Medical management of motor fluctuations and dyskinesia in Parkinson disease

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 also available to 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], focused ultrasound therapy [FUS], 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

●Motor fluctuations – As PD progresses and nigrostriatal dopaminergic neurons degenerate, presynaptic neurons lose their ability to store and release levodopa after enzymatic conversion to dopamine. As a result, the response to standard levodopa immediate-release formulations begins to mirror its short half-life (approximately 90 minutes). Such rapid-cycling kinetics and pulsatile stimulation of dopamine receptors by dopamine may contribute to the narrowing of the therapeutic window over time. In addition, levodopa levels are highly dependent on intestinal absorption, which can be impaired by poor gastric emptying, slow intestinal transit times, competing dietary protein, and small intestinal bacterial overgrowth.

●Dyskinesia – Dyskinesia is an overexpression of movement caused by dopamine receptor hypersensitivity to dopamine and a relative excess of dopamine levels. Dyskinesia in patients with PD is often attributed to levodopa therapy and is thus referred to as levodopa-induced dyskinesia (LID). However, any agent that stimulates or enhances the effect of dopamine at the receptor (eg, dopamine agonists, monoamine oxidase type B [MAO B] inhibitors, and catechol-O-methyl transferase [COMT] inhibitors) may trigger dyskinesia.

Although the relationship between levodopa and dyskinesia is generally dose-dependent, the dyskinesia threshold in any individual with PD is highly variable. In other words, dyskinesia can occur at relatively low therapeutic doses of levodopa (eg, 100 mg levodopa per dose) in some patients. Dyskinesia also tends to be more common in patients with young-onset PD (ie, before the age of 50 years) and less prominent and disabling in patients with later-onset disease (>80 years of age).

●Risk factors for motor complications – A variety of factors have been associated with earlier and more severe motor complications in patients with PD. These include younger age at disease onset, longer disease duration, more severe nonmotor symptoms (eg, anxiety and depression), levodopa dose and responsiveness, and overall disease severity [1]. Although much attention has been given to levodopa’s role in the development of motor complications, levodopa-sparing strategies are not believed to affect the natural history and can cause undue harm by depriving patients of the beneficial effects of levodopa on motor function and quality of life. (See "Initial pharmacologic treatment of Parkinson disease", section on 'When should drug therapy be started?'.)

SYMPTOM SPECTRUM — Motor complications are not uncommon in early PD, occurring in up to 30 to 40 percent of patients during the first five years of treatment. As PD advances, the majority of patients (60 percent or more by 10 years) experience some form of complication of therapy [2-5].

When levodopa therapy is first initiated in early or mild PD, patients typically experience a smooth and prolonged response to the medication and do not appreciate the onset of action ("kick-in") or "wearing off" of each dose. However, as the disease advances, the effect of a dose of levodopa may begin to wear off as quickly as three to four hours. The term "motor complications" refers to several phenomena that mark the shift from a physiologic steady-state level of dopamine release to reliance on exogenous levodopa and its short duration response.

●Motor fluctuations – Motor fluctuations are alterations in function caused by a positive or therapeutic response to dopaminergic therapy ("on") alternating with a declining or absent response to dopaminergic therapy ("off"). Types of motor fluctuations include the following:

•"Wearing off" is 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 (also referred to as "on-off") are sudden alterations in function without obvious relationship to levodopa or dopaminergic therapy dosing. (See 'Unpredictable "off" periods' below.)

•Failure of the "on" response includes failure to transition from an "off" parkinsonian state to an "on" response following a dose of levodopa. (See 'Failure of "on" response' below.)

•Freezing of gait (FOG) refers to episodic inability to step and advance in any direction, usually occurring during initiation, turns, or when encountering transition points in the environment. FOG can occur with or without dopaminergic therapy and may be independent of other motor fluctuations. It is a signature and disabling symptom of the "off" state. (See 'Freezing of gait' below.)

•Acute akinesia refers to a sudden and severe exacerbation of PD including an akinetic state that lasts for several days and does not respond to treatment with antiparkinson medication. It is differentiated from typical dose-dependent "off" periods. (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-induced dyskinesia (LID) 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. LID encompasses a variety of involuntary movements or postures, including chorea, dystonia, athetosis, ballism, and myoclonus [6], 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 involuntary muscle spasm often involving the limbs but sometimes involving the face, neck, or trunk, during "off" periods. Symptoms are most often reported early 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 – In assessing patient history, it is important to differentiate between tremor and dyskinesia when a patient uses the term "shaking." Time of examination in relation to last levodopa dose should be noted and documented.

Clinicians should inquire whether the patient takes levodopa on a fixed schedule (by the clock) or when needed (ie, when experiencing "wearing off"). Since meals and dietary protein can interfere with the absorption of levodopa in the intestine, clinicians should pay close attention to when and what the patient eats in relation to the response to levodopa dosing [7].

Review of home videos can be very useful for complicated and mixed patterns of fluctuations, since direct observation for prolonged periods in the clinic is often not possible. Properly timed telehealth visits may conceivably be used to capture different states of function. More often, "on," "off," and dyskinetic states are identified in separate visits in most general practices.

Movement disorder neurologists may perform scheduled "off-on" testing, particularly when evaluating a patient for advanced or invasive therapies or during clinical research assessments. A patient who can come to the office safely and tolerate the "off" state for assessment may hold a morning dose of levodopa. Evaluation of the "on" examination can then be accomplished as early as 30 to 60 minutes after the dose is administered.

●Symptom diaries – Symptom diaries, including video recordings, may be helpful but can be unreliable if the patient is unfamiliar with definitions of dyskinesia, tremor, dystonia, and "on" versus "off" states. Careful education, re-education, and practice are necessary so that diaries are as accurate and informative as possible [8].

●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 advanced or invasive therapies [9].

APPROACH TO "WEARING OFF" — A variety of strategies can help to mitigate "wearing off," and management requires an individualized, trial-and-error approach.

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. Ingested protein has the potential to compete with levodopa transport in the gut and brain, thereby reducing levodopa's clinical benefit [10].

Patients should be made aware of these potential interactions, and effects of diet should be examined in patients who 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 such as dose failures and unpredictable "off" periods. A protein redistribution diet (PRD), in which most dietary protein intake is reserved for the evening, has demonstrated some benefit in small studies [11,12]. However, levodopa-related side effects, inconvenience, and poor adherence limit long-term use [13], and many patients find this type of diet impractical. Nonetheless, a protein redistribution diet is worth trying in select 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 [14]. 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 [15,16]. 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 [17,18].

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 [19]. 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 [20]) 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 [21].

Occasional patients with advanced PD exhibit 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. The mechanism of this phenomenon is not well understood and is more complex than just a progressive narrowing of therapeutic window between response and dyskinesia [22].

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 useful 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 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 'Initial dosing and titration'.)

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 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 effectiveness [23], the overall evidence is inconsistent [23-26]. Two systematic reviews have concluded that CR tablets do not reliably decrease "off" time compared with IR levodopa formulations [19,27]. 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 an equivalent 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 or higher 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 (C_max) of ER capsules is significantly 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 [28]. Therefore, ER capsules have the potential to reduce C_max-related side effects such as peak-dose dyskinesia, in addition to alleviating "wearing off" effects and "off" time.

A randomized controlled trial demonstrated that ER carbidopa-levodopa capsules reduced "off" time by approximately 70 minutes a day compared with IR carbidopa-levodopa tablets. However, the final total daily levodopa dose of the ER formulation was on average approximately twice that of the IR formulation [29]. Another trial demonstrated that the ER capsules reduced "off" time compared with combined IR carbidopa-levodopa tablets and entacapone [30].

ER capsules can be expensive and variably included in health insurance drug plans, 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, hallucinations, 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.

Comparative efficacy — Among the options for adjunctive therapy, none is clearly superior to the others with regard to either efficacy or tolerability, but small differences exist that help inform drug selection in individual patients. As an example, dopamine agonists provide stronger dopaminergic effects than the other classes, which can result in slightly better motor function, but they also carry an increased risk of side effects, particularly in older adults.

Direct comparative evidence for the three main classes of drugs is available from the pragmatic PD MED trial, in which 500 patients with PD and motor complications on levodopa therapy were randomly assigned to a dopamine agonist, a COMT inhibitor (entacapone), or an MAO B inhibitor (the last two categories referred to as enzyme inhibitors) [31]. Patients who were already taking an adjunctive agent were eligible and were randomized to one of the two remaining classes. With a median follow-up of 4.5 years, mean scores on the 39-item PD Questionnaire (PDQ-39) mobility domain were improved in the dopamine agonist group compared with the enzyme inhibitor group (2.4 points, 95% CI -1.3 to 6), but the result did not reach statistical significance. Mean levodopa doses were lowest in the dopamine agonist group. Rates of drug discontinuation were similar among groups; approximately one-third of patients in each group discontinued the add-on drug at one year and just over half discontinued it by five years.

Among enzyme inhibitors in the PD MED trial, the MAO B inhibitors resulted in better mean mobility scores compared with entacapone, the only COMT inhibitor used in the trial (4.2 points, 95% CI 0.4-7.9) [31]. Whether this difference is relevant for all drugs in the class is less clear. Entacapone is recognized to be less potent than tolcapone, which is rarely used due to risk of liver toxicity, and opicapone has not been directly compared with the other COMT or MAO B inhibitors.

Dopamine agonists — Adding a nonergot dopamine agonist (pramipexole, ropinirole, or rotigotine) may help to reduce "off" periods [32-39]. However, due to the possibility of dopaminergic side effects and dyskinesia, the dose of concomitant levodopa may need to be 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 75 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) [39-42]. (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 [19,27]. 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 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 [43-46].

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.

A 200 mg tablet of entacapone can be taken with each dose of levodopa or with select doses, 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 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. In approximately 10 percent of patients, diarrhea can occur, which can be severe enough to necessitate drug discontinuation. Opicapone does not cause urine discoloration and appears to cause less diarrhea than entacapone [44,45].

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 [47]. Three reported deaths from hepatotoxicity in patients using tolcapone prompted its removal from the market in Canada and Europe [47]. 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.

Because carbidopa blocks the peripheral conversion of levodopa to dopamine, not only does it reduce peripheral dopaminergic side effects such as nausea, but it also improves the amount of levodopa available for uptake into the central nervous system. Therefore, providing supplemental carbidopa above the standard 10, 25, or 50 mg available with levodopa may improve motor symptoms beyond 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 [48]. 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 — The MAO B inhibitors (rasagiline, safinamide, or selegiline) can be used with levodopa to enhance dopamine levels and improve "wearing off" and other motor fluctuations. In add-on studies, the addition of rasagiline or safinamide to levodopa therapy provides a benefit similar to that of COMT inhibitors and decreases "wearing off" phenomena.

Rasagiline, safinamide, and selegiline are highly selective for MAO B, which is responsible for degrading dopamine centrally. Therapeutic doses of rasagiline or selegiline irreversibly inhibit brain MAO B by 95 percent or more but have little effect on MAO A. By contrast, the inhibition of MAO A located in the gut by nonselective older 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 'MAO B inhibitors'.)

Randomized trials have demonstrated rasagiline to be an effective adjunctive treatment for motor complications in PD [27,49,50]. The 18-week multicenter LARGO trial evaluated 687 patients with PD who had at least one hour of "off" daily despite optimum levodopa therapy [49]. 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 [49,50]. The frequency of dopaminergic adverse events in the LARGO trial was similar to that seen in the entacapone and placebo groups [49].

Safinamide has also been shown to be an effective adjunctive treatment with levodopa in randomized controlled trials for motor complications in PD [51-54]. 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 [51].

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 augment the effects of levodopa, although the effect is relatively mild [55]. 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 [56].

Istradefylline — Istradefylline, an oral adenosine A2A receptor antagonist, has been available in Japan since 2013. It was approved by the FDA in 2019 as an adjunctive to levodopa for treatment of "wearing off" symptoms [57].

Supporting evidence for istradefylline in PD includes several 12-week randomized trials and open-label prospective studies with longer-term follow-up [58-66]. 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 [59]. 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 [58,66]. 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, unpredictable, and prolonged "off" periods can occur in advanced PD despite best efforts to optimize dopaminergic therapy. 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 [67]. 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.

Apomorphine is administered subcutaneously with 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. Under medical supervision, a 1 or 2 mg subcutaneous injection is administered with monitoring of standing and supine blood pressure prior to the injection and repeated at 20, 40, and 60 minutes after. Premedication with trimethobenzamide (or domperidone, where available) is recommended initially to reduce the nausea and vomiting associated with apomorphine treatment. If patients are not premedicated, the lower 1 mg dose of apomorphine should be used. Over time, many patients are able to tolerate apomorphine and do not need long-term premedication.

The starting dose for intermittent apomorphine use is 1 or 2 mg and 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 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, severe orthostatic hypotension, and hemolytic anemia 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 [68]. 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 [69]. Nevertheless, the optimal dose varies for each patient, and individual titration for each patient is necessary.

●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 [70]. 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). Premedication with trimethobenzamide to prevent nausea (or domperidone, where available) is recommended, but like the injectable, the need for premedication wanes over time. Long-term safety and efficacy have yet to be established.

Inhaled levodopa — An oral, inhaled, dry powder formulation of levodopa was approved by the FDA in 2018 for the treatment of "off" periods. The inhalational product is absorbed through the alveolar membrane, delivering drug directly to the pulmonary arterial circulation and bypassing variabilities associated with intestinal absorption and hepatic metabolism. When delivered in this way, plasma concentrations of levodopa reach a maximum after approximately 15 minutes, and clinical improvement occurs as soon as five minutes after dosing [71,72].

Supporting evidence includes results of a 12-week trial in 351 patients with PD, in which patients were randomly assigned to inhaled levodopa (60 mg or 84 mg) or inhaled placebo powder [73]. Compared with the placebo group, the 84 mg of inhaled levodopa group had improved Unified Parkinson's Disease Rating Scale (UPDRS) scores at 30 minutes after dosing (mean difference of 3.9 points on the UPDRS scale) and a higher likelihood of having and maintaining an "on" response at 60 minutes (57 versus 36 percent) [73]. However, the speed of onset and magnitude of response were smaller than anticipated based on earlier studies with a smaller dose (50 mg). Total time spent in the "off" state as assessed by diaries was not reduced in the levodopa group.

Concerns have been raised that the studied effects may not translate to a clinically meaningful response in patients [74]. In the author's experience, multiple factors may limit the utility of this formulation, including inhalational technique, cough associated with the dry powder, optimal dosing, and administration challenges encountered during an "off" period.

According to the manufacturer, inhaled levodopa can be administered up to five times per day (single dose maximum 84 mg, maximum daily dose 420 mg) [75]. 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 [73]. The rate of troublesome dyskinesia was low in the clinical trials but was not an uncommon reason for discontinuation in the author's experience.

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) and focused ultrasound (FUS)

●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 [9,76]:

●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 (for DBS but not LCIG or CSAI)

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" levodopa-induced dyskinesia (LID) is by definition time-locked to doses of levodopa. Onset can occur as early as 30 minutes after a dose, tends to reach a peak at the Tmax of 60 minutes, and tends to diminish by 90 minutes after a dose. Peak-dose dyskinesia tends to be dose-dependent, predictable, and reversible due to its dependence on plasma levodopa levels.

Younger patients (<50 years of age) are more prone to developing dyskinesia, often in earlier stages of their disease compared with older patients (>75 years of age). 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 [77]. 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 [3]. Patients may not be aware of or bothered by dyskinesia (ie, nontroublesome dyskinesia) and would prefer to be "on" with dyskinesia rather than "off." However, severe troublesome dyskinesia can involve large-amplitude, ballistic movements that interfere with coordination, function, and balance 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. However, advanced patients with brittle responses may not generate an "on" response when individual doses of levodopa are below a therapeutic threshold.

Shortening intervals between doses and lowering individual doses is an effective strategy if "wearing off" and dyskinesia coexist. Switching to a controlled-release (CR) tablet is not generally useful, because the onset of action may be delayed and bioavailability and absorption may be less predictable than the immediate release preparation. (See 'Levodopa dose and interval adjustment' above and 'Role of longer-acting oral levodopa formulations' above.)

Reducing doses of or eliminating adjunctive drugs such as dopamine agonists, COMT inhibitors, MAO inhibitors, or istradefylline can also help to reduce dyskinesia by lowering dopaminergic stimulation below the threshold of inducing dyskinesia.

Paradoxically, the addition of a low-dose dopamine agonist, particularly long-acting formulations (ie, transdermal rotigotine, extended-release pramipexole, or extended-release ropinirole) can improve both dyskinesia and "wearing off" by providing more continuous rather than pulsatile dopaminergic stimulation and allowing for levodopa levels to be reduced below a dyskinesia threshold.

Amantadine for dyskinesia — Amantadine can be an effective tool for dyskinesia in advanced PD when antiparkinson medications have otherwise been optimized [19,27].

The starting dose of amantadine immediate release (IR) is 100 mg a day, increasing to 100 mg twice daily after one to two weeks. The dose can be further titrated as tolerated up to 400 mg daily, divided in two to four doses a day. 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. Minor dose-dependent side effects may include peripheral edema, livedo reticularis (mottled discoloration of skin), constipation, blurred vision, urinary retention, and nightmares. Visual hallucinations, confusion, delirium, and psychosis may occur in older adults (>80 years of age) or those with preexisting cognitive impairment and dementia. Since both the IR and ER formulations are renally excreted, dose reduction and caution should be exercised when creatinine clearance is below 50 mL/minute.

Several short-term trials have shown a benefit of amantadine IR, with approximately 25 to 50 percent relative reductions in dyskinesia scores compared with placebo [78-80]. Observational follow-up data as well as a randomized discontinuation trial suggest that the effect can be sustained for a year or more [81,82].

Amantadine ER has also been shown to be an effective treatment for dyskinesia and "wearing off"/"off" time. Supporting evidence includes results of a randomized trial of 126 patients with LID who were randomly assigned to amantadine ER (274 mg capsule at bedtime) or placebo [83]. At 12 weeks, amantadine ER reduced the duration, severity, and impact of dyskinesia as measured by the Unified Dyskinesia Rating Scale and improved mean "off" time by 0.9 hours compared with placebo. The most common significant adverse effects were mild and reversible visual hallucinations. A subsequent trial reported similar results [84]. Until there is a comparison between ER formulations of amantadine and generic amantadine, it is uncertain whether the potential benefits justify the cost [85].

Role of clozapine — The atypical antipsychotic clozapine can be considered in patients with both refractory dyskinesia and psychosis who are unable to tolerate other strategies discussed above. Close neurologic and psychiatric monitoring are likely to be needed. Low-dose clozapine (30 to 50 mg/day) reduced dyskinesia in several open-label studies [86,87]. In a randomized trial of 50 patients with severe PD and LID, low-dose clozapine (12.5 to 75 mg/day) was more effective than placebo in treating levodopa-related dyskinesia [88].

Clozapine use is limited by the rare but potentially fatal risk of granulocytopenia [89]. A Risk Evaluation and Mitigation Strategy (REMS) safety program requires clozapine prescribers to obtain white blood cell and absolute neutrophil counts at baseline and at regular scheduled intervals for as long as a patient requires therapy. Details concerning frequency of monitoring and when to interrupt or discontinue this medication are reviewed separately. (See "Schizophrenia in adults: Guidelines for prescribing clozapine", section on 'Neutrophil count'.)

TROUBLESHOOTING COMPLEX MOTOR COMPLICATIONS

Unpredictable "off" periods — Unpredictable and sudden "on" to "off" transitions may not relate directly to the timing of levodopa dosing and are distinct from 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. Immediate release levodopa tends to retain relatively stable plasma pharmacokinetics throughout the disease course and so is generally favored over controlled release tablets in this situation.

Strategies that may be helpful include the following:

●Education - The interaction between protein and levodopa absorption is a well-documented and possibly treatable factor for "off." Avoiding protein at the time of drug administration and taking levodopa on an empty stomach (30 to 60 minutes before a meal or 60 to 90 minutes after) can reduce competition from protein at the gut-blood and blood-brain barrier level. In the author's experience, it is not uncommon to find that patients and caregivers underestimate the amount of protein in certain foods such as nutrition bars and shakes. Querying for larger sources of protein in a patient's diet may uncover hidden protein loads. A protein redistribution diet, in which most dietary protein intake is reserved for the evening, is a safe and reasonable intervention to consider. (See 'Dietary adjustments' above.)

●Medication scheduling – Ensure patients are taking medication on a regimented schedule that mirrors the short duration of effect of levodopa. When possible, meal times should be built into the schedule to ensure administration on an empty stomach. Plasma levodopa levels may be particularly prone to falling below a threshold if gut absorption is erratic. Controlled-release (CR) carbidopa-levodopa tablets are usually not helpful and may exacerbate the situation.

●Diaries and direct observation – Careful documentation and review of home diaries for such episodes or direct observation through at least two dose cycles in an extended outpatient visit may help to uncover relationship of levodopa doses to "off" episodes. Patients and caregivers may perceive that their "offs" are random and unpredictable, when in fact they are occurring as an end-of-dose "wearing off" phenomenon that has not been appreciated as such. In addition, "off" periods affecting upper and lower body function should be differentiated from episodes of freezing of gait (FOG), which may occur in "on" and "off" states and are often refractory to levodopa. (See 'Freezing of gait' below.)

●Dose adjustments – In rare cases, for reasons that are unclear, sudden "off" episodes may be precipitated by a relative excess of levodopa. Strategically lowering individual doses of levodopa and/or adding an adjunctive medication (low-dose dopamine agonist, MAO inhibitor, istradefylline, amantadine, or a catechol-O-methyl transferase [COMT] inhibitor) are all mainstays of medical management of motor complications.

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

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 or "on" 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. Judicious use of any adjunctive medication can be considered, but there is very little evidence to support the use of any one drug class to alleviate FOG. Subthalamic nucleus deep brain stimulation (DBS) can be an option when "off"-associated 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 by definition poorly responsive to dopaminergic therapy and just as refractory to surgical and device-assisted therapies. 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. 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.

The mainstay of the management of severe FOG includes physical therapy and management of treatable comorbidities [90,91]. Trials of targeted neurologic and PD-focused physical therapy (PT) have shown some evidence of benefit [92], and a physical therapist experienced with patients with PD can help to identify specific strategies 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 [93]. There are conflicting data from two small randomized controlled trials regarding the utility of methylphenidate for gait freezing and hypokinesia [94,95]. 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 [96]. 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 [18]. 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. 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 peripherally acting dopamine receptor blocker 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 [97,98]. However, preclinical and clinical studies suggest that domperidone increases the risk of QT interval prolongation and cardiac arrhythmias [99,100]. Because of the cardiac risk, the European Medicines Agency recommends that domperidone not be used for longer than one week [101].

●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, sublingual 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 have been reported to occur in levodopa-naïve patients [102].

Acute akinesia should prompt a search for systemic infection or other intercurrent medical issues that may trigger sudden worsening of parkinsonism. It can also occur as a result of medication error; for example, substituting carbidopa-levodopa 25/100 mg for 25/250 mg, or inadvertently using a dopamine receptor blocking agent such as metoclopramide or an antipsychotic drug. 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 [102]. Four patients died despite medical care and treatment. Episodes of acute akinesia may be considered an emergency situation in the field of movement disorders that warrants hospitalization, investigation, and supportive treatments.

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. Early-morning dystonia often 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" [6]. 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 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)")

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

●Symptom spectrum – 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 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.)

●Approach to "wearing off" – "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:

•Dietary adjustments – 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.)

•Levodopa adjustments – 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. 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.)

•Adjunctive therapy – 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.)

•Rescue therapy – 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.)

●Approach to peak-dose dyskinesia – 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.)

●Complex motor complications – Management of 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.)

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