Continuous subcutaneous apomorphine infusion in Parkinson's disease patients with cognitive dysfunction: A retrospective long-term follow-up study

IntroductionContinuous apomorphine infusion (CAI) is an advanced therapy in fluctuating Parkinson's disease (PD). The use of CAI is controversial in PD patients with cognitive dysfunction including visual hallucinations (VHs), and orthostatic hypotension (OH). This study was set-up to analyze the effectiveness and safety of CAI in elderly PD patients with cognitive dysfunction.MethodsThis new-user cohort study identified fluctuating PD patients who started CAI treatment at the rehabilitation unit of Parkinson Expertise Center (RU-PEC) Groningen, from November 2004 until 2016. Efficacy and safety data included motor function, cognitive status, OH and VHs, and was analyzed retrospectively. Pre-existent non-motor symptoms were treated optimally before starting CAI.ResultsForty-five fluctuating PD patients (age: 70.9 ± 8.1 yrs, disease duration: 10.8 ± 4.8 yrs) were identified, with pre-existing cognitive dysfunction, VHs (71%), and OH (26%). During the stay at RU-PEC (median 52 days) apomorphine was successfully titrated without worsening of pre-existing VHs and OH. The mean daily apomorphine dose was 66 ± 28 mg, accompanied by a reduction of levodopa-equivalent daily dose (LEDD) with 17%. The duration of ON-time and OFF-time significantly improved with +2.36 h (25%) and −1.66 h (−45%), respectively, while dyskinesia duration did not change. During long-term follow-up (median of 26 months) VHs and OH worsened in 9 and 4 patients, which necessitated discontinuation in 4 cases.ConclusionThis study demonstrates that CAI is also an effective treatment in advanced PD patients with concomitant cognitive dysfunction including VHs and OH, provided that these comorbidities are treated adequately as well.     

A novel sublingual apomorphine treatment for patients with fluctuating Parkinson's disease.

We tested a novel preparation of a sublingual apomorphine hydrochloride tablet (APO) in 10 patients with advanced Parkinson's disease complicated by motor fluctuations. After a dose titration, patients took either 40 mg APO three times per day alternating with levodopa doses (eight patients) or six doses of 20 mg APO taken concurrently with levodopa doses (two patients) for 3 months. Assessments included timed tapping and ambulation tests, Unified Parkinson's Disease Rating Scale (UPDRS), and patient diaries. Tapping speed while taking only APO (12 hours after stopping levodopa) was faster than while taking only levodopa (p <0.05). The daily levodopa dose decreased by 32.1% (p <0.01), yet the total "on" time increased from 73.5% +/- 10.2% to 81.5% +/- 7.5% of the day (p <0.01) after starting APO. "On" UPDRS part II scores (p <0.05) and "on" UPDRS part III (motor examination) scores (p <0.05) also improved. Adverse events such as nausea, orthostatic hypotension, and disagreeable taste did not limit the dose of APO in any case. The short-term benefit and tolerability demonstrated in this study warrant further study of this new APO preparation.     

Cardiovascular effects of lisuride continuous intravenous infusion in fluctuating Parkinson's disease

The cardiovascular effects of a continuous intravenous infusion of lisuride plus oral domperidone were studied in 16 fluctuating parkinsonian patients as compared to their usual oral therapy with levodopa plus carbidopa. The study was performed using a 24-h ambulatory recording and an automatic noninvasive device for blood pressure monitoring. During lisuride infusion, a significant increase of systolic blood pressure was observed; however, in three patients, a decrease of systolic-diastolic blood pressure occurred; furthermore, a mild increase of atrial arrhythmias and, in two patients, a short run of atrial fibrillation were noted. Asymptomatic orthostatic hypotension, observed in seven patients during levodopa therapy, disappeared during lisuride infusion. Paradoxical hypertensive effects and disappearance of orthostatic hypotension observed in our patients seem related to the concurrent administration of domperidone.     

Subcutaneous apomorphine and non-motor symptoms in Parkinson's disease

Non-motor symptoms (NMS) are now recognized to occur across all stages of Parkinson's disease (PD) and as a result there has been an increasing focus on their diagnosis, quantification and effective management. While in some subjects, NMS may be present before diagnosis, in advanced PD, NMS can contribute to hospitalization, severe disability and a shortened life expectancy. Strategies for continuous drug delivery have been reported to have a beneficial effect on NMS in PD and while the efficacy of apomorphine on motor function in PD has been confirmed in a number of studies, in addition to its possible anti-dyskinetic effect, a number of reports have also outlined the possible beneficial effect of apomorphine on NMS. This review sets out to examine the efficacy of apomorphine in non-motor aspects of PD, including its effect on neuropsychiatric and gastrointestinal symptoms, sleep (including restless legs syndrome), urinary dysfunction, pain and impulse control disorders. The analysis takes into consideration case reports, and open-label and comparative case–control studies published to date. Results of this review suggest that although data on the effect of apomorphine on NMS in PD patients are limited there is a strong suggestion of a beneficial effect that warrants further investigation in double-blind studies.     

Efficacy and tolerability of a novel sublingual apomorphine preparation in patients with fluctuating Parkinson's disease

We tested a novel preparation of sublingual apomorphine hydrochloride (APO) in 10 patients with advanced Parkinson's disease complicated by motor fluctuations and dyskinesias. After dose titration, patients underwent a blinded comparison of APO versus placebo, and an unblinded comparison of APO versus optimally dosed carbidopa/levodopa using timed tapping and walking paradigms. APO was significantly better than placebo in both measures: Tapping speed was 30.8% faster than with placebo (p < .0005), and ambulation speed was 45.2% faster than with placebo (p < .05). Ambulation speed with APO was also 15.9% faster than that with optimal doses of carbidopa/levodopa (p < .05). The latency to onset of clinical improvement with each APO dose was 10 to 40 minutes, and the duration of effect was 60 to 130 minutes. Adverse events included nausea, orthostatic hypotension, and disagreeable taste in the patient's mouth. Aside from the bitter taste, all other side effects resolved with continued use and did not limit dosing in any case. We feel that the good short-term efficacy and tolerability demonstrated in this study warrant further study of this new preparation, as there are several potential advantages of sublingual administration compared with traditional APO preparations.     

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.     

Differences in the motor response to apomorphine between untreated and fluctuating patients with Parkinson's disease.

Behavioral hyposensitivity to repeated apomorphine administration has been observed in fluctuating parkinsonian patients. To investigate whether a similar phenomenon occurs in patients never treated with levodopa, we studied the response to apomorphine in 20 de novo patients with Parkinson's disease. Six patients showed no or minimal improvement after apomorphine injections (maximal dose 3.5 mg). Fourteen patients responded and were then given up to four repeated subcutaneous injections of apomorphine [minimal effective dose (MED)]. The responses of de novo patients were compared with responses in 10 patients with motor fluctuations previously studied by the same protocol. There was no significant difference in latency and duration of motor responses after repeated apomorphine injections in de novo patients. MED was similar in de novo and fluctuating patients, but duration of improvement induced by each apomorphine bolus was longer in the de novo group. These results indicate that response duration to apomorphine is longer in previously untreated patients and that behavioral tolerance associated with pulsatile dopaminergic stimulation by apomorphine occurs mainly in patients with more advanced disease under chronic levodopa therapy.     

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.

     

Comparative cognitive effects of bilateral subthalamic stimulation and subcutaneous continuous infusion of apomorphine in Parkinson's disease.

Bilateral subthalamic deep brain stimulation (STN-DBS) and continuous subcutaneous infusion of apomorphine (APM-csi) can provide a comparable improvement on motor function in patients with advanced Parkinson's disease (PD), but the mechanisms by which both therapies exert their effects are different. We analyzed the cognitive effects of APM-csi. We also compared neuropsychological effects induced by STN-DBS and APM-csi in advanced PD to ascertain the neuropsychological aspects relevant in determining the therapeutic procedure that is the most appropriate in a particular patient. We studied 9 patients treated with STN-DBS and 7 patients with APM-csi. Neuropsychological measures included Rey's Auditory-Verbal Learning, Stroop, Trail Making, phonetic verbal fluency, and Judgment of Line Orientation tests. In the APM-csi group, significant changes were not observed in the neuropsychological tests performance. By contrast, in the STN-DBS group, moderate worsening was found in phonetic verbal fluency and Stroop Naming scores that was partially reversible at long-term follow-up and did not have consequences on regular activities. Consequently, these findings could be interpreted as being not relevant in deciding the most suitable treatment in a given patient.     

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.     

Intravenous boluses and continuous infusions of L-dopa methyl ester in fluctuating patients with Parkinson's disease.

In six patients with Parkinson's disease exhibiting severe "on-off" phenomena, a 200-mg intravenous bolus of either L-DOPA or of its methyl ester were equally effective in reversing motor deficits, although the duration of action of the methyl ester was shorter. There were no marked differences in pharmacokinetic parameters for L-DOPA plasma levels after administration of L-DOPA and the methyl ester. In three patients, optimal infusion rates for the maintenance of mobility were established for L-DOPA and L-DOPA methyl ester. Both drugs were able to maintain patients "on" throughout a 12-h infusion period. However, on average the optimal infusion rate of L-DOPA methyl ester was 2.7 times greater than that for L-DOPA. There was no marked difference in the plasma levels of L-DOPA achieved, but 3-O-methyl DOPA levels increased more after infusion of L-DOPA methyl ester than after infusion of L-DOPA itself. The half-life of elimination and volume of distribution of L-DOPA formed from the methyl ester were markedly increased compared with values obtained after either an intravenous bolus of methyl ester or after an intravenous infusion of L-DOPA itself. An intravenous bolus of L-DOPA methyl ester produces an equivalent magnitude of clinical response to the same dose of L-DOPA. However, higher optimal infusion rates of methyl ester than L-DOPA are required to produce continuous effect. The pharmacokinetic handling of L-DOPA methyl ester given by intravenous infusion may differ from that of L-DOPA when given by the same route.     

Dopaminergic responsiveness to apomorphine after chronic treatment with subcutaneous lisuride infusion in Parkinson's disease

The aim of this study was to assess whether or not continuous infusion of lisuride in combination with intermittent levodopa-carbidopa administration was associated with tolerance. Intravenous apomorphine was given to four patients before initiation of chronic treatment with subcutaneous lisuride infusion and oral levodopa. The study was repeated under identical conditions after a mean of 18 months of treatment. In no case was the motor response induced by apomorphine infusion reduced as compared to baseline assessment. Choreic dyskinesias accompanying the "on" state were enhanced in all patients. These findings suggest that chronic continuous infusion of a dopamine agonist like lisuride, associated with oral levodopa, is not accompanied by tolerance or down-regulation of striatal dopaminergic receptors.     

Continuous subcutaneous infusion of apomorphine for the treatment of Parkinson's disease

Apomorphine administered by subcutaneous infusion has been used efficiently in parkinsonian patients to treat severe motor fluctuations and levodopa-induced dyskinesias. Despite increasing evidence of its efficacy and its relative safety, apomorphine infusion therapy is still underused. This article reviews pharmacokinetic properties, efficacy, tolerability and indications of apomorphine infusion in Parkinson's disease.