Use and misuse of domperidone in patients living with Parkinson disease in France

Abstract

Context

After observing increased sudden death risk associated with domperidone use, the European Medicines Agency (EMA) imposed usage restrictions in 2014, limiting age (≤60 years), daily dose (≤30 mg/day), and duration (≤7 days). Nausea commonly occurs as an adverse effect of dopaminergic drugs in Parkinson's disease (PD) patients, with few alternative anti‐emetic options. This study aimed to assess domperidone prescription patterns in French PD patients.

Methods

In this multicenter study, all consecutive PD patients from participating expert centers, hospitals, and private neurologists were included. We documented demographics, clinical data, comorbidities, domperidone use (indication, dose, and duration), and concurrent medications (related to PD or not). Domperidone misuse was assessed based on EMA guidelines.

Results

Between January and October 2021, 1579 patients from 16 centers (12 French PD expert centers, two general hospitals, and two private practice neurologists) were included. Among them, 109 (7%) received domperidone: 32 (29%) for nausea during apomorphine infusion, 71 (65%) for nausea during other dopaminergic therapies, and three (3%) for orthostatic hypotension. Domperidone misuse was found in 103 patients (95%): treatment duration >7 days (84%), age >60 years (79%), contraindicated drug interactions (6%), and contraindications due to cardiac comorbidity (5%). Only one patient exceeded the recommended dose (30 mg/day).

Conclusion

Domperidone is still prescribed in France for PD patients with dopaminergic‐induced nausea, mostly disregarding EMA guidelines due to patient age (>60 years) and prolonged treatment (>7 days). Our study underscores the unmet need for managing gastrointestinal symptoms in PD, highlighting the inadequacy of EMA guidelines in this population.

List of abbreviations

DUMP

Domperidone use and misuse in Parkinson disease in France

PD

Parkinson's disease

QT

QT interval

EMA

European Medicines Agency

CYP3A4

Cytochrome P450 3A4

FCRIN

French clinical research network for Parkinson's disease

UK PD Disease Society Brain Bank Diagnostic Criteria

United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria

IDRCB

Identifier in the Biomedical Research in France

NCT

National Clinical Trial

ENCEPP

European Network of Centers for Pharmacoepidemiology and Pharmacovigilance

EUPAS

European post‐authorization study

ANSM

National Agency for Medicines and Health Product Safety

MDS‐UPDRS

Movement disorder society‐unified Parkinson's disease rating scale

LEDD

Levodopa equivalent daily dose

IQR

Interquartile range

ECG

Electrocardiogram

SSRIs

Selective serotonin reuptake inhibitors

1. INTRODUCTION

Parkinson's disease (PD) is a degenerative condition which affects 1% of the population over the age of 60 [1], for which no treatment is currently available to slow down its progression. The only available therapies are symptomatic and involve dopamine replacement therapies, whether using dopamine precursors [2] or dopamine agonists [3]. In addition to motor symptoms, PD is also associated with a variety of non‐motor symptoms. Among them, gastrointestinal symptoms, specifically those related to impaired gastric emptying, occur in 70–100% of individuals with PD [4]. Gastrointestinal symptoms in PD are mainly due to dysautonomia [5, 6] or dopamine replacement therapies [7, 8, 9, 10]. Among dopamine replacement therapies, dopamine agonists, including apomorphine, are the main medication‐related contributors to nausea in patients with PD [11].

Although not available in all countries, domperidone is a commonly used treatment for nausea or diabetic gastroparesis. Unlike others neuroleptic‐like anti‐emetics, domperidone can be used in PD despite its dopamine receptor antagonist properties because it does not cross the blood–brain barrier. Occasionally, domperidone is also used in PD to treat orthostatic hypotension [12]. However, domperidone use may lead to harmful side effects because it prolongs the QT interval and cardiac repolarization, which can trigger severe forms of ventricular arrhythmia such as Torsades de Pointes. Intravenous high‐dose domperidone has long been associated with sudden death in cancer patients [13, 14]. Oral domperidone use was also associated with an increased risk of ventricular arrhythmia, especially in males over 60 years old [15], and a recent meta‐analysis revealed a 60% higher risk of sudden cardiac death or ventricular arrhythmia in domperidone users compared to non‐users [16]. Risk factors are high doses of domperidone and patients predisposed to cardiac conduction disturbance and association with QT‐prolonging medications or cytochrome P450 3A4 inhibitors [17]. In contrast, some studies of high‐dose domperidone (60–120 mg/day) in diabetic gastroparesis patients found an increased QTc interval after domperidone use but no cardiac side effects, albeit on a small patient sample [18, 19]. In PD patients, initial reports indicated a higher risk of ventricular arrhythmia or sudden cardiac death only with domperidone daily doses above 30 mg [20]. A more recent study found a non‐statistically significant 22% increased risk of ventricular tachyarrhythmia/sudden cardiac death in PD patients exposed to domperidone, independent of dose and duration of use [21]. The incidence of sudden cardiac death in the European population is estimated to be 39.7 per 100 000 person‐years (95% CI: 32.6–46.8 per 100 000) [22]. Of these cases, it is estimated that 80% are attributable to coronary artery disease, while 5–10% are linked to pro‐arrhythmogenic conditions [23]. However, no absolute incidence is available for patients with Parkinson's disease treated with domperidone, because the relevant studies were designed as case–control studies, which allow for the estimation of relative risk but not absolute risk. Another study indicated a twofold increased risk of all‐cause mortality in PD patients using domperidone [24].

Consecutively, restrictive measures had been taken by most of the regulatory agencies. In 2014, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) issued recommendations restricting the use of domperidone to patients under 60 years, with no history of cardiac pathology susceptible to induce cardiac conduction disturbance and no severe liver insufficiency, limiting the dose to 30 mg/day for a maximum treatment duration of 7 days, and prohibiting concurrent medication with drugs prolonging QT interval or acting as potent inhibitor of CYP3A4 [25]. However, these guidelines are inadequate for treating nausea in PD given that patients often surpass the age of 60, and nausea may persist beyond 7 days, especially during continuous subcutaneous apomorphine treatment. Indeed, despite the awareness among neurologists of the 2014 EMA recommendations, a recent survey conducted in France revealed that, in the absence of alternative medications, the majority of them still prescribe domperidone [26].

In this multicenter prospective study, we aimed at assessing domperidone use and misuse in PD patients in France according to EMA's guidelines.

2. METHODS

2.1. Patients and study design

DUMP (Domperidone use and misuse in Parkinson disease in France) was a French multicenter observational cross‐sectional study conducted in expert PD centers of the French clinical research network for PD (NS‐PARK/FCRIN), general hospitals and private practice neurologists. Participating centers were directed to include all consecutive patients diagnosed with PD (based on the UK PD Disease Society Brain Bank Diagnostic Criteria), consulting in the center within a concise period, not exceeding 1 month, no earlier than January 2021, and no later than October 2021. The only exclusion criterion was the patient refusal to participate. Demographic, PD history, motor and non‐motor symptoms, and current medications were collected by the neurologist during the medical consultation. Additional information on domperidone indication, dose, and duration was also collected for patients treated with domperidone.

The primary objective of the study was to estimate the prevalence of domperidone use and misuse in this real‐life PD population. Secondary objectives were in the population treated with domperidone (i) to describe its indication, dose, duration, contraindication, and precautions taken by the neurologist prior to prescription; (ii) to describe alternative therapies used by neurologists in patients with nausea; and (iii) to estimate domperidone use and misuse in the sub‐population of patients at the early stage of PD (initiating dopaminergic therapy), and in patients treated with apomorphine.

The study received approval from the ethics committee of Ile de France IV (Ref IDRCB: 2018‐A03433–52), ClinicalTrials.gov Identifier: NCT04653584. This study was conducted as part of the DUMP program, which has been registered in the ENCEPP registry (European Network of Centers for Pharmacoepidemiology and Pharmacovigilance) under the number EUPAS26319. All patients received both oral and written information about the study and the use of their medical data, and could refuse participation. By French law and according to the General Data Protection Regulation, written informed consent was not required. We employed ChatGPT to enhance the English language clarity and fluency.

2.2. Definitions

Domperidone misuse criteria were defined according to EMA recommendations on the use of domperidone: (1) duration of domperidone for more than 7 days (duration was estimated as the time span from the onset of domperidone treatment to the end of the prescribed regimen following the current consultation), (2) age >60 years, (3) domperidone dose >30 mg/day, (4) cardiologic contraindication (history of cardiac insufficiency, history of arrhythmia, and familial history of sudden death), (5) history of severe liver insufficiency, and (6) association with contraindicated drug due to interactions, as indicated by the 2020 National Agency for Medicines and Health Product Safety (ANSM) Drug Interaction Thesaurus [27], particularly in cases of liver insufficiency, that is, drugs prone to cause torsade de Pointes and drugs that are potent inhibitors of CYP3A4 (list in e‐method 1 of Appendix S1). The early‐stage population was defined as patients within 2 years of disease duration from PD diagnosis. This population was supposed to be still in the phase of adjusting treatment type or doses and subjected to have more nausea due to introduction or increasing dosages of the dopaminergic therapy. The apomorphine population was defined as the patients currently treated with subcutaneous apomorphine pumps.

2.3. Data collection

For each included patient, the treating neurologist recorded age, gender, height and weight (as reported by the patient), date of PD diagnosis, current medication, and Hoehn and Yahr score [28]. Presence/absence of PD motor and non‐motor symptoms was also collected, defined as a score = 0 (absence) or ≥1 (presence) on the corresponding items of the MDS‐UPDRS scale. The total L‐dopa equivalent daily dose (LEDD) were calculated as the dopamine equivalent (milligrams) taken daily by the patient as previously described by Tomlinson et al. [29].

For patients currently treated with domperidone or for whom domperidone was prescribed during the current consultation, we additionally collected the indication for domperidone prescription: (i) prevention or treatment of nausea under dopaminergic therapy (excluding apomorphine), (ii) prevention or treatment of nausea under apomorphine therapy, (iii) prevention or treatment of orthostatic hypotension, and (iv) other indication. Were also collected domperidone dose, date of initiation and duration of prescription, domperidone prescribed on demand or to be systematically administered, cardiologic work‐up (electrocardiogram and cardiologic consultation made before and/or after domperidone first prescription), presence of cardiologic comorbidities (history of arrhythmia, cardiac insufficiency of familial sudden death), and presence of history of severe liver insufficiency.

2.4. Statistical analysis

Characteristics of patients were described with frequencies and percentages for categorical variables, mean and standard deviation, or median and interquartile range for continuous variables. We estimated the prevalence of domperidone use and misuse among patients with PD and calculated the corresponding 95% confidence interval, based on the normal approximation for binomial proportions. Categorical variables were compared by chi‐squared or Fisher's exact test, and continuous variables were compared by Student or Wilcoxon's rank sum test, as appropriate. Two‐sided p‐value <0.05 defined statistical significance. No adjustment for multiple testing was done given the explanatory nature of this study. It was planned to include 3000 patients in this study, but the study was prematurely halted by the French drug safety agency for administrative reasons (end of funding period). All analyses were made using R software version 4.1.1.

3. RESULTS

3.1. Domperidone use in the overall PD population (Table 1)

TABLE 1.

Characteristics and Parkinson disease‐related treatments on the day of the consultation of patients according to domperidone treatment.

	Overall N = 1579	Not treated with domperidone N = 1470 (93%)	Treated with domperidone N = 109 (7%)	p‐value*
Age, years	70 [63, 76]	70 [63, 76]	63 [62, 75]	0.243
Female	648 (41)	581 (40)	67 (62)	<0.001
Site type				0.515
Expert PD center, n (%)	1282 (81)	1189 (81)	93 (85)
General hospital, n (%)	98 (6)	93 (6)	5 (5)
Private office, n (%)	199 (13)	188 (13)	11 (10)
Time from PD diagnosis, years	8.1 [4.2, 13.2]	8.3 [4.4, 13.2]	6.0 [2.2, 12.8]	0.004
Clinical characteristics
Weight, kg	71 [60, 82]	72 [61, 82]	65 [52, 78]	<0.001
Nauseas, n (%)	96 (6)	29 (2)	67 (62)	<0.001
Orthostatic hypotension symptoms	345 (22)	310 (22)	35 (33)	0.011
PD‐related symptoms
Cognitive impairment	562 (40)	535 (41)	27 (27)	0.007
Hallucination/psychosis	282 (18)	265 (19)	17 (16)	0.597
Depressed mood	572 (37)	520 (36)	52 (48)	0.014
Anxious mood	692 (45)	632 (44)	60 (56)	0.017
Apathy	447 (29)	418 (29)	29 (27)	0.816
Feature of dopamine dysregulation syndrome	174 (11)	162 (11)	12 (11)	1.000
Sleep problems	643 (41)	598 (41)	45 (42)	0.963
Day‐time sleepness	704 (45)	654 (45)	50 (46)	0.884
Urinary problems	686 (45)	641 (45)	45 (42)	0.667
Constipation problems	806 (52)	743 (52)	63 (59)	0.143
Fatigue	885 (60)	817 (59)	68 (65)	0.246
Fluctuations, n (%)	858 (55)	805 (55)	53 (49)	0.209
Dyskinesia	630 (40)	585 (40)	45 (41)	0.904
Hoehn and Yahr On, median (IQR) (NA)	2 [1, 3] (281)	2 [1, 3] (267)	2 [1, 3] (14)	0.865
Hoehn and Yahr Off, median (IQR) (NA)	2 [2, 3] (281)	2 [2, 3] (267)	2 [2, 3] (14)	0.909
PD‐related treatments
L Dopa, n (%)	1439 (91)	1344 (91)	95 (87)	0.180
Dopaminergic agonist	817 (52)	753 (51)	64 (59)	0.158
iMAO‐B	329 (21)	315 (21)	14 (13)	0.045
iCOMT	36 (2)	36 (2)	0 (0)	0.187
Anticholinergic	55 (4)	53 (4)	2 (2)	0.483
Deep brain stimulation	130 (8)	126 (9)	4 (4)	0.106
Duodopa	27 (2)	23 (2)	4 (4)	0.210
Apomorphine infusion	130 (8)	107 (7)	23 (21)	<0.001
LEDD, mg/day	656 [400, 1000]	657 [400, 1000]	600 [255, 1000]	0.339
LEDD per weight, mg/day/kg	9.1 [5.7, 14.1]	9.1 [5.9, 14.0]	9.5 [4.1, 16.2]	0.903
Other anti‐nausea treatments	13 (1)	7 (1)	6 (6)	<0.001
Métopimazine	7 (0)	3 (0)	4 (4)	0.001
Metoclopramide	2 (0)	1 (0)	1 (1)	0.133
Aprepitant	1 (0)	0 (0)	1 (1)	0.069
Ondansetron	0 (0)	0 (0)	0 (0)	‐
Other neuroleptic treatments
Clozapine	80 (5)	73 (5)	7 (6)	0.494
Quetiapine	14 (1)	13 (1)	1 (1)	1.000
Aripiprazole	1 (0)	1 (0)	0 (0)	1.000
Olanzapine	1 (0)	1 (0)	0 (0)	1.000

Note: Results are expressed in mean (SD) or N (%) otherwise specified.

PD, Parkinson disease; IQR, interquartile range; iMAO‐B, inhibitor Monoamine Oxydase B; ICOMT, inhibitor of catecholamine O methyl transferase.

Overall, 1579 patients were included from 16 centers (12 expert PD centers, two general hospitals, and two private practice neurologists) between January 13, 2021 and October 25, 2021. Among those, 109 patients (7%, 95% confidence interval 6–8%) were treated with domperidone. There were more women treated with domperidone than men (62% of patients treated with domperidone were women versus 40% of patients non‐treated with domperidone, p < 0.001). Of note, overall, women had a higher LEDD/kg dose than men (median inter quartile range [IQR] 9.9 mg/kg/day [6.4, 15.5] versus 8.7 mg/kg/day [5.4, 13.3], respectively, p < 0.001) and were more frequently currently treated with apomorphine (10% versus 7%, p = 0.035), as described in Appendix S1 e‐table 1. In addition, patients treated with domperidone had a shorter disease duration (median 6.0 years versus 8.3 years, p = 0.004), less frequent cognitive impairment (27% versus 41%, p = 0.007), but showed more frequent signs of depression (48% versus 36%, p = 0.014) and anxiety (56% versus 44%, p = 0.017). There was no difference on domperidone frequency or patient profiles according to the type of center, although patients were younger and had longer PD duration in expert PD centers than other type of practice (Appendix S1 e‐table 2).

3.2. Domperidone indications and reason for domperidone misuse following EMA recommendations (Table 2 and Figure 1)

TABLE 2.

The 109 patients treated with domperidone, domperidone indication, and type of domperidone misuse.

N	109
Domperidone indication (0 NA)
Prevention or treatment of nausea under dopaminergic therapy (excluding apomorphine infusion)	71 (65)
Prevention or treatment of nausea under apomorphine infusion	32 (29)
Treatment of orthostatic hypotension	3 (3)
Other indication a	4 (4)
Domperidone systematic or on demand (22 NA)
On demand	63 (72)
Systematic	24 (28)
Misuse of domperidone
At least one type of misuse (0 NA)	103 (95)
Misuse due to duration >7 days (3 NA)	89 (84)
Misuse due to age >60 years (0 NA)	86 (79)
Misuse due to dose >30 mg/day (2 NA)	1 (1)
Misuse due to cardiologic contraindication (5 NA)	5 (5)
Misuse due to liver‐related contraindication (0 NA)	0 (0)
Misuse due to contraindicated treatment interaction (0 NA)	6 (6)
Domperidone duration
Delay between domperidone initiation and current consultation (3 NA)
0 day (initiation)	47 (44)
1–7 days	8 (8)
7–120 days	18 (17)
Superior 120 days	33 (31)
Domperidone duration prescribed at the current consultation (32 NA)
Inferior to 7 days	20 (26)
7–120 days	40 (52)
Superior to 120 days	17 (22)
Cardiologic contraindication
Familial sudden death, N (%) (NA)	1 (1) (6)
Cardiac insufficiency	1 (1)
History of cardiac arrythmia, N (%) (NA)	4 (4) (1)
Cardiologic work‐up
Cardiologic consultation a before first prescription, N (%) (NA)	9 (9) (3)
ECG alone before first prescription, N (%) (NA)	36 (34) (2)
ECG after first prescription, N (%) (NA)	23 (23) (7)
Contraindicated associations (due to interactions)
Hydroxyzine	1 (1)
Escitalopram	4 (4)
Citalopram	1 (1)

Note: Results are expressed in mean (SD) or N (%) otherwise specified.

^a Other: Nausea under metformin therapy (1), gastro‐esophageal reflux (1), gastroparesis (1), and occasional use (1); ECG: electrocardiogram: cardiologic consultation included ECG; contraindicated interactions: fluconazole; CYP3A4 inhibitors: protease inhibitors, antifungics, and macrolids; torsadogenics: amiodarone, citalopram, escitalopram, dronedarone, erythromycine, hydroquinidine, hydroxyzine, equitazine, moxifloxacine, piperaquine, quinidine, sotalol, spiramycine, toremifene, vandetanib, and vincamine.

FIGURE 1.

Total and type‐specific domperidone misuse percentages, among patients treated with domperidone. This figure outlines domperidone misuse among patients treated with domperidone following the EMA recommendations. Ninety‐five percent exhibited at least one misuse criterion, with 84% surpassing the recommended treatment duration (>7 days) and 79% being over 60 years old. Additionally, 1% exceeded the dose (>30 mg/day), 5% had cardiologic contraindications (history of cardiac arrhythmia, cardiac insufficiency, and/or familial history of sudden death), and 6% were on contraindicated co‐medications (escitalopram, citalopram, and hydroxyzine).

Among the 109 prescriptions of domperidone, the indication was prevention or treatment of nausea related to apomorphine infusion in 32 (29%) patients, 23 (21%) for patients currently treated with apomorphine infusion and nine (8%) for patients initiating apomorphine infusion at the current visit. Among the 32 patients, prescribed domperidone in relation to apomorphine infusion, 16 (50%) received it preventively, while the remaining 16 (50%) were given domperidone as a treatment for nausea (after its onset). The indication of domperidone was nausea due to other dopaminergic therapy for 71 (65%) patients (29 [41%] for prevention and 42 [59%] for treatment after nausea onset) and orthostatic hypotension for three (3%) patients.

At least one criterion of domperidone misuse was found in 103 (95% [CI 95%: 88%, 98%]) patients. The two most representative misuses were treatment duration >7 days in 89 patients ([84%]) and age >60 years in 86 patients ([79%]). Only one patient had a domperidone dose superior to 30 mg/day. Six (6%) patients treated with domperidone had a contraindicated comedication (four with escitalopram, one citalopram, and one hydroxyzine). Five patients (5%) were treated with domperidone while having a cardiologic contraindication (history of cardiac arrhythmia [4], cardiac insufficiency [1], and/or familial history of sudden death [1]). Only nine patients (9%) had a consultation with a cardiologist before domperidone use (in particular, none of the patients had a known cardiologic contraindication), and only 36 (34%) had an electrocardiogram (ECG) before domperidone first prescription (two of the five patients with cardiologic contraindication). No patient had history of severe liver insufficiency.

3.3. Domperidone prescriptions and alternative therapies in patients with nauseas (Table 3)

TABLE 3.

Characteristics of the 96 patients complaining for nauseas, treated or not with domperidone.

	Not treated with domperidone N = 29 (30.2%)	Initiation of treatment with domperidone N = 21 (21.8%)	Treated with domperidone N = 46 (47.9%)	p
Age	68 [63, 74]	73 [67, 77]	66 [60, 74]	0.112
Female	17 (59)	13 (62)	31 (67)	0.733
Weight, kg, mean (SD) (NA)	70.4 (16.7)	67.6 (13.5)	66.45 (17.2)	0.646
Place of consultation				0.322
University hospital	26 (90)	17 (81)	37 (80)
Non‐university hospital	2 (7)	0 (0)	4 (9)
Private office	1 (3)	4 (19)	5 (11)
Time from PD diagnostic, years	8.76 [5.87, 12.39]	3.10 [2.15, 7.93]	10.43 [3.82, 17.18]	0.022
Levodopa equivalent dose, mg/day	676 [450, 1160]	600 [188, 898]	833 [558, 1191]	0.113
Levodopa equivalent dose, mg/kg/day, mean (SD) (NA)	12.2 [7.0, 19.0]	8.8 [3.2, 12.8]	13.7 [7.4, 18.8]	0.092
Apomorphine infusion current treatment	3 (10)	1 (5)	15 (33)	0.009
Any other treatment for nauseas, N (%) (NA)	7 (24)	4 (19)	2 (4) (1)	0.038
Metopimazine	3 (10)	3 (14)	1 (2)	0.269
Metclopramide	1 (3)	1 (4)	0 (0)	0.371
Aprepitant	0 (0)	0 (0)	1 (2.2)	1.000
Setrons	0 (0)	0 (0)	0 (0)	‐
Other treatments	3 (10)	0 (0)	0 (0)	0.035
Esomeprazole	1 (3)	0 (0)	0 (0)
Paracetamol	1 (3)	0 (0)	0 (0)
Venlafaxine	1 (3)	0 (0)	0 (0)
Non‐drug treatment	3 (10)	0 (0)	0 (0)	0.035
Ginger	1 (3)	0 (0)	0 (0)
Homeopathy	2 (7)	0 (0)	0 (0)

Note: Results are expressed in mean (SD) or N (%) otherwise specified.

Ninety‐six patients (6% of all patients) complained of nausea at the time of the visit. Among them, 67 (70%) were either undergoing treatment with domperidone (n = 46) or had a prescription for initiating domperidone (n = 21). Most of the prescriptions were made “on demand” by the neurologist. The majority (22/29 patients [76%]) of the remaining patients with nausea but untreated with domperidone received no treatment. Only a few of them were prescribed alternative therapies: three with metopimazine (an antiemetic phenothiazine derivative, with the same expected adverse effects as domperidone), one with esomeprazole, one with paracetamol, one with venlafaxine, two with homeopathy, and one with ginger. For patients initiating domperidone at the current visit, 45% experienced nausea, while for those already receiving the medication, 74% reported ongoing issues with nausea.

3.4. Domperidone use in specific sub‐populations

We then looked at domperidone prescriptions in two pre‐specified sub‐populations of interest; patients at the early stage of PD and patients treated with subcutaneous apomorphine infusion. Among the 164 patients at the early stage of PD, 24 (15%) were undergoing domperidone or were initiated with domperidone at the current visit (Appendix S1 e‐table 3). These patients complained more frequently from nauseas than early PD patients not treated with domperidone (42% versus 1%, p < 0.001), although they had lower LEDD per kilogram (median [IQR] 3.2 [1.3, 4.7] versus 5.2 [2.4, 6.9] mg/kg/day, p = 0.030). Early PD patients treated with domperidone tended to be more frequently treated with dopamine receptor agonists, although this difference did not reach significance (42% versus 23%, p = 0.074).

In the whole cohort, 123 patients (8%) were currently treated with apomorphine pump. Among these patients, 23 (19%) received concomitant therapy with domperidone (Appendix S1 e‐table 4). Apart from nausea (70% versus 3%, p < 0.001) and a slightly higher proportion of women (70% versus 46%, p = 0.063), there was no major difference between those treated or not treated with domperidone.

4. DISCUSSION

In this cross‐sectional multicentric French study, 7% (6–8%) of patients living with PD were prescribed with domperidone. Importantly, the overwhelming majority (95%) of prescriptions met at least one criterion for misuse according to the 2014 EMA's recommendations.

In our cross‐sectional study, while only 7% of the whole population was treated with domperidone, this proportion rose to 14% for patients at an early stage of PD and to 19% for patients treated with an apomorphine pumps were prescribed domperidone. This is in accordance with the high prevalence of nausea following dopaminergic therapy introduction or during treatment with apomorphine pumps, affecting up to 20–40% of patients included in clinical trials [7, 8, 9, 10, 11]. Our findings revealed a higher proportion of women among patients receiving domperidone, confirming other studies on domperidone use [30], possibly related to higher frequency of gastrointestinal symptoms in Parkinsonian women [31]. Interestingly, we found a higher LEDD/kg in women than men, which may also explain the higher frequency of nausea and higher use of domperidone. This may also reflect the unavailability of small dosage of dopaminergic drugs for patients with lower weight.

In our study, 95% of the prescriptions of domperidone deviated from the restriction guidelines of the EMA. However, these deviations were mainly due to the older age (over 60 years) and the longer duration of domperidone prescription (over 7 days), suggesting an inadequacy of these guidelines for treating nausea in the PD population. Indeed, PD is commonly a late‐onset disease, the mean age at diagnosis being 70 years old [32]. The initiation and titration of dopaminergic therapy takes commonly several weeks or months with progressive dose escalation, and nausea under apomorphine pumps may persist during the whole duration of the treatment in some patients. Only one patient had a dose of domperidone exceeding the recommended daily dose of 30 mg/day. However, among patients currently treated with domperidone, 74% reported ongoing nausea, suggesting insufficient doses or efficacy of domperidone. These deviations from EMA recommendations probably reflect an unmet need for treating gastrointestinal symptoms in PD rather than an insufficient knowledge of such guidelines. Indeed, a recent survey of 253 neurologists conducted in France between June 2018 and February 2019 highlighted that, despite the fact that 83% of neurologists were aware of the recommendations, they continued to prescribe domperidone without age limitation and beyond 7 days for nauseas (notably for patients receiving continuous apomorphine treatment) [26]. In our current study, only a few patients were treated with domperidone for hypotension, an indication for which other treatments are available, suggesting that neurologist restrict the use of domperidone for other potential off‐label indications. The persistence of prescribing domperidone is also explained by the lack of alternative options. Indeed, common anti‐emetic drugs with dopamine receptor antagonist properties cannot be used in PD because of the risk of worsening motor symptoms. Domperidone has a unique pharmacological profile with anti‐emetic properties also related to antidopaminergic properties, but, because it barely crosses the blood–brain barrier, it has a low risk of worsening parkinsonian symptoms. Accordingly in our study, among patients with nausea who did not receive domperidone, 76% had no treatment. Among alternative therapies used by neurologists, one was a relative contraindication in PD because of its neuroleptic‐like properties (metopimazine), while the others have not demonstrated efficacy in this indication (esomeprazole, paracetamol, venlafaxine, homeopathy, and ginger). To note, some of the therapies mentioned were reported by patients as being used as anti‐emetic, even though they may have been prescribed for other indications (e.g., paracetamol and venlafaxine). Furthermore, in our study, setrons were not utilized as alternative therapies for nausea in Parkinson's disease, highlighting the limited use of this therapeutic class for this indication in France.

Although less common, other deviations from the EMA recommendations were identified, such as prescription of domperidone in the context of cardiac disease history or concomitant use of contraindicated medication. Cardiovascular disease are prevalent in the elderly PD population and are often associated with dysautonomia [33]. Sudden death has increasingly been recognized as a significant cause of mortality PD [34, 35, 36, 37]. To minimize the potential complications associated with domperidone, it is thus essential to evaluate the patients' personal and familial history of cardiovascular disease. Furthermore, a notable potential drug interaction arises from our study with selective serotonin reuptake inhibitors (SSRIs), frequently used in PD but known to potentially cause torsade de Pointes when combined with other arrhythmogenic drugs. Given the frequent occurrence of depressive symptoms in PD, and the higher prevalence of anxiety and depression symptoms in patients receiving domperidone in our study, it is crucial to highlight the risk associated with combining these drugs to the neurological community [38].

In this respect, countries in which domperidone is marketed have addressed the risk associated with its prescription. In the United States, the Food and Drug Administration (FDA) has issued an alert prohibiting the use of domperidone in 2004. Domperidone usage is only permitted through the Expanded Access to Investigational Drugs program, which is restricted to patients with severe gastrointestinal motility disorders that are unresponsive to available therapies. As a result, the use of domperidone in the United States is nearly negligible. In South Korea, in 2014, authorities advised caution in prescribing domperidone to patients aged 65 and older, taking into account potential cardiac side effects, concurrent medications, comorbidities, and limiting the duration of domperidone use to less than 7 days. As a result, there was a 96% decrease in domperidone prescriptions for patients over 65 between 2011 and 2016. However, in 2016, in this population, 43% of domperidone prescriptions still exceeded the recommended 7‐day limit [30]. In contrast, a study conducted in 2015 in Ireland found that the EMA recommendation had a minimal effect on domperidone prescription rates, particularly regarding the dispensing of domperidone and concurrent medication use, mainly SSRIs. It is worth noting that this study may have been conducted too soon after the EMA recommendation to capture any significant change in prescriptions [38]. In France, there is a lack of data regarding the changes in domperidone usage post‐EMA recommendation; further studies using national claims database are necessary.

The study's strengths lie in its multicentric approach, encompassing various practices such as expert centers, general hospitals, and private practices. It involved a precise therapeutic and neurological evaluation of participants. However, limitations include focusing on domperidone prescription analysis rather than actual usage by the patient, assessing a population primarily sourced from expert centers that may limit the generalizability of the results to a broader population or to less specialized care settings, and influence the outcomes due to optimized management and closer follow‐up in these centers. Additionally, it is a cross‐sectional study and does not explore the trends of domperidone prescription over the years.

5. CONCLUSION

Domperidone continues to be prescribed in France in a proportion of PD patients experiencing nausea induced by dopaminergic therapy. The majority of these prescriptions deviate from the EMA guidelines, primarily due to the advanced age of patients (>60 years) and extended treatment duration (>7 days). Our findings reveal the unmet need for addressing gastrointestinal symptoms in PD and highlight the inadequacy of EMA guidelines for the use of domperidone in this population.

AUTHOR CONTRIBUTIONS

Concept and design: Jean Christophe Corvol, Maryse Lapeyre‐Mestre, Olivier Rascol, and Florence Tubach. Acquisition, analysis, or interpretation of data: All authors and DUMP study group. Drafting of the manuscript: Edouard Januel, Jean Christophe Corvol, and Florence Tubach. Critical revision of the manuscript for important intellectual content: Philippe Remy, Wassilios G. Meissner, Claire Thiriez, Aymeric Lanore, Cecilia Bonnet, Jean‐Philippe Azulay, Caroline Giordana, David Maltete, Solene Frismand, Christine Tranchant, Francois Sellal, Alain Jager, Matthieu Béreau, Giovanni Castelnovo, Anne Evelyne Vallet, Maryse Lapeyre‐Mestre, and Jean‐Denis Turc. Statistical analysis: Edouard Januel. Supervision: Jean Christophe Corvol, Maryse Lapeyre‐Mestre, Olivier Rascol, and Florence Tubach.

CONFLICT OF INTEREST STATEMENT

Edouard Januel: none; Jean Christophe Corvol: JCC has served in advisory boards for Alzprotect, Bayer, Biogen, Denali, Ferrer, Idorsia, iRegene, Prevail Therapeutic, Servier, Theranexus, and UCB; and received grants from Sanofi and the Michael J Fox Foundation outside the submitted work; Philippe Remy: none; Wassilios G. Meissner: Outside the present work, WGM has served as consultant for Lundbeck, Alterity, Servier, Inhibikase, and Takeda; Claire Thiriez: no financial disclosure; congress travel grant from Orkyn, Abbvie, Homeperf, Adelia, Asdia, and Ipsen, outside the submitted work; Aymeric Lanore: none; Cecilia Bonnet: none; Jean‐Philippe Azulay: Boards, congresses, and clinical trial funding from Aguettant, AbbVie, Boston Sc, Elivie, NHC, HAC Pharma, Medtronic, and Merz, outside the submitted work; Caroline Giordana: fees from Abbott and Abbvie Orion pharma; David Maltete: none; Solene Frismand: Abbvie, Ipsen board; congress travel grant by Elivie, outside the submitted work; Christine Tranchant: none related to this work; Francois Sellal: fees for scientific communications for Novartis Pharma, Sanofi, and Lilly; Alain Jager: none; Matthieu Béreau: M.B. reports grants from France Parkinson Foundation, reimbursement of travel expenses to scientific meetings from Asten, Boston Scientific, Elivie, and Medtronic; honoraria from AbbVie, Aguettan, Allergan, Asdia, and Merz Pharma for lecturing outside the submitted work; Giovanni Castelnovo: GC has served advisory boards Novartis, Biogen, Sanofi, Genzyme, Merck Serono, Abbvie, Merz, BMS, Alexion, Janssen, Ipsen, outside the submitted work; Anne Evelyne Vallet: congress travel grant from LFB, Abbvie, Novartis, and Lundbeck et Adelia, outside the submitted work; Maryse Lapeyre‐Mestre: none; Jean‐Denis Turc: none; Olivier Rascol: none related to this work; Florence Tubach: FT is the head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique – Hôpitaux de Paris and of the Clinical Research Unit of Pitié‐Salpêtrière hospital, both these structures have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies that have contributed indiscriminately to the salaries of its employees. Florence Tubach is not employed by these structures and did not receive any personal remuneration from these companies.

ETHICS APPROVAL STATEMENT

The study received approval from the ethics committee of Ile de France IV (Ref IDRCB: 2018‐A03433‐52).

Supporting information

Appendix S1. e‐method, 4 e‐tables, DUMP study Group

Januel E, Corvol JC, Remy P, et al. Use and misuse of domperidone in patients living with Parkinson disease in France. Fundam Clin Pharmacol. 2025;39(2):e70002. doi: 10.1111/fcp.70002

DATA AVAILABILITY STATEMENT

Requests for access to the data reported in this paper will be considered by the corresponding author.