Terminal Care in Parkinson’s Disease: Real-Life Use of Continuous Subcutaneous Apomorphine Infusion to Improve Patient Comfort

INTRODUCTION

Palliative care (PC) is a growing field of interest in neurology, particularly in late-stage Parkinson’s disease (LSPD) [1–3]. Beyond motor symptoms, LSPD patients exhibit a variety of nonmotor symptoms (fatigue, pain, and neuropsychiatric disorders) that greatly affect their quality of life and that of their relatives, especially at the end of their life [1, 4]. Progressive or sudden swallowing difficulties are common in the terminal stage, leading to a compromised oral route and subsequent dopaminergic deprivation [5, 6]. Complications such as withdrawal syndromes and aspiration pneumonia may arise, further exacerbating clinical decline, and precipitating death in some cases [5–8]. Compensating for an inaccessible oral route therefore seems critical at this stage [4, 8]. Alternative routes of administration, such as rotigotine patch, have been explored, but not without significant side effects requiring ethical considerations [4, 5, 9–11]. One case report pointed to the benefit of apomorphine as a subcutaneous injection in the context of comfort care [10]. Here, we describe the initiation of continuous subcutaneous apomorphine infusion (CSAI) for symptoms relief and terminal care.

METHODS

In this retrospective case series, clinical data from 14 deceased PD patients who benefited from CSAI as terminal care were collected. Ethics committee approval was granted by Comité Est II.

In this cohort, the classic palliative medications used in France, namely scopolamine, opiates, and benzodiazepines, were unsuccessful in relieving signs of PD-related discomfort. This, associated with persistent swallowing disorders, prompted the initiation of CSAI as comfort care, either as an outpatient (home, nursing home) or inpatient setting. Demographic data, PD characteristics, trajectory of decline, predictors of end-of-life, clinical condition after CSAI initiation, side effects, and medications use were analyzed. Patient comfort was assessed based on medical files, evaluations by neurologists, PC physicians, PD nurses, and caregivers’ reports when available.

RESULTS

Patients characteristics are described in Tables 1–4, according to their trajectory of decline (acute: Tables 1 and 2; slow: Tables 3 and 4) and place of death (home: Tables 1 and 3; hospital: Tables 2 and 4). On average, patients were 79 years old (62–94) with a mean PD duration of 15,3 years (2–32). All were LSPD patients presenting end-of-life predictors [12] and swallowing disorders, as evidenced by erratic adherence (N = 5) or nil-by-mouth condition (N = 9). Two patients already benefited from a device-aided therapy, excluding apomorphine pump. Most patients (N = 9) were apomorphine naïve.

Following days or weeks-long erratic adherence, progressive tapering, or sudden discontinuation of antiparkinsonian medications, all patients exhibited severe resurgence of PD symptoms. In some cases, symptoms were suggestive of the onset of malignant syndrome due to levodopa withdrawal (rigidity, reduced alertness, dysautonomia, dysphagia, autonomic impairment) [8]. In all cases, dopaminergic deprivation led to functional limitations (including impaired communication, pain and/or severe rigidity) with marked decline that prompted neuropalliative assessments.

Outpatient [13] or inpatient CSAI initiation was provided under the supervision of a neurologist and/or a PC physician (see Tables 1–4). A PD nurse (either from the hospital or home care services) was systematically involved to ensure PD evaluation, optimal use of infusion material, provide skin care, and monitor CSAI-related side effects.

In all cases, neuropalliative assessment leading to the initiation of low dose CSAI (0.5 up to 3 mg/h/24-h) rapidly and dramatically alleviated PD symptoms, improving patient comfort and facilitating nursing care. Five patients were able to communicate again with their relatives until death. No patient suffered from any behavioral manifestations (visual hallucinations, psychosis, or terminal agitation).

All patient died peacefully without the need for palliative sedation, and half of the patients received terminal care at home.

DISCUSSION

This retrospective cohort illustrates the potential usefulness of a low-dose, 24-h CSAI for symptom management in the context of PD terminal care. Patient identification, non-oral PD therapy choice and CSAI practical management in the broader context of PC remain crucial issues.

The baseline profile of our patients was representative of LSPD [1], with i) diffuse PD phenotype, ii)≥1 prognostic predictors relevant to end-of-life PC [12], iii) acute (infection, surgery) or chronic (cancer, altered general condition) factors precipitating terminal decline, and iv) compromised oral route.

In line with a previous report [10] and owing to its pharmacological properties [14, 15], apomorphine was indicated for symptoms relief (both during day and night [16]) and administered as a 24-h infusion to optimize patient’s comfort while avoiding repeated injections, deemed unsuitable in this context. Less invasive than the intravenous route, the subcutaneous route is widely used in PC, especially in the terminal phase, with good safety [17]. In our case, only one injection site per day was required, allowing its use in outpatient settings with good end-of-life quality of care.

Interestingly, low doses of CSAI (≤3 mg per hour on 24 h) were sufficient to improve patient comfort. The context of terminal care may partly account for these low dopaminergic requirements, as most of the patients were bedridden, had suffered weight loss in the previous weeks/months and may have suffered from organ failure, leading to pharmacodynamic and pharmacokinetic changes [18]. Importantly, CSAI was well tolerated, without triggering or worsening neuropsychiatric symptoms, regardless of the previous dopaminergic oral regimen, and even in the case of a previous intolerance at higher dose (patient 4). The short period of time between CSAI initiation and death in all patients (mean duration of 13.9 days), and the previous exposure to clozapine in some patients may have favored good tolerance of apomorphine. In the 7 patients with an acute trajectory of decline (Tables 1 and 2), the mean CSAI duration of 6.1 days (<1–10 days) was similar to the previously described neurological terminal phase duration (8.8 days) [19]. Thus, CSAI seems to improve patient comfort without prolonging survival. For the seven patients with a slow trajectory of decline and swallowing disorders as the main indication for CSAI (Tables 3 and 4), treatment lasted from a few days to a few weeks and prevented or compensated the occurrence of withdrawal syndromes [6, 8], suggesting a possible new indication [14] as part of an advance care planning perspective.

Classic PC medications (scopolamine, opiates, and/or benzodiazepines) were not required in all patients, probably due to a good symptomatic control. Midazolam was used for its anxiolytic properties and not for palliative sedation¹. Opioid analgesics were used at low dose, mostly to relieve pressure sore-related or cancer-related pain. Antipsychotics as antiemetics were not prescribed in this cohort. In line with recent data highlighting that both sublingual and subcutaneous apomorphine can be initiated without antiemetic pretreatment when using a slow titration scheme [20–22], only one patient experienced nausea, successfully relieved by domperidone. To be noted, palliative sedation was not needed, which may underline the potential interest of CSAI as part of the spectrum of good clinical practice in PD terminal care regarding patient comfort and quality of death. Practical advice on how to implement this therapy (including advised dosing regimen) are summarized in Box 1.