Terminal Care in Parkinson’s Disease: Real-Life Use of Continuous Subcutaneous Apomorphine Infusion to Improve Patient Comfort
Abstract
Background:
There are currently no recommendations on the therapeutic management of Parkinson’s disease (PD) patients at the end of life.
Objective:
To describe a cohort of patients with PD who benefited from continuous subcutaneous apomorphine infusion (CSAI) initiation at the end of their life as comfort care.
Methods:
This real-life cohort includes 14 PD patients, who benefited from 24-h, low-dose CSAI (0.5–3 mg/h) in the context of terminal care. Patient’s comfort (pain, rigidity, and/or ability to communicate) and occurrence of CSAI-related side-effects (nausea/vomiting, cutaneous and behavioral manifestations) were evaluated based on medical records.
Results:
All patients (age 62–94 years, disease duration 2–32 years) presented with late-stage PD and a compromised oral route. Treatment lasted from a few hours to 39 days. CSAI led to substantial functional improvement, with a good safety profile. Overall clinical comfort was deemed improved by the medical team, the patient, and/or caregivers.
Conclusions:
CSAI might be a promising approach in PD terminal care, as it reduces motor symptoms and overall discomfort, with an apparent good safety profile. Use of the apomorphine pen, sublingual film or a classic syringe pump might be considered when apomorphine pumps are not available. Larger observational cohorts and randomized controlled trials are needed to establish the efficacy and tolerability of apomorphine in the context of terminal care and more broadly, in an advance care planning perspective.
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.
Table 1
Case 1 | Case 2 | ||
Patients’ demographics | Age (y) | 75 | 81 |
Sex | M | F | |
Parkinson’s disease | Disease duration (y) | 8 | Unknown |
characteristics | Hoehn &Yahr stage | 5 | 5 |
and treatment | Levodopa Equivalent Daily Dose (mg) | 670 | 450 |
Current use of LCIG | No | No | |
Current use of DBS | No | No | |
Current use of CSAI | No | No | |
Apomorphine naïve | Yes | Yes | |
Clozapine (chronic use) | No | No | |
End-of-life characteristics | Trajectory of decline | Acute (following a benign skin resection surgery) | Acute |
End-of-life predictors (according to Akbar et al. [12]) | •Weight loss•decline in body condition•worsening of motor signs•cognitive decline | •Decline in body condition•hyperthermia suggestive of NLMS | |
Relevant comorbidities (cancer, organ failure) | N/A | N/A | |
Withdrawal from oral dopaminergic medications | Yes/documented/21 days | Yes/documented/4 days | |
Nil by mouth (at the time of evaluation) | Yes | Yes | |
CSAI as terminal care | Decision to initiate CSAI | Neurologist | Neurologist |
Place of CSAI initiation | Home (following patient’s request) | Nursing home | |
Clinical condition before CSAI initiation | •Patient bedridden and in pain•Marked axial and segmental rigidity•Patient no longer able to communicate or to take his medications | •Severe swallowing disorders•Dystonia •Pain•Amimia | |
Apomorphine dose (initial and final) | Titration up to 3 mg/h during the day1 mg/h at night: total 36 mg/day | 1 mg/h up to 2 mg/h over 24 h | |
Clinical condition after CSAI initiation | •Improvement in rigidity•patient able to communicate with his relatives | •Less painful mobilizations during comfort care •Dystonia reduction •General soothing effect | |
CSAI duration | 10 days | 7 days | |
CSAI side effects | None reported | Increased sleepiness | |
CSAI-induced clozapine initiation | Yes (Clozapine 25 mg: 0.5 tablet/day) | No | |
CSAI-induced domperidone initiation | No | No | |
Terminal management | Palliative sedation | No | No |
Scopolamine | No | No | |
Opiates | No | Transdermal fentanyl | |
Benzodiazepines | No | Midazolam IV | |
Others | N/A | N/A | |
Place of death | Home (following patient’s request) | Nursing home |
LCIG, Levodopa-carbidopa intestinal gel; DBS, deep brain stimulation; CSAI, continuous subcutaneous apomorphine infusion; PD, Parkinson’s disease; PC, palliative care; LTCF, long term care facility. *Palliative sedation or continuous deep sedation until death as defined by French Act n° 2016-87 of February 2, 2016, known as the Clayes Leonetti law.
Table 2
Case 3 | Case 4 | Case 5 | Case 6 | Case 7 | ||
Patients’ demographics | Age (y) | 77 | 77 | 81 | 80 | 62 |
Sex | F | F | F | F | F | |
Parkinson’s disease | Disease duration (y) | 32 | 12 | 8 | 9 | 2 |
characteristics | Hoehn &Yahr stage | 5 | 5 | 4 | 4 | 5 |
and treatment | Levodopa Equivalent Daily Dose (mg) | 700 | 1680 | 600 | 400 | 310 |
Current use of LCIG | No | Yes | No | No | No | |
Current use of DBS | Yes | No | No | No | No | |
Current use of CSAI | No | No | No | No | No | |
Apomorphine naïve | Yes | No (2016–2019, previous history of behavioral side effects: hallucinations, psychosis) | Yes | Yes | Yes | |
Clozapine (chronic use) | Yes (stopped 5 days before death) | Yes (stopped 48 h before death) | No | Yes, stopped 48 h before death. | No | |
End-of-life characteristics | Trajectory of decline | Acute (neurostimulator infection) | Acute (acute pancreatitis+stroke) | Acute (aspiration pneumonia) | Acute (sepsis, abdominal pain) | Acute (cancer) |
End-of-life predictors (according to Akbar et al. [12]) | •Onset of swallowing disorders•cognitive decline | •Worsening of axial motor signs•increased frequency of falls due to postural instability and dysautonomia•cognitive decline | •Dramatic loss of body weight•recurrent aspiration pneumonia | •Worsening of axial motor signs•increased frequency of falls due to postural instability and dysautonomia•cognitive decline | •Decline in body condition•weight loss•swallowing disorders•worsening of motor condition | |
Relevant comorbidities (cancer, organ failure) | N/A | N/A | Peritoneal carcinomatosis | Colorectal cancer with liver metastases | Small cell carcinoma with multi-metastatic spread | |
Withdrawal from oral dopaminergic medications | Yes/documented/7 days | Yes (gastrointestinal issues)/unknown duration | No, but erratic adherence | No, but erratic adherence | Yes/documented/a few days | |
Nil by mouth (at the time of evaluation) | No | Yes | Yes | No | Yes | |
CSAI as terminal care | Decision to initiate CSAI | Neurologist+PC specialist | Neurologist | Neurologist | Neurologist | Neurologist+PC specialist |
Place of CSAI initiation | PC unit | PC Unit | PC Unit | PC Unit | PC Unit | |
Clinical condition before CSAI initiation | •Patient bedridden•Marked axial and segmental rigidity•Patient unable to walk and communicate | •Segmental rigidity•Pain with even the smallest movement•Pressure sores and sore on right ear•Triple flexion | •Patient bedridden•In pain•Unable to communicate | •Onset of segmental rigidity•Painful movement | •Important akineto-rigid syndrome•Amimia•Diffuse pain (mobilizations)•Constipation | |
Apomorphine dose (initial and final) | Titration up to 2 mg/h over 24 h | 0.5 mg/h over 24 h | Titration up to 1 mg/h over 24 h | 1 mg/h over 24 h | 1 mg/h up to 2 mg/h over 24 h, 2 mg bolus as needed | |
Clinical condition after CSAI initiation | •Improvement in rigidity•Pain relief | •Decreased stiffness in upper limbs •Less whimpers during nursing care | •Pain relief•Decreased rigidity during nursing care | •Pain relief•Improvement in rigidity | •Disappearance of the akineto-rigid syndrome and pain•Decrease in amimia•Normalization of transit •Improvement of communication abilities | |
CSAI duration | 5 days | Less than 24 h | 9 days | 1 day | 10 days | |
CSAI side effects | None reported | None reported | None reported | None reported | None reported | |
CSAI-induced clozapine initiation | No (previous use) | No (previous use) | No | No (previous use) | No | |
CSAI-induced domperidone initiation | No | No | No | No | No | |
Terminal management | Palliative sedation | No | No | No | No | No |
Scopolamine | No | No | No | No | Yes (single administration of 20 mg) | |
Opiates | Morphine up to 24 mg/day 4 mg bolus on demand | Morphine 20 mg/day via IVincreased a few hours before death to 40 mg/day | Morphine up to 24 mg/day6 mg bolus on demand | Slow-release Oxycodone 60 mg/day and interdose of 10 mg if needed Switch to IV morphine 30 mg/day+3 mg boli, 24 h before death | Morphine IV: 12 mg/day then 19 mg/day then lowered to 14 mg/day the last 24 hBolus of 2 mg | |
Benzodiazepines | No | Diazepam 5 mg (before care) | No | Oxazepam 10 mg x 3/day at admissionswitch to IV Diazepam 5 mg twice a day, 24 h before death | Midazolam IV: 0.5 mg/h; lowered to 0.3 mg/hr secondarily, 0.5 mg bolus | |
Others | N/A | N/A | N/A | N/A | N/A | |
Place of death | PC unit | PC Unit | PC Unit | PC Unit | PC Unit |
LCIG, Levodopa-carbidopa intestinal gel; DBS, deep brain stimulation; CSAI, continuous subcutaneous apomorphine infusion; PD, Parkinson’s disease; PC, palliative care; LTCF, long term care facility. *Palliative sedation or continuous deep sedation until death as defined by French Act n° 2016-87 of February 2, 2016, known as the Clayes Leonetti law.
Table 3
Case 8 | Case 9 | Case 10 | Case 11 | Case 12 | ||
Patients’ demographics | Age (y) | 84 | 82 | 80 | 94 | 88 |
Sex | M | F | F | F | M | |
Parkinson’s disease | Disease duration (y) | 8 | Unknown | Unknown | 25 | 20 |
characteristics | Hoehn &Yahr stage | 5 | 5 | 5 | 5 | 5 |
and treatment | Levodopa Equivalent Daily Dose (mg) | 500 | 300 mg | 400 | Unknown | 230 |
Current use of LCIG | No | No | No | No | No | |
Current use of DBS | No | No | No | No | No | |
Current use of CSAI | No | No | No | No | No | |
Apomorphine naïve | Yes | No | No | No | Yes | |
Clozapine (chronic use) | No | No | No | No | No | |
End-of-life characteristics | Trajectory of decline | Late-stage PD (difficulty swallowing, cessation of oral treatments) | Late-stage PD | Late-stage PD | Late-stage PD | Late-stage PD |
End-of-life predictors (according to Akbar et al. [12]) | •Motor deterioration, became bedridden•dysautonomia | •Decline in body condition•swallowing disorders•falls | •Decline in body condition•swallowing disorders | •Decline in body condition•swallowing disorders | •Decline in body condition•swallowing disorders•worsening of motor condition | |
Relevant comorbidities (cancer, organ failure) | N/A | N/A | N/A | N/A | N/A | |
Withdrawal from oral dopaminergic medications | Yes/documented/3 days | Yes/documented/3 weeks | Erratic adherence | Erratic adherence | Erratic adherence | |
Nil by mouth (at the time of evaluation) | No | Yes | No | No | Yes | |
CSAI as terminal care | Decision to initiate CSAI | Neurologist+PC specialist | Neurologist+PC specialist | PC specialist | Neurologist | Neurologist+General practitioner |
Place of CSAI initiation | Geriatric Unit | Nursing home | Nursing home | Home | Home | |
Clinical condition before CSAI initiation | •Patient bedridden•Patient seized up with general stiffness•Unable to communicate or eat/be fed | •Severe swallowing disorders•Painful dystonia•Pain•Amimia | •Hypertonia•Pain•Swallowing disorders | •Swallowing disorders•Pain | •Severe cognitive decline•Altered motor status (increased retropulsion, stiffness, severe morning dystonia)•Patient unable to swallow nor communicate | |
Apomorphine dose (initial and final) | 0.5 mg/h over 24 h, then 1.5 mg/h over 24 h | 1 mg/h up to 2 mg/h over 24 h | 1 mg/h up to 2 mg/h over 24 h | 1 mg/h (7am to 7pm) up to 3 mg/h over 24h | 1 mg/h over 24 h | |
Clinical condition after CSAI initiation | •Pain relief•Patient able to speak •Improved swallowing •Less clear effectiveness regarding stiffness | •Reduction of dystonia•Improved communication•Improved participation in care, transfer to chair possible | •Reduction of hypertonia during nursing care•Pain relief (hetero-evaluation by the care team) | Pain and stiffness requiring increased pump flow rates | •Significant reduction in suffering signs •Improvement in lower limbs stiffness•Decrease in nocturnal agitation | |
CSAI duration | 21 days | 21 days | 25 days | 39 days | 19 days | |
CSAI side effects | None reported | Increased sleepiness | None reported | None reported | None reported | |
CSAI-induced clozapine initiation | No | No | No | No | No | |
CSAI-induced domperidone initiation | Yes | No | No | No | No | |
Terminal management | Palliative sedation | No | No | No | No | No |
Scopolamine | No | No | No | No | No | |
Opiates | No | Morphine (following the fall, 48 h prior to the death) | Morphine | Morphine 12 mg/day | No | |
Benzodiazepines | No | Midazolam IV (following the fall, 48 h prior to the death) | Midazolam | Midazolam 2 mg/h | No | |
Others | N/A | N/A | N/A | N/A | N/A | |
Place of death | Home (following patient’s request) | Nursing home | Nursing home | Home | Home |
LCIG, Levodopa-carbidopa intestinal gel; DBS, deep brain stimulation; CSAI, continuous subcutaneous apomorphine infusion; PD, Parkinson’s disease; PC, palliative care; LTCF, long term care facility. *Palliative sedation or continuous deep sedation until death as defined by French Act n° 2016-87 of February 2, 2016, known as the Clayes Leonetti law.
Table 4
Case 13 | Case 14 | ||
Patients’ demographics | Age (y) | 66 | 82 |
Sex | F | M | |
Parkinson’s disease | Disease duration (y) | 29 | Unknown |
characteristics | Hoehn &Yahr stage | 5 | 5 |
and treatment | Levodopa Equivalent Daily Dose (mg) | Unknown | 570 |
Current use of LCIG | No | No | |
Current use of DBS | Yes (18 years) | No | |
Current use of CSAI | No | No | |
Apomorphine naïve | Yes | No | |
Clozapine (chronic use) | No | No | |
End-of-life characteristics | Trajectory of decline | Late-stage PD | Late-stage PD (loss of the oral route, hyperalgesic arterial wounds of the lower limbs, infectious pneumonia) |
End-of-life predictors (according to Akbar et al. [12]) | Decline in body condition | •Swallowing disorders•falls | |
Relevant comorbidities (cancer, organ failure) | N/A | Ischemic stroke, chronic lymphocytic leukemia | |
Withdrawal from oral dopaminergic medications | Yes/Unknown duration | Yes/documented/7 days | |
Nil by mouth (at the time of evaluation) | Yes | Yes | |
CSAI as terminal care | Decision to initiate CSAI | Neurologist+PC specialist | Neurologist+PC specialist |
Place of CSAI initiation | PC unit | LTCF then PC Unit | |
Clinical condition before CSAI initiation | •Hypertonia•Pain•Swallowing disorders | •Patient bedridden and in pain•Marked axial and segmental rigidity•No longer able to communicate or to take his medications •Hyperthermia •Leukocytosis | |
Apomorphine dose (initial and final) | 1 mg/h up to 3 mg/h over 24h | 1 mg/h up to 3 mg/h during the day and 1.5 mg/h during the night | |
Clinical condition after CSAI initiation | •Reduction of hypertonia during nursing care•Relaxed facial expression •Pain relief (hetero-evaluation by the care team and husband) | •Decrease of the akineto-rigid syndrome and pain•Improvement of communication abilities | |
CSAI duration | 20 days | 7 days | |
CSAI side effects | Cutaneous (inflammatory infusion sites) | None reported | |
CSAI-induced clozapine initiation | No | No | |
CSAI-induced domperidone initiation | No | No | |
Terminal management | Palliative sedation | No | No |
Scopolamine | No | 40 mg/24 h IV | |
Opiates | Morphine 4.8 mg/day | Morphine up to 56 mg/day | |
Benzodiazepines | Midazolam IV 0.2 mg/h | Midazolam 0.3 mg/h during the day0.4 mg/h during the night | |
Others | N/A | Ketamine IV 48 mg/day | |
Place of death | PC unit | PC Unit |
LCIG, Levodopa-carbidopa intestinal gel; DBS, deep brain stimulation; CSAI, continuous subcutaneous apomorphine infusion; PD, Parkinson’s disease; PC, palliative care; LTCF, long term care facility. *Palliative sedation or continuous deep sedation until death as defined by French Act n° 2016-87 of February 2, 2016, known as the Clayes Leonetti law.
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.
Box 1: Five pragmatic tips on how to initiate apomorphine infusion to improve patient comfort in PD terminal care. |
•Based on a neuropalliative care approach, focused on end-of-life quality and multidisciplinary care (preferred apomorphine prescribers: movement disorders specialist, general neurologist; possible apomorphine prescribers with neurological support as needed: palliative care specialist, geriatrician, general practitioner . . .) |
•Outpatient or inpatient initiation, using apomorphine infusion pump or classic syringe pump and available subcutaneous apomorphine formulations (vial or solution for infusion in cartridge) |
•Prophylactic treatment with an antiemetic (domperidone) is not mandatory. Neuroleptics (e.g., metoclopramide, metopimazine) are not to be used |
•PD nurse supervision (mandatory at first and then as needed) to ensure PD evaluation, optimal use of infusion material, provide appropriate skin care, and monitor CSAI-related side effects |
•Advised dosing regimen: start at 0.5 mg/h/24-h and increase with daily increments of 0.5 mg/h until clinical relief (rigidity, pain) and patient comfort are obtained |
Limitations
As an uncontrolled, real-life, retrospective study, this work presents inherent limitations: a small sample size and clinical assessment based on medical files.
Conclusion
At the intersection of palliative medicine, geriatric medicine, and neurology, LSPD patients’ terminal care management requires a transdisciplinary approach [2–4]. CSAI may be of great interest in this context, regardless of the trajectory of decline, as it reduces motor symptoms and overall discomfort, with an apparently good safety profile. Level of palliative medication in our series was comparable or below those in other end-of-life PD cohorts [9, 11], which reinforces the idea that apomorphine does not cause excessive symptoms in this population. Use of the apomorphine pen, sublingual film or of a classic syringe pump could be considered when apomorphine infusion pumps are not available.
Considering that management was satisfactory in this cohort in both inpatient and outpatient care, CSAI use deserves to be considered in different settings, notably in an advance care planning perspective. Larger observational cohorts and randomized controlled trials are needed to establish its efficacy and safety in the context of neuropalliative care.
ACKNOWLEDGMENTS
The authors wish to thank the Adelia® care team (notably Régis Bouillot, Morgane Bérée & Séverine Autret), Régis Aubry, Héloïse Chassier, Adélaïde Müller, the Asten® care team (notably Mickaël Chapuis & Isabelle Martin) and all the clinicians who participated in taking care of the patients in different settings. The authors thank Jennifer Dobson for proofreading the manuscript. Finally, MA, MB, MG, and MV also wish to thank France Parkinson and Plateforme Nationale pour la Recherche sur la fin de vie for supporting their different projects related to palliative care in Parkinson’s disease (APO-PALLIA project & SPARK network). The preliminary results of this study have been presented as a poster at the 74th American Academy of Neurology annual meeting (AAN, Seattle, USA), at the 2022 International Congress of Parkinsons’s disease and movement disorders (MDS, Madrid, Spain), at the 2022 virtual congress of the International Neuropalliative Care Society (INPCS) and at the 2023 World Parkinson’s Congress (WPC, Barcelona, Spain).
FUNDING
The authors have no funding to report.
CONFLICT OF INTEREST
MB reports grants from France Parkinson, Plateforme Nationale pour la Recherche sur la Fin de Vie, reimbursement of travel expenses to scientific meetings from Asten, Boston Scientific, Elivie, Orkyn and Medtronic, honoraria from Abbvie, Aguettant, Allergan, Merz Pharma, Orkyn for lecturing outside the submitted work.
MG reports travel grants and speaker honoraria from Aguettant, and research grant from Plateforme Nationale pour la recherche sur la Fin de Vie.
GD reports one travel grant from Mundipharma.
LT reports honoraria from Allergan, Merz Pharma and Ipsen.
MV served on scientific advisory boards, received research support and received travel grant from Aguettant, Adelia Medical, Asdia, Britannia Pharmaceutical Ltd, Elivie, LVL, France Parkinson, Plateforme Nationale pour la Recherche sur la Fin de Vie, Orkyn.
MA reports travel grants, speakers & consultancy honoraria and/or research grants from France Parkinson, Plateforme Nationale pour la Recherche sur la Fin de Vie, Institut des Neurosciences Cliniques de Rennes, Aguettant, Britannia Pharmaceutical Ltd, Adelia Medical, Linde Homecare, Homeperf, Asdia, Orkyn, France Développement Electronique & Society for Dental Science. Dr Auffret is employed by France Développement Electronique (FDE) and works as a hosted researcher at the Pontchaillou University Hospital & University of Rennes.
All other authors have no conflict of interest to report.
DATA AVAILABILITY
The data supporting the findings of this study are available within the article.
REFERENCES
[1] | Coelho M , Ferreira JJ ((2012) ) Late-stage Parkinson disease, Nat Rev Neurol 8: , 435–442. |
[2] | Kluger BM , Shattuck J , Berk J , Sebring K , Jones W , Brunetti F , Fairmont I , Bowles DW , Sillau S , Bekelman DB ((2019) ) Defining palliative care needs in Parkinson’s disease. Mov Disord Clin Pract 6: , 125–131. |
[3] | Taylor LP , Besbris JM , Graf WD , Rubin MA , Cruz-Flores S , Epstein LG Humanities Committee, a joint committee of the American Academy of Neurology, American Neurological Association, and Child Neurology Society ((2022) ) Clinical Guidance in Neuropalliative Care: An AAN Position Statement. Neurology 98: , 409–416. |
[4] | Katz M , Goto Y , Kluger BM , Galifianakis NB , Miyasaki JM , Kutner JS , Jones CA , Pantilat SZ ((2018) ) Top ten tips palliative care clinicians should know about Parkinson’s disease and related disorders. J Palliat Med 21: , 1507–1517. |
[5] | Alty J , Robson J , Duggan-Carter P , Jamieson S ((2016) ) What to do when people with Parkinson’s disease cannot take their usual oral medications. Pract Neurol 16: , 122–128. |
[6] | Koschel J , Ray Chaudhuri K , Tönges L , Thiel M , Raeder V , Jost WH ((2022) ) Implications of dopaminergic medication withdrawal in Parkinson’s disease. J Neural Transm (Vienna) 129: , 1169–1178. |
[7] | Hobson P , Meara J ((2018) ) Mortality and quality of death certification in a cohort of patients with Parkinson’s disease and matched controls in North Wales, UK at 18 years: A community-based cohort study, BMJ Open 8: , e018969. |
[8] | Bonuccelli U , Piccini P , Corsini GU , Muratorio A ((1992) ) Apomorphine in malignant syndrome due to levodopa withdrawal. Ital J Neurol Sci 13: , 169–170. |
[9] | Ibrahim H , Woodward Z , Pooley J , Richfield EW ((2021) ) Rotigotine patch prescription in inpatients with Parkinson’s disease: Evaluating prescription accuracy, delirium and end-of-life use. Age Ageing 50: , 1397–1401. |
[10] | Dewhurst F , Lee M , Wood B ((2009) ) The pragmatic use of apomorphine at the end of life. Palliat Med 23: , 777–779. |
[11] | Wilson EA , King-Oakley E , Richfield EW (2023) Parkinson’s disease: Symptoms and medications at the end of life. BMJ Support Palliat Care, doi: 10.1136/spcare-2023-004389. |
[12] | Akbar U , McQueen RB , Bemski J , Carter J , Goy ER , Kutner J , Johnson MJ , Miyasaki JM , Kluger B ((2021) ) Prognostic predictors relevant to end-of-life palliative care in Parkinson’s disease and related disorders: A systematic review. J Neurol Neurosurg Psychiatry 92: , 629–636. |
[13] | Zagnoli F , Leblanc A , Viakhireva-Dovganyuk I , Delabrousse-Mayoux J-P , Pouyet A , Ziegler M , Sogni L , Patat M , Bouillot R , Vérin M APOKADO Group ((2023) ) Feasibility and benefits of home initiation of subcutaneous apomorphine infusion for patients with Parkinson’s disease: The APOKADO study. J Neural Transm (Vienna) 130: , 1463–1474. |
[14] | Auffret M , Drapier S , Vérin M ((2018) ) The many faces of apomorphine: Lessons from the past and challenges for the future. Drugs RD 18: , 91–107. |
[15] | Auffret M , Drapier S , Vérin M ((2018) ) Pharmacological insights into the use of apomorphine in Parkinson’s disease: Clinical relevance. Clin Drug Investig 38: , 287–312. |
[16] | Cock VCD , Dodet P , Leu-Semenescu S , Aerts C , Castelnovo G , Abril B , Drapier S , Olivet H , Corbillé A-G , Leclair-Visonneau L , Sallansonnet-Froment M , Lebouteux M , Anheim M , Ruppert E , Vitello N , Eusebio A , Lambert I , Marques A , Fantini ML , Devos D , Monaca C , Benard-Serre N , Lacombe S , Vidailhet M , Arnulf I , Doulazmi M , Roze E ((2022) ) Safety and efficacy of subcutaneous night-time only apomorphine infusion to treat insomnia in patients with Parkinson’s disease (APOMORPHEE): A multicentre, randomised, controlled, double-blind crossover study. Lancet Neurol 21: , 428–437. |
[17] | Wernli U , Dürr F , Jean-Petit-Matile S , Kobleder A , Meyer-Massetti C ((2022) ) Subcutaneous drugs and off-label use in hospice and palliative care: A scoping review, J Pain Symptom Manage 64: , e250–e259. |
[18] | Franken LG , de Winter BCM , van Esch HJ , van Zuylen L , Baar FPM , Tibboel D , Mathôt R a. A , van Gelder T , Koch BCP ((2016) ) Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol. Expert Opin Drug Metab Toxicol 12: , 669–680. |
[19] | Hussain J , Adams D , Allgar V , Campbell C ((2014) ) Triggers in advanced neurological conditions: Prediction and management of the terminal phase. BMJ Support Palliat Care 4: , 30–37. |
[20] | Happel C , Grall M , Formella A ((2023) ) Use of real-world data to evaluate the importance of antiemetic pretreatment for apomorphine hydrochloride [APO, Apokyn®] subcutaneous injection initiation and maintenance in people with Parkinson disease (P13-11.016), Neurology 100: (17 Suppl 2), 2443. |
[21] | Hauser RA , Ondo WG , Zhang Y , Bowling A , Navia B , Pappert E , Isaacson SH CTH-301 Study Investigators ((2023) ) Dose optimization of apomorphine sublingual film for OFF episodes in Parkinson’s disease: Is the prophylactic use of an antiemetic necessary? J Parkinsons Dis 13: , 403–414. |
[22] | Isaacson SH , Dewey RB , Pahwa R , Kremens DE ((2023) ) How to manage the initiation of apomorphine therapy without antiemetic pretreatment: A review of the literature. Clin Park Relat Disord 8: , 100174. |
Notes
1 Or continuous deep sedation until death as defined by French Act n° 2016-87 of February 2, 2016, known as the Clayes Leonetti law.