Keywords
children - functional dyspepsia - anti-nausea bands - Placebo
Schlüsselwörter
Kinder - funktionelle Dyspepsie - anti-Nausea Bänder - Placebo
FD Functional dyspepsia
FGIDs Functional gastrointestinal disorders
IB Iberogast-Group
IBPL IberogastPlacebo-Group
PONV postoperative nausea and vomiting
WB Wristband-Group
WBPL Wristband Placebo-Group
VAS Visual Analogue Scale
What is known
▪many children suffer from functional epigastric discomfort ▪ the pathophysiology
is
complex, therefore no standard guidelines for the treatment exist
What is new
▪STW-5 and anti-nausea wristbands are a cheap and effective options to treat children
suffering from functional dyspepsia ▪a reduction of gastrointestinal symptoms did
not correlate with an improvement of cognitive performance
Background
Functional gastrointestinal disorders (FGIDs) are very common in children of all
ages. It is an umbrella term for discomfort in any part of the gastrointestinal
tract, which cannot be explained by structural or biochemical abnormalities [1]. FGIDs are diagnosed according to the
symptom-based Rome criteria, which have been revised in 2016 (Rome IV criteria,
[2]) and rely on the medical history
and physical examination. Dyspepsia refers to the Greek words ‘dys’ and ‘peptos’ and
is translated with ‘hard to digest’. Functional dyspepsia (FD) is a sub-group of
FGIDs, it is a clinical syndrome comprising chronic symptoms arising from the
gastroduodenal region. According to the Rome criteria, the prototypical symptoms are
postprandial fullness, early satiation, epigastric pain or burning not associated
with defecation. The diagnosis of FD can be made in children and teenagers, once one
of those symptoms occur a minimum of four times a month for at least two months and
after appropriate evaluation, to ensure that the symptoms cannot be explained by
another medical condition [2]. The
pathophysiology is still not fully understood, but it seems to rely on a combination
of visceral hypersensitivity, motility disturbances, alteration in gastrointestinal
microbiota, mucosal and immune function and central nervous processing [3].
Treatment of FD is challenging and based on empiric strategies due to the lack of
published treatment trials on chronic nausea, especially in children. Studies
suggest that hypnotherapy targets the aetiologic biopsychosocial factors and
therefore modifies visceral hypersensitivity [4].
Herbal medications have multiple mechanisms of action in virtue of diverse components
potentially regulating various, complex aetiologies simultaneously and
comprehensively improve symptoms of FGIDs. The herbal combination STW-5 (Iberogast)
was shown to relax muscle activity in the fundus area of the stomach but to enhance
the contractions in the antrum area in an animal study [5]. In a study with healthy adults,
administration of STW-5 led to a significant increase in proximal gastric volume
measured with a gastric barostat, whilst the antral pressure wave increased [6]. STW-5 is a liquid preparation
including fresh plant extracts from eight dried herbs and is sold across Europe as
over-the-counter medication. Overall, it regulates motility by acting on the
gastrointestinal smooth muscles in an area-specific manner, stimulates gastric
secretion and exerts spasmolytic, choleretic, anti-inflammatory and carminative
effects [7]
[8]. Several studies proved its efficacy
in adults suffering from FD [9]
[10], but no data for children is
available.
Another – on first sight unusual – approach to overcome nausea is the use of
acupuncture (needling), acustimulation (electrical stimulation) or constant pressure
(acupressure) to the P6 acupuncture point (located on the side of the wrist), which
is recognized as a target pint in Chinese and acupuncture medicine for reducing
nausea and vomiting. It seems, that the effect of this method is an electrical
stimulus of low frequency on sensory receptors in the skin, which are activators of
A delta and A beta fibers. These fibers synapse in the posterior horn and this might
result in release of endorphin in the hypothalamus [11]. The increase in beta-endorphin
concentration in human CSF after acupuncture stimulus has been described [12].
The aim of this study is to compare the therapeutical effect of plant extracts and
acupressure in children with functional dyspepsia and perform a standardized test
of
cognitive psychology.
Methods
This is a randomized controlled double-blind trial of paediatric patients with FD.
Children between the age of 6 and 18 years, who complained about gastric symptoms
(pain, nausea, fullness) and had a normal full blood count, a normal thyroid
function, a negative coeliac screening (normal t-transglutaminase antibodies, normal
total IgA) and most importantly normal macro- and microscopic findings on
oesophago-gastro-duodenoscopy (all had biopsies taken from duodenum, stomach and
oesophagus) were informed about the study between September 2016 and September 2020.
Exclusion criteria were gastrointestinal infection less than two weeks ago, an
underlying gastrointestinal disease, use of drugs two weeks prior to starting the
study. After signing the informed consent by the participant and/or legal
representative respectively, patients were asked to fill in the Kidscreen-52, a
cross-cultural validated questionnaire consisting of 52 questions to assess the
health-related quality of life [13], as
well as the extent of their discomfort (using a standardized visual analog scale
(VAS), points 1–10). In addition, participants had to take a quick test on the
computer: Eriksen flanker task [14], a
validated task used to study cognitive processing, attention and control processes
(e. g. interference, activation and inhibition). Patients themselves drew a lot,
where the type of treatment (Iberogast/wrist band) was determined, of course neither
the patient nor the study nurse knew whether an original product or the placebo
equivalent was given. Patients were randomized allocated to four different
treatment-groups
1. Children get treated with STW-5 (Iberogast (IB)), dosage as per recommendation
of
the producer (Children<12 years: 3x 20 drops a day; Children<12 years: 3x15
drops a day): They received the original STW-5 in a neutral bottle without primary
package and label
2. Children get treated with an Iberogast-Placebo (IBPL), same dosage as original
STW-5: They received the same neutral bottle, containing Placebo. To get the same
acerbity as the original product, quinine and brown food coloring for the appearance
was used. This was also prepared and blinded by the Hospital Pharmacy.
3. Children receive a wristband (WB) with the effect of an acupressure (psiBands):
They received an official acupressure wrist band, that must be worn over the whole
time (the correct area is in between the two tendons on the underside of the wrist-
two finger widths from first crease in wrist) without the original packaging
4. Children receive a Placebo wristband ((WBPL), same wristband without an effect
of
acupressure), which must be worn all the time (the correct area is in between the
two tendons on the underside of the wrist- two finger widths from first crease in
wrist) without the original packaging.
Participants had to take the allocated medication or wear the wristbands for a total
of four weeks and keep a diary about the daily complaints. At the end of the four
weeks, participants had to fill out the same questionnaire concerning quality of
life and extent of medical condition, and they were asked to re-do the flanker task.
[Fig. 1] displays the course of the
study.
Fig. 1 Study method.
Statistical analysis
Statistical analysis was performed with SPSS 22.0 for Windows. As the visual
analog scale possesses interval and ratio properties, it was treated as
numerical data. One-way ANOVA was used to compare baseline values between the
four groups. Subsequently, 4 groups by 2 (time: baseline, post-intervention)
ANOVA with repeated measures on the second factor was employed to analyse the
effect of therapy on functional nausea. Main effects and interactions were
reported. When significant F-ratios were obtained, Bonferroni was used as post
hoc test for individual comparison. For all statistical comparisons, an alpha
level of p≤0.05 was considered significant. Eta-squared (eta2) was
measured as effect size and interpreted after Cohen [15] as following: > 0.01 (small),
> 0.06 (medium) and >0.14 (large).
Ethical statement
The present study was approved by the ethical committee. Furthermore, the study
was conducted in accordance to the ethical principles laid down in the
Declaration of Helsinki and its later amendments.
Results
From 273 children suffering from nausea with normal macroscopic and histological
findings in an upper endoscopy, 60 patients agreed to participate in the study, of
which 27 terminated the participation due to fading symptoms whilst the trial.
Therefore, a total of 33 patients were included in the study: 12 male and 21 female
with an average age of 12.09 years (7–17 years), an average weight of 47.2 kg
(range: 22–105 kg) and an average length of 151 cm (range: 120–179 cm). For further
patient characteristics and allocation to the different treatment groups, we refer
to [Table 1].
Table 1 Patient’s characteristics
|
Male
|
Female
|
In total (female and male)
|
|
n
|
Mean age (years)
|
Mean weight (kg)
|
Mean height (cm)
|
n
|
Mean age (years)
|
Mean weight (kg)
|
Mean height (cm)
|
n
|
age in years (range)
|
weight in kg (range)
|
Height in cm (range)
|
|
IBPL
|
2
|
13.5
|
48.2
|
155.5
|
4
|
14
|
67
|
168
|
6
|
13.8 (12–16.5)
|
60.7 (34–90)
|
163.8 (153–179)
|
|
IB
|
1
|
13.5
|
42.5
|
168
|
6
|
12.4
|
47.4
|
149.8
|
7
|
12.6 (8.3–17.8)
|
46.7 (18.8–105)
|
152.4 (122–179)
|
|
WB
|
6
|
9.9
|
31.8
|
134.2
|
9
|
11.4
|
40.8
|
147.7
|
15
|
10.8 (7.5–17)
|
37.3 (20–65)
|
142.3 (117–170)
|
|
WBPL
|
3
|
9.8
|
38.8
|
136.6
|
2
|
11.25
|
35.5
|
142
|
5
|
10.4 (6.5–12.5)
|
37.5 (26–59.5)
|
138.8 (122–155)
|
IBPL: Iberogast-Placebo; IB: Iberogast; WB: Wrist band; WBPL: Wrist band
Placebo
Subjectively, symptoms improved after four weeks of intervention in most
treatment-groups: By 68% in children, who received Iberogast (IB), by 40% in the
wristband (WB)- group and by 35% in the wrist-band-Placebo-group (WBPL). Patients
receiving Iberogast-Placebo (IBPL) showed an increase in symptoms by 10% over the
treatment course of four weeks. [Fig.
2] illustrates the subjective, overall state of health pre- and
postinterventional of the four treatment-groups as described above.
Fig. 2
a The course of the overall, subjective state of health b ) The
course of the overall, subjective state of health.
The analysis of the Kidscreen-52 showed, that she sleeping pattern and physical state
improved in all four treatment groups, also the number of symptom-free days
increased in all patients. Overall happiness showed a positive shift after four
weeks of treatment, except for the patients treated with IBPL.
When comparing the results of the Flanker task, there were no statistically
significant changes after the intervention, except for the WBPL intervention group,
which showed a significant improvement in the accuracy of reaction. All results
mentioned and further statistical results can be found in [table 2].
Table 2 Results
|
|
|
pre-intervention
|
post-intervention
|
|
|
|
|
|
mean (range)
|
SD
|
mean (range)
|
SD
|
d
|
F
|
p
|
eta2
|
|
Results Questionnaire Quality of life
|
Overall
(degree of symptoms in the previous 7 days, from 0–10 using the VAS)
|
IB
|
4.14 (2–6)
|
2.04
|
1.29 (0–4)
|
1.50
|
1.60
|
|
|
IBPL
|
3.00 (0–6)
|
2.00
|
3.33 (0–6)
|
1.75
|
− 0.18
|
|
WB
|
4.00 (0–8)
|
1.81
|
2.40 (0–8)
|
2.69
|
0.70
|
|
WBPL
|
2.80 (0–6)
|
1.79
|
1.80 (0–3)
|
1.10
|
0.67
|
|
Symptom-free
(on how many days of the previous week was the patient completely
without any symptoms; 1–7)
|
IB
|
3.14 (0–7)
|
2.91
|
4.14 (2–7)
|
1.68
|
− 0.42
|
|
IBPL
|
2.38 (0–7)
|
2.88
|
3.63 (0–7)
|
2.39
|
− 0.47
|
|
WB
|
2.06 (0–7)
|
1.92
|
3.12 (0–7)
|
2.37
|
− 0.49
|
|
WBPL
|
4.33 (2–7)
|
1.73
|
4.78 (2–7)
|
1.92
|
− 0.24
|
|
Sleep
(difficulty falling/staying asleep, amount of distress about sleep;
0–28 points)
|
IB
|
8.86 (4–17)
|
5.34
|
6.14 (o-21)
|
7.27
|
0.43
|
|
IBPL
|
11.25 (2–18)
|
6.63
|
9.00 (0–21)
|
8.23
|
0.30
|
|
WB
|
8.53 (0–19)
|
5.70
|
6.16 (0–16)
|
5.24
|
0.43
|
|
WBPL
|
8.44 (1–20)
|
5.22
|
6.44 (0–23)
|
7.30
|
0.32
|
|
Physical state
(did the patient feel fit and able-bodied, be comfortable; 4–20
points)
|
IB
|
15.00 (11–22)
|
4.58
|
18.71 (10–22)
|
4.27
|
− 0.84
|
|
IBPL
|
16.50 (13–23)
|
4.34
|
17.25 (12–22)
|
4.65
|
− 0.17
|
|
WB
|
17.79 (10–24)
|
4.44
|
19.11 (7–24)
|
5.05
|
− 0.28
|
|
WBPL
|
16.67 (12–22)
|
3.35
|
18.22 (10–23)
|
3.99
|
− 0.42
|
|
Emotion
(was the patient happy, content and pleased to be alive in the last
7 days; 6–30 points)
|
IB
|
23.00 (19–29)
|
3.37
|
25.86 (19–30)
|
3.63
|
− 0.82
|
|
IBPL
|
25.00 (18–30)
|
4.21
|
24.38 (18–29)
|
4.47
|
0.14
|
|
WB
|
25.32 (15–28)
|
3.83
|
26.63 (23–30)
|
2.54
|
− 0.40
|
|
WBPL
|
23.22 (12–28)
|
4.94
|
23.89 (12–30)
|
6.23
|
− 0.12
|
|
Results Flanker-Test
|
Interference
(response time due to inhibition)
|
IB
|
0.55
|
94.94
|
15.41
|
63.20
|
− 0.18
|
0.18
|
0.91
|
0.02
|
|
IBPL
|
18.99
|
44.37
|
31.29
|
25.69
|
− 0.34
|
|
WB
|
43.43
|
56.70
|
52.38
|
68.01
|
− 0.14
|
|
WBPL
|
− 42.33
|
164.54
|
0.43
|
24.69
|
− 0.36
|
|
Switching
(response time due to switching)
|
IB
|
515.54
|
170.31
|
589.25
|
243.64
|
− 0.35
|
1.52
|
0.24
|
0.16
|
|
IBPL
|
600.26
|
112.37
|
509.99
|
116.98
|
0.79
|
|
WB
|
598.45
|
202.72
|
538.34
|
125.51
|
0.36
|
|
WBPL
|
471.98
|
122.96
|
513.55
|
111.79
|
− 0.35
|
|
Accuracy
(Accuracy at flanker, corresponds to inhibition)
|
IB
|
0.95
|
0.07
|
0.99
|
0.014
|
0.67
|
1.16
|
0.34
|
0.13
|
|
IBPL
|
0.95
|
0.06
|
0.97
|
0.01
|
0.46
|
|
WB
|
0.98
|
0.03
|
0.95
|
0.12
|
− 0.32
|
|
WBPL
|
0.83
|
0.29
|
0.96
|
0.04
|
0.61
|
|
Switching accuracy
(Accuracy in switch trials of the flanker task, corresponds to
cognitive flexibility)
|
IB
|
0.76
|
0.17
|
0.86
|
0.11
|
0.68
|
0.96
|
0.42
|
0.07
|
|
IBPL
|
0.89
|
0.08
|
0.88
|
0.08
|
− 0.12
|
|
WB
|
0.90
|
0.07
|
0.90
|
0.11
|
0.00
|
|
WBPL
|
0.90
|
0.07
|
0.88
|
0.09
|
− 0.30
|
One patient complained about a wristband, which was too tight, but he solved the
problem by over-stretching it. Otherwise, no adverse events occurred.
Discussion
This randomized double-blind, placebo-controlled pilot-study in children suffering
from FD revealed following key-findings: Over the course of four weeks, patients of
all treatment groups had a subjectively improved sleeping pattern, an overall better
physical state and were symptom-free on more days per week. All interventions
-except for IBPL- also lead to a more positive state of mind and a reduction of
symptoms, represented by VAS.
The pathophysiology of FGDI’s is a complex, multifaceted interaction of visceral
hypersensitivity, central sensitization, gut microbiota and its metabolic products
(such as short-chain fatty acids), early-life programming (surgeries, infections
etc.), gastrointestinal motility, neuroimmune interaction [16] and psychological factors.In our
study, the objective and subjective findings did not correlate, which is absolutely
in line with literature, demonstrating the correlation of psychosocial factors and
the presence of FGDI’s: Children and adolescents with FGDI’s tend to have a poorer
mental health, elevated levels of anxiety, depression, higher stress levels,
exposure to stressful life events, a lower quality of life and present with a higher
frequency of extra-intestinal somatic symptoms, such as headaches, fatigue and sleep
disturbances, compared to their healthy peers [17]. Also, social contextual factors, such as parental chronic pain, have
been associated with a higher frequency of pain episodes in children [18]. Evidence suggests, that parental
influence -explained by frameworks such as social learning theory and the social
communication model of pain- plays a crucial role in shaping children’s pain
perception [19]
[20]. Meaning, parents may inadvertently
encourage their children to mimic their pain expressions, thereby influencing the
child’s pain experience and behavior. Given that functional disorders are understood
to be multifactorial in origin, with socio-emotional factors and pain management
playing a significant role in the perception of pain, it is not surprising that the
efficacy of pharmacological approaches (e. g. antispasmodics, antibiotics,
antihistaminic, antiemetic) in children with FGDIs is not satisfying [21].
In this study, most of the patient’s condition subjectively improved regardless of
the intervention. One contributing factor might be the security the patients
received from learning that the result of the endoscopy was normal, although it was
shown that a negative endoscopy alone does not improve the clinical outcome of
children with FGIDs [22]. Hollier et al.
[23] have shown that somatization
and catastrophizing are mediating anxiety and depression, which increases the
abdominal discomfort. Therefore, early prevention of somatization by objective
parameters could prevent long-term functional abdominal pain, but with the
possibility that the tendency to somatization disorder may persist and focus on
another organ.
The debate of the role of wristbands in the treatment of nausea is still on-going.
A
randomized controlled trial of 90 women suffering from hyperemesis gravidarum showed
milder symptoms in patients receiving acupressure via wristband vs. the control
group having standard medication [24]. A
meta-analysis of twelve studies assessing the effectiveness of acupressure in
preventing chemotherapy-induced nausea and vomiting was performed [25]: Over 1400 patients were included and
showed that acupressure reduced statistically significant the severity of acute and
delayed nausea, but no beneficial effect on the incidence or frequency of vomiting
was found. A randomized, single-blind, placebo-controlled clinical trial [26] involving 90 patients with acute
myocardial infarction and persistent nausea despite the use of anti-emetic
medications found a significant (p<0.05) reduction in vomiting in the acupressure
group, using the same wrist-bands we used in this study, compared to the placebo and
control groups.Lately, acupressure seems to be undergoing an image change to a
serious science, which is reflected by a publication in The British Journal of
Anaesthesia, the highest-ranking journal worldwide in the field of anaesthesia: Wang
et al. [27] performed a study in almost
300 women undergoing hysteroscopic surgery, where besides pain, postoperative nausea
and vomiting (PONV) is the most common complication of surgery and anaesthesia.
Patients received a bracelet with transcutaneous electrical acupoint stimulation for
24h postoperatively and were compared to patients wearing the same bracelets being
switched off. The incidence of vomiting was statistically significant lower in the
intervention group (36% vs. 18%, p= 0.003), whereas the nausea was not significantly
different.
Whilst adults benefit from anti-nausea wristbands to some extent, literature search
revealed that no data from paediatric trials are yet available. In our cohort,
children did improve after an intervention with the wristband, however, so did the
children wearing WBPL. An extensive education about the disease might explain the
good response rate to the WBPL: Not only children, but also parents were intensively
informed about the aetiology and the different therapeutical approaches in FD to
ensure they do not fear any disadvantages arising from participating in the study.
American psychologists [28] tested a
cognitive-behavioral intervention delivered to parents of children with FGID’s and
found an improvement of the child’s symptoms by educating/strengthening parents.
This theory, however, does not explain that the IBPL-group did not benefit from the
intervention, although they did receive the same education.
STW-5 (Iberogast), an herbal combination, has been developed over 5 decades ago to
treat patients suffering from FD. It was not only shown to increase antral motility
[5], reduce inflammation [29], but a review of 12 clinical trials
of double-blind and randomized studies found statistically significant effects on
patient’s symptoms with a comparable efficacy to a standard prokinetic, and a
favorable tolerability, which is relevant for long-term treatment [30]. A double-blind, randomized,
placebo-controlled crossover trial in adult patients with FD and reflux symptoms
demonstrated a significant reduction in the total number of acidic reflux events
following four weeks of treatment with STW-5 compared to placebo, confirmed by
pH-metry studies [31]. Authors concluded
that while STW-5 had no observable effect on oesophageal motility, it significantly
reduced acid exposure time. This finding implies that a reduced volume of refluxed
acid, possibly due to improved gastric emptying and enhanced gastric motility, may
underlie the pharmacological effects of STW-5. This might also explain the benefit
our patients experienced, as a swift gastric emptying clearly prohibits fullness and
discomfort.
As FD causes considerable strain on many children’s lives, an international pediatric
committee performed a systematically assessment of evidence, efficacy and safety of
pharmacological treatments of FD in children aged 4–18 years [32], where no evidence was found to
support the use of pharmacological drugs. It was recommended to treat the different
subtypes of FD (epigastric pain and postprandial distress syndrome) based on adult
data and customized. For the postprandial distress type, the committee recommends
the use of fundal relaxant medications, which equals STW-5. Our findings of a good
response to STW-5 are therefore not only in line with those recommendation, but also
with a prospective observational study of 980 children between 3 and 14 years [33], where a very good effect of STW-5
was shown with only 0.7% reporting adverse events. STW-5 seems to be a good and safe
option for children suffering from FD with a pharmacologic effect, which is
underlined by the fact, that the placebo-group did not show any improvement of
symptoms, in contrast.
A clear limitation of the present study is the small number of included patients.
Although over 200 children were offered participation in the study, only a few
agreed to participate in the trial. The most frequently mentioned reasons for
declining participation were, that ‘they only wanted to rule out somatic diseases’
and ‘a lack of time’- both reasons were provided by the parents. Also, only a
fraction of patients fully completed the 4-week intervention with pre- and
post-testing, many participants suddenly did not answer calls and/or Emails and
therefore dropped out. From a statistical perspective, this presented us with the
problem of an absent statistical significance, indicated as p-values, as this
correlates strongly with the sample size. In awareness of this problem, the effect
size (eta2) was calculated, which showed a big effect for the overall subjective
improvement of condition. The high drop-out rate of our participants might be
explained by findings from different studies [34]
[35], showing that parents
of children with chronic pain struggle with the time consumption of attending doctor
and therapy appointments, which is only possible when a strong social support
network is in place to provide assistance and flexibility for the changing needs,
whilst a low socioeconomic status is associated with a higher frequency of recurrent
pain in children [36]
[37]. In short, the care of children with
chronic pain is extremely time-intensive, which can push parents to their limits of
capacity and, consequently, leave them feeling overwhelmed by the prospect of
participating in a study.
As a side study, participants had to perform the Flanker task. The idea behind this
test was our hypothesis, that chronic epigastric discomfort could impair cerebral
performance, consequentlyan improvement in symptoms could be objectified with an
improved mental function. There are no data available on this subject. Surprisingly,
only the WBPL-intervention group, which also showed a subjective improvement in
symptoms, showed an improvement in cerebral responsiveness. The data from the
Flanker task are not coherent with the reported, subjective gastrointestinal
symptoms, which is most likely due to the patient groups being too small.
Conclusion
The pathophysiology of FD is complex and multifactorial, involving hypersensitivity,
altered microbiota and central nervous processing as well as behavioral patterns.
Our double-blind, placebo-controlled pilot study showed, that STW-5 and/or
anti-nausea wristbands are a cheap and effective option to treat children and
teenagers suffering from FD. It certainly is only a method to reduce discomfort
selectively, long-term data are not available.
Contributor’s Statement
C.Légeret and R. Furlano formed the study concept and provided the funding. M.
D’Aujourdhui, S. Schneider, A. Acket and H.Köhler performed data acquisition, S.
Ludyga performed statistical analysis, C. Légeret wrote the first draft of the
manuscript, all authors read and agreed to the latest version of the manuscript.
Fundref Information
Gottfried and Julia Bangerter-Rhyner-Foundation —
