Federico Carbone 1, Atbin Djamshidian 1, Klaus Seppi 1, Werner Poewe 1,✉
Abstract
Satisfactory management of Parkinson’s disease is a challenge that requires a tailored approach for each individual. In the advanced phase of the disease, patients may experience motor complications despite optimized pharmacological therapy. Apomorphine, a short-acting D1- and D2-like receptor agonist, is the only drug proven to have an efficacy equal to that of levodopa, albeit with a shorter time to onset and effect duration. Clinical trials have shown that intermittent apomorphine injections provide rapid and effective relief from unpredictable “off” periods. Continuous apomorphine infusion reduced around 50% of the daily “off” time in several studies. Dopaminergic side effects such as nausea, somnolence and hypotonia, as well as administration site reactions, are often mild or treatable, but somnolence and skin reactions in particular can sometimes be reasons for premature discontinuation. We provide an overview of the pharmacological mechanism of action of the drug in light of its effects on Parkinson’s disease symptoms. We then summarize the evidence regarding the efficacy and tolerability of apomorphine, both in its established formulations (subcutaneous intermittent injection and continuous infusion) and in the new preparations currently under investigation.
Key Points
| Apomorphine is the oldest dopaminergic drug available for Parkinson’s disease, and—to date—it remains the only drug with efficacy comparable to that of levodopa. |
| Subcutaneous apomorphine, delivered as a continuous infusion or as intermittent injections, has proven well-tolerated and effective. |
| Several alternative routes to simplify delivery of the drug have been tested, and some are in active clinical development. |
Introduction
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease, affecting 1% of the population aged > 60 years and reaching 3% in the highest age groups [1, 2]. Neuropathological hallmarks are progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra, causing striatal dopamine deficiency, and intracellular inclusions containing aggregates of alpha-synuclein. PD is clinically defined by the presence of bradykinesia and at least one additional cardinal motor feature (rigidity or rest tremor). In addition, most patients with PD also experience non-motor symptoms (NMS), adding to the overall burden of parkinsonian morbidity [2].
PD was the first neurodegenerative disease for which highly efficacious treatments became available. Dopamine replacement with oral levodopa is still the gold standard of symptomatic therapy, matched only by apomorphine in its effect size on motor symptoms [3]. The response to levodopa is maintained in the long term, but many patients develop challenging motor complications such as motor fluctuations and dyskinesia as the disease progresses [4, 5]. The current role of apomorphine in the treatment of PD is in the management of levodopa-related motor complications—as either intermittent subcutaneous pen injections or continuous subcutaneous mini-pump delivery. We review the pharmacology and clinical studies of the efficacy and safety of subcutaneous apomorphine administration in treating motor fluctuations in PD and give a brief overview of alternative apomorphine formulations currently in clinical development.
History of the Molecule Across the Centuries
Today, apomorphine is known as a dopamine agonist for the treatment of advanced PD, but its first use very likely dates to ancient civilizations, with fascinating analogies between cultures as far apart as those of the Mayas and the ancient Egyptians. Abundant clues rest in the iconography of these two civilizations testifying to the central role of Nymphaea plants (water lilies) in magical-religious rites. We know today that several aporphines, including apomorphine, can be isolated in the roots and bulbs of water lilies. The plants were most likely used as an emetic in purifying rituals and as an aphrodisiac and hallucinogenic for the higher castes [6–8]. Interestingly, the effects sought and experienced by these ancient civilizations are the very same that were clinically assessed thousands of years later, after the discovery of synthetic apomorphine.
The credit for discovering apomorphine is given to the studies of Matthiessen and Wright [9], who in 1868 synthetized apomorphine hydrochloride by heating morphine with concentrated hydrochloric acid. The compound was named apomorphia to highlight its origin and its difference from the mother compound, morphine. While it was only after the experiments by Matthiessen and Wright that apomorphine started to attract interest in both human and veterinary medicine, it is fair to note that Arppe [10] was probably the first to synthetize the molecule in 1845 by heating morphine with an excess of sulphuric acid, therefore naming it sulphomorphide.
In the years following its discovery, apomorphine was used in different experiments in animals and humans, showing a range of effects leading to its use in several fields of medicine. By virtue of the studies conducted by Gee, Hare, Pierce, Siebert and Harnack [11–15] in humans and animals, the effects of apomorphine were linked to action on the central nervous system. Most notably, an emetic response was almost invariably observed in humans and dogs with oral and parenteral administrations. An unwanted effect of today’s use of apomorphine, emesis became the main indication for the drug for several decades and led to its use in removing foreign objects from the esophagus or in treating poisoning. This emetic response was also used to induce adverse conditioning by administering the drug with the undesired stimulus in cases of drug, alcohol and smoking dependence [16].
Oral apomorphine is subject to extensive first-pass metabolism resulting in low bioavailability, and parenteral delivery of the drug was the preferred administration route in most studies and experiments [17, 18]. The clinical use of apomorphine between the end of the nineteenth century and beginning of the twentieth century covered almost every field of medicine. The sedative effects of the drug were employed in a variety of psychiatric conditions, such as mania, hysteria, schizophrenic excitement, anxiety, dementia and, most importantly, alcohol-related disorders [19]. In these studies, spontaneous erection was noted as an unexpected effect, which would much later lead to the commercialization of apomorphine as an agent to treat erectile dysfunction [20].
It was Weil, in 1884, who first hypothesized that apomorphine could be useful in patients with PD, but without any specific rationale [21]. This was still lacking when sub-emetic doses (0.6–0.9 mg subcutaneously) of apomorphine were finally tried in patients with PD by the American neurologist Schwab and colleagues [22] almost 70 years later. These authors noted marked improvement in rigidity and tremor lasting from 1 to 6 h with enhanced feeling of subjective wellbeing once the initial side effects of nausea and hypotension had resolved. The marked anti-tremor effects of subcutaneous or intramuscular single-dose injections of apomorphine were confirmed shortly after by the German neurologists Struppler and Von Uexkull [23]. However, the peripheral adverse effects and the need for parenteral administration of apomorphine led to its limited use in clinical practice after these early observations on its antiparkinsonian efficacy. About a decade later, the miraculous efficacy of oral levodopa in PD was discovered, and this superseded all interest in apomorphine [24, 25]. Nevertheless, Cotzias—one of the fathers of levodopa therapy for PD—continued to pursue the drug as an agent to treat PD and described the potent antiparkinsonian effects of subcutaneous apomorphine in 15 patients, albeit with marked emetic side effects in a proportion of subjects [26]. In 1979, Corsini et al. [27] showed that nausea deriving from apomorphine injections could be controlled via the administration of domperidone, a peripheral dopamine antagonist that does not cross the blood–brain barrier. This opened the door for successful introduction into clinical practice pioneered by Stibe et al. [28] in London in the mid-1980s. These researchers were able to show the remarkable efficacy of intermittent subcutaneous injections and continuous infusion of apomorphine in reducing the “off” periods in patients with advanced PD [28]. Over the following years, multiple studies confirmed their findings, leading to the approval of apomorphine as an adjunct therapy to reduce “off” time in advanced PD.
Pharmacological Properties
Apomorphine is an aporphine alkaloid derived from acidification of morphine. Its molecular formula is C17H17NO2. Its structure, consisting of a tetracycline aporphine ring, is responsible for the lipophilicity and the affinity to dopaminergic receptors. Specifically, the structural similarity to dopamine is conferred by the ortho-catechol group [29]. Like many antipsychotic drugs, apomorphine also possesses a piperidine moiety. Apomorphine is often described as a dopamine agonist, but it has some differences from other oral dopamine agonists used in PD. Thanks to its catechol moiety, apomorphine acts as a potent dopamine receptor agonist with a broad spectrum on all D1- and D2-like receptors (D1, D2S, D2L, D3, D4, D5) [30]. In comparison, the oral dopamine agonists ropinirole and pramipexole mainly bind to D2 and D3 receptors without significant affinity to D1 receptors [31]. Apomorphine’s mode of action is therefore more like that of dopamine or its precursor levodopa. In addition, apomorphine has antagonist properties on serotonergic 5HT2A, 5HT2B and 5HT2C and adrenergic α2A, α2B and α2C receptors and agonist properties at serotonergic 5HT1A receptors [32]. Unlike its mother compound, morphine, apomorphine has no affinity for opioid receptors [33].
Apomorphine has very limited oral bioavailability (< 4%) [34] because of almost complete first-pass hepatic metabolism where the molecule is metabolized following different pathways, including sulfation, glucuronidation and catechol-O-methylation. Therefore, different parenteral administration routes have been applied in clinical experiments. As a licensed treatment for PD, apomorphine is currently administered via subcutaneous injections or infusions. The drug absorption (bioavailability 100%), volume of distribution, plasma clearance and half-lives (t½) of subcutaneous injections or infusions are comparable to those of intravenous infusion [35]. However, the latter is not suitable for chronic use because of the possible crystallization of apomorphine in the catheter, leading to the formation of thrombi [36]. Several factors can influence the subcutaneous absorption of the drug: injection site (abdominal injection seems to have the best results), state of the skin (vascularization, skin temperature, body fat), volume and depth of injection [a greater volume leads to a greater area of subcutaneous absorption and influences the time to peak concentration (tmax)] and the presence of subcutaneous nodules that may hinder absorption, both mechanically and via inflammation-related alteration of the blood flow [35, 37, 38]. After subcutaneous injection, peak concentration in the blood (Cmax) is reached in around 10 min, with a maximum concentration in the cerebrospinal fluid achieved after 30 min [35].
Apomorphine is extremely lipophilic so it has a considerable volume of distribution and, unlike levodopa, can cross the blood–brain barrier freely. Additionally, it seems to concentrate in the brain, reaching a brain-to-blood concentration ratio of 8:1 [39]. Its rather rapid metabolism and clearance means that apomorphine has a t½ of around 33 min [35, 38]. Overall, inter-individual variability in tmax, Cmax, and area under the plasma concentration–time curve (AUC) is high [35, 38, 40] because of a variety of factors, including regional fat, blood flow and differences in metabolic enzymatic profiles. On the other hand, intra-individual variability is low. In clinical practice, this translates into a need for individual titration when starting apomorphine therapy. After a single dose in patients with PD, the onset of a clinical response usually occurs within 7–10 min after the subcutaneous injection and lasts for about 45–60 min [40], making intermittent subcutaneous injections of apomorphine a highly suitable rescue therapy for patients experiencing “on/off” fluctuations during chronic levodopa therapy.
Efficacy
Since the pioneering studies in the 1980s [28], multiple open-label series have confirmed the efficacy of apomorphine in reversing severe, sudden “off” states in advanced PD despite optimized oral therapy [28, 33, 41–45]. In most cases, the primary outcome was the reduction of time spent in “off” obtained with continuous subcutaneous apomorphine infusion (CSAI) or intermittent subcutaneous pen injections. Reduction of dyskinesia severity with chronic subcutaneous infusions was also reported but was inconsistent between studies [18, 46–48]. Studies comparing the efficacy of apomorphine and levodopa have repeatedly shown the two drugs to have equivalent effect sizes [3, 49]. Only a few studies assessing intermittent subcutaneous injection or continuous infusions of apomorphine were placebo controlled, but these have confirmed results from a large body of evidence from open-label use [45, 50].
Efficacy of Apomorphine Compared with Levodopa
Apomorphine and levodopa show an almost overlapping efficacy when treating PD motor symptoms.
In one crossover open-label study, no difference was observed between apomorphine and levodopa in all outcome variables, including hand tapping scores, walking time, severity of tremor, dyskinesia score and a modified Webster disability scale to evaluate disability due to PD. The mean duration of the motor effect was 56 min (range 30–80) for apomorphine and 211 min (range 145–315) for oral levodopa. Time to onset was 3–14 min for apomorphine (mean 7.9) and 19–75 min for levodopa (mean 35.4) [3]. This comparative study proved for the first time that apomorphine has virtually indistinguishable efficacy on motor symptoms compared with levodopa but a considerably shorter duration of effect. These results were later confirmed in a double-blind single-dose study using apomorphine or levodopa [49].
Efficacy of Intermittent Apomorphine Injections
Chronic treatment of PD with levodopa is compromised by the development of motor fluctuations despite optimized oral dopaminergic therapy [51]. This lack of a stable response to therapy has a significant negative impact on quality of life because of the many motor and non-motor disabilities associated with the “off” state and reduced autonomy in planning activities because of the unpredictability of “off” phases. A large observational study in 1000 patients with PD experiencing “off” episodes despite best medical management showed that they had to live with an average of 2–3 h of “off” time per day [52].
Numerous studies have assessed the efficacy of apomorphine injections in patients with PD with fluctuations [18, 28, 42, 46, 50, 53] (Tables 1 and 2). These studies consistently reported a marked reduction in the number of daily “off” periods and other “off”-related phenomena such as early morning dystonia, urinary disfunction and pain.
Table 1.
Summary of open-label studies assessing the efficacy of intermittent subcutaneous injections of apomorphine in patients with Parkinson’s disease
| Study | Pts (N) | Study duration, months | Mean injection dose/mean total daily dose, mg | Minutes to clinical onset | Duration of effect, minutes | Average daily “off” reduction, hours | Average daily “off” reduction, % | Levodopa reduction, mg | Levodopa reduction, % |
|---|---|---|---|---|---|---|---|---|---|
| Poewe et al. [102] | 12 | 6.5 | 4.0/9.6 | 5–15 | 60–150 | 2.7 | 56 | NR | NR |
| Poewe et al. [103] | 17 | 7.2 | 3.8/12.2 | NR | NR | 3.0 | 64 | − 77 | − 8 |
| Frankel et al. [46] | 30 | 13.5 | 2.2/10.2 | 7.5 | 60 (20–120) | 4 | 58 | − 39 | − 5 |
| Kempster et al. [3] | 14 | Single dose | 2/2 | 7.9 | 56 (30–80) | NR | NR | NR | NR |
| Hughes et al. [17] | 15 | 6 doses | 3.4/NR | 5–25 | 10–107 | NR | NR | NR | NR |
| Hughes et al. [104] | 49 | 27 | 2–5/11.7 | NR | NR | 3.6 | 50 | − 61 | − 7 |
| Esteban Muñoz et al. [105] | 11 | 23 | 3/9 | 9.5 | 60.9 | 2.8 | 45 | + 109 | + 15 |
| Pietz et al. [47] | 24 | 22 | 1.9/9.7 | 10 | 47.5 (25–90) | NR | 20.5 | + 225 | + 27 |
NR not reported, PD Parkinson’s disease, pts patients
Table 2.
Summary of double-blind studies assessing the efficacy of intermittent subcutaneous injections of apomorphine in patients with Parkinson’s disease
| Study | Pts (N) | Study duration | Study design | Primary efficacy endpoint | Mean injection dose/mean total daily dose, mg | Minutes to clinical onset | Duration of effect, minutes | Efficacy findings |
|---|---|---|---|---|---|---|---|---|
| Van Laar et al. [106] | 5 | 10 doses | Randomized, double-blind, placebo-controlled, crossover study | Columbia Parkinson’s Disease score | 2.7/NR | 7.3 | 96 | Significant efficacy of apomorphine in improving all scores of the Columbia scale |
| Ostergaard et al. [107] | 22 | 2 months | Double-blind, placebo-controlled study | “Off” time reduction | 3.4/NR | NR | NR | Mean daily “off” duration reduced by 58%; “off” severity also significantly reduced |
| Merello et al. [49] | 12 | Single dose | Double-blind, active comparator (dispersible levodopa) | Change in modified Webster disability scale score | 3/3 | 8.1 | 56.6 | Mean effect latency and duration for apomorphine vs. levodopa: 8.08 |
| Dewey et al. (APO202) [50] | Phase 1: 29 | Single dose | Placebo-controlled, parallel-group inpatient evaluation | Change in UPDRS motor score | 5.4/NR | NR | NR | Significant motor improvement (respectively − 23.9 vs. − 0.1 change in UPDRS motor score) |
| Phase 2: 26 | 1 month | Placebo-controlled, parallel-group outpatient evaluation | “Off” time reduction | 5.8/14.5 | 22 | NR | Significant reduction of reported “off” time (respectively 2.0 vs. 0.0 h) | |
| Pfeiffer et al. (APO302) [108] | 62 | Single dose | Prospective, placebo-controlled, parallel-group study | Change in UPDRS motor score after 20 min | TED or TED plus 2.0 mg | 7.3 | NR | Significant improvement for pooled apomorphine vs. placebo (− 24.2 vs. − 7.4 mean reduction in UPDRS) |
| Pahwa et al. (APO301) [56] | 56 | Single dose | Dose-escalation study, randomized, placebo-controlled, crossover evaluation | Change in UPDRS motor score after 20 min | 4.0–10.0 | NR | NR | Significant improvement in UPDRS motor scores in apomorphine group vs. placebo at 20, 40, 90 min |
| Hattori et al. [109] | 31 |
3 months (open label) Single dose (blinded evaluation) |
Placebo-controlled blinded efficacy assessment following a 12-week unblinded outpatient phase | Change in UPDRS motor score after 20 and 40 min | 1.55/4.49 | 14.2 | 62.6 | Significant improvement in UPDRS motors scores with apomorphine vs. placebo at 20 and 40 min |
NR not reported, pts patients, TED typically effective dose, UPDRS Unified Parkinson’s Disease Rating Scale
Three pivotal randomized, placebo-controlled trials were conducted in the USA between 2001 and 2007, leading to the approval of the drug in an injection pen for the acute intermittent treatment of “off” episodes in advanced PD [33, 54–56].
The first of these US registration studies (APO202) was a randomized, double-blind, placebo-controlled, parallel-group trial assessing the safety and efficacy of subcutaneous injections of apomorphine hydrochloride for “off” state periods in apomorphine-naive patients with PD with motor fluctuations despite aggressive oral therapy. The study was divided into two phases. Phase one consisted of an inpatient uptitration of the apomorphine dose to reverse a practically defined “off” period. Phase two involved a 1-month period of outpatient observation of drug effectiveness for reversal of “off”-state events. A 2-week observation period before the inpatient phase allowed the average “off” hours for each patient to be established at baseline. On the first day of the inpatient phase, all subjects underwent an unblinded levodopa challenge with their normal morning levodopa dose to establish their clinical response to dopaminergic therapy. On the second day, patients started in an “off” state and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor response was evaluated with increasing doses of apomorphine or placebo. Apomorphine was started at 2 mg and increased in 2-mg steps to a 10-mg maximum; the dose was uptitrated until patients reached a reduction of the UPDRS motor score of at least 90% of that recorded with the levodopa challenge. The primary efficacy indicator was the change UPDRS part III from predose to postdose. Apomorphine showed a reduction of 23.9 points (62% improvement) compared with placebo. Apomorphine’s inter-individual variability in both pharmacokinetic parameters and efficacy was addressed in this study, with an individual titration reaching an optimal dose. The average inpatient apomorphine dose needed to reach a satisfying “on” (5.4 mg) closely matched the average dose used in the outpatient phase (5.8 mg). No placebo effect was described, and almost all subjects reached the maximum placebo dose in uptitration. During the outpatient phase of the study, apomorphine was decidedly more effective in aborting “off” episodes (95%) than was placebo (23%), measured via patient home diaries. Apomorphine showed an average reduction in “off” time of 2.0 h per day compared with baseline. This was the first study to assess the efficacy of intermittent treatment with apomorphine in reducing “off” time, in both inpatients and outpatients and compared with placebo. Moreover, the predictive nature of inpatient test responses on outpatient therapeutic response was established.
APO301 was a crossover trial enrolling apomorphine-experienced patients: participants received their usual apomorphine dose or a placebo, followed by the other treatment on the next day. Using the motor score of the UPDRS as a primary outcome measure, the study showed the superiority of apomorphine versus placebo at 10, 20 and 60 min post-administration. APO302 was a placebo-controlled, single-visit study to assess the efficacy of apomorphine in patients already receiving apomorphine and who were experiencing “off” periods during the day despite their oral dopaminergic therapy. A subgroup of patients received their usually effective apomorphine dose and an additional 2 mg to evaluate the tolerability of excess drug during administration and to determine whether patients with motor fluctuations receiving chronic apomorphine therapy would benefit from a higher apomorphine dose. The study showed that apomorphine brings fast relief from “off” periods even after long-term treatment. Moreover, once the optimal dose is defined for a patient, no significant advantage (measured as improvement in UPDRS part III) is gained by increasing that dose. Indeed, the only consequence of raising the apomorphine dose in the study was an increased rate of adverse events. These results mirror the common clinical experience that the optimal dose of apomorphine to relieve “off” time in individuals rarely needs to be changed.
APO303 [57] was an open-label dose-escalation study with a placebo-controlled crossover evaluation to further explore the safety and efficacy of apomorphine in patients with advanced PD naïve to apomorphine treatment. The study results again confirmed apomorphine’s efficacy in “off” periods assessed as UPDRS motor improvement at 20, 40 and 90 min post-injection compared with placebo. Both efficacy and adverse events were dose related. At doses > 6 mg, motor improvements were not significant, but the incidence of adverse events kept increasing. This finding suggests no further benefit from increasing the dose of apomorphine in patients who are already receiving their optimal therapeutic dosage. Intermittent apomorphine maintained its effectiveness in improving mobility after 6 months of open-label treatment. APO303 was conducted as a substudy of the larger open-label trial assessing the safety profile of continued use of intermittent subcutaneous apomorphine to treat “off” episodes in patients with advanced PD [57].
Additional evidence on the efficacy of the drug came from a recent phase IV multicenter study (AM IMPAKT) assessing the effect of apomorphine injections in patients with prolonged morning akinesia despite their levodopa morning dose [42]. A dose failure was defined as the inability to reach an “on” phase in 60 min after levodopa intake. Patients completed a 7-day levodopa baseline period by recording their time to “on” after each morning levodopa dose. Patients who experienced dose failures were then titrated to an optimal dose of apomorphine (2–6 mg) and started a 7-day treatment period with morning apomorphine injections instead of their normal morning levodopa dose. To prevent nausea and vomiting, subjects were started on antiemetic therapy with trimethobenzamide. The reduction in time to “on” (mean reduction 37.14 min) and the rate of dose failure (46% with levodopa vs. 7% with apomorphine) provided further evidence in favor of intermittent apomorphine injections. The study showed that subcutaneous apomorphine injections provided a rapid and reliable “on” state for patients experiencing morning akinesia, possibly resulting from bypassing problems associated with gastrointestinal delivery and levodopa absorption.
Efficacy of Continuous Subcutaneous Apomorphine Infusion (CSAI)
CSAI, together with deep-brain stimulation (DBS) and intestinal gel infusions of levodopa/carbidopa (LCIG) is one of the therapeutic cornerstones for advanced PD [58, 59]. Unlike oral therapies, infusion therapies are based on constant drug delivery, aiming for continuous dopaminergic stimulation. Continuous striatal dopamine receptor stimulation not only reduces response oscillations but also has the potential to prevent or reduce drug-induced dyskinesias.
Unlike intermittent apomorphine injections, until recently there has been a striking lack of randomized placebo-controlled studies assessing the efficacy of CSAI. Several uncontrolled open-label studies consistently reported the efficacy of CSAI as monotherapy or in addition to levodopa [47, 60–63], with an average “off” time reduction of 59.3% and a reduction of dyskinesia severity of 32.4% [64]. In line with these results, a prospective study confirmed a marked reduction in the frequency and severity of dyskinesias in patients with PD treated with CSAI [65]. Table 3 summarizes the results of the different studies.
Table 3.
Summary of open-label studies assessing the efficacy of subcutaneous apomorphine infusion in patients with Parkinson’s disease
| Study | Pts (N) | Study duration, months | Infusion duration, h/day | Apomorphine total DD, mg | Daily time in “off” decrease, % | Daily levodopa decrease, % |
|---|---|---|---|---|---|---|
| Frankel et al. [46] | 25 | 22 | NR | 89 | 45 | 22 |
| Hughes et al. [104] | 22 | 36 | 16.9 (at 12 months) | 80.8 | 40 | 14 (at 12 months) |
| Pietz et al. [47] | 25 | 44 | 24 | 112.5 | 50 | 50 |
| Stocchi et al. [112] | 30 | 60 | 12 | 51.6 | NR | 47 |
| Manson et al. [67] | 64 | 34 | 12–24 | 98 | 49 | 63.5 |
| Tyne et al. [113] | 80 | 25 | 13.5 | 69.8 | NR | 24 (after 2 months) |
| García Ruiz et al. [62] | 82 | 20 | 14 | 72 | 79.5 | 80 |
| Drapier et al. [114] | 23 | 12 | 15.1 | 62.6 | 36 | 26 |
| Kimber et al. [115] | 36 | 21.5 | NR | NR | NR | 22.7 (LEDD decrease) |
| Rambour et al. [116] | 81 | 28 | NR | NR | NR | 37.8 |
| Martinez-Martin et al. [70] | 43 | 6 | 15.9 | 105.9 | NR | 30 |
| Drapier et al. [117] | 142 | 6 | 12.7 | 58.5 | NR | 24 |
| Borgemeester et al. [63] | 125 | 32.3 | 16.6 | 66 | NR | 32 |
| Sesar et al. [118] | 230 | 26.3 | 16.3 | 78 | 77.7 | 20.4 |
DD daily dose, NR not reported, LEDD levodopa equivalent daily dose, pts patients