ORIGINAL ARTICLE

Domperidone: Limited Benefits With Significant Risk for

Sudden Cardiac Death
Luc M. Hondeghem, MD, PhD
See accompanying commentary on pages 215217.
Background: Domperidone (antinausea/vomiting agent) was
recently shown by several groups to increase sudden cardiac death
(SCD). Drug-induced disturbances of cardiac repolarization may be
a major mechanism.
Methods and Results: Experiments were executed in isolated
female rabbit hearts perfused for 150 minutes with domperidone 30,
60, or 100 nM. Domperidone signicantly prolonged the action
potential duration: +9% at 30 nM, +32% at 60 nM, and +48% at
100 nM. Domperidone induced signicant disturbances of repolarization in 83% of hearts at 60 nM and in 100% at 100 nM, including early
afterdepolarizations and polymorphic ventricular tachycardia. Maximum therapeutic free drug plasma concentration of domperidone
(19 nM) yields a safety index of only ;2.5, that is, 12-fold below
the accepted minimum. Gastrointestinal benets and risks for SCD
were derived from the literature. The dened daily dose of domperidone (30 mg/day) fails to show unequivocal gastrointestinal benets
beyond a placebo effect. In contrast, 5 of 5 population-based studies
show that oral domperidone signicantly increases the odds ratio for
SCD to 2.8 (1.536.21) and it increases sharply above 30 mg/day.
Conclusions: Because domperidone has placebo-like benets but is
associated with increased SCD and a narrow safety margin, it should
not be used in medicine.
Key Words: domperidone, proarrhythmia, sudden cardiac death,
safety index, riskbenet
(J Cardiovasc Pharmacol
2013;61:218225)

INTRODUCTION
Domperidone is a dopamine receptor blocker used orally
against nausea and vomiting1,2 (available over the counter in
numerous countries). In 2005, a large-scale population-based
study,3 focusing on sudden cardiac death (SCD) in noncardiac
drugs that prolong the QTc interval, reported that clinically
recommended doses of domperidone signicantly increase the
odds ratio for SCD to 5.4 [95% condence intervals (CI), 2.2
12.7]. Signicant increase of SCD was conrmed in 4 additional epidemiological studies.47
Received for publication September 5, 2012; accepted October 25, 2012.
From the Department of Pharmacology, Catholic University of Leuven, Leuven,
Belgium.
The authors report no conicts of interest.
Reprints: Luc M. Hondeghem, Westlaan 85, B-8400 Oostende, Belgium
(e-mail: luc.hondeghem@screenqt.com).
Copyright 2013 by Lippincott Williams & Wilkins

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Numerous clinical reports814 on intravenous use for

antiemesis in chemotherapy demonstrate that domperidone
can elicit arrhythmias, QT interval prolongation, Torsades de
Pointes, ventricular brillation, and SCD. In vitro studies in
isolated guinea pig and rabbit hearts15,16 show that domperidone has cardiac electrophysiological effects similar to those
of class III antiarrhythmic drugs and of cisapride,17 another
prokinetic agent withdrawn because of its proarrhythmic
effects. Domperidone prolongs ventricular action potential
duration (APD),15,16 but also disturbs fast repolarization16 by
increasing Triangulation, Reverse use dependence, Instability
and Dispersion (TRIaD) of the action potential.18 Voltage
clamp studies in human ether-a-go-go related gene (hERG)
transfected cells showed that domperidone reduces the major
cardiac repolarizing potassium current Ikr (IC50 = 57 nM).15,19
Such preclinical and clinical evidence prompted the Food
and Drug Administration to refuse approval of domperidone
into the United States, even declaring its use illegal.20 Previous
in vitro experiments, using only 15-minute equilibration with
domperidone,16 determined that the therapeutic index of domperidone was only 5, that is, 6-fold lower than the margin of 30
considered as a strict minimum for safe drug use in patients.21
Because short equilibration times with isolated cardiac tissues
may overestimate domperidones safety margin,22 the Federal
Agency for Medicines and Health products (FAMH) of Belgium showed interest in studies with longer exposures.
To obtain a better evaluation of the risks and benets for
domperidone, the present study evaluated (1) the safety margin
for domperidone in isolated rabbit hearts using 150-minute
equilibration periods (10-fold longer than in previous studies);
(2) the published clinical data on domperidones potential
benets in gastrointestinal indications; (3) the clinical dosage
dependence for risk of SCD; (4) nally, using these preclinical
and clinical data in concert, the riskbenet for domperidone
was assessed.

MATERIALS AND METHODS

Experiments in Isolated Rabbit Hearts
The experiments were executed to conform to the rules
and the standard operating procedures as approved by the
Institutional Animal Welfare Committee and AVMA/ILAR
guidelines.23,24 The experimental procedures have been
described in previous publications.18,25 Briey, 18 female albino
rabbits (;2.5 kg) were stunned by a penetrating captivating bolt.
The heart was perfused at a pressure of 80 cm with a buffer of
the following composition: NaCl 118, KCl 4, NaHCO3 22,
MgCl2 1.1, NaH2PO4 0.4, CaCl2 1.8, dextrose 5, pyruvate 2,
creatine 0.038 mM, 95%O2, and ;5%CO2. The pH was
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maintained at 7.35 6 0.05 by computer-controlled adjustment of

the CO2.
The His bundle was sectioned and electrodes were
inserted on both sides for stimulation at 1.5 threshold
stimulation current. Septal and epicardial monophasic action
potentials were recorded at 1 kHz and conduction data at
10 kHz (12 bits resolution). When automaticity and escape
cycle length were .1000 milliseconds, threshold stimulation
current ,300 mA, coronary perfusion .12 mL/min, ectopic
rate ,40 beats per 10 minutes, and cardiac activation
time ,60 milliseconds, then the heart was stimulated until
instability of the last 20 trains became ,10 milliseconds.

Protocol
Throughout the equilibration periods, trains of 30 action
potentials at 1 Hz were recorded every minute for determination
of APD10APD90 (upstroke till 10, 20 . 90% repolarization).
TRIaD was measured over 3 minutes: triangulation was measured as average APD30 to APD90 (ms); reverse use dependence
was measured as the difference between the mean APD60 of 10
rst action potentials and the last 20 action potentials of three 30
beat trains; instability of APD60 was computed using the best
easy systematic for the last 20 action potentials in 3 trains26;
and dispersion was measured as the average difference between
septal and epicardial APD60. After a 10-minute baseline, the
preparations were perfused for 150 minutes with 30, 60, or
100 nM domperidone (n = 6, at each concentration).

Chemicals
Domperidone was obtained from Sigma (Brussels,
Belgium). A stock solution in dimethylsulfoxide was freshly
prepared and diluted in buffer to the required concentrations. The
nal dimethylsulfoxide concentration remained ,0.1%. The free
drug plasma concentrations of domperidone at the clinical
advised oral dose regimens in man range from 5 to 19 nM.21,27

Statistical Analysis

Data are presented as mean 6 SD with n = 6, unless

otherwise stated. Difference between 2 means was tested with
a Student t test. Deviations exceeding the 97.5% CI (CI97.5)
derived from 100 control experiments are counted as drug
induced,28 and incidences were tested for signicance with
a Fisher exact test (P , 0.05 considered signicant). Odds
ratios are presented as mean with 95% CIs.

Literature Analysis for Risk For SCD and

Gastrointestinal Benefits
To estimate domperidones risk in patients for SCD
versus its potential benets for gastrointestinal indications,
the National Library of Medicine was systematically searched.
Of 2172 articles on domperidone (September 3, 2012), 41
associated the drug with arrhythmias, including 3 large population studies.3,6,7 Exhaustive additional searching increased
this number to 5 large studies.37
For evaluation of benets in gastrointestinal disorders,
recent English expert review articles were searched. Of 44
review articles on use of domperidone in oesophageal reux,
2 recent articles systematically reviewed domperidones
effects.29,30 Of 6 recent review articles on diabetic gastroparesis,
 2013 Lippincott Williams & Wilkins

Domperidone: Negative RiskBenefit

one systematically reviewed all available trials.31 Of 9 recent

reviews on prokinetic actions for use against nausea or vomiting, none provided a systematic evaluation nor included
large enough trials to provide a clear conclusion. Only one
large multicenter, double-blind original study could be
located.32
No prospective double-blind study with sufcient power
to determine efcacy versus risk could be found. Because
domperidones liability for SCD was signicant while systematic reviews did not detect signicant benets beyond placebo,
the FAMH was requested for the evidence for a positive risk
benet prole, for which they kindly provided 20 references
(Table 1). To the extent possible, these documents were obtained and reviewed in the present study.

RESULTS
Experiments in Isolated Rabbit hearts
Effects of Domperidone Upon APD
At 100 nM domperidone, APD90 prolonged from 260 6
38.4 to 282 6 31.1 milliseconds (+8.4%) during a 15-minute
equilibration, which is similar to ndings in guinea pig
hearts.15 However, after 150 minutes, APD90 reached 385 6
35.7 milliseconds (+48%; Table 2). In all 6 preparations, the
control CI97.5 for prolongation of APD60 (45 ms) was exceeded (P , 1027). Because of this larger than previously
observed prolongation,15,16 long exposures at lower concentrations were also tested.
At 60 nM of domperidone (gray bar superimposed on
abscissa in Fig. 1), APD increased after some delay to
approach a steady state in ;45 minutes. After 150 minutes
equilibration for all 5 hearts, APD90 increased by 83 6 36.9
milliseconds (+32%). Again, the CI97.5 for APD60 prolongation was exceeded in all 6 preparations (P , 1027). At 30 nM
of domperidone, APD90 prolongation was 23 6 21.8 milliseconds (+9%) and the CI97.5 for APD60 prolongation was
exceeded in 3 of 6 preparations (P , 0.002).

Effects of Domperidone Upon TRIaD

Prolongation of APD by itself is normally antiarrhythmic33 but when combined with TRIaD, its proarrhythmic
actions usually prevail.18 In Figure 1, domperidone (60 nM)induced development of triangulation is seen as progressive
separation of APD30, APD60, and APD90, whereas instability
can be seen as increasing widening of these 3 traces. This
concentration and time dependence of TRIaD development
is summarized in Figure 2.
Triangulation
APD90 can be prolonged by a prolongation of the plateau (frequently antiarrhythmic), by slowing of fast repolarization from APD30 to APD90 (triangulation = proarrhythmic), or
by both.34 In control experiments, triangulation usually shortens somewhat during the experiment (214 6 17 ms; n =
100).28 A similar reduction of triangulation was also observed
at 30 nM of domperidone (224 6 9.1 ms; P . 0.05) with no
triangulation exceeding the control CI97.5 (23 ms). At 60 nM,
domperidone prolonged triangulation by 13 6 17 milliseconds
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Hondeghem

TABLE 1. References Supplied by the FAMH on Domperidones Benefit

Authors

Title

References

Pts

Bader et al

Unpublished Report 1978

NA

Von Matushka

Janssen 1979

NA

De Loose et al

Janssen 1980

NA

Soewono et al

Unpublished Report 1990

NA

Hersh

Janssen 1985

NA

Martin

Janssen 1980

NA

Shea

Unpublished Report 1977

NA

De Loose

Haarmann et al

10

Verhaegen et al

11

Van Outryve et al

12

Van Ganse et al

13

Van de Mierop et al

Multicentre, double-blind, cross-over, placebocontrolled study with Motilium tablets

A multicentre double-blind evaluation of
domperidone in the treatment of
postprandial dyspepsia
Double-blind comparison of domperidone with
placebo in the treatment of chronic postprandial
gastrointestinal distress. A multicenter study
Clinical study of domperidone in non-ulcer
dyspepsia
A randomized, double-blind, cross-over comparative
trial of domperidone and placebo in the treatment of
symptoms of idiopathic gastric stasis
Domperidone in the treatment of dyspeptic
symptoms; A double-blind placebo-controlled study
Domperidone in the symptomatic treatment of
atulent dyspepsia: a double-blind placebocontrolled study
Domperidone in chronic dyspepsia: a pilot open
study and a multi-centre general practice crossover
comparison with metoclopramide and placebo
A double-blind study of domperidone in the
symptomatic treatment of chronic postprandial upper
gastrointestinal distress
Orale anwendung von Domperidon zur behandlung
der chronischen dyspepsie
Domperidone for the symptomatic treatment of
chronic post-prandial nausea and vomiting
Chronic dyspepsia: Double-blind treatment with
domperidone (R 33 812) or placebo; A multicentre
therapeutic evaluation
Oral domperidone in chronic postprandial dyspepsia

14

Englert et al

15

Arts et al

16

Tatsuta et al

17

Bekhti et al

18

Agorastos et al

19

Nagler et al

20

Corazzao et al

A double-blind crossover trial of domperidone in

chronic postprandial dyspepsia
Domperidone in the treatment of dyspepsia:
A double-blind placebo-controlled study
Effect of treatment with cisapride alone or in
combination with domperidone on gastric emptying
and gastrointestinal symptoms in dyspeptic patients
Domperidone in the treatment of functional
dyspepsia in patients with delayed gastric emptying
Double-blind evaluation of domperidone in acute
vomiting and dyspeptic disorders
Clinical evaluation of domperidone in the treatment
of chronic postprandial idiopathic upper
gastrointestinal distress
Levosulpiride in functional dyspepsia: a multicentric,
double-blind controlled trial

Pharmatherapeutica
1979;2:140146
Postgrad Med J
1979;55:2427
Munch Med Wschr
1978;120:16891690
Postgrad Med J
1979;55:3335
Curr Ther Res
1978;23:695701

40, 67

23 D, 18 P

10
16 D, 22 P
36 D, 37P

Digestion
1979;19:244250
Postgrad Med J
1979;55:2829
J Int Med Res
1979; 7:158161
Aliment Pharmacol Ther
1992;6:221228

17 D, 15 P

Postgrad Med J
1979;55:3032
J Int Med Res
1981;9:143147
Am J Gastroenterol
1981;76:495499

20 D, 20 P

Ital J Gastroenterol
1996;28:317323

48
7D, 7P
8

9 DP, 9 PD
11

227 D, 401 P

Pts (Patients); NA (Not Available): FAMH (Federal Agency for Medicines and Health products) is restricted by condentiality and Janssen acknowledged request for the articles
but did not provide them; D: domperidone, P: placebo. The references were kindly provided by the FAMH.

and in 3 of 6 hearts the CI97.5 was exceeded (P , 0.002). At

100 nM, triangulation increased by 56 6 55.7 milliseconds
and 4 of 6 preparations exceeded the CI97.5 (P , 0.0001).
Reverse Use Dependence
At 30 nM of domperidone, the CI97.5 for reverse use
dependence (7 ms) was never exceeded. At 60 nM, reverse use
dependence increased by 11 6 17.6 milliseconds and

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exceeded the CI97.5 in 3 of 6 experiments (P , 0.002). At

100 nM, reverse use dependence also increased by 11 6 13.6
milliseconds, but the CI97.5 was now exceeded in 4 of 6 hearts
(P , 0.0001).
Instability
At 30 nM, domperidone did not increase instability of
APD beyond the control CI97.5 (15 ms). At 60 nM, instability
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Domperidone: Negative RiskBenefit

TABLE 2. Prolongation of APD

APD30
APD60
APD90

30 nM (n = 6)

60 nM (n = 5)*

100 nM (n = 5)*

44 6 15.2 (25)
26 6 21.7 (12)
23 6 21.8 (9)

84 6 42.1 (44)
82 6 37.3 (35)
83 6 37 (32)

87 6 59.8 (48)
109 6 47.3 (48)
125 6 60.3 (48)

APD was measured at a basic cycle length of 1000 milliseconds. APD prolongations
are represented as mean 6 SD after ;150 minutes equilibration at each concentration.
Percent changes are shown in parentheses. All observed prolongations were signicant
(P , 0.05) with reference to baseline as well as to 100 control experiments.
*At 60 and 100 nM one experiment dropped out, respectively, because of repetitive
Torsades de Pointes and excessive APD prolongation (preventing to follow the
computer stimulation).

reached 13 6 19.3 milliseconds and in 2 of 6 experiments

exceeded the CI97.5 (P , 0.05). At 100 nM, instability
was 10 6 20.8 and exceeded the CI97.5 in 3 of 6 experiments
(P , 0.002).
Dispersion
At 30 nM, the differences in APD between left
ventricular septal endocardium and epicardium increased by 9
6 6.8 milliseconds, but the control CI97.5 (23 ms) was exceeded only once (P . 0.05). At 60 nM, dispersion reached
11 6 18.5 milliseconds, but again the CI97.5 was exceeded
only once (P . 0.05). At 100 nM, dispersion increased to

FIGURE 2. Development of TRIaD as a function of domperidone concentration and of equilibration time. The incidence
of TRIaD is given as the sum of triangulation, reverse use
dependence, instability and dispersion.

19 6 11 milliseconds and now the CI97.5 was exceeded in

3 of 6 experiments (P , 0.002).
TRIaD
At 30 nM of domperidone, one component of TRIaD
(dispersion) was exceeded in only 1 of 6 experiments
(P . 0.05). At 60 nM, 5 of 6 experiments exceeded TRIaD
limits (P , 1024) and at 100 nM, all 6 experiments exceeded
this limit (P , 1025).

FIGURE 1. Effects of domperidone upon APD in experiment

24,855 (median APD prolongation). During the gray bar
overlay on the abscissa, domperidone was perfused at 60 nM.
Data before the bar are baseline results and data after the bar
are those during washout. The data points represent APD for
30-second trains at 1 Hz (between the trains other experimental
measurements were made). APD30 (open squares), APD60 (filled black circles) and APD90 (open diamonds). Note that the
marked domperidone induced APD prolongation as associated
with triangulation (spread between APD30 and APD90) and
increased instability of the APD (widening of the APD30, APD60,
and APD90 traces). Because the widening by instability exceeds
the spread by triangulation, the traces start to overlap.
 2013 Lippincott Williams & Wilkins

Early Afterdepolarizations and Polymorphic Ventricular

Tachycardia
As TRIaD develops, repolarization weakens, becomes
less stable and more dispersed; at some point, this may result
in depolarization before complete repolarization (Early
afterdepolarizations, EAD), which may in turn trigger
additional depolarization(s), including polymorphic ventricular tachycardia (PVT). From Figure 3 (after ;42 minutes
equilibration in 100 mM), one can clearly see that APD not
only prolonged (APD1090 shifts downwards) but that in
addition repolarization became unstable. This yielded the
rst EADs that quickly lead to more than 1 EAD, which
eventually can progress to PVT.
At 30 nM, domperidone neither elicited EAD nor
PVT. At 60 nM, 3 of 6 experiments (24,844, 24,853, 24,855;
P , 0.001) showed EADs and 2 experiments (24,844,
24,855; P , 0.01) PVT. At 100 nM, 1 experiment
(24,785) terminated because APD became too long (.600
ms). EADs developed in 4 experiments (24,799, 24,801,
24,803, 24,805; P , 1025) and PVT occurred in 2 experiments (24,803, 24,805; P , 0.01).
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FIGURE 3. Prolongation of APD and

proarrhythmia development in domperidone 100 mM (experiment
24805). Left panel is at baseline; right
panel ;42 minutes into perfusion
with 100 mM domperidone. Top 9
traces represent APD10 to APD90:
show APD10 (brown), APD20 (red),
APD30 (orange), APD40 (yellow),
APD50 (green), APD60 (blue), APD70
(violet), APD80 (black) and APD90
(gray). The monophasic action
potential at a basic cycle length of
1000 milliseconds is shown as the
bottom trace. Arrhythmias (not
stimulated by computer) are flagged
by a red upstroke. First 2 EADs appear
as depolarizations occurring before
repolarization finalizes; the next 2
disturbances attempt to start a PVT.

Literature Analysis
Risk of SCD
In a large population study3 on noncardiac medication
that prolongs QTc, the odds ratio for SCD by oral domperidone increased 5.4-fold (2.212.7). After adjustment for diabetes mellitus, arrhythmias, heart failure, hypertension,
smoking, alcohol abuse, cerebrovascular and cardiovascular
ischemia, current use of diuretics, and cardiac glycosides,
the odds ratio remained 3.8 (1.59.7). Furthermore, among 7
offending drugs, domperidone scored the greatest increased
risk for SCD. A prospective in-hospital casecontrol study4
for cardiac arrest by non-antiarrhythmic QTc prolonging drugs
showed similarly that domperidone generated the highest odds
ratio for cardiac arrest 4.7 (1.416).
A large epidemiological study5 identied 41 incidents
related to domperidone exposure in 12,096 person-years (incidence = 0.0034). In the population at large, SCD has an average incidence of ;0.00125 (0.00050.002)5 and thus the odds
ratio for domperidone computes to 2.72 (1.76.8). In all 3
above studies,35 the incidence of SCD with domperidone substantially exceeds that of cisapride, a prokinetic agent withdrawn from market because of its arrhythmogenic liability.
A remake of the original Straus study3 was requested by
the marketing authorization holder to focus on domperidone
singly, using a larger population and also taking into account
dose dependence. During use of domperidone, the odds ratio
for SCD remained signicant: 3.72 (1.728.08).6 However, for
patients using only 30 mg/day, the odds ratio dropped to 2.57
(0.798.36), but when using .30 mg/day, the odds ratio
steeply increased to 16 (3.4973.6). In parallel, authors
used/supported by Johnson & Johnson also published that
domperidone signicantly increased the odds ratio for SCD
to 1.59 (1.281.98),7 and this increased risk for SCD remained
after adjustment for multiple covariates.
Thus, in all 5 large population-based studies,37 oral
domperidone consistently increased the odds ratio for SCD
and its average weighed to the inverse of the variance of the
estimates computes to 2.8 (1.536.21).

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Benets in Gastrointestinal Disorders

Diabetic Gastroparesis
In a systematic review of 28 trials covering 1016 patients,
the authors concluded: poor evidence either in support of or
against the use of domperidone in the treatment of diabetic
gastroparesis.31
Gastroesophageal Reux
A systematic review29 of 4 available randomized controlled trials concluded that domperidone does not appear to
be no more effective than placebo. A later, evidence-based
systematic evaluation similarly concluded that domperidones
benet was troublingly inconsistent or inconclusive.30
A double-blind crossover study, in which patients
received domperidone 80 mg/day35 concluded, even at this
high dose: No signicant difference was demonstrated in
symptomatic improvement between placebo [and] domperidone. Unexpectedly, there was also no difference between
patients with normal or with delayed gastric emptying.
Gastrokinetic Effects
Recently, 2 crossover studies showed that a standard
tablet of 10 mg domperidone had no effect on gastric
emptying.36,37 At 40120 mg/day, 2 of 5 studies could detect
a signicant improvement of gastric emptying when reaching
80 mg/day.38 Such doses are expected to reach the high end of
therapeutic free plasma concentrations (;20 nM),21,27,38
where effective block of DA2 receptors (IC50 ;30 nM in
guinea pig gastric muscle) is expected.39 Thus, gastric prokinetic effects sometimes become detectable around 80 mg/day.
Functional Dyspepsia
Functional dyspepsia, that is, without organic lesions, is
frequently associated with anorexia, nausea, vomiting, epigastric
discomfort, and postprandial fullness and often also exhibits
delayed gastric emptying. Hence, the presumed prokinetic action
of domperidone has widely become assumed to be useful in the
treatment of functional dyspepsia. However, an extensive review
of these symptomatic benets of domperidone38 acknowledges
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that much of the data suffers from: methodological limitations

such as inadequate numbers of patients, lack of randomization,
lack of placebo control and poor denition of inclusion and
exclusion criteria for patient selection. Actually, the authors
provide 12 references38 supposed to support symptomatic improvements by domperidone: 8 are abstracts only, 3 are data
stored at Janssen Pharmaceutica, and only one reviewed paper.40
The latter is an enriched study: of 20 patients with gastropathy,
12 of 13 who responded to high doses of domperidone (40
80 mg/day) were selected; 8 of these 12 exhibited benets on
domperidone and only 3 on placebo. Thus, at dosages exceeding
the dened daily dose (30 mg/day), domperidone could still only
elicit a nonsignicant trend toward benets (P = 0.09; Fisher
exact test).
No other expert review of substantive articles on
functional dyspepsia could be found; only one randomized,
large, multicenter double-blinded study in 1298 patients with
functional dyspepsia in whom organic lesions were endoscopically excluded, exists.32 Of these patients, 227 were treated with
domperidone 30 mg/day orally and compared with 410 patients
on placebo (remaining patients receiving other treatments). At
the start of the study, the scores for gastrointestinal disturbances
were similar for placebo (14.05 6 5.03) and domperidone
(14.02 6 4.98). After 28 days of treatment, the scores improved
markedly to 5.72 6 4.73 for domperidone and 6.28 6 5.28 for
placebo, but the benecial effects of domperidone were not
signicantly different from those of placebo (P = 0.19).

RiskBenefit Data Provided by the FAMH

The above clinical data show consistently that domperidone increases SCD without solid evidence for benet beyond
placebo. These data were shared with the FAMH together with
a request for evidence for a positive riskbenet. The FAMH
explained that functional dyspepsia (without organic lesion) is
the only approved indication and that for this indication the
benets were well established. The institute provided 20 references in support of this position (Table 1).
Articles 1 to 7 are nonrefereed/unpublished condential
reports that are unavailable for evaluation. Articles 8 through
15 included patients with organic diseases (in article 8, 32/40
and 34/67 patients; in article 9, 37/42 patients; 10, 8/10
patients; 11, 10/16 patients; 12, 13/36 patients; 13, 7/17
patients; 14, 48/48 patients, and 15, 5/14 patients). Article 16
deals primarily with cisapride. Thus, only 4 of the supplied
articles may qualify for evaluation of domperidones potential
benets in functional dyspepsia.
Article 17: 40 patients were veried by radiological
examination to have no organic disturbances. After 4
weeks of treatment both the domperidone (30 mg/day
orally) and placebo group had 5 of the 6 symptoms
improved, but these changes were not different between
domperidone and placebo.
Article 18: in a randomized, crossover double-blind trial,
9 patients each were treated with domperidone followed
by placebo, or placebo followed by domperidone for 3 +
3 weeks. Both groups showed signicant improvement
with respect to dyspepsia, but the improvement was
without signicant differences between them. (However,
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Domperidone: Negative RiskBenefit

a signicant benet with respect to atulence was

reported.)
Article 19: domperidone and placebo were compared in
random order for a month in 11 patients. No signicant
superiority of domperidone over placebo could be detected.
Article 20 is the only article, which is a sufciently large,
double-blind, randomized multicenter study, to reliably
evaluate the effects of domperidone in idiopathic dyspepsia.32 However, as described in detail above, domperidones benet was not different from that of placebo.
In summary, clinical publications on use of domperidone in organic disease or functional dyspepsia conclude that
domperidones benets do not exceed those of placebo.

DISCUSSION
The present experimental results show that concentrations as low as 30 nM domperidone signicantly prolong
APD, whereas 60 nM also induces disturbances of repolarization (TRIaD), EADs, and serious proarrhythmia (PVT). In
5 of 5 large population studies, domperidone signicantly
increases SCD 2.8-fold (1.536.21-fold). At the same time,
expert reviews and a large blinded trial show that the benets
of oral domperidone at the dened daily dose of 30 mg/day
do not exceed those of placebo. Only at 80 mg/day does the
prokinetic effects of domperidone sometimes become detectable, but then the risk for SCD is markedly increased.

Domperidone Prolongs the APD, Disturbs

TRIaD, and Has a Low Safety Margin
The prolongation of APD by 100 nM domperidone,
already described in detail by Drolet et al in 2000,15 was conrmed in the present study, but found to be larger than previously reported (125 vs. 31 ms). This larger prolongation may
result from (1) longer equilibration times (150 vs. 15 minutes),
(2) longer cycle lengths (1000 vs. 250 ms) for a drug that
exhibits reverse use dependence,15,16 and (3) use of rabbit
hearts (high sensitivity to Ikr block)41 instead of guinea pig.
As a result, APD prolongation became signicant at 30 nM,
which is compatible with a 34.5% block of hERG channels at
30 nM in voltage clamp experiments.19
Because at 30 nM disturbances of repolarization were
rare and not signicant, but at 60 nM domperidone induced
signicant TRIaD, EADs, and PVT, domperidones proarrhythmic liability must increase steeply around 45 nM. The
free plasma concentrations of domperidone range from 5 to 19
nM,21 resulting in a safety margin of only ;2.5 (45/19), that
is, far below the widely accepted norm of 30, which is considered as a strict minimum for safe drug use in patients.21 This
is especially bothersome because inhibition of domperidones
metabolism by CYP3A4 can increase its free plasma concentration in man up to 10-fold.16,42 In this way, the free drug
plasma levels can fully overlap with proarrhythmic concentrations in vitro and thus predict a proarrhythmic liability. In
addition, the hERG receptor is accessible from the cytoplasm,
where intracellular drug disposition was recently shown to be
modulated by drug transporters.43 Because drugs and disease
can regulate these transporters, whereas interaction between
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drugs can alter cytoplasmic drug levels (including for domperidone),44 marked modulation of drug toxicity can occur.

Risk of SCD
It is then not surprising that numerous cases of SCD
have been reported with domperidone.814 However, spontaneous reporting of relatively rare events and small case
control studies do not have the power to establish a correct
incidence of side effects.45 That all 5 population studies
detected a signicant increase in SCD is quite worrisome,
as epidemiological studies are notoriously ineffective to
detect such liability, even for drugs known to prolong the
QTc interval and to posses proarrhythmic liabilities.5,45 Thus,
the 2.8-fold increase of SCD may be somewhat optimistic,
especially at dosages above 30 mg/day, where an odds ratio
for SCD of 16 (3.49 to 73.6) has been reported.6 It must also
be pointed out that the reported odds ratios in the literature
were not fully adjusted, that only one study6 considered dose
response and most studies were not large enough so that the
condence intervals around the estimate are rather large. Nevertheless, the fact that all 5 studies detected a signicant
increase of SCD is strong evidence for a high risk, but there
remains a large uncertainty about its precise magnitude.
In 2010 (last year available at Pharma.be), 32,484,962
dened daily doses of domperidone (30 mg) were sold
in Belgium. This is enough to medicate 88,999 patients throughout the year. In 88,999 patients not on domperidone, one estimates ;111 SCD/year (88,999 0.00125), which in patients on
domperidone increases to ;310 SCD/year (88,999 0.00125
2.8), that is, ;199 excess SCD/year with a lowest estimate of
only 60 SCD/year, but 580 extra SCD/year can also not be
ruled out. Extrapolation of these Belgian numbers to the more
than 100 countries where domperidone is used renders even the
most optimistic estimate tragic.
Alarmingly, domperidone is now also used for (unapproved) stimulation of milk production, in dosages up to
160 mg/day.46 The dangers of such usage for mother and
baby are unknown, but the incidence of SCD at lower dosages
renders the potential for sudden maternal death dreadful.

J Cardiovasc Pharmacol   Volume 61, Number 3, March 2013

are signicant, whereas the benets appear similar to those of

placebo. Such riskbenet violates the rst principle of clinical
pharmacology: Primum non nocere [rst do no harm],
which requires that efcacy and safety be adequately documented and balanced before a drug is widely used. In the case
of domperidone, it was introduced to the market in 1978, that
is, before hERG-related liabilities were well recognized. However, starting in 1982, clinical lethal proarrhythmia (primarily
intravenous use of domperidone) became well established913;
in 2000 the electrophysiological mechanisms for this liability
were described15; between 2005 and 2010 the increased risk
for SCD by oral use became known.37 A compound with
placebo-like benets that increases the risk for SCD cannot
be an acceptable medication. This is especially true when its
plasma concentration can unexpectedly markedly increase (eg,
by CYP3A4 inhibition or modulation of transporters).42,43,47
The Food and Drug Administration s adagio that a drug is
useless unless proven effective, and dangerous unless proven
safe, probably has saved numerous lives by having correctly
banned domperidone from wide use in the United States.

CONCLUSIONS
1. Cardiac electrophysiology: domperidone signicantly prolongs APD starting at 1.5 the therapeutic concentration.
Around 3 times the therapeutic concentration domperidone
markedly disturbs repolarization (TRIaD) with EADs and
PVT.
2. Domperidones safety index (;2.5) is 12-fold below
the minimum margin for a safe drug.
3. In clinical use, domperidone signicantly increases the odds
ratio for SCD, which steeply increases with increasing doses.
4. Domperidones benets against various gastrointestinal disorders and symptoms do not signicantly differ from
placebo.
A placebo-like agent with narrow safety margin and
lethal side effects should not be used in medicine.

Benefits for Gastrointestinal Indications

Expert reviews on domperidones effects in patients with
gastroesophageal reux,29,30 diabetic gastroparesis,31 and prokinetic benets3640 generally conclude that benets for domperidone are inconclusive or no greater than for placebo. Many
clinical studies on the benets of domperidone intermix functional and organic disease suffer from small size and a less than
optimal study design. Only one large, double-blind study on
the effects of oral domperidone in functional dyspepsia which
specically excluded organic disease could be found32:
although domperidone signicantly reduced the symptoms,
this reduction was also not different from that with placebo.

RiskBenefit Assessment
In 2002, De Ponti et al45 warned that use of drugs with
published reports on ventricular arrhythmias,314 especially
when associated with APD/QT prolongation,15,16,45,47 Torsades
de Pointes,14 or ofcial warnings,20 should prompt careful
riskbenet assessment. For domperidone, the risks for SCD

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ACKNOWLEDGMENTS
The author thanks Bruno Hespel and Elisabeth Beck for
their assistance with the experimental work and Dr Johan Frans
for his careful reviewing and numerous good suggestions.
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