Intermittierende Apomorphin-Injektionen als Rescue-Therapie beim fortgeschrittenen M. Parkinson

Intermittent subcutaneous apomorphine therapy should be considered in patients with advanced Parkinson's disease who experience recurrent off periods despite optimised oral treatment (according to guidelines), for reliable and quick reversal of these otherwise refractory periods. Such treatment is also called rescue therapy. At present, apomorphine injections with the apomorphine pen are underutilised, considering its current indications and contraindications. In the present consensus statement, concepts for the use of apomorphine are presented and discussed based on existing study results, indications, and contraindications. Recommendations for a practical approach are also provided.     

Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome

OBJECTIVES: Nocturnal disabilities leading to fragmented sleep arising from parkinsonian off period related complications are common, under-reported and are difficult to treat. In this study, we evaluate the use of nocturnal continuous subcutaneous overnight apomorphine infusion in Parkinson's disease and restless legs syndrome. METHODS: Six parkinsonian patients and 2 patients with restless legs syndrome with nocturnal disabilities refractory to conventional oral therapy were assessed using a sleep diary while on standard treatment and during nocturnal apomorphine infusion. Three patients agreed to assessments during placebo infusion with normal saline. RESULTS: Apomorphine led to a dramatic reduction of nocturnal awakenings, nocturnal off periods, pain, dystonia and nocturia in parkinsonian patients. In patients with restless legs syndrome, apomorphine reduced nocturnal discomfort, reduced leg movements and improved pain and spasm scores significantly. Placebo infusion reproduced pain, nocturnal spasms and sleep disruption. CONCLUSION: This study suggests that overnight apomorphine infusion may be effective in overcoming refractory nocturnal disabilities in selected patients with Parkinson's disease and restless legs syndrome.     

Sublingual administration of apomorphine in the treatment of motor fluctuations in Parkinson disease]

Apomorphine, a mixed dopaminergic agonist was given sublingually to 12 patients with Parkinson's disease disabled by severe on-off fluctuations. The patient's mean age was 57 years and the duration of Parkinson's disease was 12 years. All patients were also given domperidone (60 mg/day). Apomorphine was administered as soon as the off periods appeared. On periods were observed in 11 patients, with a mean apomorphine dose of 40 mg for each administration (extremes values: 20-60 mg). One patient had no motor benefit after an apomorphine dose of 120 mg. The mean duration of daily off periods was reduced by 64 per cent in 11 patients, for a mean duration of 8 months (extremes values: 2-12 months). Four patients developed stomatitis or gingival edema and stopped treatment. This pilot study shows that sublingual apomorphine, during a mean period of 8 months, significantly decreases off periods in parkinsonian patients. Others studies are necessary to confirm these results.     

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.     

Intranasal apomorphine in parkinsonian on-off fluctuations.

The efficacy of intranasal apomorphine was assessed in seven patients with Parkinson's disease and severe levodopa (L-dopa)-related "off-period" disabilities. All patients responded favorably to treatment with intranasal apomorphine. The speed and the quality of motor response and the pharmacokinetic profile showed results similar to those seen after subcutaneous injection of apomorphine administered by insulin pen syringe. The simplicity in the technique of intranasal apomorphine administration was found to be superior by all patients.     

Subcutaneous administration of apomorphine in motor fluctuations in Parkinson's disease

Apomorphine, a dopaminergic agonist was given over a period of 12 months to 14 parkinsonian patients suffering from severe L-dopa induced on-off effects. Nine patients (mean age: 52 years; mean age at onset of the disease: 37 years), were treated by continuous infusion with a portable minipump, and 5 others by multiple injections with a penject. The mean duration of daily off periods was reduced by two thirds in all patients. The motor fluctuation intensity was only diminished in the 9 patients treated by continuous infusion. These patients received a mean apomorphine daily dose of 93 mg and L-dopa dosage was reduced by 53 p. 100. Red fibrous subcutaneous nodules occurred at the injection sites in all patients treated by infusion. This study confirms the effectiveness of subcutaneous apomorphine administration in the treatment of severe motor fluctuations.     

Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges.

Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.     

Sublingual apomorphine in Parkinson's disease: a clinical and pharmacokinetic study.

The clinical response and the pharmacokinetic parameters of 3 mg subcutaneous (SC) and 30 mg sublingual (SL) apomorphine were compared in nine patients with Parkinson's disease. The magnitude of the motor responses (evaluated by tapping and walking tests and the Webster scale) was similar for SC and SL apomorphine. However, the onset to action was delayed after SL when compared with SC apomorphine. No significant difference was found in bioavailability (area under the curve: AUC) or peak plasma concentration (Cmax) between SC and SL apomorphine, whereas time to peak plasma concentration (Tmax) was shorter after SC apomorphine. Eight other patients were treated for a mean time of 4 months with SL apomorphine with a significant reduction in daily "off" hours. However, four of these eight patients developed stomatitis after some weeks of treatment. These results indicated that (a) pharmacokinetics parallel the clinical response to SL apomorphine, (b) SL apomorphine can reduce severe off periods in parkinsonian patients when used chronically, and (c) its long-term use is limited by a severe side effect (stomatitis).     

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.     

Effects of central dopaminergic stimulation by apomorphine on speech in Parkinson's disease

OBJECTIVE: To determine the effect of central dopaminergic stimulation with apomorphine on speech in PD. BACKGROUND: Most patients with PD have a speech disorder. Of those, 89% have involvement of laryngeal function, and 45% have additional articulatory dysfunction. The effect of dopaminergic medications on these two dimensions of speech impairment in PD has not been selectively studied. METHODS: In a randomized, double-blind, placebo-controlled crossover design, patients with PD and speech impairment, Hoehn and Yahr stages 2 to 4 "off," and without severe dyskinesias were given placebo or apomorphine injections 0.05 mg/kg subcutaneously during two consecutive outpatient visits. They were pretreated with domperidone for 48 hours and were tested off their parkinsonian medications for 12 hours. Laryngeal function was assessed by maximum sustained vowel phonations and comfortable vowel phonations. Articulatory function was evaluated by speech intelligibility score, speaking rate, and efficiency ratio. RESULTS: Ten patients, mean age 73.4 years (SD = 6.6), disease duration 8.7 years (SD = 6.3), were tested. The baseline motor score on the Unified Parkinson's Disease Rating Scale (UPDRSm) and all experimental speech variables were equivalent on both placebo and apomorphine days. At a dose of apomorphine that provoked improvement in UPDRSm (p = 0.0078), no index of either laryngeal or articulatory function improved significantly after apomorphine administration. CONCLUSION: Laryngeal and articulatory speech components are not under prominent dopaminergic control in PD. Treatment regimens should focus on nondopaminergic pharmacology and other therapies.     

Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.     

Subcutaneous apomorphine in late stage Parkinson's disease: a long term follow up

OBJECTIVES—Despite the recent introduction of newperoral drugs as well as neurosurgical methods for Parkinson'sdisease, treatment of late stage parkinsonian patients remainsdifficult and many patients become severely handicapped because offluctuations in their motor status. Injections and infusions ofapomorphine has been suggested as an alternative in the treatment ofthese patients, but the number of studies describing the effects ofsuch a treatment over longer time periods is still limited. Theobjective was to investigate the therapeutic response and range of sideeffects during long term treatment with apomorphine in advancedParkinson's disease.
METHODS—Forty nine patients (30 men, 19 women; agerange 42-80 years) with Parkinson's disease were treated for 3 to 66 months with intermittent subcutaneous injections or continuousinfusions of apomorphine.
RESULTS—Most of the patients experienced a longterm symptomatic improvement. The time spent in "off" wassignificantly reduced from 50 to 29.5% with injections and from 50 to25% with infusions of apomorphine. The quality of the remaining"off" periods was improved with infusion treatment, but wasrelatively unaffected by apomorphine injections. The overall frequencyand intensity of dyskinesias did not change. The therapeutic effects ofapomorphine were stable over time. The most common side effect waslocal inflammation at the subcutaneous infusion site,whereas the most severe were psychiatric side effects occurring in 44%of the infusion and 12% of the injection treated patients.
CONCLUSION—Subcutaneous apomorphine is a highlyeffective treatment which can substantially improve the symptomatologyin patients with advanced stage Parkinson's disease over a prolongedperiod of time.

     

Continued efficacy and safety of subcutaneous apomorphine in patients with advanced Parkinson's disease

The study purpose was to assess the efficacy of intermittent subcutaneous apomorphine (APO) as acute therapy for off episodes in advanced Parkinson's disease (PD) patients who had previously received APO for 3 months. Patients (n=62) were randomized to receive double-blind treatment with APO at their typically effective dose (TED; APO), APO at their TED+0.2mL (2.0mg; APO+2), placebo at volume equal to their TED (PL), or placebo at volume equal to their TED+0.2mL (PL+2), for a single off episode. Significantly greater improvement in mean Unified PD rating scale motor scores was seen with pooled APO versus pooled placebo 20min after administration (-24.2 vs. -7.4; p<0.0001); the difference was also significant at 10min (p<0.0001). Overall adverse event incidence did not significantly differ between pooled APO and pooled PL. This study supports the long-term use of intermittent APO as effective acute therapy for off episodes in advanced PD patients.     

Apomorphine in treatment of Parkinson''s disease: comparison between subcutaneous and sublingual routes.

The efficacy of two routes of apomorphine, subcutaneous (SC) and sublingual (SL), successively administered in 7 Parkinsonian patients with motor fluctuations, was compared in reducing the daily duration of "off" phases. The mean duration of SC and SL treatment was 7.7 and 6.8 months respectively. The mean time spent in "off" phase was 55% after SC and 68% after SL treatment. The mean time before turning "on" after an "off" period was 14 minutes after SC and 28 minutes after SL treatment. Two patients developed stomatitis after SL route. SL apomorphine may be helpful in the treatment of motor fluctuations in PD.     

Subcutaneous apomorphine in patients with advanced Parkinson's disease: a dose-escalation study with randomized, double-blind, placebo-controlled crossover evaluation of a single dose

OBJECTIVE: To further explore the efficacy and safety of subcutaneous apomorphine (APO) in treating off episodes in APO-na?ve patients with advanced Parkinson's disease (PD). METHODS: 56 patients receiving optimized oral anti-PD medication were evaluated on separate days for response to single increasing doses of APO. Acute response to oral anti-PD medication and APO dose escalation (2-10 mg) was evaluated under unblinded conditions. At the 4 mg APO dose, placebo was randomly introduced under double-blind crossover conditions. RESULTS: Mean changes from pre-dose in Unified Parkinson's Disease Rating Scale motor scores indicated significant improvement following APO 4 mg versus placebo at 20 min (p=0.0002), 40 min (p<0.0001; maximum improvement) and 90 min (p=0.0229). Improvements showed significant dose-response at 20 min, 40 min (both p<0.0001) and 90 min (p=0.0049). Adverse events were more common with APO than placebo, and also showed significant dose-response (p<0.0001). Common adverse events associated with APO included yawning, dizziness, nausea, somnolence and dyskinesias, and were generally mild to moderate. There were no significant differences between APO and placebo in the incidence of hypotension associated with a postural change from a sitting to standing position. CONCLUSIONS: Subcutaneous APO provided rapid, effective relief of off episodes associated with advanced PD.     

Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson's disease: long-term follow-up study of 64 patients.

Continuous subcutaneous infusion of apomorphine is now increasingly recognized as an effective treatment for refractory off periods and peak-dose dyskinesias in Parkinson's disease. We have reviewed our experience with apomorphine infusions, after a strategy decision in 1995 based on emerging preclinical data, to treat all patients with steady-state plasma levels of apomorphine throughout the waking day, minimizing additional pulsatile stimulation either by oral dopaminergic medication or bolus parenteral injections of apomorphine. Sixty-four patients have been treated with apomorphine pumps and 45 of these successfully converted to monotherapy, managing to discontinue all other forms of dopaminergic stimulation during the daytime treatment period with apomorphine. Patients were followed up for a mean of 33.8 months (range, 4-108 months) and clinical data analyzed retrospectively. The mean maintenance dose of apomorphine was 98 mg per 24 hours (monotherapy group: 103 mg/24 hours; polytherapy group: 93 mg/24 hours), which did not significantly increase at final follow-up. There was a mean maximum dyskinesia reduction of 64% (S.D. = 20) in the monotherapy group, compared to 30% (S.D. = 33) in those continuing on polytherapy (P < 0.001), despite a maintained increase in on time (monotherapy group: 55%, P < 0.005; polytherapy group: 50%, P = 0.05). Fifteen patients failed to successfully convert to monotherapy but benefited nonetheless, and only 3 failed apomorphine infusional therapy altogether. Reasons for failure were mixed, including difficulty with compliance and adverse effects such as daytime somnolence, skin complications, and painful dystonias. There was a significantly higher success rate in patients able to manage the treatment either independently or with the help of their caregiver. These results confirm that subcutaneous apomorphine monotherapy can reset peak-dose dyskinesia threshold in levodopa-treated patients and further reduce off-period disability after all available forms of oral medication, including long-acting dopamine agonists, have been tried.     

Deep brain stimulation of the subthalamic nucleus: effectiveness in advanced Parkinson's disease patients previously reliant on apomorphine

OBJECTIVES: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication. METHODS: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. RESULTS: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. CONCLUSIONS: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.     

Levodopa consumption reduces dopaminergic receptor responsiveness in Parkinson's disease

In seven patients with Parkinson's disease with daily motor fluctuations, we found that the same subcutaneous apomorphine dose that improved motor function when given in the morning after a normal night without taking levodopa failed to turn patients "on" during afternoon and evening "off" periods, and on a different morning after receiving levodopa during the night. No significant changes in levodopa or 3-O-methyldopa plasma levels that could explain these variations were detected. These findings suggest that increased daily levodopa consumption may reduce striatal responsiveness to dopaminergic stimulation.     

Comparison of motor response to apomorphine and levodopa in Parkinson''s disease.

The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.     

Motor response following repeated apomorphine administration is reduced in Parkinson's disease

Ten patients with Parkinson's disease (PD) with motor fluctuations under levodopa treatment were given repeated equal subcutaneous injections of apomorphine [minimal effective dose (MED)] in 1 day. The MED was defined as the dose of apomorphine necessary to induce at least 60% reduction of motor disability for a minimum period of 10 min. MED was found for each patient in previous study days. In eight a subcutaneous infusion of apomorphine was performed on a different day. Four patients with simple fluctuations ("wearing off") showed a progressive reduction of the motor response to apomorphine injections, but three of the four had a stable response (continuous "on") to apomorphine infusion. Six patients with complicated fluctuations also exhibited a decreasing response to successive apomorphine injections and often completely failed to respond to some of the boluses. The response to a subcutaneous infusion of apomorphine was unstable in three of four cases. These findings indicate that a reduction of striatal dopaminergic receptor sensitivity is associated with repeated "pulsatile" apomorphine administration in parkinsonian patients with oscillations of motor performance. It is suggested that altered regulation of dopaminergic receptor sensitivity following pulsatile stimulation with levodopa may be a relevant phenomenon in the pathogenesis of motor fluctuations in PD.