa and entacapone may improve upon results of traditional dosing. A phase II randomized trial evaluated the efficacy of add-on carbidopa (65 mg and 105 mg) in 117 patients treated with escalating doses of levodopa and typical doses of carbidopa and entacapone [46]. Modest improvement in "on" time was achieved with only mild adverse effects, including dyskinesia and nausea. Further study is needed to confirm these findings.

Monoamine oxidase type B (MAO B) inhibitors — Use of an MAO B inhibitor (rasagiline, safinamide, or selegiline) along with levodopa may prolong the half-life of dopamine in the brain and thereby decrease "wearing off" phenomena. In add-on studies, the addition of rasagiline or safinamide to levodopa therapy provides a benefit similar to that of COMT inhibitors.

Rasagiline, safinamide, and selegiline are selective MAO B inhibitors. They have potential long-term enhancing effects on dopamine transmission because of inactivation of MAO B, one of the main enzymes involved in the catabolic metabolism of levodopa. Therapeutic doses of rasagiline or selegiline inhibit brain MAO B by 95 percent or more, but have little effect on MAO A. The inhibition of MAO A by older nonselective MAO inhibitors is the mechanism behind tyramine-related hypertensive crises. In general, the selective MAO B inhibitors do not carry the same risks when used at the recommended doses for PD. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Adverse effects'.)

Randomized trials have demonstrated rasagiline to be an effective adjunctive treatment for motor complications in PD [26,47,48]. The 18-week multicenter LARGO trial evaluated 687 patients with PD who had motor fluctuations for at least one hour every day despite optimum levodopa therapy [47]. Patients were randomly assigned to adjunctive therapy with either rasagiline 1 mg daily, entacapone 200 mg with every levodopa dose, or placebo. Both rasagiline and entacapone reduced mean daily "off" time (the primary outcome measure) by approximately one hour compared with placebo, and both increased daily "on" time without troublesome dyskinesia compared with placebo. The beneficial effect of rasagiline was independent of age (<70 versus ≥70 years) and independent of adjunctive use of dopamine agonists. Rasagiline was well tolerated in these studies [47,48]. The frequency of dopaminergic adverse events in the LARGO trial was similar to that seen in the entacapone and placebo groups [47].

Safinamide was also effective in randomized controlled trials for motor complications in PD when used as adjunctive treatment with levodopa [49-51]. Compared with placebo in these trials, safinamide increased mean daily "on" time without troublesome dyskinesia and improved motor function. For example, a 24-week trial of 549 patients with PD taking oral levodopa who had "off" time ≥1.5 hours/day found that treatment with safinamide increased the mean "on" time without troublesome dyskinesia by approximately 1.4 hours, compared with 0.6 hours for placebo [49].

Selegiline is the original selective MAO B inhibitor approved for PD. Unlike rasagiline and safinamide, selegiline is partly metabolized to amphetamine derivatives, but the clinical effect of this property is negligible. Selegiline can help to extend the duration of levodopa, although the effect is relatively mild [52]. Results from a small randomized controlled trial suggest that orally disintegrating selegiline may also be beneficial, although the study did not report changes in levodopa dose [53].

Istradefylline — Istradefylline, an oral adenosine A2A receptor antagonist that has been available in Japan since 2013, was approved by the FDA in August 2019 as an adjunctive to levodopa for treatment of "wearing off" symptoms [54].

Supporting evidence for istradefylline in PD includes several 12-week randomized trials and open-label prospective studies with longer-term follow-up [55-63]. In a trial of 373 patients with advanced PD and motor complications, daily istradefylline (20 and 40 mg doses) reduced daily "off" time by approximately one hour, compared with approximately 15 minutes with placebo [56]. The most common treatment-emergent adverse effect was dyskinesia, which occurred more often with istradefylline (12 to 13 percent) than placebo (4 percent). Open-label follow-up studies in over 800 patients have found sustained benefits over 12 months and no new safety or tolerability concerns [55,63]. Aside from dyskinesia, the most common adverse effects include dizziness, constipation, nausea, hallucinations, and insomnia. Rare cases of impulse control disorders that resolve with dose reduction or discontinuation have been observed in postmarketing surveillance. (See "Initial pharmacologic treatment of Parkinson disease", section on 'Impulse control disorders'.)

The recommended starting dose is 20 mg daily with or without meals. The maximum approved dose is 40 mg daily (20 mg in patients with moderate hepatic impairment). The drug is primarily metabolized by CYP1A1 and CYP3A4, and drug levels are affected by concomitant use of strong CYP3A4 inhibitors (resulting in increased istradefylline levels) or inducers (resulting in decreased levels).

Further studies and clinical experience will help determine the risks and benefits of istradefylline relative to other adjunctive medications.

On-demand rescue strategies — Sudden and unpredictable "off" periods can occur in advanced PD despite best efforts to optimize dopaminergic therapy with the strategies described above. In such cases, patients may benefit from an on-demand rescue medication.

Apomorphine — Apomorphine is a potent dopamine agonist that has been formulated for subcutaneous and sublingual film delivery for sudden "off" periods.

Subcutaneous injection – Subcutaneous injection of apomorphine is an effective rescue therapy for sudden "off" periods, for early-morning "off" states, and as a bridge to shorten the "wearing off" effect between scheduled levodopa doses [64]. Prior to regular self-administration, the effective dose for a patient is established by test administration in the office or at home with a specially trained health care professional. A baseline electrocardiogram (ECG) is advised, particularly for patients with risk factors for prolonged QT.

Doses are administered subcutaneously by an injection pen. The onset of action is rapid (usually within 10 minutes). A challenge test dose must precede routine use due to the risk of hypotension. This is usually done with a 2 mg subcutaneous injection under medical supervision and monitoring of standing and supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after. Premedication with trimethobenzamide (or domperidone, where available) is required initially to reduce the nausea and vomiting associated with apomorphine treatment. However, many patients are able to discontinue trimethobenzamide shortly after starting apomorphine.

The usual starting dose for intermittent apomorphine use is 2 mg. The dose may be increased by 1 mg per dose every two to four days to a maximum of 6 mg per dose. The average dosing frequency is three times daily and should not exceed five-times-a-day dosing or a total daily dose of 20 mg.

Adverse events with apomorphine are usually mild and consist predominantly of skin nodules, cutaneous reactions, somnolence, nausea, dyskinesia, and neuropsychiatric symptoms. The incidence of these problems is higher in patients receiving continuous infusion than in those receiving intermittent subcutaneous injections. Chest pain, angina, and severe orthostatic hypotension are rare but serious adverse events. Dose-related QT prolongation has been observed in the therapeutic range, and doses greater than 6 mg are not recommended.

In a randomized, double-blind, placebo-controlled study of 29 patients with advanced PD and two hours or more of "off" time, administration of subcutaneous apomorphine (2 to 10 mg) resulted in successful relief of "off" state events following 95 percent of injections compared with 23 percent receiving placebo injection [65]. Apomorphine is a much more potent and effective dopamine agonist than the oral agonists. One review concluded that the magnitude and pattern of the motor response to a single subcutaneous dose of apomorphine was qualitatively comparable to that of oral levodopa; a 4 mg dose achieved a clinically significant improvement in 75 percent of patients [66]. Nevertheless, the optimal dose varies for each patient, and individual titration for each patient is necessary. A sublingual apomorphine preparation is in development [67] but has not yet received regulatory approval.

Continuous subcutaneous infusion – Continuous subcutaneous apomorphine infusion (CSAI) is available in many European countries and is under review by the FDA. CSAI is effective for reducing "off" time and increasing "on" time, as discussed in detail separately. (See "Device-assisted and lesioning procedures for Parkinson disease", section on 'Continuous subcutaneous apomorphine'.)

Sublingual film – A sublingual film formulation of apomorphine was approved by the FDA in May 2020 for on-demand use. Absorption from the oral cavity bypasses extensive first-pass metabolism associated with gastrointestinal administration. A multicenter trial in 141 patients with advanced PD found that sublingual apomorphine improved motor scores at 30 minutes post-dose and increased the proportion of patients with a self-rated full "on" response within 30 minutes (35 versus 16 percent) compared with placebo [68]. Mild to moderate oropharyngeal events (eg, mucosal edema, dry mouth, tongue pain) occurred in approximately one-third of the apomorphine group and led to treatment discontinuation in approximately half of these patients. Other common side effects were nausea (28 percent), somnolence (13 percent), and dizziness (9 percent). Long-term safety and efficacy are yet to be established.

Inhaled levodopa — An oral, inhaled formulation of levodopa, consisting of a dry powder, was approved by the FDA in December 2018 for the treatment of "off" periods and may prove useful as a rescue strategy in some patients. Inhaled levodopa bypasses variabilities associated with intestinal absorption and hepatic metabolism.

In a randomized trial, inhaled levodopa (84 mg) improved Unified Parkinson's Disease Rating Scale (UPDRS) scores at 30 minutes after dosing compared with inhaled placebo powder (mean difference of 3.9 points on the UPDRS scale) and improved the proportion of patients who had and maintained an "on" response at 60 minutes (57 versus 36 percent) [69]. However, the speed of onset and magnitude of response were smaller than anticipated based on earlier studies, and there is some concern that effects may not translate to a clinically meaningful response in some patients [70]. Total time spent in the "off" state as assessed by diaries was not reduced in the levodopa group, which may also indicate that further optimization of this therapy is needed.

Manufacturer dosing instructions indicate that inhaled levodopa can be administered up to five times per day (single dose maximum 84 mg, maximum daily dose 420 mg) [71]. Side effects that were more common with inhaled levodopa compared with placebo in the trial included cough (15 versus 2 percent), upper respiratory tract infection, nausea, and discolored sputum; the rate of dyskinesia was low [69].

Device-assisted and surgical therapies — For patients who fail medical therapies for motor fluctuations and dyskinesia, referral to a movement disorder specialist is warranted to discuss device-assisted and surgical options, including:

Deep brain stimulation (DBS)

Continuous levodopa-carbidopa intestinal gel (LCIG) infusion delivered through a percutaneous gastrojejunostomy tube by battery-powered pump

Continuous subcutaneous apomorphine infusion (CSAI) administered by a battery-powered pump

Indications for device-assisted therapies for PD include the following [8,72]:

Severe, troublesome motor fluctuations despite optimal oral or transdermal levodopa or adjunctive therapies

Motor fluctuations causing disability or reduced quality of life

Inconsistent response to treatment

Dyskinesia or motor fluctuations that require frequent treatment adjustment without apparent benefit

Levodopa dosing required four or more times daily

Severe medication-refractory tremor (as an indication for DBS only)

It is important to note that in order for DBS, LCIG, and CSAI to be effective, the patient should still retain a response to levodopa (albeit compromised by motor complications or other side effects of therapy). The only exception would be the case of disabling levodopa- and medication-refractory tremor, which can respond well to DBS.

Device-assisted therapies are discussed in detail separately. (See "Device-assisted and lesioning procedures for Parkinson disease".)

APPROACH TO PEAK-DOSE DYSKINESIA — Peak-dose or "on" dyskinesia can occur in any patient with PD if the levodopa dose is high enough, typically starting 30 to 90 minutes after a dose. Younger patients are more susceptible earlier in the disease course. First-line treatment strategies include lowering the dose of levodopa and/or adjunctive dopaminergic therapies, when possible, and use of a medication to help suppress dyskinesia, such as amantadine or clozapine.

When is treatment required? — Not all dyskinesia requires treatment [73]. A retrospective study suggested that the rate of dyskinesia requiring medication adjustment at 5 and 10 years after levodopa treatment is 17 and 43 percent, respectively [2]. Many patients are unaware of the presence of dyskinetic movements, since they prefer being "on" with dyskinesia to being "off." However, severe dyskinesia may take the form of large-amplitude, ballistic movements that interfere with function and become very disturbing to patients and their caregivers.

Reduction in levodopa or adjunctive therapies — Early in the course of PD, troublesome peak-dose dyskinesia can be managed by lowering the levodopa dose, shortening the interdose interval (ie, more frequent, lower individual doses) if associated with "wearing off," and switching to a longer-acting formulation of oral levodopa (beware slower onset of benefit and late-day dyskinesia with controlled-release [CR] tablets). (See 'Levodopa dose and interval adjustment' above and 'Role of longer-acting oral levodopa formulations' above.)

Reducing adjunctive drugs such as dopamine agonists, entacapone, selegiline, or anticholinergic drugs can also help dyskinesia. However, at some point in more advanced patients with brittle responses, reducing the dose of levodopa below therapeutic threshold may result in complete failure to generate an "on" response. In this situation, the dose of the dopamine agonist should be increased to compensate for the lower dose of levodopa; dopamine agonists are less likely to induce dyskinesia than levodopa.

Amantadine for dyskinesia — Amantadine is generally well tolerated and can be useful for treating dyskinesia in advanced PD when antiparkinson medications have otherwise been optimized [18,26].

The starting dose of amantadine for dyskinesia is one tablet (100 mg immediate release [IR]) a day, increasing to 100 mg twice daily after one to two weeks. Doses of up to 400 mg daily, divided in two to four doses a day, can be used with individualized titration according to degree and duration of response and tolerability. Extended-release (ER) formulations are available for once-daily dosing but do not appear to be more effective than regular amantadine and are often more expensive. Side effects may include peripheral edema, increased confusion or psychosis, livedo reticularis (mottled skin), nightmares, and hallucinations. Both the IR and ER formulations are excreted in the urine, and considerable caution is required in patients with renal dysfunction.

Several short-term trials have shown a benefit of amantadine, with approximately 25 to 50 percent relative reductions in dyskinesia scores compared with placebo [74-76]. Observational follow-up data as well as a randomized discontinuation trial suggest that the effect can be sustained for a year or more [77,78]. In the largest trial, 126 patients with levodopa-induced dyskinesia were randomly assigned to ER amantadine (274 mg capsule at bedtime) or placebo [79]. At 12 weeks compared with placebo, the active drug reduced the duration, severity, and impact of dyskinesia as measured by the Unified Dyskinesia Rating Scale. In addition, treatment with the active drug reduced mean "off" time by 0.6 hours, while mean "off" time increased 0.3 hours with placebo. The most common significant adverse effects were mild and reversible visual hallucinations. A subsequent trial reported similar results [80]. Until there is a comparison between ER formulations of amantadine and generic amantadine, it is uncertain whether the potential benefits justify the cost [81].

Role of clozapine — The atypical antipsychotic clozapine can be considered in patients with refractory dyskinesia and psychosis who will likely need both close neurologic and psychiatric monitoring. Low doses of clozapine (30 to 50 mg/day) reduced dyskinesia in several open-label studies [82,83], and low-dose clozapine (12.5 to 75 mg/day) was more effective than placebo in treating levodopa-related dyskinesia in a double-blind, randomized controlled trial of 50 patients [84].

The usefulness of clozapine is limited by its potential for inducing granulocytopenia [85], but this risk may be acceptably low with monitoring. Clozapine treatment requires obtaining the white blood cell count and absolute neutrophil count at baseline and weekly for the first six months of continuous treatment. Details concerning frequency of monitoring and when to interrupt or discontinue this medication are presented separately. (See "Guidelines for prescribing clozapine in schizophrenia", section on 'Neutrophil count'.)

TROUBLESHOOTING COMPLEX MOTOR COMPLICATIONS

Unpredictable "off" periods — Transitions from being "on" to being "off" can be sudden and unpredictable in some patients, and usually bear no obvious relationship with the timing of levodopa dosing, unlike the "wearing off" phenomenon at the end of a levodopa dose cycle. These periods typically occur in patients with advanced PD who are also experiencing other motor fluctuations and severe dyskinesia.

Unpredictable "off" episodes may be due to a number of factors including erratic absorption of levodopa from the gut and presynaptic and postsynaptic receptor changes in the brain. Levodopa plasma pharmacokinetics tend to remain relatively stable throughout the disease course.

Strategies that may be helpful include the following:

Document that "off" periods are in fact unpredictable and long lasting. Management is often improved by careful home diaries and direct observation through at least two dose cycles in an extended outpatient visit to help determine the relationship of levodopa doses to "off" episodes. Although some patients and caregivers may perceive that their "offs" are random and unpredictable, it often turns out that the "off" periods actually are occurring as an end-of-dose "wearing off" phenomenon that has not been appreciated as such. True "off" periods usually affect the whole body and should be differentiated from episodes of sudden transient freezing of gait (FOG), which can be random and not related to levodopa fluctuations. (See 'Freezing of gait' below.)

Avoid protein at the time of drug administration and/or take levodopa on an empty stomach (30 to 60 minutes before a meal or 60 to 90 minutes after). A protein redistribution diet, in which most dietary protein intake is reserved for the evening, is worth trying. (See 'Dietary adjustments' above.)

Consider adjusting the levodopa dosing schedule. Plasma levodopa levels may be falling below the therapeutic threshold, especially if erratic absorption from the gut is suspected. Controlled-release (CR) carbidopa-levodopa tablets are usually not helpful and occasionally exacerbate the situation.

Alternatively, consider lowering the levodopa dose or adding and titrating a dopamine agonist or catechol-O-methyl transferase (COMT) inhibitor. In rare cases, sudden "off" episodes may be due to excessive levodopa effects.

Freezing of gait — FOG can occur as a transient "off" phenomenon (also referred to as levodopa-responsive FOG) or randomly at variable frequency and duration in the "on" state in patients with advanced PD (also referred to as levodopa-related FOG). It is crucial to determine when and how FOG relates to the timing of levodopa doses, as treatment strategies and prognosis vary.

Levodopa-responsive FOG occurs during end-of-dose "off" periods and usually responds to shortening levodopa dose intervals or increasing the levodopa dose to avoid "off" episodes. Adding or increasing dopamine agonists is usually not as effective and may even aggravate FOG. Subthalamic nucleus deep brain stimulation (DBS) can be an option when FOG occurs in the context of other DBS-responsive motor fluctuations. (See 'Levodopa dose and interval adjustment' above and 'Device-assisted and surgical therapies' above.)

Freezing occurring in the "on" state is poorly responsive to any of the available treatment modalities, including antiparkinson medications and device-assisted therapies such as DBS of the brainstem pedunculopontine nucleus [86-88] or continuous levodopa-carbidopa intestinal gel (LCIG) infusion. However, if it occurs at peak levodopa effect, reducing the dose of a dopamine agonist, if being used, followed by reducing the levodopa dose, if necessary, is worth trying, although the downside of this strategy is a possible compromise of the levodopa response of other motor symptoms. Fortunately, FOG in the "on" state is uncommon, accounting for only 5 percent of cases of FOG, and is usually shorter in duration than levodopa-responsive FOG.

Management of more severe and prolonged FOG despite these strategies includes nonpharmacologic strategies and assessment of comorbidities [89,90]. Trials of physical therapy (PT) have shown some evidence of benefit [91], and PT and can help to determine if there are specific precipitants such as starting, turning, and pivoting may lead to methods to avoid FOG. Movement strategies or cues that may help the patient "get into gear" include shifting weight, making wider turns, concentrating on taking larger steps forward, or using visual imagery as if to step over an obstacle. A regular cane or special laser cane may also be helpful for FOG [92]. There are conflicting data from two small randomized controlled trials regarding the utility of methylphenidate for gait freezing and hypokinesia [93,94]. Occasionally, amantadine can have a beneficial effect on freezing.

Failure of "on" response — Patients with motor fluctuations sometimes fail to turn "on" following a dose of levodopa, resulting in a delayed "on," dose failure, or "no-on" response [95]. Dose failures may be due to poor absorption of a dose of levodopa due to delayed gastric emptying of levodopa into the duodenum or to a prolonged "off" period due to unresponsive striatal receptors.

Strategies that may be useful for managing failure of "on" response are:

Avoid protein at the time of drug administration and/or take levodopa on an empty stomach (30 to 60 minutes before a meal or 60 to 90 minutes after). A protein redistribution diet, in which most dietary protein intake is reserved for the evening, is worth trying. (See 'Dietary adjustments' above.)

Evaluate for gastroparesis and constipation, two common and inherent nonmotor features of PD [17]. Gastrointestinal absorption can be interrogated using isotope testing of gastrointestinal transit time (gastric emptying study). Options to treat gastroparesis in patients with PD are limited, however. The prokinetic drug metoclopramide should not be used in PD as it is a dopamine receptor blocker that invariably worsens parkinsonian symptoms.

By contrast, domperidone is a dopamine receptor blocker with selective peripheral activity that does not aggravate parkinsonian symptoms. It is not available in the United States but is available in Canada and other countries. Although data are limited, domperidone (starting at 10 mg four times daily) may be useful as a prokinetic agent to treat delayed gastric emptying in patients with PD [96,97]. However, preclinical and clinical studies suggest that domperidone increases the risk of QT interval prolongation and cardiac arrhythmias [98,99]. Because of the cardiac risks, the European Medicines Agency recommends that domperidone not be used for longer than one week [100].

Minimize "off" episodes; failure or delay of the "on" responses often occurs after prolonged "off" periods. (See 'Approach to "wearing off"' above.)

Adjust the levodopa dosing schedule to preempt failure of "on" response. If predictable (eg, in the midafternoon), one strategy is to add a dose of levodopa one hour before the usual failure of "on" time.

Use rescue therapies such as subcutaneous apomorphine or inhaled levodopa. (See 'On-demand rescue strategies' above.)

Acute akinesia — Acute akinesia is a sudden exacerbation of PD characterized by an akinetic state that lasts for several days and responds poorly to treatment with antiparkinson medication. This phenomenon is different from "wearing off" and unpredictable "offs" and may sometimes occur in patients not previously treated with levodopa [101].

Acute akinesia should prompt a search for systemic infection or other intercurrent medical problems that are capable of causing a sudden worsening of parkinsonism, though it can also be caused by medication error (eg, substituting carbidopa-levodopa 25/100 mg instead of 25/250 mg, or inadvertently using a dopamine receptor blocking agent such as metoclopramide or an antipsychotic drug with dopamine blocking properties). In a review of this problem in 26 patients, acute akinesia appeared after a flu-like syndrome in six patients, hip joint surgery or bone fractures in eight patients, gastrointestinal disturbances in three patients, and various medication manipulations in the remaining patients [101]. Four patients died in spite of treatment.

Episodes of acute akinesia may have serious consequences that sometimes warrant hospitalization in order to identify and correct the underlying cause.

Dystonia — Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonic postures usually involve the limbs but can affect the face, neck, or trunk.

Dystonia can be a manifestation of early untreated PD (especially foot dystonia) or may appear as a complication of levodopa treatment. A careful history is required since dystonia due to levodopa can occur either as a peak levodopa effect or during "off" periods due to levodopa withdrawal. Withdrawal dystonia most commonly occurs in the early morning, when it produces painful foot flexion and inversion and/or hyperextension of the great toe; this usually resolves shortly after taking the first dose of levodopa.

"Off" period dystonia that occurs early in the morning is managed by taking CR levodopa before retiring, by taking levodopa or a dopamine agonist during the night or first thing in the morning before arising, or by using a rescue agent such as an apomorphine injection. "Off" period dystonia during the day is managed similarly to other forms of the "wearing off" effect (eg, shortening the levodopa dose intervals or adding a dopamine agonist). (See 'Approach to "wearing off"' above.)

Peak-dose dystonia, which is usually not painful, is managed similarly to peak-dose dyskinesia. (See 'Approach to peak-dose dyskinesia' above.)

Prominent levodopa-induced cranial/facial dystonia may be a clue to an alternative diagnosis of an "atypical parkinsonism" such as multiple system atrophy. (See "Diagnosis and differential diagnosis of Parkinson disease", section on 'Differential diagnosis'.)

Akathisia — Akathisia or motor restlessness is a form of levodopa withdrawal, which may resemble restless legs syndrome and usually occurs at night, several hours after the last dose of levodopa. This is managed by providing CR levodopa or a dopamine agonist before retiring.

Of note, some patients with PD have what seems to be clear restless legs syndrome and not akathisia, even though they are very similar. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)

Diphasic dyskinesia — Diphasic dyskinesia is an uncommon form of dyskinesia in which dyskinesia peaks twice after each dose, first when patients turn "on" and again when they begin to turn "off" [5]. In the second phase, dyskinesia (often large-amplitude movements involving the legs) in one body part may coexist with the emergence elsewhere in the body of parkinsonian signs such as tremor and bradykinesia. This pattern is often unrecognized and may only be appreciated if the patient is observed during an extended outpatient visit.

The diphasic pattern is notoriously difficult to manage and usually requires more frequent levodopa dosing to prevent "wearing off" and the reemergence of "off" dyskinesia prior to each dose. However, this strategy may lead to progressively increasing peak-dose dyskinesia as the day goes on or prolonged nighttime dyskinesia. Addition of a dopamine agonist and a marked reduction in the levodopa dose may help.

CR levodopa is best avoided in patients with severe or complex patterns of dyskinesia since absorption may be delayed and dyskinesia tends to progressively increase into the afternoon and evening.

Continuous LCIG, DBS, or continuous subcutaneous apomorphine infusion (CSAI; where available) should be considered if other strategies for management are unsuccessful. However, some patients with diphasic dyskinesia may develop a marked worsening of dyskinesia over time with LCIG infusion if the clinician is not strictly monitoring infusion rates and bolus doses. (See "Device-assisted and lesioning procedures for Parkinson disease".)

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)")

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

Patients with Parkinson disease (PD) who take levodopa chronically are increasingly likely to develop motor fluctuations and dyskinesia as the disease progresses and nigrostriatal dopaminergic neurons continue to degenerate and lose presynaptic dopamine storage capacity. (See 'Pathophysiology' above.)

Motor fluctuations are alterations between periods marked by a positive response to medication ("on"), and periods marked by reemergence of parkinsonian symptoms ("off"). Dyskinesia consists of various types of abnormal involuntary movements, most often choreiform, which are brought on by levodopa or other dopaminergic agents. (See 'Symptom spectrum' above.)

"Wearing off" near the end of the levodopa dose interval is often the first and most commonly encountered motor fluctuation. An individualized, trial-and-error approach to "wearing off" may include any or all of the following:

Patients who report that protein-rich meals impair the levodopa benefit should avoid protein at the time of drug administration and/or take levodopa on an empty stomach. Efforts to reduce or redistribute the amount of consumed protein are sometimes essential, particularly in patients with complex fluctuations, including delayed or "no-on" responses and unpredictable "off" periods. (See 'Dietary adjustments' above.)

For most patients who experience "wearing off" on a low dose of levodopa (eg, ≤200 mg per dose), we suggest increasing the dose of levodopa (Grade 2C). For those who do not tolerate higher doses of levodopa due to dyskinesia or who experience "wearing off" at higher doses, we suggest reducing the dose interval (with smaller individual doses of levodopa) and adding additional doses at the end of the day, as needed (Grade 2C). (See 'Levodopa dose and interval adjustment' above.)

For patients with morning "wearing off" on immediate-release (IR) levodopa, a bedtime dose of the controlled-release (CR) tablet formulation of carbidopa-levodopa may be helpful. However, daytime use of CR tablets may exacerbate motor fluctuations and can lead to delayed-onset dyskinesia. Newer carbidopa-levodopa extended-release (ER) capsules show promise in reducing motor complications, but more widespread use is limited by cost and difficulties of converting from levodopa tablets to ER capsules. (See 'Role of longer-acting oral levodopa formulations' above.)

If levodopa adjustments for "wearing off" are not adequate or tolerated, we suggest addition of a dopamine agonist, a catechol-O-methyl transferase (COMT) inhibitor, or a monoamine oxidase type B (MAO B) inhibitor (Grade 2B). All have similar effects, and selection of a specific drug should be individualized. The main limiting factor to adjunctive medications is worsened dyskinesia and nonmotor dopaminergic side effects (eg, orthostasis, impulse control disorders). (See 'Adjunctive therapies' above.)

Subcutaneous apomorphine injections are an option for patients with sudden and unpredictable "off" periods despite best efforts to optimize dopaminergic therapy. Inhaled levodopa and sublingual apomorphine may be alternative rescue strategies for patients who do not desire injections. (See 'On-demand rescue strategies' above.)

Peak-dose dyskinesia can occur in any patient with PD if the levodopa dose is high enough and is a common counter-effect of strategies to treat "wearing off" and other motor fluctuations.

Early in the course of PD, troublesome peak-dose dyskinesia can be managed by lowering the levodopa dose, shortening the interdose interval (ie, more frequent, lower individual doses) if associated with "wearing off," and switching to a longer-acting formulation of levodopa (beware slower onset of benefit and late-day dyskinesia with CR tablets). (See 'Reduction in levodopa or adjunctive therapies' above.)

For patients with troublesome dyskinesia despite medication adjustments, we suggest amantadine (Grade 2B). Both IR and ER formulations of amantadine are available and appear to have similar effects. With required monitoring, clozapine can be considered in patients with refractory dyskinesia and psychosis. (See 'Amantadine for dyskinesia' above and 'Role of clozapine' above.)

Management of more complex motor complications in advanced PD, including unpredictable "off" periods, freezing of gait (FOG), dose failures, dystonia, and diphasic dyskinesia, is individualized and typically includes a combination of the above strategies. (See 'Troubleshooting complex motor complications' above.)

Acute akinesia should prompt a search for systemic infection or other intercurrent medical problems that are capable of causing a sudden worsening of parkinsonism. (See 'Acute akinesia' above.)

For patients who fail oral and transdermal medical therapies for motor fluctuations and dyskinesia, options include deep brain stimulation (DBS), continuous levodopa-carbidopa intestinal gel (LCIG) infusion delivered through a percutaneous gastrojejunostomy tube by battery-powered pump, and continuous subcutaneous apomorphine infusion (CSAI) administered by a battery-powered pump. (See 'Device-assisted and surgical therapies' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ludy Shih, MD, who contributed to an earlier version of this topic review.

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Topic 4893 Version 45.0

References

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7 : Parkinson's disease home diary: further validation and implications for clinical trials.

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10 : Protein redistribution diet remains effective in patients with fluctuating parkinsonism.

11 : Practical application of a low-protein diet for Parkinson's disease.

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13 : Helicobacter pylori eradication for Parkinson's disease.

14 : Helicobacter pylori-induced reduction of acute levodopa absorption in Parkinson's disease patients.

15 : Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations.

16 : The role of small intestinal bacterial overgrowth in Parkinson's disease.

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33 : A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group.

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35 : Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study.

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37 : Ropinirole Patch Versus Placebo, Ropinirole Extended-Release Tablet in Advanced Parkinson's Disease.

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44 : Randomized, Controlled Study of Opicapone in Japanese Parkinson's Patients with Motor Fluctuations.

45 : COMT inhibitors and liver toxicity.

46 : Increased dose of carbidopa with levodopa and entacapone improves "off" time in a randomized trial.

47 : Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial.

48 : A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study.

49 : Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial.

50 : Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease.

51 : Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations.

52 : Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease.

53 : Zydis selegiline reduces off time in Parkinson's disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study.

54 : Zydis selegiline reduces off time in Parkinson's disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study.

55 : A long-term study of istradefylline safety and efficacy in patients with Parkinson disease.

56 : Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson's disease.

57 : Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study.

58 : Safety and effectiveness of istradefylline in patients with Parkinson's disease: interim analysis of a post-marketing surveillance study in Japan.

59 : Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005).

60 : A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease.

61 : Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations.

62 : Istradefylline for Parkinson's disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study.

63 : A long-term study of istradefylline in subjects with fluctuating Parkinson's disease.

64 : Subcutaneous apomorphine in the treatment of Parkinson's disease.

65 : A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events.

66 : Subcutaneous apomorphine : an evidence-based review of its use in Parkinson's disease.

67 : Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson's disease.

68 : Apomorphine sublingual film for off episodes in Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 study.

69 : Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson's disease: a randomised, double-blind, placebo-controlled phase 3 trial.

70 : CVT-301 for Parkinson's disease: dose and effect size issues.

71 : CVT-301 for Parkinson's disease: dose and effect size issues.

72 : Practical approaches to commencing device-assisted therapies for Parkinson disease in Australia.

73 : Patient perception of dyskinesia in Parkinson's disease.

74 : Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson's disease.

75 : The effect of amantadine on levodopa-induced dyskinesias in Parkinson's disease: a double-blind, placebo-controlled study.

76 : Duration of amantadine benefit on dyskinesia of severe Parkinson's disease.

77 : Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.

78 : Long-term antidyskinetic efficacy of amantadine in Parkinson's disease.

79 : ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study): A Randomized Clinical Trial.

80 : Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson's disease (EASE LID 3).

81 : Extended-Release Amantadine-A Smart Pill for Treatment of Levodopa-Induced Dyskinesia but Does the Evidence Justify the Cost?

82 : Low-dose clozapine improves dyskinesias in Parkinson's disease.

83 : Suppression of dyskinesias in advanced Parkinson's disease. II. Increasing daily clozapine doses suppress dyskinesias and improve parkinsonism symptoms.

84 : Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study.

85 : The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease.

86 : Unilateral pedunculopontine stimulation improves falls in Parkinson's disease.

87 : Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.

88 : A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation.

89 : Freezing of gait: a practical approach to management.

90 : Nonpharmacological, nonsurgical treatments for freezing of gait in Parkinson's disease: A systematic review.

91 : Effectiveness of Physiotherapy on Freezing of Gait in Parkinson's Disease: A Systematic Review and Meta-Analyses.

92 : Laserlight cues for gait freezing in Parkinson's disease: an open-label study.

93 : Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial.

94 : Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial.

95 : Waiting for ON: a major problem in patients with Parkinson disease and ON/OFF motor fluctuations.

96 : Effect of chronic oral domperidone therapy on gastrointestinal symptoms and gastric emptying in patients with Parkinson's disease.

97 : Gastrointestinal motility problems in patients with Parkinson's disease. Effects of antiparkinsonian treatment and guidelines for management.

98 : Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine.

99 : Domperidone and Risk of Ventricular Arrhythmia and Cardiac Death: A Systematic Review and Meta-analysis.

100 : Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease--Clinical practice recommendations.

101 : Acute akinesia in Parkinson disease.