FormalPara Key Summary Points

On-demand therapies for Parkinson’s disease provide rapid, reliable relief for patients who are experiencing OFF periods

To many healthcare providers, it may be unclear how these on-demand therapies fit into the existing treatment paradigm

OFF periods occur in nearly all patients with PD with long-term use of levodopa

On-demand treatments that have a more rapid onset than oral medications are useful additions for OFF periods, and can have a positive impact on a patient’s quality of life at any stage of the disease

Healthcare providers should consider offering on-demand therapies to patients with OFF periods

Introduction

On-demand therapies for Parkinson’s disease (PD) are available to provide rapid, reliable relief for patients who are experiencing OFF periods [1, 2]. Oral levodopa (LD), administered with an l-dopa decarboxylase inhibitor such as carbidopa (CD), remains the gold-standard treatment for PD. Other medications, such as dopamine agonists, catechol-O-methyltransferase (COMT) and monoamine oxidase-B (MAO-B) inhibitors, adenosine A2A antagonists, and N-methyl-d-aspartate (NMDA) antagonists, provide adjunctive treatment. In patients with medication-resistant motor fluctuations and dyskinesia, other treatment options include CD/LD enteral suspension (CLES) and deep brain stimulation (DBS) [3].

To many healthcare providers (HCPs), it may be unclear how on-demand therapies fit into the existing treatment paradigm, and how to initiate these therapies. The purpose of this review is to provide practical recommendations on the use of on-demand treatments for OFF periods in patients with PD.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Role of On-demand Therapies for Parkinson’s Disease

The first rescue treatment for PD OFF periods, apomorphine for subcutaneous injection, was approved in the USA approximately 20 years ago [4].

In the authors’ opinion, on-demand treatments are underutilized as there are no guidelines on the use of these therapies, and experts often differ on when to use them. The International Parkinson and Movement Disorder Society Evidence-Based Medical Review for motor symptoms in Parkinson’s disease and the American Academy of Neurology guidelines only mention the use of subcutaneous apomorphine as on-demand therapy, but do not discuss when or how it should be used in clinical practice [5, 6]. Even most treatment guidelines have not clearly defined when to use them [7,8,9,10,11,12].

In migraine headaches, rescue therapy is a widely used and understood term [13], but there is no standard or consensus term for these therapies in PD. HCPs use terms such as on-demand, rescue, as needed, or acute treatments of OFF periods to describe them. For this review, we will use the term on-demand therapy.

Defining OFF Periods

In general, oral CD/LD provides an approximately 25% improvement in PD motor symptoms [14] and, in initial stages of the disease, this improvement is consistently present throughout the day (sometimes referred to as the honeymoon period). An OFF period is when an individual dose of oral carbidopa/levodopa (CD/LD) is not providing the usual symptomatic benefit in PD symptoms. OFF time refers to the cumulative duration of all the OFF periods during a day. Eventually, nearly all patients develop motor fluctuations and OFF periods. The type, duration, and severity of OFF-period symptoms may vary during the day [2, 15,16,17]. In addition to motor symptoms like tremor, bradykinesia, gait, and balance difficulties, nonmotor symptoms, such as fatigue, anxiety, cognitive difficulties (brain fog), attention problems, panic attacks, depression, and apathy, may occur as part of OFF periods [18,19,20]. In some patients, nonmotor OFF symptoms can have a greater impact on a patient’s quality of life than motor symptoms [21]. OFF periods can have a significant impact on the patient and caregiver [22, 23], and can affect the patient’s quality of life and increase caregiver burden.

Development of OFF Periods

Long-term use of LD results in motor fluctuations (OFF periods) and dyskinesia [24, 25]. Patients with PD who take LD are believed to have long-duration and short-duration responses [26, 27]. In early disease, the long-duration response, resulting from the buffering capacity of dopaminergic neurons, masks the effects of plasma LD fluctuations due to individual dosing. OFF periods are often predictable at first, but, with disease progression, they become unpredictable. As the disease progresses and striatal dopaminergic neurons are lost, the ability of these neurons to buffer the fluctuating LD levels from oral administration becomes impaired, and the fluctuating plasma LD levels, along with the short half-life of LD, are associated with the occurrence of OFF periods. It is believed that fluctuating plasma LD levels may correlate with neuronal dopamine levels, and, when the level of LD declines below a certain point, PD symptoms reoccur. Eventually, the symptom response becomes parallel to the level obtained from each dose of LD, and mimics the LD half-life of 90 min [15, 26, 28].

In addition to the loss of the buffering capacity of dopaminergic neurons and the short half-life of LD, gastrointestinal (GI) issues play an important role in OFF periods. GI tract dysfunction is common in patients with PD, with GI symptoms experienced in approximately 60–80% of patients [29,30,31]. GI dysfunction and delayed gastric emptying impair the absorption of LD, which occurs in the proximal small intestine [32, 33]. Helicobacter pylori infection is also more frequent in patients with PD, and may additionally impair absorption of oral LD in the GI tract [31, 34]. Furthermore, a protein-rich meal is likely to impair LD absorption, as large neutral amino acids compete with LD for the active-transport system that allows them to cross the small intestine and blood–brain barrier [35, 36]. Finally, small intestinal bacterial overgrowth can also impair LD absorption in the gut [37]. These GI issues affect the rise in plasma LD levels, and therefore play a role in motor fluctuations and the occurrence of OFF periods.

In the authors’ experience, patients often use oral CD/LD from their own baseline medication regimen as on-demand therapy, with or without HCP guidance, to manage their OFF periods. Although it may be helpful for some patients, the GI issues make the use of oral CD/LD an unreliable on-demand therapy. In addition, oral CD/LD does not provide a consistent or rapid rise in plasma LD levels. Table 1 shows that alternative oral LD formulations and adjunct medications have only a limited effect on reducing daily OFF time.

Table 1 Alternative levodopa formulations and adjunct medications have a limited effect on daily OFF time
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Identifying PD Patients with OFF Periods

The principal types of OFF periods are shown in Fig. 1. The American Academy of Neurology recommends that physicians should ask patients with PD about the presence of OFF periods at every clinic visit [38]. The best way to evaluate if a patient is having OFF time is by obtaining a thorough history, specifically inquiring about OFF periods. This is critical, because often patients may not realize that they are experiencing them. This can be done by, for example, asking the patient to describe their symptoms throughout the day. Is the patient having an OFF period when they wake up? Early morning OFF is often under-recognized. In one study using a monitoring wrist device, it was reported that 85% of the PD patients with motor fluctuations had early morning OFF periods [39]. Some of the questions that may help HCPs recognize if their patients are experiencing OFF periods are shown in Fig. 2. A good question to ask the patient is: how long does it take for your first day’s dose of oral CD/LD to start working? A standard dose of CD/LD usually becomes effective about 20 min after ingestion. If a patient continues to be in the OFF state after 40 min, they should be considered to be having a delayed ON [40]. The duration of benefit of a single oral CD/LD dose determines the presence of end-of-dose wearing OFF. Some patients report having OFF periods when they miss a CD/LD dose, or if they delay taking a dose. For these patients, the time to ON becomes an important consideration for on-demand therapy use. If the patient does not show any improvement in their symptoms after taking an oral dose of LD, the patient has dose failure or “no ON.” Often, a free-flowing line of questioning is more helpful than asking patients directly if they have OFF periods, because their understanding of OFF may be limited. The use of this kind of dialogue is supported by the results of a survey of physicians, patients, and care partners [41]. An issue that may arise when talking with patients about OFF periods is that there can be lexicological and other miscommunications between physicians and patients. For example, in one study, many patients misunderstood why their physician was asking them how often and when they had PD symptoms and thought they were asking about their medication adherence [42]. The same study also reported that patients tended to talk in terms of anecdotal, personal life narratives, and, in this case, only 3 out of 29 patients and no care partners used the term “wearing OFF”. In the OFF-PARK survey, Matthews et al. showed that 30% of patients and 17% of care partners, who previously had said they understood wearing OFF, in reality gave the wrong answer to a question about the relationship between OFF-period symptoms and medication timing, and 53% of these patients and 36% of care partners did not answer when they were asked what wearing OFF meant [43].

Fig. 1
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Different types of OFF: Early-morning OFF, or morning akinesia, is when the first oral dose of the day takes a long time to work. End-of-dose wearing OFF is the process when the oral dose no longer relives symptoms leading to the patients being OFF. Delayed ON (similar to morning akinesia) is when the oral dose takes very much longer to relieve symptoms than usual (often because of GI dysfunction). Dose failure or no ON is when oral CD/LD does not produce an ON state [15, 16, 82, 83]. CD/LD carbidopa/levodopa, GI gastrointestinal

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Fig. 2
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Examples of questions that can be used to ask patients about their OFF periods

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There are a number of questionnaires that assess patient status, for example, the Wearing OFF Questionnaires (WOQ), WOQ-32, WOQ-19, and WOQ-9 [44]. The WOQ-9, in particular, was designed to be completed easily in a clinic. There are also patient home diaries, in which patients record their ON or OFF states during a set period of time at regular intervals during the day [45].

Wearable sensors provide an opportunity to obtain more consistent data, in the form of wrist-worn activity sensors, or other sensors attached to different areas of the body that can detect tremor, bradykinesia, and dyskinesia [46, 47]. The advantage of wearable sensors is that they can provide continuous measurement over long periods and do not rely on the patient completing diaries or questionnaires. Therefore, the accuracy of defining OFF periods could increase. Sensors are currently not widely used, and their utility in clinical settings needs to be further studied. However, as algorithms that analyze the data from wearable sensors further improve, it seems very likely that their use will increase in the future.

Selecting Patients for On-Demand Therapy

On-demand therapy can be used for PD patients experiencing OFF periods including early morning OFF; delayed ON; (end of dose) wearing OFF; dose failure, or no ON; or OFF periods after food intake (Fig. 1) [1, 2, 15, 48]. The majority of PD patients with motor fluctuations experience early morning OFF periods which can significantly impact their quality of life [49, 50]. Early morning OFF periods are reported even in patients on multiple adjunctive therapies including CD/LD infusion therapies [51]. Delayed ON is another major contributor to the total OFF time during the day. One study reported that delayed ON comprised nearly 70% of the total daily OFF time for the day [52]. Although wearing OFF is frequently predicted by the patients, dose failures are often unpredictable. OFF periods due to food intake might limit protein intake by patients and lead to weight loss, especially muscle volume loss [31].

Current On-Demand Treatments

On-demand treatments bypass the GI tract and provide dopaminergic therapy directly to the blood stream, by subcutaneous injection, through the buccal mucosa, or by inhalation into the pulmonary circulation (Table 2). There are currently three approved on-demand therapies to treat OFF periods: subcutaneously injected apomorphine [4], sublingual apomorphine, and inhaled LD. They produce a rapid, reliable benefit because they are absorbed directly into the circulation and do not have to pass through the GI tract [1, 2]. It has been shown with pharmacokinetic studies that using oral LD produces a slower and more inconsistent increase in plasma LD compared with inhaled LD (Fig. 3). As a result of on-demand therapies’ rapid and consistent absorption, onset of relief of motor symptoms is fast (within about 10–20 min), with a duration of effect of 60–90 min [53,54,55].

Table 2 On-demand treatments available in the United States
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Fig. 3
figure 3

Adapted from Safirstein et al. [87]

Individual plasma LD profiles after a single inhaled dose of LD inhalation powder and after a single ingested dose of CD/LD in patients with PD and in a fed state. In this study, levodopa was more rapidly absorbed when inhaled as LD inhalation powder (84 mg) than when ingested via an oral CD/LD tablet (100 mg), with C10min and C30min values of 522.9 and 531.5 ng/mL for LD inhalation powder, respectively, and 247.3 and 300.9 ng/mL for oral LD/CD. The patients’ plasma LD profiles also had much less variability after LD inhalation powder than after oral CD/LD ingestion (range of tmax values was 5–90 min for LD inhalation powder vs. 57–240 min for oral CD/LD. LD inhalation powder n = 20, CD/LD n = 17. C10min, C30min, observed concentrations at 10 and 30 min; CD carbidopa, LD levodopa, tmax time to maximum plasma concentration.

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In clinical trials with on-demand therapies, the primary outcome measure was improvement in the Unified Parkinson’s Disease Rating Motor (UPDRS III) scores [1, 2, 48], where improvements of 4–20 points were observed over placebo depending on the study, drug, and sample population [54,55,56,57]. Significant improvements in motor function after administration have also been observed after 30–60 min [54, 55]. Onset of action (as seen by better UPDRS III scores) start at about 10–15 min post-dose [53,54,55]. Duration of effect is about 60–90 min [53,54,55]. OFF time reductions have also been observed (e.g., an improvement of 2 h for subcutaneous apomorphine over placebo) [56]. Nonmotor symptoms have not been investigated in randomized controlled trials of on-demand therapies, but many nonmotor symptoms during OFF periods could improve with dopaminergic treatment [15, 18, 58]. On-demand medication can be administered up to five times daily. Only one dose should be used for an individual OFF period [4, 59, 60].

Subcutaneous Apomorphine

Apomorphine is a non-ergot dopamine agonist with D1 and D2 receptor affinity and with potent antiparkinsonian benefits [53], which were recognized in the 1950s [61]. Apomorphine is extensively and rapidly sulfonated in the GI tract, and hence cannot be administered orally. Subcutaneous apomorphine is administered through a pen injector [4]. The usual dose to obtain an ON state is between 2 and 6 mg (0.2–0.6 mL). Subcutaneous apomorphine improved UPDRS III scores by 23.9 points compared to 0.1 for placebo and resolved OFF periods in 95% of the patients [56]. The beneficial effect usually begins in 10–15 min and lasts for up to 90 min [2, 57, 62]. In an open label study to assess the effect of apomorphine on time to ON in PD patients with morning akinesia, patients receiving subcutaneous apomorphine achieved ON in approximately 24 min compared to 61 min with oral CD/LD. In addition, fewer patients had dose failures with apomorphine (7%) compared to oral CD/LD (46%) [63].

Common adverse events for subcutaneous apomorphine include nausea, vomiting, somnolence, dizziness or light-headedness, and yawning. Many patients also experience injection site skin reactions [26%], including bruising [16%], granuloma [4%], and pruritus [2%]) [4]. Skin reactions can be minimized by rotating the site of injection, local massage, ultrasound, or injecting steroids in the nodules. In clinical practice, the first dose of subcutaneous apomorphine must be given under medical supervision. The authors recommend initiating the first dose with 0.1 mL subcutaneously and observing the patient for any acute side effects including nausea, vomiting, or orthostatic hypotension. Blood pressure should be monitored for approximately 60 min, or longer if the patient continues to have an orthostatic drop in blood pressure. We recommend continuing the 0.1-mL dose for 2–4 days and then increasing the dose to 0.2 mL for 2–4 days and keep increasing the dose to efficacy. If the patient has nausea, 5HT3 antagonists (including anti-emetics, like ondansetron, granisetron, dolasetron, etc.) are contraindicated [4].

Sublingual Apomorphine

Due to the limitations and lack of widespread acceptance of subcutaneous apomorphine, a sublingual formulation was approved by the FDA. The apomorphine strip consists of a bilayer film with apomorphine in one layer and a buffer designed to minimize mucosal irritation in the other layer. Sublingual apomorphine is absorbed from the oral cavity and bypasses the first-pass metabolism in the GI tract. The approved dose of sublingual apomorphine is 10–30 mg [55, 64]. In a phase III study [55], sublingual apomorphine improved MDS-UPDRS III scores by 7.6 points compared to placebo at week 12. In the home environment sublingual apomorphine provided a full ON response within 30 min in approximately 79% of subjects compared to 31% with placebo. Improvements began as soon as 15 min after administration. Oropharyngeal adverse effects are the most common side effects, occurring in approximately 31% of the patients and leading to 17% of patients discontinuing therapy. They included oral mucosal erythema, dry mouth, lip swelling, lip edema, throat irritation, and glossodynia. Other adverse effects were similar to subcutaneous apomorphine [55].

In clinical practice, similar to subcutaneous apomorphine, the first dose of sublingual apomorphine must be given under medical supervision [60]. The authors recommend initiating the first dose with 10 mg placed under the tongue, and the patient should be instructed to not chew or swallow for approximately 3 min, the time it takes for the film to disintegrate. Orthostatic blood pressure should be monitored for approximately 60 min unless the patient continues to have an orthostatic drop in blood pressure. We recommend continuing the 10-mg dose for 2–4 days and then increasing the dose to 15 mg for 2–4 days and then keep increasing the dose to efficacy. If the patient has nausea, 5HT3 antagonists including anti-emetics such as ondansetron, granisetron, and dolasetron are contraindicated.

Levodopa Inhalation Powder

The challenges with oral CD/LD include the variability in absorption and bioavailability that would produce reliable and consistent plasma levodopa levels and hence brain dopamine levels. Bypassing the GI tract, inhaled levodopa was developed to provide a rapid and consistent rise in plasma LD levels and in brain dopamine levels. LD inhalation powder is formulated as dry powder particles (diameter < 5.6 µm), highly porous for lung deposition. A single dose requires the inhalation of the contents of two capsules (each containing 42 mg LD) using the supplied inhaler. Each dose supplies 84 mg LD (equivalent to approximately 50 mg of oral LD), and it rapidly enters the blood stream via the pulmonary circulation [65, 66].

In a phase III study, inhaled LD provided a mean improvement of 3.9 points compared to placebo in the UPDRS III score 30 min after administration [54]. A small safety study (n = 36) was also conducted using inhaled levodopa for early morning akinesia. LD inhalation powder (even without additional carbidopa) taken immediately after the first morning oral CD/LD dose was well tolerated, and the median time to ON was 25 min compared to 35.5 min with placebo [67]. The most significant adverse event occurring in about 15% of patients was cough, due to the irritant effect of dry powder entering the lungs [54]. Other adverse effects included upper respiratory tract infection, sputum discoloration, and nausea. The use of LD inhalation powder is not recommended in patients with concomitant lung disease, especially asthma or chronic obstructive pulmonary disease [59]. In clinical practice, the first dose of inhaled LD does not need to be given under medical supervision. Due to throat irritation with the dry powder, we recommend patients take some water before the inhalation to moisten the throat and reduce the likelihood of cough. There is no dose titration required.

Selecting On-Demand Therapy

On-demand therapies are most useful for patients who can identify when they are having, or are beginning to experience, OFF. For those patients whose symptoms are highly variable or who have difficulties identifying their OFF periods, it may be difficult for the patient to know when best to take the treatment. We recommend patients use on-demand therapy at the beginning of the OFF period and upon awakening for early morning akinesia. Rarely, patients with severe motor OFFs or tremor may find it difficult to use these on-demand therapies. A caregiver may be required to help in these cases. The need for medical supervision of the initial titration of the apomorphine may be a barrier for some patients [48]. Although on-demand treatments are approved for use up to five times a day, in the pivotal clinical trials they were used only on average 2–2.5 times per day [54, 56]. In a recent survey of theoretical on-demand treatment options, people with PD (98% had OFF periods) preferred on-demand treatments that were non-invasive, that produced a rapid ON in 15 min, that controlled symptoms for longer (≥ 2 h), and that had no out-of-pocket costs associated with their use [68]. In real-world settings, and considering patient preferences and potential adverse events, the choice of on-demand treatments has to be individualized after consideration and discussion with the patient.

Although there are advantages of using on-demand therapies, there can be some drawbacks to their use. The cost of the drug could be a major disincentive. In addition, not every patient can tolerate on-demand therapy. Some patients may prefer having OFF symptoms rather than experience the adverse effects of the therapy, and some may not be able to recognize the OFF periods, or might find the OFF periods not bothersome enough to take additional medications.

Conclusion

Long-term LD use is associated with OFF periods which, as PD progresses, become more frequent and intractable. Patients may have difficulty describing their OFF periods, and HCPs often do not query about them specifically. Given the availability of new on-demand treatments (injectable apomorphine, sublingual apomorphine, and inhaled LD), fast-acting therapies that bypass the GI tract, it is time to reevaluate when these therapies should be used. As they are safe and effective for OFF periods, and due to the marked negative impact of the OFF periods, we need to consider using them earlier when patients have motor fluctuations. Figure 4 shows a summary of treatments for PD that include on-demand therapies which should especially be considered for early-morning OFF, delayed ON, dose failures, and for OFF periods due to food interactions, since oral adjunctive therapies are often not helpful in such cases.

Fig. 4
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Treatment options for motor fluctuations from early to advanced PD incorporating on-demand treatment [84,85,86]. CD carbidopa, CLES CD/LD enteral suspension, COMT catechol-O-methyltransferase, CR controlled release, DBS deep brain stimulation, ER extended release, IR immediate release, LD levodopa, MAO-B monoamine oxidase-B, NMDA N-methyl-d-aspartate, SC subcutaneous

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