Hypersensitivity for capsaicin in patients with functional dyspepsia

Article (PDF Available)inNeurogastroenterology and Motility 20(2):125-33 · March 2008with66 Reads
DOI: 10.1111/j.1365-2982.2007.00997.x · Source: PubMed
Abstract
The pathophysiology of functional dyspepsia is poorly understood, thus diagnostic and therapeutic options for this disease are limited. We assessed the relevance of a simple test for chemical hypersensitivity by applying an oral capsaicin load. After a preliminary dose-finding study, 61 healthy controls and 54 functional dyspepsia patients swallowed a capsule containing 0.75 mg capsaicin. A graded questionnaire evaluated severity of symptoms before and after capsule ingestion; an aggregate symptom score was calculated by adding all symptom scores. Controls developed moderate symptoms (symptom score: 6.0+/-4.1; median: 5.0). The 75% quartile (9.0) was considered the upper limit of normal. Functional dyspepsia patients had significantly higher symptom scores (10.0+/-6.5) than controls. About 54% of functional dyspepsia patients tested positive; clinically this group was not different from the group testing negative besides being on average younger and suffering more from bloating. In additional 13 patients with functional dyspepsia who tested positive (symptom score: 15.8+/-0.9), symptom response to placebo capsules (1.9+/-0.6) was similar to controls. In reliability testing, the Cronbach alpha-value of the capsaicin test was 0.86. The capsaicin test is a simple and non-invasive method to detect a subgroup of functional dyspepsia with chemical hypersensitivity.
Hypersensitivity for capsaicin in patients with functional
dyspepsia
J.HAMMER,M.FU
¨
HRER,L.PIPAL&J.MATIASEK
Abteilung fu
¨
r Gastroenterologie und Hepatologie, Medical University of Vienna, Vienna, Austria
Abstract The pathophysiology of functional dyspep-
sia is poorly understood, thus diagnostic and thera-
peutic options for this disease are limited. We
assessed the relevance of a simple test for chemical
hypersensitivity by applying an oral capsaicin load.
After a preliminary dose-finding study, 61 healthy
controls and 54 functional dyspepsia patients swal-
lowed a capsule containing 0.75 mg capsaicin. A
graded questionnaire evaluated severity of symptoms
before and after capsule ingestion; an aggregate
symptom score was calculated by adding all symp-
tom scores. Controls developed moderate symptoms
(symptom score: 6.0 ± 4.1; median: 5.0). The 75%
quartile (9.0) was considered the upper limit of nor-
mal. Functional dyspepsia patients had significantly
higher symptom scores (10.0 ± 6.5) than controls.
About 54% of functional dyspepsia patients tested
positive; clinically this group was not different from
the group testing negative besides being on average
younger and suffering more from bloating. In addi-
tional 13 patients with functional dyspepsia who
tested positive (symptom score: 15.8 ± 0.9), symptom
response to placebo capsules (1.9 ± 0.6) was simi-
lar to controls. In reliability testing, the Cronbach
a-value of the capsaicin test was 0.86. The capsaicin
test is a simple and non-invasive method to detect a
subgroup of functional dyspepsia with chemical
hypersensitivity.
Keywords capsaicin, dyspepsia, hypersensitivity,
sensation, stomach.
INTRODUCTION
Functional dyspepsia has been defined as chronic or
recurrent pain or discomfort in the upper abdomen
without structural or biochemical abnormalities iden-
tifiable by conventional diagnostic means.
1
Sensori-
motor disorders have been proposed to be a key
mechanism leading to the emergence of symptoms in
functional dyspepsia.
2
However, mechanical hypersen-
sitivity and abnormal gastric emptying can be detected
in less than halve of the patients.
3–5
Other pathophys-
iological mechanisms, such as intestinal motor disor-
ders, Helicobacter pylori infection or an alteration in
brain–gut communication, have also been suggested to
play a role in the pathophysiology of functional
dyspepsia, although their role in symptom generation
is disputed.
6
In clinical practice diagnostic methods to evaluate
functional alterations in patients with functional dys-
pepsia have not found wide application, because of the
invasive nature of these tests and their lack of thera-
peutic relevance, as therapeutic options presently are
limited.
7
Recent data have suggested that chemical
stimulation with capsaicin might be useful for gastro-
intestinal sensory assessment independent of mecha-
noreceptors.
8–10
Capsaicin has long been used as
valuable tool in the study of chemonociception and
thermonociception elsewhere in the body.
11
The alge-
sic effects of this vanilloid arise from stimulation of
specific receptors called vanilloid receptors of type 1
(VR1), also termed transient receptor potential of the
type V1. These receptors are cation channels in the cell
membrane and are located on nociceptive afferent
neurones.
12
They serve as transducers for both noxious
thermal and chemical stimuli
12,13
and thus are not
only activated by capsaicin and related chemicals,
14
but also by, e.g. protons,
13
ethanol
15
and intracellular
lipid mediators.
16,17
Although the potential role of chemoreceptors in
gastrointestinal nociception in the intact gut has only
recently been appreciated, they have long been
Address for correspondence
Dr Johann Hammer, Universita¨tsklinik fu
¨
r Innere Medizin III,
Abteilung fu
¨
r Gastroenterologie und Hepatologie, Wa¨hringer
Gu
¨
rtel 18–20, A-1090 Vienna, Austria.
Tel: +43(0) 1 40400 4741; fax: +43(0) 1 40400 4735;
e-mail: johann.hammer@meduniwien.ac.at
Received: 14 May 2007
Accepted for publication: 11 July 2007
Neurogastroenterol Motil (2008) 20, 125–133 doi: 10.1111/j.1365-2982.2007.00997.x
Ó 2007 The Authors
Journal compilation Ó 2007 Blackwell Publishing Ltd
125
suspected to be regulators of gastrointestinal function
and to mediate local reflexes that control motility,
secretion and vascular perfusion.
11,14
They are in-
volved in viscero-visceral reflexes and in nociception
due to mediator release induced by inflammation and
ischaemia.
18,19
We hypothesized that in view of the
integrative role of VR1 in the perception of noxious
stimuli, VR1 might represent a chemosensor for
endogenous mediators that may play a role in the
pathogenesis of symptoms in functional dyspepsia.
20
Thus, chemosensory testing might be of clinical
relevance in the setting of painful gastrointestinal
disease such as the functional bowel disorders. In the
present study after preliminary dose-finding exper-
iments we aimed to (i) evaluate whether capsules
filled with a defined amount of capsaicin can repro-
ducibly induce sensations from the upper gastrointes-
tinal tract in healthy subjects and patients with
functional dyspepsia. Additionally, we aimed to (ii)
test for repeatability of the symptoms induced by the
ingestion of capsaicin capsules and (iii) determine
whether hypervigilance rather than hypersensitivity
might be causing augmented symptoms in a subgroup
of patients with functional dyspepsia.
METHODS
Healthy subjects and patients
Healthy volunteers were recruited by public advertise-
ment. None had a history of gastrointestinal com-
plaints and abdominal surgery (except appendectomy
and cholecystectomy) and none used medication on a
regular basis. Additionally, 54 consecutive outpatients
participated who had confirmed functional dyspepsia
after a complete check-up. Functional dyspepsia was
defined according to the Rome II criteria except that
patients who had symptoms of functional dyspepsia
and irritable bowel syndrome (IBS) were classified to
have functional dyspepsia and not IBS.
21
All subjects
gave written informed consent to the protocol that was
approved by the Ethics Committee of the University
Hospital of Vienna, Austria.
Chemical sensitivity testing
In a preliminary dose-finding study, healthy subjects
(n = 23, 12 females) received hydroxypropyl methylcel-
lulose capsules containing either 0.25 mg (n = 10) or
0.75 mg capsaicin powder (n = 11). Two participants
swallowed 1.50 mg capsaicin by ingesting two capsules
containing 0.75 mg (Fig. 1). Capsules were swallowed
after fasting overnight for at least 8 h.
After the dose-finding experiments in healthy sub-
jects, 61 healthy volunteers [age: 26.5 ± 4.3 years;
females: n = 34 (56%)] and patients received capsules
containing 0.75 mg capsaicin powder after fasting
overnight for at least 8 h. Patients were kept on their
usual medication, e.g. they did not stop therapy with
acid suppressing drugs before the capsaicin capsule
test. Capsules were ingested with a small sip of water.
Before and 30 min after, capsule ingestion subjects
were asked to score the perception they had at the
moment or within the last 10 min on a graded
questionnaire to evaluate the intensity and type of
sensation they perceived.
Perception questionnaire
The questionnaire consisted of nine graphic rating
scales for scoring: (1) sensation of abdominal pressure
or fullness, (2) sensation of cramps or colics, (3)
stinging or sharp sensation, (4) feeling of nausea, (5)
feeling of heartburn or pressure behind the sternum, (6)
flutter-like sensation in the stomach, (7) warmth
sensation, (8) sensation of vacuum and (9) pain. Each
rating scale was graded from 0 to 5. A score of zero
represented no perception, score 1 represented vague,
inexplicit perception, score 2 definite perception of a
mild sensation, scores 3 and 4 represented moderately
and highly intense perception of sensation, respec-
tively, score 5 represented an extremely uncomfortable
sensation. All participants received standard instruc-
tions and were told that they could mark half unit
scores if it was more appropriate to their sensations.
This type of questionnaire has been validated to be
reproducible during repeated stimuli,
8,22
and to dem-
onstrate significant and reproducible changes in per-
ception under different experimental conditions,
8,26
and differential responses to various stimuli.
23,27
The
questionnaire was proof read by several researchers,
staff, healthy subjects and patients before its first use
0
5
10
15
20
0.25 mg 0.75 mg 1.50 mg
Perception score
Figure 1 Dose-dependent effect of capsaicin ingestion.
Aggregate perception scores 30 min after ingestion of 0.25
(n = 10), 0.75 (n = 11) and 1.50 mg (n = 2) capsaicin. Data are
given as mean ± SEM.
J. Hammer et al. Neurogastroenterology and Motility
Ó 2007 The Authors
Journal compilation Ó 2007 Blackwell Publishing Ltd
126
in research protocols and wording was designed
accordingly.
Further analyses of the capsaicin capsule test (in
additional subjects)
Further analyses were performed in 13 patients with
functional dyspepsia and 19 healthy subjects. This
ancillary study was performed to determine whether
functional dyspepsia patients who tested positive to
capsaicin according to our definitions (see below), also
test positive after application of placebo (as it would be
expected if hypervigilance would be the reason for a
positive test) or not (which would suggest hypersensi-
tivity). Healthy subjects received 0.75 mg capsaicin or
placebo in a double-blind manner and otherwise
followed the procedure of the capsule test as described
above. Thirteen patients, who were not included in the
initial study and who tested positive for capsaicin in
the initial test, received a second capsule that con-
tained placebo 1 week after the first test. Before
receiving the placebo capsule, subjects were instructed
that their initial test had to be repeated.
Reliability of the capsaicin capsule test Another 25
patients who have participated in this trial and who
agreed to be evaluated for another, therapeutic study,
received another 0.75 mg capsaicin capsule 1 week after
the initial capsule to evaluate reliability of the test.
Data and statistical analysis
Perception scores of each type of sensation were
analysed immediately before and 30 min after inges-
tion of the capsules. Aggregate perception scores were
calculated by summing the scores for each type of
sensation evaluated by questionnaires. Final scores
were calculated as the differences between pretest and
post-test aggregate perception scores. There was no
sample size calculation performed for this study as it
was based on an opportunistic sample of patients in the
outpatient unit of the department of gastroenterology
and hepatology.
To establish the optimal threshold value for the
capsaicin capsule test, a receiver operating character-
istic (ROC) curve and Youden-index (parametric esti-
mation method,
24
) was plotted over all possible
threshold values.
Data are given as mean ± SEM unless stated other-
wise (median, 25 and 75th percentiles). For statistical
comparisons between two groups, StudentÕs t-test or
Mann–Whitney U-test were used as appropriate. For
the statistical comparison of more than two groups
(intensity of different types of sensations), Friedman
two-way
ANOVA tests were performed. If ANOVA test
statistic was significant, analysis between two groups
were performed for further analysis. A two-sided a level
of <0.05 was considered significant.
RESULTS
Initial dose-finding experiments
Capsules containing 0.25 mg capsaicin induced very
mild symptoms (aggregate perception score, median:
2.0; 25th percentile: 0.0; 75th percentile: 2.8), while
1.50 mg capsaicin (n = 2) induced severe discomfort
(median: 17.75) that precluded further studies with this
dose. As 0.75 mg capsaicin induced mild but consis-
tent upper abdominal symptoms in most healthy
participants (Fig. 1; median: 3.0; 25th percentile: 2.0;
75th percentile: 6.0), this dose was further evaluated.
Sensation induced by capsaicin in healthy
participants
Fig. 2 shows individual results of the perception scores
induced by the ingestion of 0.75 mg capsaicin in 61
healthy participants. The median aggregate perception
score was 5.0 (25th percentile: 2.0; 75th percentile: 9.0;
the mean ± SEM of the skewed data were 6.0 ± 4.1).
According to ROC curve and Youden-index calcula-
tion(Fig. 3A, B), the 75th percentile in healthy volun-
teers was further used as the upper limit of normal.
There was no significant difference in the aggregate
perception scores between genders [male participants:
–10
–5
0
5
10
15
20
25
30
Delta perception score
Healthy
controls
Functional
dyspepsia
Figure 2 Difference in upper abdominal perception scores
before vs 30 min after ingestion of 0.75 mg capsaicin in
healthy controls and patients with functional dyspepsia.
Individual data and median ± (25/75th percentile) are given.
The horizontal lines denote, apart from the zero line, the 75th
percentile observed in healthy volunteers that was selected
as upper limit of normal (dotted line).
Volume 20, Number 2, February 2008 Chemical hypersensitivity in FD
Ó 2007 The Authors
Journal compilation Ó 2007 Blackwell Publishing Ltd
127
5.0 (25th percentile: 2.0; 75th percentile: 8.0) vs
females: 5.0 (25th percentile: 2.0; 75th percentile: 9.0)
P = 0.95]. There was also no significant difference
between aggregate perception scores among subjects
younger than 30 years (4.8; 25th percentile: 1.0; 75th
percentile: 9.0) and subjects 30 years or older (7.0; 25th
percentile: 5.3; 75th percentile: 9.0; P = 0.20).
The quality and intensity of perception evoked by
the ingestion of capsaicin are summarized in Fig. 4.
Intensity scores for pressure (median: 1 ; 25 and 75th
percentile: 0 and 2), heartburn (median: 0; 0 and 1.5)
and warmth (median: 1; 0 and 2) were significantly
higher compared with the other six symptoms evalu-
ated (P < 0.05).
Sensation induced by capsaicin in patients with
functional dyspepsia
The characteristics of patients studied are given in
Table 1. Patients were significantly older than healthy
controls and in contrast to the control group there was
a marked preponderance of females in the patient
group. Patients with functional dyspepsia reported
significantly higher perception scores (median: 10;
25th percentile: 3.25; 75th percentile: 16.75; mean ±
SEM; 10.0 ± 6.5) induced by 0.75 mg capsaicin com-
pared with healthy controls (P = 0.002; Fig. 2). After
the capsaicin test, symptoms of nausea, flutter like
sensation, warmth and pain were scored significantly
higher when compared with healthy controls (Fig. 4A).
Among the patients with functional dyspepsia,
53.7% of patients (n = 29) had a positive test defined
as a score above 9 (Fig. 3A, B), while 46.3% (n = 25) had
a negative test. Table 2 shows clinical characteristics
of capsaicin-positive and -negative patients; patients
with a positive capsaicin test were significantly youn-
ger (35.8 ± 2.5 years; four males, 25 females) than
capsaicin-negative patients (45.7 ± 3.2; eight males,
17 females). Pain and non-painful symptoms (fullness,
early satiety, nausea and bloating) as the most severe
upper abdominal symptom were equally frequently
reported by capsaicin-positive and -negative patients
(Table 2). Moreover, the intensity of upper gastrointes-
tinal symptoms that the patients had experienced in
the past 12 months was comparable in the two groups,
except for the severity of bloating, that was experi-
enced as more intense in capsaicin-positive patients
(P < 0.05). Patients who had a positive test had higher
intensity scores in all perception qualities after capsa-
icin application compared with control subjects, while
capsaicin-negative patients did not score significantly
different to healthy controls (Fig. 4B). Twenty-one of
the capsaicin-positive patients reported to know the
symptoms induced by capsaicin as their usual symp-
toms, while eight subjects had not experienced these
symptoms (either intensity or quality) before. In the
capsaicin-negative group, capsaicin mimicked their
usual symptoms in 12 patients but not in the 13 other
patients.
Both capsaicin-positive and -negative patient groups
were significantly older compared with healthy
controls (P < 0.001) and the percentage of males
was significantly lower in the capsaicin-positive
ROC-curve
0.0
0.2
0.4
0.6
0.8
1.0
1.0
0.80.60.4
0.2
0.0
1- Specificity
Sensitivity
Perception
score = 9
Youden-index
–0.10
0.00
0.10
0.20
0.30
0.40
2520151050
Youden-index
AUC = 0.64
Perception score
B
A
Figure 3 Optimal threshold value, comparing healthy volun-
teers vs patients with functional dyspepsia: receiver operating
characteristic (ROC) curve and Youden-index.
J. Hammer et al. Neurogastroenterology and Motility
Ó 2007 The Authors
Journal compilation Ó 2007 Blackwell Publishing Ltd
128
patient group compared with the control group
(P < 0.05) (capsaicin-negative patient group vs control:
P = 0.4). In patients with a negative test, the intensity
of each symptom evaluated was similar to the inten-
sity of symptoms in healthy controls (P > 0.05),
except the sensation of pressure, that was less intense
in patients (median: 0; 25th and 75th percentile: 0 and
1) compared with controls (P = 0.03). In patients
with a positive test, the intensity of all symptoms
was significantly higher than in controls (P < 0.05),
except sensation of vacuum (P = 0.09) and flutter
(P = 0.07).
Further analyses of the capsaicin capsule test
Sensitivity of the capsaicin capsule test was 0.54; the
specificity was 0.82, with a positive predictive value of
72.5 and a negative predictive value of 66.7.
Subsequently, we tested whether symptoms induced
by the ingestion of capsules might be due to hyper-
vigilance rather than chemical hypersensitivity in
patients with functional dyspepsia. Therefore, addi-
tional 13 patients who tested positive for 0.75 mg
capsaicin capsules received placebo thereafter. Nine-
teen healthy subjects also received placebo in a double-
blind manner (Fig. 5). In healthy volunteers, perception
scores were 1.0 ± 0.6 after placebo and 2.5 ± 0.6 after
0.75 mg capsaicin (P = 0.05), the score difference
between placebo and capsaicin capsules was 1.4 ± 1.9.
In the selected patient group with functional dyspep-
sia, perception scores after placebo was 1.9 ± 0.6 (not
significant vs controls), significantly less than after
capsaicin (15.8 ± 0.9; P = 0.001). The score difference
between placebo and capsaicin capsules was 13.9 ± 3.1
(P < 0.001 vs healthy controls).
Reliability testing was performed in 25 patients
(Fig. 6); 14 patients were positive in the first test, 13
remained positive in the second, while 11 patients were
negative in the first test and nine remained negative in
the second, giving a Cronbach alpha-value of 0.86, the
correlation between scores from the first and second test
was highly significant (r = 0.63; P < 0.001).
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Sensation score
Control
NUD
WarmthHeartburnStingingCrampsPressure Flutter Vacuum PainNausea
*
*
*
*
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Symptom score
Controls NUD Test neg
NUD Test pos
*
**
**
*
*
*
Warmth
Heartburn
StingingCrampsPressure Flutter Vacuum PainNausea
B
A
Figure 4 Sensations evoked by the
ingestion of capsaicin capsules. Sensa-
tion scores are given as the difference
between scores before and 30 min after
ingestion of the capsules. Median, 25
and 75th percentile are shown. (A)
Healthy controls (r) vs functional
dyspepsia as a whole group (
). Aster-
isks denote significant difference to
healthy controls. (B) Healthy controls
(r); functional dyspepsia with negative
capsaicin test (
); functional dyspepsia
with positive capsaicin test (
). Aster-
isks denote significant difference to
healthy controls. NUD, –non ulcer
dyspepsia.
Volume 20, Number 2, February 2008 Chemical hypersensitivity in FD
Ó 2007 The Authors
Journal compilation Ó 2007 Blackwell Publishing Ltd
129
DISCUSSION
Hypersensitivity against intraluminal stimuli has long
been implicated in the pathophysiology of symptoms
in functional bowel disorders, but studies were mainly
confined to mechanical stimulation.
6,25
The potential
role of chemoreceptor in gastrointestinal diseases has
so far been ignored, partly because of the lack of
pathophysiological human in vivo models and diag-
nostic options.
8
Here, we have presented a simple
capsule-based test to study chemosensory function of
the human upper gut and have demonstrated hyper-
sensitivity for chemical stimulation with capsaicin in
patients with functional dyspepsia. These data give
insights into presently unexplored mechanisms that
might be involved in the development of symptoms in
functional dyspepsia, provide information on a novel
Table 1 Characteristics of participants
Functional
dyspepsia
Healthy
controls
Number of patients (n) 54 61
Age (mean ± SEM) 40.5 ± 2.1 26.5 ± 4.3
Female gender (%) 77.8 44.3
Helicobacter pylori positive % 13
Most severe upper abdominal symptoms
None or no answer given, n % 4 (7)
Pain, n % 19 (35)
Discomfort (non-painful), n % 31 (57)
Medications (n)
No medication 30
Acid-suppressing drugs 14
Motility altering drugs 10
NSAID 0
Other medications 4
Concurrent IBS 22
Abbreviation used:
IBS, irritable bowel syndrome; NSAID, Non-steroidal anti-
inflammatory drugs.
Table 2 Characteristics of functional dyspepsia patients
with positive vs negative tests
Capsaicin
positive
(n = 29)
Capsaicin
negative
(n = 25) P-value
Age (years) 35.8 ± 2.5 45.7 ± 3.2 0.02
Male/female (n) 4/25 8/17 0.11
Helicobacter
pylori-positive (n)
3 4 0.44
Medication
No medication 17 13 0.78
Acid-suppressing
drugs
6 8 0.37
GI-motility altering
drugs
4 6 0.49
NSAID 0 0
Other drugs 3 1 0.62
Most severe symptom (n)
Upper abdominal pain 9 10 0.82
Discomfort
(non-painful)
18 13 0.37
No specification 2 2
Severity scores of symptoms in previous year [median
(25/75th percentile)]:
Pain 4 (3/5) 3 (3/5) 0.21
Fullness 3 (1/5) 2 (0.25/3.75) 0.24
Nausea 2 (0/3.25) 1 (0/3.75) 0.65
Early satiety 3 (0/4.25) 1.5 (0.25/3.75) 0.21
Bloating 4 (3/5) 3 (2/4) 0.03
Concurrent IBS 12 10 0.99
Severity scores of symptoms were rated on a scale from 0 (no
problem) to 6 (severe)
NSAID, non-steroidal anti-inflammatory drugs; IBS, irritable
bowel syndrome; GI, gastro intestine.
–5
0
5
10
15
20
25
Delta of perception score
Placebo
controls
Capsaicin
controls
Placebo
functional
dyspepsia
Capsaicin
functional
dyspepsia
Figure 5 Difference in upper abdominal perception scores
after the ingestion of placebo and 0.75 mg capsaicin in healthy
controls (n = 19) and the selected functional dyspepsia
patients who tested positive in the capsaicin capsule test
(n = 13). Individual data and mean ± SEM are given.
–15
–10
–5
0
5
10
15
20
25
30
Delta of perception score
1st Test
2nd Test
Figure 6 Reliability testing in 25 patients with functional
dyspepsia. Data are given as difference in upper abdomi-
nal perception scores before vs 30 min after ingestion of
0.75 mg capsaicin on two different occasions. Individual data
are given. The dotted horizontal line denotes the upper limit
of normal.
J. Hammer et al. Neurogastroenterology and Motility
Ó 2007 The Authors
Journal compilation Ó 2007 Blackwell Publishing Ltd
130
and simple test to identify subgroups of patients with
functional dyspepsia and reveal new possible targets for
the development of therapeutic strategies in functional
bowel disorders.
It has only recently been appreciated that intralumi-
nal application of capsaicin in the healthy gastrointes-
tinal tract dose-dependently induces upper abdominal
symptoms evoked by stimulation of a specific receptor,
likely VR1, whose activation gives rise to a ÔhotÕ
perception quality.
12,13,15
Previous studies have shown
that the symptoms caused by intraluminal capsaicin
were similar, but not identical, to symptoms induced
by mechanical distension,
26,27
and motor activity and
mechanosensory function of the gut remained unal-
tered.
8
Only when capsaicin induced discomfort
8,28
changes in sensorimotor functions were detectable in
the healthy gut, suggesting that reflex mechanisms
were responsible for this alteration rather than a direct
capsaicin effect.
Vanilloid receptors of type 1, which is a polymodal
receptor, is not only activated by capsaicin, but also by
noxious heat, with a threshold temperature that acti-
vates the receptor at around 42 °C, for instance during
tissue inflammation.
13
Under certain conditions the
threshold temperature for heat activation of VR1
receptors can be reduced to body temperature.
29
More-
over, genetic deletion of VR1 in mice leads to impaired
chemonociception and impaired inflammatory thermal
hyperalgesia.
30,31
No data exist to date that could reject
or support the hypothesis, whether a lowered temper-
ature threshold of VR1 is responsible for the observed
hypersensitivity for capsaicin in patients with func-
tional dyspepsia. Alternatively, the expression of the
capsaicin receptor might be upregulated in the stom-
ach, similarly to the increased immunoreactivity for
VR1 in the colorectal wall in patients with faecal
urgency or chronic inflammatory bowel disorders.
32,33
In our patients, however, infection with H. pylori, that
causes chronic inflammation of the gastric mucosa,
was not associated with a positive capsaicin test.
Noteworthy, the prevalence of H. pylori infection
was low, because of the low prevalence of H. pylori
infestation in the Austrian population and a high rate
of eradication therapy.
The strength of the current paper is the finding of
chemical hypersensitivity in a large subset of patients
with functional dyspepsia and the description of a
novel, and simple test to identify this subset of
patients. However, as this study was primarily
designed to explore the possibility of chemical hyper-
sensitivity in functional dyspepsia, it naturally was not
designed as placebo-controlled study. Thus, as it
turned out that a subgroup of functional dyspepsia
patients were hypersensitive for capsaicin; we
extended the study design to include the application
of placebo in capsaicin-positive patients in a single
blinded manner to exclude the possibility of hypervig-
ilance or context-dependent response to taking a pill,
as the cause for the symptom response in functional
dyspepsia. Although this ancillary study cannot replace
a placebo-controlled design, the present data suggest
that hypervigilance has a minor role in the develop-
ment of symptoms after the ingestion of capsaicin
capsules.
After determining a significant difference of the
symptom response between the control group and the
group of functional dyspepsia patients as a whole, we
evaluated the cut-off level that best discriminated
capsaicin-positive from capsaicin-negative patients by
ROC-method and confirmed the results by Youden-
index.
24
Although the capsaicin test performs moder-
ately in terms of sensitivity, specificity and predictive
value a fact that is not surprising in a disease whose
pathophysiology is as diverse as in functional dyspep-
sia our results suggest that the test might proof useful
for determination of the subgroup of patients with
chemical hypersensitivity and for confirmation of the
diagnosis in a subgroup of patients. It is also notewor-
thy that a considerable number of control subjects had
symptom scores above the cut-off level; whether these
controls differ in their future clinical course, in
psychopathology or other intrinsic or extrinsic factors
from other control subjects and from symptomatic
patients needs further study.
The reliability of the test was acceptable in the
patient group. Patients were kept on their usual
medication during the capsaicin test as no data exist
that would suggest that any drug alters capsaicin-
induced chemosensitivity. Moreover, the results of the
capsaicin test were independent of the medication the
patients took. There was also no detectable gender
difference in the results of the capsaicin test, neither in
healthy volunteers nor in functional dyspepsia
patients. In healthy volunteers we also did not detect
significant age-related differences of the capsaicin test
results, but only few older healthy subjects were
tested. In functional dyspepsia patients, younger sub-
jects tended to have higher aggregate perception scores
compared with older subjects. Thus, although the
study design did not provide an age- (and gender-)
matched control group, the present results suggest that
the capsaicin test results in lower aggregate perception
scores in older subjects; therefore an even higher
percentage of capsaicin-positive patients might be
expected when in the future appropriately age-
matched controls will be tested.
Volume 20, Number 2, February 2008 Chemical hypersensitivity in FD
Ó 2007 The Authors
Journal compilation Ó 2007 Blackwell Publishing Ltd
131
We did not evaluate the region of the gastrointestinal
tract where capsaicin capsules induced symptoms.
However, several findings suggest that the stomach
was the main source of symptoms rather than the
intestine: firstly, the development of heartburn in
some subjects and the fast resolution of symptoms
when capsaicin was diluted by ingestion of water
would argue for gastric instead of more distal action.
26
Secondly, the observation, that TabascoÒ Sauce
(McIlhenny Co., Avery Island, LA, USA) induced upper
gastrointestinal symptoms when applied into the gas-
tric lumen,
28
support the notion of chemosensitivity of
the stomach. Finally, in two patients with functional
dyspepsia who received endoscopy 30 min after inges-
tion of a capsaicin capsule, the contents of the capsules
were spread over the whole stomach as a white layer,
with the major portions visible in the gastric corpus,
the shells of the capsules were not visible.
Functional dyspepsia is a heterogeneous disorder
characterized by a symptom complex including epi-
gastric pain, bloating, fullness, early satiety, nausea
and vomiting.
6
Several pathophysiological mecha-
nisms have been implicated, but presently the patho-
physiology of functional dyspepsia is only partially
elucidated. The association between H. pylori infection
and functional dyspepsia is weak
34
and eradication
therapy has only little effect on symptom improve-
ment.
35–37
Abnormalities in sensorimotor function
have been associated with functional dyspepsia but
cannot be detected in all patients.
6
Moreover, symp-
toms do not predict the presence of specific gastroin-
testinal motor disorders or hypersensitivity for
mechanical distension.
6,38
Similarly, our data demon-
strate that capsaicin sensitivity was also not associated
with specific symptoms or symptom severity, suggest-
ing that quality of symptoms is a poor predictor of the
underlying pathophysiology in dyspepsia.
39
Only upper
abdominal bloating over the past 12 months was more
intense in capsaicin-positive patients compared with
capsaicin negative patients.
The blockade of VR1 may be a novel therapeutic
approach to the treatment of patients suffering from
functional dyspepsia, at least in a subset of patients
with functional dyspepsia who are hypersensitive for
capsaicin. Capsaicin analogues that block the function
of VR1-bearing nociceptors but lack an excitatory
effect
40
and competitive VR1 receptor antagonists
41
are currently being developed as novel antinociceptive
agents and might be useful in functional bowel disor-
ders, as they might not only affect chemoperception,
but also mechanoperception.
22
The described capsaicin
test might prove useful for therapeutic selection in a
subgroup of patients with functional dyspepsia.
In conclusion, chemonociception participates in
intestinal perception of intraluminal stimuli. Target-
ing the VR1 receptor might offer a novel therapeutic
approach for the treatment of functional bowel disor-
ders. As new therapeutic options evolve, simple clin-
ical tests that allow the detection of the mechanism or
combination of mechanisms that are responsible for
the symptoms of the patients might allow individual
tailoring of an effective therapy.
ACKNOWLEDGMENTS
Supported by research grant P18101_B09 from the
Austrian Science Fund (FWF, Fonds zur Fo
¨
rderung der
wissenschaftlichen Forschung) to Dr J. Hammer. The
authors thank Dr M. Homoncik, Dr G. Novacek and
Dr H. Vogelsang for their kind assistance in the
recruitment of patients.
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133
    • "In this study, a lower amount of capsaicin was required to induce pain in patients with FD compared to healthy subjects [29] . However, Hammer et al. failed to show any correlation between hypersensitivity to capsaicin and any specific symptom or severity of symptoms in FD patients [30]. Additionally, hypersensitivity has been suggested to be perceived at a central sensory level, with glutamate as the potential neurotransmitter involved. "
    [Show abstract] [Hide abstract] ABSTRACT: Functional dyspepsia is a common disorder which imposes significant diagnostic and treatment challenges for patients and physicians. The most recent update of the diagnostic criteria subdivides functional dyspepsia into two subcategories based on the main symptom of epigastric pain or postmeal fullness. As we discuss in this review, several studies have shown significant overlap in symptoms and pathophysiology between functional dyspepsia, irritable bowel syndrome, and the spectrum of reflux disorders. This overlap in symptoms can be informative in helping us to understand the underlying pathophysiology, diagnostic approaches, and treatment strategies. The addition of diagnostic testing such as pH impedance manometry of the distal esophagus to the current common diagnostic tests might be helpful in distinguishing between functional dyspepsia and reflux disease. Importantly, various treatment modalities may be more effective than others if the main symptom is burning rather than pain or postmeal fullness rather than early satiation.
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    • "Hypersensitivity to endogenous and exogenous chemicals, gastric acid or nutrients has been suggested to be associated with dyspeptic symptoms.75-77 Since patients with visceral hypersensitivity are considered to have enhanced sensory nerve activity, stimulation of luminal chemoreceptors in the upper GI mucosa may generate or aggravate dyspeptic symptoms. "
    [Show abstract] [Hide abstract] ABSTRACT: Environmental factors such as food, lifestyle and prevalence of Helicobacter pylori infection are widely different in Asian countries compared to the West, and physiological functions and genetic factors of Asians may also be different from those of Westerners. Establishing an Asian consensus for functional dyspepsia is crucial in order to attract attention to such data from Asian countries, to articulate the experience and views of Asian experts, and to provide a relevant guide on management of functional dyspepsia for primary care physicians working in Asia. Consensus team members were selected from Asian experts and consensus development was carried out using a modified Delphi method. Consensus teams collected published papers on functional dyspepsia especially from Asia and developed candidate consensus statements based on the generated clinical questions. At the first face-to-face meeting, each statement was reviewed and e-mail voting was done twice. At the second face-to-face meeting, final voting on each statement was done using keypad voting system. A grade of evidence and a strength of recommendation were applied to each statement according to the method of the GRADE Working Group. Twenty-nine consensus statements were finalized, including 7 for definition and diagnosis, 5 for epidemiology, 9 for pathophysiology and 8 for management. Algorithms for diagnosis and management of functional dyspepsia were added. This consensus developed by Asian experts shows distinctive features of functional dyspepsia in Asia and will provide a guide to the diagnosis and management of functional dyspepsia for Asian primary care physicians.
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    • "Upregulation of TRPV1 in the mucosa, with a correlation to pain sensitivity in irritable bowel syndrome and in inflammatory bowel disease with irritable bowel syndrome-like symptoms Esophagus, stomach, intestine and pancreas Acid-induced oesophagitis, gastric acidevoked injury of the stomach, trinitrobenzene sulfonic acid-induced pancreatitis and colitis in rodents Upregulation of TRPV1 in vagal and spinal afferent neurons Schicho et al., 2004; Banerjee et al., 2007; Miranda et al., 2007; Xu et al., 2007 Esophagus, stomach and small intestine Abdominal pain in human volunteers Induction by intraluminal capsaicin Schmidt et al., 2004; Hammer, 2006a Hammer, , 2006b Hammer & Vogelsang, 2007; Hammer et al., 2008; Führer & Hammer, 2009; Kindt et al., 2009; Chen et al., 2010; van Boxel et al., 2010 Stomach Behavioral pain response to intragastric acid challenge in rats Prevention by TRPV1 antagonism Lamb et al., 2003 Stomach and upper small intestine Functional dyspepsia Hypersensitivity to the algesic effect of capsaicin Hammer et al., 2008 Stomach and upper small intestine Attenuation by TRPV1 antagonism Ileum and colon Abdominal pain and viscerosomatic reflexes in humans Intraluminal administration of capsaicin to ileostomy and colostomy patients Drewes et al., 2003; ArendtNielsen et al., 2008 Colon Abdominal pain in rodents Induction by intraluminal capsaicin Laird et al., 2001; Mansikka et al., 2004; Christoph et al., 2006 Sponsored Document Pancreas Islet inflammation in non-obese diabetic mice (genetic model of type I diabetes) Prevention by TRPV1 ablation Razavi et al., 2006; Suri & Szallasi, 2008 Pancreas Pain behavior, referred allodynia/ hyperalgesia and spinal c-Fos expression associated with experimental pancreatitis in rodents Attenuation by TRPV1 antagonism Wick et al., 2006; Xu et al., 2007; Peritoneal cavity Behavioral pain response to intraperitoneal injection of acetic acid or oleoylethanolamide in rodents Attenuation by TRPV1 antagonism "
    [Show abstract] [Hide abstract] ABSTRACT: Approximately 20 of the 30 mammalian transient receptor potential (TRP) channel subunits are expressed by specific neurons and cells within the alimentary canal. They subserve important roles in taste, chemesthesis, mechanosensation, pain and hyperalgesia and contribute to the regulation of gastrointestinal motility, absorptive and secretory processes, blood flow, and mucosal homeostasis. In a cellular perspective, TRP channels operate either as primary detectors of chemical and physical stimuli, as secondary transducers of ionotropic or metabotropic receptors, or as ion transport channels. The polymodal sensory function of TRPA1, TRPM5, TRPM8, TRPP2, TRPV1, TRPV3 and TRPV4 enables the digestive system to survey its physical and chemical environment, which is relevant to all processes of digestion. TRPV5 and TRPV6 as well as TRPM6 and TRPM7 contribute to the absorption of Ca²⁺ and Mg²⁺, respectively. TRPM7 participates in intestinal pacemaker activity, and TRPC4 transduces muscarinic acetylcholine receptor activation to smooth muscle contraction. Changes in TRP channel expression or function are associated with a variety of diseases/disorders of the digestive system, notably gastro-esophageal reflux disease, inflammatory bowel disease, pain and hyperalgesia in heartburn, functional dyspepsia and irritable bowel syndrome, cholera, hypomagnesemia with secondary hypocalcemia, infantile hypertrophic pyloric stenosis, esophageal, gastrointestinal and pancreatic cancer, and polycystic liver disease. These implications identify TRP channels as promising drug targets for the management of a number of gastrointestinal pathologies. As a result, major efforts are put into the development of selective TRP channel agonists and antagonists and the assessment of their therapeutic potential.
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