Worsened motor test performance following acute apomorphine injection in previously untreated patients with Parkinson's disease

Instrumental tests and clinical rating assess motor disability in Parkinson's disease (PD) patients. Previous long-term dopaminergic substitution influences the behaviour following acute dopaminergic stimulation. Objective of this study was to investigate the motor response following an apomorphine application in previously untreated-, treated- and before treated PD patients, who received placebo. Outcomes of instrumental tests worsened in previously untreated-, but not in before treated PD patients after apomorphine injection and in the PD subjects under the placebo condition. Generally, rating scores of motor symptoms significantly improved after apomorphine administration, whereas placebo application showed no effects. Tolerance to sedative effects of apomorphine in treated PD patients or sensitivity of employed motor tests to presynaptic dopaminergic autoreceptor mediated inhibition of endogenous dopamine release or postsynaptic dopaminergic overstimulation with resulting decreased cognitive function in previously untreated PD patients hypothetically caused this discrepancy between outcomes of subjective clinical rating and objective motor test performance.     

Short- and long-term dopaminergic effects on dysarthria in early Parkinson’s disease

While the beneficial effect of levodopa on motor impairment in Parkinson’s disease (PD) has been well documented, its effect on speech has rarely been examined and the respective literature is inconclusive. The aim of our study was to analyze the effect of short-term levodopa admission and long-term dopaminergic treatment on speech in PD patients in early stages of the disease. Motor examination according to UPDRS III and speech testing were performed in 23 PD patients (9 males; median age 68, 42–78 years) in the early morning after having abstained from dopaminergic medication overnight (“off” state, t0) after administration of 200 mg of soluble levodopa (t1), and at follow-up after 12–14 weeks under stable dopaminergic medication (t2). Speech examination comprised the perceptual rating of global speech performance and an acoustical analysis based upon a standardized reading task. While UPDRS III showed a significant amelioration after l-dopa application, none of the parameters of phonation, intonation, articulation and speech velocity improved significantly in the “on” state, neither under short-term levodopa administration (t1) nor on stable dopaminergic treatment (t2). However, there was a positive effect of dopaminergic stimulation on vowel articulation in individual patients. Results indicated significant beneficial effect of short-term levodopa administration or long-term dopaminergic medication on different dimensions of speech in PD patients. As some improvement of vowel articulation was seen in individual patients, the pre-existing pattern of speech impairment might be responsible for the different response to pharmacological treatment.     

Speech treatment for Parkinson's disease

Researchers estimate that 89% of people with Parkinson's disease (PD) have a speech or voice disorder including disorders of laryngeal, respiratory, and articulatory function. Despite the high incidence of speech and voice impairment, studies suggest that only 3-4% of people with PD receive speech treatment. The authors review the literature on the characteristics and features of speech and voice disorders in people with PD, the types of treatment techniques available, including medical, surgical, and behavioral therapies, and provide recommendations for the current efficacy of treatment interventions and directions of future research.     

Speech treatment for Parkinson's disease

Researchers estimate that 89% of people with Parkinson's disease (PD) have speech and voice disorders including disorders of laryngeal, respiratory and articulatory function. Despite the high incidence of speech and voice impairment, studies suggest that only 3-4% of people with PD receive speech treatment. Here, we review the literature on the characteristics and features of speech and voice disorders in people with PD and the types of treatment techniques available (medical, surgical and behavioral), with a focus on behavioral therapies. We provide a summary of the current status of the field of speech treatment in PD and recommendations for implementation of the current efficacy of treatment interventions. Directions for future research, including a speculative viewpoint on how the field will evolve in 5 years time, are discussed.     

Cognitive and motor function in patients with Parkinson's disease with and without depression

The objective of this study was to define risk factors for depression in patients with idiopathic Parkinson's disease (PD) and to evaluate the correlation of depression with cognitive function and the primary domains of parkinsonian motor dysfunction tremor, bradykinesia, rigidity, gait and balance impairment. The risk factors for depression in patients with PD remain controversial. Several investigators have demonstrated a significant association between cognitive dysfunction and depression, but motoric and disease variables can confound this evaluation and have shown an inconsistent relation to depression. A consecutive series of 88 patients with PD were examined using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRSm), Hoehn-Yahr stage (HY), and Hamilton Rating Scale for Depression (HRSD). Major depression was diagnosed according to the criteria in the Diagnostic and Statistic Manual of Mental Disorders, 4th edition. Gender, age, handedness, PD duration, side of PD onset, motor fluctuations, UPDRSm total score, daily Levodopa dose, and Mini-Mental State Examination score (MMSE) were analyzed using multivariate and univariate logistic regression, Fisher's Exact test, and Pearson correlations. Major depression was diagnosed in 12 patients (7.3%). Low MMSE score, axial bradykinesia, gait and balance impairment were strongly significant predictors of depression. In conclusion, depression and physical function are important factors impairing the quality of life for patients with PD, and regular depression screening and treatment should focus on patients with PD who have cognitive impairment, high axial bradykinesia, gait and balance impairment.     

Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study

OBJECTIVE: To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment. METHODS: This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS). RESULTS: Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score. CONCLUSIONS: Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment.     

Placebo response in Parkinson's disease: Comparisons among 11 trials covering medical and surgical interventions

Placebo‐associated improvements have been previously documented in small series of Parkinson's disease (PD) patients. Using a strict definition of placebo‐associated improvement, we examined rates and timing of placebo responses to identify patient‐ and study‐based characteristics, predicting positive placebo response in several PD clinical trials. We collected individual patient data from the placebo groups of 11 medical and surgical treatment trials involving PD patients with differing PD severities and placebo‐assignment likelihoods. We defined a positive placebo response as ≥50% improvement in total Unified Parkinson's Disease Rating Scale motor (UPDRSm) score or a decrease by ≥2 points on at least two UPDRSm items compared to baseline. We calculated positive placebo response rates at early (3–7 weeks), mid (8–18 weeks), and late (23–35 weeks) stages of follow‐up. Odds ratios for patient‐ and study‐based characteristics were obtained from a model fitted using generalized estimating equations. There were 858 patients on placebo who met inclusion criteria for analysis. Three studies involved patients without need of symptomatic treatment, two involved patients without motor fluctuations needing symptomatic treatment, and six (three medical and three surgical) involved patients with motor fluctuations. The overall placebo response rate was 16% (range: 0–55%). Patients with higher baseline UPDRSm scores and studies that focused on PD with motor fluctuations, surgical interventions, or those with a higher probability of placebo assignment showed increased odds of positive placebo response. Placebo responses were temporally distributed similarly during early, mid, and late phases of follow‐up. Placebo‐related improvements occur in most PD clinical trials and are similarly distributed across all 6 months of follow‐up. Recognition of factors that impact placebo response rates should be incorporated into individual study designs for PD clinical trials. © 2008 Movement Disorder Society     

Levodopa response in early Parkinson's disease

To further characterize the short‐term levodopa response in early PD, we performed a retrospective analysis of the ELLDOPA study which randomized 361 early PD subjects to placebo, levodopa 150, 300, or 600 mg/day. We evaluated change in UPDRS motor scores (UPDRSm) from baseline to weeks 9 and 24, and identified changes in UPDRSm that best discriminated treatment with levodopa from placebo. Linear regressions were used to determine associations between baseline characteristics and changes in UPDRSm. Mean percent improvement in UPDRSm in levodopa‐treated subjects was greater than that for placebo‐treated subjects (27.4% vs. 5.8% at 9 weeks, P < 0.001 and 26.2% vs. 4.0% at 24 weeks, P < 0.001). UPDRSm change at 9 weeks ranged from –92.9% (improvement) to 85.7% (worsening) for levodopa and –86.7% to 160% for placebo, and at 24 weeks ranged from –100.0% to 242.9% for levodopa and –87.5% to 112.5% for placebo. UPDRSm improvements of 22.0% at 9 weeks and 23.8% at 24 weeks best discriminated treatment with levodopa 300 mg/day (a common initial maintenance dosage in clinical practice) from placebo. Significant associations were not observed between baseline subject characteristics and magnitude of response from baseline to week 24. We conclude that although levodopa treatment significantly improved PD signs when compared with placebo, there was a wide range and considerable overlap in clinical responses to levodopa and placebo. A substantial proportion of subjects with early PD did not experience a robust response to levodopa. An improvement in UPDRSm of ～22% best discriminated levodopa treatment from placebo. © 2009 Movement Disorder Society     

Postural stability of Parkinson''s disease patients is improved by decreasing rigidity

Postural instability has a big impact on the quality of life of patients with Parkinson's disease (PD) as it often leads to an insecure stance and fall. We investigated if postural stability in these patients improves by decreasing rigidity with a dopaminergic agonist. In our study, we tested eight PD patients with no concomitant diseases. Their age was 61 +/- 2 years (mean +/- SE) and their Hoehn-Yahr score was 3 +/- 0.1. The patients were evaluated according to the Unified Parkinson's Disease Rating Scale for motor function (mUPDRS) and with stabilometric measurements of forward-backward and side-to-side body oscillations during free stance with eyes open. Both evaluations were performed in an "off "state and in an apomorphine-induced "on" state. As expected, the mUPDRS score was significantly decreased in the "on" state with posture being improved in six patients, gait in eight patients and postural stability in seven of eight patients. In addition, apomorphine caused a significant reduction of the relative amplitude of lower frequencies and an increase of the relative amplitude of higher frequencies of forward-backward body oscillations. The results of stabilometry and mUPDRS evaluations are in agreement with the effect of apomorphine on rigidity, indicating that postural stability of PD patients is improved by decreasing rigidity.     

Modafinil for daytime somnolence in Parkinson's disease: double blind, placebo controlled parallel trial

BACKGROUND: Excessive daytime somnolence (EDS) commonly complicates Parkinson's disease (PD). The aetiology of EDS is probably multifactorial but is probably exacerbated by dopaminergic medications. Modafinil is a wake-promoting agent approved for use in narcolepsy, but it is often used to treat a variety of somnolent conditions. METHOD: A double blind, placebo controlled parallel design trial was conducted to assess the efficacy of modafinil (200-400 mg/day) for the treatment of EDS in PD. The primary efficacy measure was the Epworth Sleepiness (ES) scale score. Secondary efficacy points included the Unified Parkinson's Disease Rating Scale (UPDRS), the Fatigue Severity Scale, the Hamilton Depression Scale, and the multiple sleep latency test (MSLT). RESULTS: Of a total of 40 subjects (29 men, mean (SD) age 64.8 (11.3) years), randomised to modafinil or placebo, 37 completed the study. Modafinil failed to significantly improve ES scores compared with placebo (2.7 v 1.5 points improvement, respectively, p = 0.28). MSLT failed to improve with modafinil relative to placebo (-0.16 v -0.70, respectively, p = 0.14). UPDRS, global impressions, Fatigue Severity Scale, and Hamilton Depression Scale scores were unchanged. Adverse events were minimal. CONCLUSION: Modafinil failed to significantly improve EDS in PD compared with placebo. The drug did not alter motor symptoms in PD and was well tolerated.     

Apomorfina w zaawansowanej chorobie Parkinsona

Apomorphine is the most potent dopamine receptor agonist and its symptomatic effectiveness is comparable to levodopa. Subcutaneous apomorphine is rapidly and completely absorbed. Plasma peak concentrations are achieved after 5–15 minutes and onset of clinical effect is within 20 minutes. Apomorphine intermittent subcutaneous injections are effective as rescue therapy for unpredictable off periods in advanced Parkinson disease (PD). More often apomorphine is administered as a subcutaneous infusion which secures the continuous dopaminergic stimulation. The benefit on ‘off’ periods is consistent across all studies, but dyskinesia improvement is not so obvious. Two infusion therapies (apomorphine and intraduodenal levodopa) and deep brain stimulation (DBS) are effective in advanced PD patients with untreatable motor complications. Apomorphine infusions should be considered in patients unable to undergo DBS because of cognitive impairment and neurosurgical contraindications.     

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

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.     

Speech production in Parkinson's disease: II. Acoustic and electropalatographic investigation of sentence,word and segment durations

Previous investigations employing electropalatography (EPG) have identified articulatory timing deficits in individuals with acquired dysarthria. However, this technology is yet to be applied to the articulatory timing disturbance present in Parkinson's disease (PD). As a result, the current investigation aimed to use EPG to comprehensively examine the temporal aspects of articulation in a group of nine individuals with PD at sentence, word and segment level. This investigation followed on from a prior study (McAuliffe, Ward and Murdoch) and similarly, aimed to compare the results of the participants with PD to a group of aged (n = 7) and young controls (n = 8) to determine if ageing contributed to any articulatory timing deficits observed. Participants were required to read aloud the phrase “I saw a ___ today” with the EPG palate in‐situ. Target words included the consonants /l/, /s/ and /t/ in initial position in both the /i/ and /a/ vowel environments. Perceptual investigation of speech rate was conducted in addition to objective measurement of sentence, word and segment duration. Segment durations included the total segment length and duration of the approach, closure/constriction and release phases of EPG consonant production. Results of the present study revealed impaired speech rate, perceptually, in the group with PD. However, this was not confirmed objectively. Electropalatographic investigation of segment durations indicated that, in general, the group with PD demonstrated segment durations consistent with the control groups. Only one significant difference was noted, with the group with PD exhibiting significantly increased duration of the release phase for /la/ when compared to both the control groups. It is, therefore, possible that EPG failed to detect lingual movement impairment as it does not measure the complete tongue movement towards and away from the hard palate. Furthermore, the contribution of individual variation to the present findings should not be overlooked.     

Speech production in Parkinson's disease: II. Acoustic and electropalatographic investigation of sentence, word and segment durations

Previous investigations employing electropalatography (EPG) have identified articulatory timing deficits in individuals with acquired dysarthria. However, this technology is yet to be applied to the articulatory timing disturbance present in Parkinson's disease (PD). As a result, the current investigation aimed to use EPG to comprehensively examine the temporal aspects of articulation in a group of nine individuals with PD at sentence, word and segment level. This investigation followed on from a prior study (McAuliffe, Ward and Murdoch) and similarly, aimed to compare the results of the participants with PD to a group of aged (n = 7) and young controls (n = 8) to determine if ageing contributed to any articulatory timing deficits observed. Participants were required to read aloud the phrase "I saw a _ today" with the EPG palate in-situ. Target words included the consonants /l/, /s/ and /t/ in initial position in both the /i/ and /a/ vowel environments. Perceptual investigation of speech rate was conducted in addition to objective measurement of sentence, word and segment duration. Segment durations included the total segment length and duration of the approach, closure/constriction and release phases of EPG consonant production. Results of the present study revealed impaired speech rate, perceptually, in the group with PD. However, this was not confirmed objectively. Electropalatographic investigation of segment durations indicated that, in general, the group with PD demonstrated segment durations consistent with the control groups. Only one significant difference was noted, with the group with PD exhibiting significantly increased duration of the release phase for /la/ when compared to both the control groups. It is, therefore, possible that EPG failed to detect lingual movement impairment as it does not measure the complete tongue movement towards and away from the hard palate. Furthermore, the contribution of individual variation to the present findings should not be overlooked.     

Evaluation of speech impairment in early stages of Parkinson’s disease: a prospective study with the role of pharmacotherapy

Despite the initial reports showing beneficial effects of dopaminergic treatment on speech in Parkinson’s disease (PD), more recent studies based upon valid measurements have not approved any improvement of speech performance under pharmacotherapy. The aim of this study was to analyze the effect of treatment initiation on the progression of speech impairment in PD, using novel evaluation criteria. Nineteen de novo patients with PD were tested and retested within 2 years after the introduction of antiparkinsonian therapy. As controls, 19 age-matched individuals were recorded. Speech examination included sustained phonation, fast syllable repetition, reading text, and monolog. Quantitative acoustic analyses of the key aspects of speech based on Gaussian kernel distribution, statistical decision-making theory, and healthy speech observation were used to assess the improvement or deterioration of speech. A trend for speech performances to improve was demonstrated after treatment mainly in quality of voice, intensity variability, pitch variability, and articulation. The treatment-related improvement differed in various aspects of speech for individual PD patients. Improvements in vowel articulation and pitch variability correlated with treatment-related changes in bradykinesia and rigidity, whereas voice quality and loudness variability improved independently. Using a novel approach of acoustic analysis and advanced statistics, improvements in speech performance can be demonstrated in PD patients after the introduction of antiparkinsonian therapy. Moreover, changes in speech articulation and pitch variability appear to be related with dopaminergic responsiveness of bradykinesia and rigidity. Therefore, speech may be a valuable marker of disease progression and treatment efficacy in PD.     

Apomorphine effects on the hippocampus

Apomorphine is a non-specific dopamine receptor agonist that has been used in the treatment of some diseases and mental disorders. Its use has particularly well documented in Parkinson's disease(PD). The dopaminergic agonists like apomorphine are related to oxidative processes that could induce cell damage and the functional impairment of some structures in the brain. However, most information about apomorphine in literature is focused on the improvement of the motor problems characteristic of PD, but little is known about the effects on cognitive behaviors and brain structures indirectly related to motor function. The presence of dopaminergic receptors in the hippocampus has recently been discovered, in connection with cognitive behaviors like learning and memory, these receptors are needed in neuronal plasticity. There has been a growing interest to know if this structure could be compromised by the effect of apomorphine and elucidate if part of the cognitive impairment present in the PD is due to the effect of apomorphine. In this mini-review, we summarized how apomorphine has been used since its creation, we discuss the latest information about its effect on the hippocampus and also the future perspectives to fully understand the effects of this compound.     

Quantitative assessment of motor speech abnormalities in idiopathic rapid eye movement sleep behaviour disorder

ObjectivePatients with idiopathic rapid eye movement sleep behaviour disorder (RBD) are at substantial risk for developing Parkinson's disease (PD) or related neurodegenerative disorders. Speech is an important indicator of motor function and movement coordination, and therefore may be an extremely sensitive early marker of changes due to prodromal neurodegeneration.MethodsSpeech data were acquired from 16 RBD subjects and 16 age- and sex-matched healthy control subjects. Objective acoustic assessment of 15 speech dimensions representing various phonatory, articulatory, and prosodic deviations was performed. Statistical models were applied to characterise speech disorders in RBD and to estimate sensitivity and specificity in differentiating between RBD and control subjects.ResultsSome form of speech impairment was revealed in 88% of RBD subjects. Articulatory deficits were the most prominent findings in RBD. In comparison to controls, the RBD group showed significant alterations in irregular alternating motion rates (p = 0.009) and articulatory decay (p = 0.01). The combination of four distinctive speech dimensions, including aperiodicity, irregular alternating motion rates, articulatory decay, and dysfluency, led to 96% sensitivity and 79% specificity in discriminating between RBD and control subjects. Speech impairment was significantly more pronounced in RBD subjects with the motor score of the Unified Parkinson's Disease Rating Scale greater than 4 points when compared to other RBD individuals.ConclusionSimple quantitative speech motor measures may be suitable for the reliable detection of prodromal neurodegeneration in subjects with RBD, and therefore may provide important outcomes for future therapy trials.     

The effect of unilateral electrostimulation of the subthalamic nucleus on respiratory/phonatory subsystems of speech production in Parkinson's disease—a preliminary report

This paper reports findings on the respiratory/phonatory subsystems from an on‐going study investigating the effect of unilateral electrostimulation of the subthalamic nucleus (STN) on different speech subsystems in people with Parkinson's disease (PD). Speech recordings were made in the medication‐off state at baseline, three months post surgery with stimulation‐on, and with stimulation‐off, in six right‐handed PD patients. Subjects completed several speech tasks. Acoustic analyses of the maximally sustained vowel phonation were reported. The results were compared to the scores of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS‐III) obtained under the same conditions. Results showed that stimulation‐on improved UPDRS‐III scores in all six subjects. While mild improvement was observed for all subjects in the Stimulation‐on condition, three subjects received left‐STN stimulation showed a significant decline in vocal intensity and vowel duration from their baseline indicating the speech function was very susceptible to micro lesions due to the surgical procedure itself when the surgical site was in the dominant hemisphere.     

Restless legs syndrome in Parkinson's disease

INTRODUCTION: Recent clinical and functional imaging data suggest impaired central dopaminergic transmission in restless legs syndrome (RLS). As RLS responds to dopaminergic medications, an etiologic link between RLS and Parkinson's disease (PD) has been proposed. However, few studies have examined this association. OBJECTIVE: To investigate the prevalence of RLS amongst PD outpatient population. METHOD: The prevalence of RLS was determined by the diagnostic criteria of the International Restless Legs Syndrome Study Group (IRLSSG). Consecutive PD patients (n=125) were prospectively evaluated in our clinic. RESULTS: There were 77 (61.6%) males and 48 (38.4%) females with a mean age of 65.1+/-9.3 (SD) years (range 34-83), and mean age of onset of disease at 59.6 years+/-10.7 (SD) years (range 30-81). Nineteen (15.2%) patients had motor restlessness. Of these, one (0.8%) patient had RLS-like symptoms closely correlated to wearing "off" effect of levodopa. None of the patients satisfied the IRLSSG diagnostic criteria of RLS. This was not significantly different compared to the 0.6% and 0.1% RLS prevalence in our general population and clinic population. CONCLUSIONS: Our study demonstrates that motor restlessness was present in 15.2% of our PD patients. However, prevalence of RLS in our PD patients was not significantly different from our general population or clinic population, suggesting that these two diseases may not share the same pathophysiologic mechanism.     

Apomorphine for the acute treatment of "off" episodes in Parkinson's disease

Many patients with advanced Parkinson's disease (PD) experience motor complications, which negatively impact quality of life, despite optimized oral therapy. It is important for patients to have a treatment option that may provide rapid relief from "off" episodes. In three pivotal, randomized, placebo-controlled trials, subcutaneous apomorphine was effective in acutely treating "off" episodes, significantly improving Unified Parkinson Disease Rating Scale motor scores and reducing the number of "off" hours per day, with a significantly shorter time to patient-declared onset of relief than placebo. Thus, clinical trial data support the efficacy of intermittent subcutaneous apomorphine as a rapid acute treatment for "off" episodes in advanced PD.