Evaluating the Efficacy of Nocturnal Continuous Subcutaneous Apomorphine Infusion in Sleep Disorders in Advanced Parkinson’s Disease: The APO-NIGHT Study

INTRODUCTION

Sleep disorders are extremely common in the advanced Parkinson’s Disease (PD), affecting 60 to 98% of patients [1]. These problems are closely related to the severity of the disease. Multiple factors give rise to sleep disorders, such as bad motor control during the night (rigidity, hypokinesia, off dystonia), non-motor symptoms (pain, psychosis), dementia or even antiparkinsonian medication. Apart from substantia nigra pars compacta, neurodegeneration in PD involved multiple brainstem nuclei and other neurotransmitters. Brainstem cholinergic (laterodorsal tegmental and pedunculopontine nuclei) and monaminergic centers (locus coeruleus, periaqueductal grey matter and raphe nucleus) integrate the two branches of the ascending reticular activating system and allow arousal and alertness from the depolarization of thalamocortical networks and hypothalamus [2]. Specifically, monoaminergic centers (including noradrenergic, serotoninergic, histaminergic and dopaminergic neurons) have an excitatory output during the wakefulness and decreasing their firing rates during the sleep [3]. Hypothalamus specific neurons (associated with orexin and melatonin) exert control over different stages of sleep. Neuronal loss in these areas causes changes in sleep structure and is largely responsible for particular disorders such as REM-sleep behaviour disorder (RBD), restless legs syndrome (RLS) and excessive daytime sleepiness (EDS) [4].

The relevance of sleep disorders not only lies in the discomfort it provokes. REM-sleep behaviour disorder, with prevalence between 15 to 40%, also works as a preclinical marker of PD, such as other non-motor symptoms (hyposmia and depression). It may predate by several years the onset of the cardinalsymptoms [5].

Apomorphine is a potent dopamine agonist (DA) mainly active on D2, D3 and D4 receptors, less active on D1 receptors. It has also moderate affinity to alpha-adrenergic receptors (1D, 2B and 2C) and serotoninergic receptors (5HT_1A, 5HT_2A, 5HT_2B and 5HT_2C) [6]. Extensive first-pass metabolism results in a nephrotoxic large oral intake, making subcutaneous administration necessary [7]. The beneficial effect of continuous apomorphine infusion on motor symptoms of advanced PD has been well established throughout the literature. Recently some studies have shown efficacy in controlling non-motor symptoms [8, 9]. To our knowledge, there is an important lack of evidence to assess its role in PD related sleeping problems.

MATERIALS AND METHODS

Between January 2014 and December 2015 we included 18 advanced PD patients well controlled with continuous subcutaneous apomorphine therapy (13 to 16 hour during day time for at least 6 months). All the patients met the UK Brain Bank Criteria [10] and suffered from severe insomnia related with nocturnal hypokinesia. We focused on symptoms such as impaired bed mobility, awakenings and difficult to get out of bed, early morning dystonia or pain. Nocturnal apomorphine infusion was started applying a local protocol designed to apomorphine therapy (Fig. 1). Patient with nocturnal infusion have two pumps with different infusion rate, one for daytime and one for nighttime. Dose was adjusted over the following weeks by clinician expertise criteria. Infusion is stopped for a period of 30 minutes between day-night and night-day infusion therapies. This way the patient is on apomorphine infusion for already 23 hours a day. We registered demographic and disease evolution data. All patients had baseline assessment of on-state (Unified Parkinson’s Disease Rating Scale -UPDRS-, Hoeh and Yahr stage -HY-). Sleep quality and health-related quality of life were evaluated at baseline (Scales for Outcomes in Parkinson’s Disease -SCOPA-SLEEP- [11], Parkinson’s Disease Sleep Scale -PDSS- [12], Parkinson’s Disease questionnaire -PDQ8-) and six weeks after initiation of therapy. The patient and caregivers completed questionnaires. Roughly, SCOPA-SLEEP gives information about sleep quality and excessive daytime sleepiness, while PDSS makes great emphasis in accompanying symptoms that worsen night rest and sleep (pain, muscle cramps or numbness). Higher score and lower score mean poor sleep quality in SCOPA-SLEEP and PDSS, respectively. In SCOPA-SLEEP scale, one item does not count for the final score. This item is an additional question that evaluates overall sleep quality on a 7-point scale (ranging to very well to very bad). All patients signed an informed consent before inclusion. Our Hospital Ethics Committee approved the study. Authors BA, AS and AC made initial evaluation of sleep disturbances; author GFP completed blinded six weeks follow-up evaluation. For analysis, baseline data was compared to the six weeks follow-up data.

RESULTS

17 advanced PD patients accomplished 6-weeks follow-up (mean age 68.9±10.1 years, disease duration 11.6±5.2 years, median HY score 4). Baseline demographic and disease evolution data are shown in Table 1. All information related with NCSAI therapy is described on Table 2. One patient did not finish the 6-week follow-up due to discomfort related with NCSAI (data are not included in statisticalanalysis).

Sleep scales for PD applied revealed several sleep disturbances in all patients. At baseline,mean SCOPA-SLEEP was 16.12±4.82 and mean PDSS was 75.65±14.79. Six weeks later, both scalesshowed quite remarkable improvement in sleep quality, mean SCOPA-SLEEP was 7.12±3.26 (Z=–2.384, p<0.0001) and mean PDSS was 108.24±13.52 (Z=4.398, p<0.0001). Daytime somnolence was measured by SCOPA-SLEEP DaytimeSleepiness (SCOPA DS). Baseline score (6.35±3.98) improved after NCSAI therapy (3.41±2.62), reaching a significant statistical difference (Z=–2.447, p=0.006) (see bloxpots in Fig. 2). Significantly, all 17 PD patients in APO-NIGHT study improved their baseline overall SCOPA-SLEEP item after NCSAI therapy (Table 3).

In our study, the improvement in the quality of sleep is not parallel to improvement in quality of health as measured by the PDQ-8 scale (Z=–0.745, p=0.2333) (Fig. 2). Follow-up period (6 weeks) is too short to evaluate properly any change in advanced PD quality of life. Nonetheless, there is a positive statistical trend, it does not reach statistical significance probably due the small sample size.

The present study reaches a size effect >2 in all scales employed, except for PDQ-8 scale (size effect 0.23), which is equivalent to high evidence between before and after NCSAI treatment.

DISCUSSION

Dopamine plays an important role in PD sleep disturbances, from insomnia related to off state during the night to specific sleep disorders such as RBD or RLS. Several mechanisms have been proposed to explain nocturnal hypokinesia in PD, but nocturnal dopamine undermedication appears to be the main factor involved in poor sleep quality.

Linking antiparkinsonian therapies and PD sleep disorders is complex. Continuous dopaminergic stimulation by long-acting drugs (DA or sustained-release L-Dopa) has resulted in improved nocturnal motor symptoms, maybe due to avoidance of plasmatic peaks and the physiological need of less dopamine during sleep [13]. There is also a beneficial effect on RBD and RLS [14]. On the other hand, DA may give rise to excessive daytime somnolence (EDS) and sleep attacks. This appears to be related to high dosage (lower doses have a positive impact on sleep), titration and affinity to D3 receptor [15]. EDS is also associated with severe and more rapid progression of PD, cognitive decline and any dopaminergic agent, including L-Dopa [16]. In addition, DA may precipitate symptoms such as psychosis and impulse control disorders, which worsen insomniaas well.

Chronic subcutaneous apomorphine infusion during daytime (12 to 16 hours) has demonstrated improvement in sleep quality [8]. A retrospective clinical trial recently published assesses this beneficial effect on nighttime sleeping problems [9]. In this trial, 12 patients with more severe insomnia received additional nocturnal apomorphine infusion but the authors do not indicate therapy and clinical response data. Furthermore, only one study emphasizes the beneficial effect on sleep of NCSAI, in 6 PD patients, measured mainly by nocturnal freezing and difficulty in turning in bed, nocturnal awakenings or nocturia [17]. García-Ruiz reported its beneficial effect on sleep/wake cycle [18]. In spite of this, expertise reviews recommended properly sleep studies to assess the beneficial relationship between apomorphine therapy and sleep disturbances on PD [19].

The aim of our study is to evaluate the effect of the NCSAI in sleeping problems and insomnia associated with advanced PD. The patients in our study reported several disturbances in their sleep and nocturnal rest caused by nocturnal hypokinesia, despite subcutaneous apomorphine infusion during daytime. Sleep scales applied confirmed the poor quality of sleep in all patients, and were used to measure the change after NCSAI therapy. We observed an important improvement in both scales after six weeks on NCSAI therapy. Interestingly, 16 PD patients continue with NCSAI after the end of this study. One patient stopped apomorphine therapy after deep brain stimulation (DBS). DBS was judged the best choice for him. Apomorphine therapy was administered temporally in order to decrease his troublesome PD symptoms.

We believe alleviation of motor symptoms during the night is the major determinant to improve sleep quality in advanced PD. Continuous dopaminergic stimulation during nighttime does not require doses as high as during the daytime [13]. NCSAI infusion rate in our study is lower than daytime infusion rate. Notwithstanding, other mechanisms may be involved. Specific impact in this fact of apomorphine or other antiparkinsonian drugs remains unclear, and further investigations are required.

All patients included in this study were treated with continuous apomorphine infusion during the day at least for six months, which was effective to control PD symptoms. Adverse effects are supposed to be more likely when the patient is on infusion therapy the whole day and night. Nevertheless, this was not the case. Major adverse events related with apomorphine therapy (visual hallucinations, orthostatic hypotension, impulse control disorder or cognitive decline) were not recorded (Table 1). Only one patient suffered worsening of previous subcutaneous nodules. Treated conservatively the outcome was good. The reason for this lack of side effects may stem in the low initial nocturnal dose, which is roughly half the effective daytime dose. This suggests that a lower infusion rate is well tolerated in patients with previous good tolerance to apomorphine. Anyway carefully neuropsychological evaluation is advisable.

Despite the association between DA and excessive daytime sleepiness, our study has shown improvement in daytime somnolence measured by the SCOPA DS scale. This fact is obviously related with the great improvement in sleep quality, but we must not exclude the differences in pharmacokinetics between apomorphine and other DA. In this way, Martínez-Martín et al. observed a reduction in daytime sleepiness with apomorphine infusion therapy [8]. The mechanisms how different dopaminergic therapies aggravate somnolence are not well understood and controversial.

Our study has some important limitations. The first is the relatively small number of patients included. In general, treatment with continuous apomorphine infusion is given to a small proportion of all PD patients. Sleep quality scales employed are highly subjective, sometimes difficult to fill in by the patient or caregiver, but largely validated over the years. Actually, so far there is not better method for evaluating the quality of sleep in patients with PD. Actigraphy is not adequate to measure axial rotation, mainly in nocturnal hypokinesia, while rotational sensors and triaxial accelerometters are still limited to research work [13]. Polysomnographic recording is expensive and only applied in selected cases.

Our study emphasizes the role of apomorphine therapy in insomnia related to motor symptoms during the night. Neither RLS nor RBD were considered inclusion criteria. The follow-up period of our study is short, but enough to assess the effect of NCSAI. Following this, 16 of 17 patients enrolled remain on NCSAI, 6 of them for over 24 months. This is particularly relevant as greatly enhances the safety and tolerability of the treatment.

We concluded nocturnal continuous subcutaneous apomorphine infusion (NCSAI) is a well-tolerated and effective treatment to alleviate insomnia and disturbing motor sleep symptoms in advance PD. This therapy might be indicated exclusively at night in selected patients.

AUTHOR’S ROLES

Fernández-Pajarín, G: conception and design of the study, acquisition of data and analysis and interpretation of data

Sesar, A: conception and design of the study, acquisition of data, revising the article and critically for important intellectual content.

Ares, B: conception and design of the study and acquisition of data.

Castro, A: conception and design of the study, acquisition of data and final approval of the version to be submitted.

FINANCIAL DISCLOSURES

The authors have no conflicts of interest or competing financial interests to report.