Review Article: The Current Treatment of Non-Cardiac Chest Pain

Alimentary Pharmacology and Therapeutics
Review article: the current treatment of non-cardiac chest pain

N. George*, J. Abdallah*, C. Maradey-Romero*, L. Gerson & R. Fass*
*Division of Gastroenterology and

Hepatology, The Esophageal and
Swallowing Center, MetroHealth
Medical Center, Case Western
Reserve University, Cleveland, OH,
USA.
Division of Gastroenterology,
California Pacic Medical Center,
University of California, San Francisco,
San Francisco, CA, USA.
Correspondence to:
Prof R. Fass, Division of
Gastroenterology and Hepatology,
Esophageal and Swallowing Center,
MetroHealth Medical Center, Case
Western Reserve University, 2500
MetroHealth Drive, Cleveland, OH
44109, USA.
E-mail: ronnie.fass@gmail.com
Publication data
Submitted 22 September 2015
First decision 2 October 2015
Resubmitted 13 October 2015
Accepted 14 October 2015
EV Pub Online 23 November 2015
This commissioned review article was
subject to full peer-review and one of
the authors received an honorarium from
Wiley, on behalf of AP&T.
SUMMARY
Background
Non-cardiac chest pain is one of the most common functional gastrointestinal disorders. By recognising that gastro-oesophageal reux disease
(GERD), oesophageal dysmotility and oesophageal hypersensitivity are the
main underlying mechanisms of NCCP, a more directed therapeutic
approach has been developed.
Aim
To determine the value of the current therapeutic modalities for NCCP.
Methods
Electronic (Pubmed/Medline/Cochrane central) and manual search.
Results
Double-dose PPI treatment for two months is a reasonable rst choice
approach in patients with NCCP because GERD is the most common
aetiology. Studies evaluating the role of medical therapy in NCCP patients
with hypercontractile oesophageal motility suggest a limited value to muscle relaxants like calcium channel blockers (nifedipine, diltiazem), nitrates
and sildenal. While most trials evaluating pain modulators are small and
many are not placebo-controlled, these type of medications appear efcacious in both patients with NCCP due to oesophageal dysmotility and
those with functional chest pain. Cognitive behavioural therapy has been
extensively studied in patients with functional chest pain with good results.
Other psychological techniques such as hypnotherapy, group therapy or
coping skills have been scarcely studied but appear to be effective in NCCP
patients.
Conclusion
Medical, endoscopic and surgical therapeutic options are available for the
treating physician, although some patients with non-cardiac chest pain may
require a multimodal therapeutic approach.
Aliment Pharmacol Ther 2016; 43: 213239
2015 John Wiley & Sons Ltd

doi:10.1111/apt.13458
213
N. George et al.
INTRODUCTION
Gastro-oesophageal reux disease is the most common
underlying mechanism of NCCP, with an estimated
prevalence ranging between 30% and 60%.13 Medical
treatment for GERD-related NCCP has included primarily histamine-2 receptors blockers (H2-blockers) and proton pump inhibitors (PPIs) with varying degrees of
success. In addition, PPIs have been shown to be both a
sensitive and specic diagnostic tool for GERD-related
NCCP. PPIs are considered rst-line therapy for GERDrelated NCCP and are associated with the highest rates
of symptomatic improvement and resolution35
(Table 1). Endoscopic and surgical management of
GERD-related NCCP, including endoluminal gastroplication and partial/full fundoplications, have also been
demonstrated to be successful in a subset of patients
with NCCP.68 Oesophageal motility disorders account
for 30% of non-GERD-related NCCP, with nutcracker
oesophagus and hypotensive lower oesophageal sphincter
as the most common ndings on oesophageal manometry.9 Medical therapy with smooth muscle relaxants
including calcium channel blockers, nitrates and phosphodiesterase-5 inhibitors have been utilised in NCCPrelated motor disorders. Endoscopic and surgical therapy
for NCCP due to oesophageal dysmotility include, balloon and pneumatic dilation, endoscopic injection of
botulinum toxin A to the lower oesophageal sphincter,
peroral endoscopic myotomy (POEM) and surgical
oesophagomyotomy with or without partial fundoplication.
Oesophageal hypersensitivity has been demonstrated
as the underlying mechanism for symptom generation in
most patients with NCCP due to oesophageal dysmotility
and those with functional chest pain.10 As a result, treatment has focused on pain modulation, including tricyclic
antidepressants (TCAs), selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake
inhibitors (SNRIs), trazadone and adenosine antagonists.
Furthermore, psychological interventions such as cognitive behavioural therapy (CBT) and hypnotherapy have
been used as well as complimentary medicine
approaches, such as Johrei treatment. In this review, the
efcacy of all these aforementioned therapies will be discussed.
MATERIALS AND METHODS
We performed a search of the medical literature using
PUBMED, MEDLINE and the Cochrane central register
of controlled trials for the period of 19502014. We used
214
the PRISMA statement checklist for reporting of systematic review methodology. We included relevant peerreviewed human studies, randomised controlled trials
and casecontrol studies that were published in the English-language. The search included the following terms
or keywords: non-cardiac chest pain, functional chest
pain, atypical chest pain, unknown chest pain, oesophageal motility disorders and hypersensitive oesophagus.
We excluded meeting abstracts, case reports, letters and
editorials. Additionally, the list of included studies were
checked and compared by three independent researchers
(NG, JA and CMR), who performed the literature
searches and selection. An independent reviewer (RF)
resolved discrepancies. We performed a search of the
medical literature using PUBMED, MEDLINE and the
Cochrane central register of controlled trials for the period of 19502014.
RESULTS
GERD-related NCCP
Medical therapy. H2-blockers: Several uncontrolled trials have shown that patients with GERD-related NCCP
demonstrate symptomatic response to H2-blockers.5, 11
An open-label study evaluated the efcacy of high-dose
ranitidine (150 mg orally q.d.s.) in thirteen symptomatic
patients with both uninvestigated chest pain and reux
symptoms given for 8 weeks.12 Seventy seven per cent
(10 out of 13) of the patients had evidence of GERD by
pH testing. All patients demonstrated subjective
improvement of chest pain on high-dose ranitidine
(mean chest pain score pre- and post-treatment
2.9 0.3 vs. 0.7 0.03 at 8 weeks; P < 0.001). However, there was no correlation between positive symptom index (SI) for chest pain and reux events and
response to ranitidine treatment (pre-treatment symptom scores of patients with positive SI 3.0 0.5 vs.
patients with negative SI 2.7 0.5; P = N.S., and posttreatment symptom scores: patients with positive SI
1.0 0.3 vs. patients with negative SI 0.3 0.3
P = N.S.).
Proton pump inhibitors (PPIs): The PPIs that were evaluated in randomised placebo-controlled trials included
omeprazole, rabeprazole, lansoprazole and esomeprazole
(Table 1).
OmeprazoleOf all PPIs, omeprazole has been the most
frequently studied in clinical trials of GERD-related
N. George et al.
Table 5 | Pain modulators in NCCP
Author,
year
Type of trial
Study
size (N)
Medication
name,
Dose, schedule
Duration
Symptom assessment
Outcome
Cannon
199449
Double-blind,
placebocontrolled
with crossover
60
Clonidine
0.1 mg b.d.
vs. Imipramine
50 m at
bedtime vs.
placebo b.d.
10 weeks
Symptom diary of
chest pain fre
quency, intensity,
and magnitude of
pain per week
41% (n = 22/54) had

provocative oesopha
geal testing with
chest pain symptoms
Mean reduction in
chest pain frequencyimipramine: 52 25%,
clonidine: 39 51%
placebo: 1 86%
Imipramine with reduced
chest pain frequency
vs. placebo (P = 0.03)
Chest pain intensity
lower with imipramine
(P = 0.001) and clonidine
(P = 0.002) vs. placebo
No central nervous system
side effects reported
Cox
199850
Randomized,
Double-blind
placebocontrolled
with crossover
18 women
Imipramine
50 mg daily
vs. placebo
12 weeks:
5 weeks of
treatment or
placebo with
2 week
washout,
then
crossover to
for 5 weeks
Chest pain diaries

(onset, duration,
severity)
Chest pain severity
using visual ana
logue scale (VAS)
Nottingham Health
Prole questionnaire
Decreased median
total number of chest
pain episodes with
imipramine vs. pla
cebo (11 vs. 21; P = 0.01)
Decreased number of
moderate severity of
chest pain episodes with
imipramine vs. placebo
(5 vs. 12; P = 0.05)
No difference in max
imal duration of chest
pain episodes
Dry mouth and dizzi
ness most common
side effects
Park
201351
Randomized,
open-label
36
Amitriptyline
10 mg with
rabeprazole
20 mg once
daily vs.
raperazole
20 mg b.d.
8 weeks
Daily symptom
diary
Global symptom
score (visual ana
logue scale)
SF-36
Beck Depression
Inventory (BDI)
Mean difference in
global symptoms
scores not statistically
signicant between
two groups
Between group differ
ence in global symp
tom scores were sig
nicant (P < 0.001)
Amitriptyline + stan
dard dose PPI had
greater symptom
improvement vs. dou
ble-dose PPI (71% vs.
26%, with greater
than 50% symptom
improvement;
P = 0.008)
228

N. George et al.
Table 1 | (Continued)
PPI (Author,
year)
Type of
trial
Study
size (N)
PPI dose,
schedule
Rabeprazole
(Kim
200916)
Open-label
comparing 1
and 2 week
therapy
42
20 mg in AM
20 mg in
PM
2 weeks
Symptom
intensity
score (severity
(scale 14) 9
frequency)
Week 1: GERD positive has

50% symptom intensity score
improvement vs. GERD
negative 23% improvement
(P = 0.1)
No signicant difference in
duration or frequency of
symptoms
2 weeks: GERD positive with
81% symptom intensity score
improvement vs. 27% in GERD
negative patients (P = 0.001)
Lansoprazole
(Xia 200317)
Single blind,
placebocontrolled
68
30 mg daily
vs. placebo
4 weeks
Symptom
scores
(severity
9 frequency)
No signicant difference in
overall chest pain symptoms
vs. placebo (53% vs. 34%;
P = 0.127)
GERD positive: 92% patients
with symptom improvement vs.
33% placebo
GERD negative: no statistical
signicance with medication
vs. placebo (33% vs. 35%;
P = N.S.)
Lansoprazole
(Bautista
200418)
Double-blind,
placebocontrolled
with crossover
40
60 mg in AM
20 mg in
PM
7 days, with
crossover
for 7 days
Chest pain
intensity
score
40% overall symptom

response
GERD positive: 78% patients
with symptom improvement of
> 50% vs. 22% placebo
(P = 0.014)
GERD positive: 50% with
complete symptom resolution
on medication
GERD negative: no difference
between medication and
placebo
Lansoprazole
(Borjesson
200319)
Double-blind,
placebocontrolled
with crossover
19 nutcracker
patients
30 mg b.d.
vs. placebo
8 weeks, with
crossover
for 8 weeks
Weekly pain
duration using
visual
analogue
scale
63% NCCP patients were

GERD positive
No difference between
medication and placebo in
improving chest pain
symptoms
On subgroup analysis, no
difference between GERD
positive and negative
patients in
symptom response to
medication vs. placebo
216
Duration
Symptom
assessments
Outcome

Review: non-cardiac chest pain

PPI (Author,
year)
Type of
trial
Study
size (N)
PPI dose,
schedule
Esomeprazole
(Flook
201320)
Double-blind,
parallel
group,
placebocontrolled,
stratied
599
Esomeprazole
40 mg b.d.
vs. placebo,
Stratum 1:
GERD
negative
symptoms
Stratum 2:
GERD
positive
symptoms
Duration
4 weeks
NCCP. Trials evaluating omeprazole 20 mg b.d., 40 mg

b.d. and omeprazole 40 mg in the morning and 20 mg
at night-time have shown statistically signicant
improvement in chest pain in those patients with abnormal pH test as compared to placebo. Overall, 5295% of
the GERD-related NCCP patients reported symptom
improvement or resolution with various dosing schedules
of omeprazole as compared to 1050% of patients receiving placebo.3, 4, 13 However, there has also been some
level of treatment response in NCCP patients without
proven acid reux on pH studies, ranging from 7% to
39%.3, 4
A non-randomised controlled trial evaluating
omeprazole 40 mg at bedtime in patients with NCCP
(with normal coronary anatomy) (n = 23) and those
with documented cardiovascular disease (control)
(n = 10) showed a statistically signicant decrease in
chest pain episodes in the NCCP group compared to
the control group (NCCP: 16.2 9.9 vs. 12.0 13.2;
P = 0.02 control: 19.61 11.9 vs. 17.1 11.0;
P = N.S.). Interestingly, the presence of a positive pH
test did not predict symptom response to omeprazole
in either group.14
Symptom
assessments
Reux
Disease
Questionnaire
(RDQ)
Short
Form-36
(SF-36)
Hospital
Anxiety and
Depression
Questionnaire
(HAD)
McGill Pain
Questionnaire
(MPQ)
Chest pain
visual
analogue
scale (VAS)
Brief Pain
Inventory
(BPI)
Quality of Life
in Reux and
Dyspepsia
(QOLRAD)
Outcome
GERD negative: 38% resolution
of chest pain on treatment vs.
26% with placebo (P = 0.018)
GERD positive: no statistical
difference between medication
and placebo (27% vs. 24%;
P = 0.54).
Post hoc analysis of both strata:
treatment was more effective
than placebo (33% vs. 25%;
P = 0.035, NNT = 12).
RabeprazoleRabeprazole in a dosage of 20 mg b.d.,

has been studied in a randomised placebo-controlled trial
with a cross-over design and in an open-label trial comparing efcacy rates in GERD and non-GERD patients
over a period of 1 and 2 weeks of treatment. Dickman
et al. evaluated rabeprazole 20 mg b.d. for 1 week in a
randomised placebo-controlled trial in NCCP patients.
All patients underwent pH testing prior to randomisation.15 Symptom intensity scores (daily severity scores
multiplied by daily frequency during each week) were
used to evaluate degree of chest pain during treatment.
Patients with evidence of abnormal acid exposure on pH
testing had demonstrated a statistically signicant
improvement in symptom intensity scores for non-cardiac chest pain while on rabeprazole 20 mg b.d. as compared to placebo (P = 0.029). In comparison, there was
no difference in symptom intensity scores between
rabeprazole and placebo in patients with normal pH proles (P = 0.0660). Kim et al. investigated the efcacy of
1 and 2 week course of rapebrazole 20 mg b.d. in controlling symptoms of 42 NCCP patients with (n = 16)
and without (n = 26) documented acid reux based on
endoscopy and pH testing, using an open-label trial
217
N. George et al.
design.16 Longer duration of treatment (2 weeks)
resulted in a signicant difference in the percentage of
patients who reported symptom resolution. Overall, 45%
(7/16) of the GERD-related NCCP patients and 12% (3/
26) of the non-GERD-related NCCP patients demonstrated complete symptom resolution (P = 0.03).
LansoprazoleVarying dosages of lansoprazole have

been used with signicant improvement of NCCP symptoms in three randomised placebo-controlled trials. One
trial treated a cohort of Chinese NCCP patients with
lansoprazole 30 mg daily for 4 weeks. Patients with positive pH testing demonstrated statistically signicant
improved chest pain symptom scores (severity multiplied
by frequency) as compared to placebo (92% vs. 33%).17
There was a similar response rate to both placebo and
lansprazole in patients without documented acid reux
(33% vs. 35% respectively; P = N.S.). In another trial,
NCCP patients with evidence of acid reux (n = 18) (by
pH test and/or endoscopic ndings of erosive oesophagitis) were treated with lansoprazole 60 mg in the morning and 30 mg before dinner for 7 days. Chest pain
intensity scores (severity multiplied by frequency) were
signicantly improved in GERD-related NCCP patients
receiving lansoprazole as compared with placebo (78%
vs. 22% respectively; P = 0.0143).18 NCCP patients without acid reux (n = 22) who were treated with either
placebo or lansoprazole had no signicant improvement
in symptoms (P = 0.75). Interestingly, most responders
felt symptomatic improvement within 2 days of starting
the lansoprazole, suggesting that those patients with
more frequent symptoms tend to have more rapid
response to treatment as compared to those with less
frequent symptoms.18 Another randomised controlled
trial with crossover design tested the administration of
lansoprazole 30 mg b.d. in nineteen NCCP patients with
nutcracker oesophagus during an 8 week period.19 Chest
pain symptoms were evaluated by weekly recording of
pain frequency, intensity and duration. The average
chest pain intensity score was obtained by using a visual
analogue scale (VAS). Despite signicant improvement
in the number (P < 0.005) and intensity of chest pain
episodes (P < 0.006) over time, there was no statistically
signicant difference in symptom response between lansoprazole and placebo in this group of patients. Sixty
three percent (n = 12/19) of the patients had evidence
of abnormal oesophageal acid exposure on pH testing,
but did not demonstrate better chest pain symptom
improvement on lansoprazole when compared with
placebo.19
218
EsomeprazoleA single randomised placebo-controlled

study evaluated symptoms scores in 599 NCCP patients
treated with esomeprazole 40 mg b.d. for 2 weeks.20 Several questionnaires; the Reux Disease Questionnaire
(RDQ), Short Form-36 (SF-36), Hospital Anxiety and
Depression Questionnaire (HAD), McGill Pain Questionnaire (MPQ), Chest pain visual analogue scale (VAS),
Brief Pain Inventory (BPI), Quality of Life in Reux and
Dyspepsia (QOLRAD), were used for symptom assessment in this study. Chest pain symptom relief was
dened as being less than or equal to 1 day of minimal
symptoms during the last 7 days of treatment. Patients
were stratied into two groups based on clinical judgment of the presence or absence of GERD-related symptoms. Importantly, pH testing was not done to
demonstrate pathologic acid reux. Patients without
GERD symptoms demonstrated signicant improvement
in chest pain symptoms on esomeprazole as compared
to placebo (38.7% vs. 25.5% respectively; P = 0.018). Post
hoc analysis of the combined populations (patients with
and without GERD symptoms) indicated positive treatment response to esomeprazole for chest pain in patients
with acid reux related symptoms as compared with
placebo (33.1% vs. 24.9% respectively; P = 0.035).20
Endoscopic therapies. Only one trial has been published
using the Endocinch endoluminal gastroplication (ELGP)
as a treatment modality for atypical GERD symptoms,
including non-cardiac chest pain. ELGP is an endoscopic
suture technique that places sutures, using the Endocinch
device, 1 cm below the oesophagogastric junction
(OGJ).21 In an open-label trial evaluating ELGP in
patients with atypical GERD symptoms (n = 39), including non-cardiac chest pain (18/39), the authors demonstrate that 72% (n = 13/18) of patients reported
improvement in symptoms of chest pain at 6 months
post-procedure as compared to baseline symptoms
(P = 0.0003).6
Surgery. There are no studies of GERD-related NCCP as
the sole indication for surgical treatment. Both complete
and partial surgical fundoplications have been performed
in patients with GERD-related NCCP using primarily
open-label trials. Studies have shown that 8196% of
NCCP patients with symptom correlation with reux
events occurring at least 40% of the instances on pH studies, demonstrated better symptom improvement after
complete or partial fundoplication as compared with
those without symptom correlation (Table 2).1, 7, 22
Patients with NCCP who demonstrated prior response to

PPI therapy were more likely to have typical GERD symptoms and higher satisfaction scores with fundoplication as
compared with NCCP patients who failed PPI treatment.23 NCCP patients with typical GERD symptoms,
tended to have greater symptom resolution compared to
patients without typical symptoms.8, 2325 Chest pain
symptom resolution in these studies ranged from 48% to
96% with fundoplication, regardless of the type of
surgery.7, 2224 In one study, 87% of patients with NCCP
treated with surgical fundoplication stated that they would
consider the operation again if needed22 (Table 2).
Some studies have shown no difference in chest pain
symptom scores after surgical fundoplication in patients
with documented oesophageal dysmotility as the underlying cause of NCCP.1, 7, 23 In one study, a signicant
improvement in atypical symptoms (including chest
pain) was seen in patients with normal and spastic oesophageal motility patterns treated with surgical fundoplication (72.4% vs. 83.9%, respectively) compared to preoperative symptom scores (P = 0.04). Those patients
with hypocontractile oesophageal motor disorders had
improved symptoms (21.7%), but at a lower rate of
improvement compared to those with spastic or normal
oesophageal motility patterns (Table 2).24
NCCP due to oesophageal dysmotility

Medical therapy. Nifedipine: Although administration of
nifedipine in varying doses has been associated with
improvement in manometric measures of LES basal pressure, distal oesophageal amplitude contraction and duration in nutcracker oesophagus patients, translation to
clinical improvement has not been consistent.26, 27 In a
placebo-controlled trial, the authors could not demonstrate
any statistical difference between the various doses of
nifedipine 1030 mg given three times daily and placebo
in improving chest pain symptoms of those patients with
either diffuse oesophageal spasm or nutcracker oesophagus.28 In contrast, a trial that evaluated NCCP patients
with nutcracker oesophagus who were treated with
nifedipine (1030 mg t.d.s.) showed a signicant improvement of mean chest pain index scores (beginning of treatment: 10.3 2.0 vs. end of treatment: 3.2 0.8;
P < 0.005) after a mean follow-up of 16.6 months vs. those
who received placebo. However, there was no signicant
improvement in duration and frequency of chest pain, as
compared to placebo.26 Another placebo-controlled trial
with a crossover design demonstrated a signicant
improvement of chest pain scores (P < 0.01) in NCCP
patients with hypertensive LES treated with nifedipine 10
mg t.d.s. as compared to placebo.29
Signicant adverse events of facial ushing, headache,

dizziness, and anxiety have been noted in several of the
clinical trials, often being cited as the cause for patients
discontinuation of medication.26, 29, 30
Diltiazem: Three randomised placebo-controlled trials

have shown different results regarding the efcacy of diltiazem in doses ranging from 60 to 150 mg for the treatment of NCCP patients with oesophageal dysmotility. In
a small cohort of diffuse oesophageal spasm patients
(n = 8) treated with diltiazem, the overall symptoms of
chest pain signicantly improved on treatment. However,
there was no statistical difference in chest pain index
(dened as chest pain frequency multiplied by daily
intensity of chest pain symptoms) when compared to
placebo.31 This nding was in contrast to two other
studies in patients with nutcracker oesophagus, where
both chest pain index and mean chest pain score signicantly improved on treatment compared to placebo.32, 33
In one study, administration of diltiazem in doses
ranging from 60 to 150 mg, resulted in a signicant
decrease in amplitude and duration of oesophageal contractions.32
Side effects such as headache and pedal oedema were
infrequent and tolerated well by most patients.3133
Nitrates: To date, all of the published trials using
nitrates have been open-label evaluating both short and
long acting nitrates in the treatment of NCCP-related
oesophageal dysmotility. Glyceryl trinitrate infusion, a
short acting nitrate, at a dose of 200 lg/kg/h improved
symptoms of chest pain and dysphagia as well as manometric ndings of increased latency and decreased mean
contraction duration in a small cohort of NCCP
patients.34 In contrast, success rates for longer acting
nitrates have been somewhat mixed. In a small trial of
ve patients with oesophageal dysmotility-related NCCP
(pre-treated with bethanecol to induce dysmotility and
symptoms), treatment with isosorbide resulted in no
notable improvement of symptoms or manometric
parameters.35 In a study of ve patients with diffuse
oesophageal spasm without GERD treated with sublingual nitroglycerin and long acting nitrates patients
demonstrated improved symptoms of chest pain and
normalisation of manometric abnormalities.36
Sildenal: There are no trials quantifying chest pain
symptom improvement with sildenal treatment. One
double-blind, randomised, placebo-controlled trial evaluated the effect of sildenal infusion (0.8 mg/kg) vs. pla219
N. George et al.
Table 2 | Open-label trials evaluating anti-reux endoscopic therapy and surgery for NCCP
Author,
year
Surgery
type
Study
size (N)
Lui 2006
Endoluminal
gastroplication
(Endocinch)
39, 46% with

chest pain
symptoms
13 years
Heartburn
symptom
score (HSS)
Regurgitation
frequency
score (RFS)
72% improvement of chest

pain symptoms at 6 months
(P = 0.0003) vs. baseline
scores
DeMeester
19821
Nissen
fundoplication
(n = 10)
Esophagomyotomy
(n = 1)
Partial and full
fundoplication
11, all GERD

positive by pH
testing
23 years
Chest pain score

(score 03)
91% patients had improved

chest pain symptoms
165, 34% with

chest pain
symptoms
13 months
Chest pain score

(05)
96% of patients with >40%

positive symptom index (SI)
had improved chest pain
symptoms (pre-op: 3.0 1.1
vs. post-op 1.0 1.1; P < 0.05)
79% of patients with 40%
positive SI improved chest pain
symptoms (pre-op 3.0 0.8
vs. post-op 1.0 0.4);
P < 0.05)
65% of patients with no SI cor
relation had improved
symptoms (pre-op 3.0 1.1
vs. post-op 1.0 1.1; P < 0.05)
Rakita
200622
Laparoscopic Nissen
fundoplication
158
50 months
83 months
Chest pain score

(03)
Post-op symptom
scores: excellent,
good, fair or poor
81% NCCP with excellent/good

outcome
87% NCCP patients would
undergo the operation again
based on survey
So 200823
Laparascopic Nissen
fundoplication
12
22 months,
median
Symptom
questionnaire
(score 010)
Previous medical therapy with

H2 blockers or PPI predicted
treatment response
Typical reux patients had
better outcomes than those
with atypical symptoms
(typical symptoms: post-op:
6.2 vs. atypical
symptoms post-op: 4.4;
P = 0.01)
58% symptom improvement
(chest and epigastric pain)
(P = 0.4)
Patti 20027
220
Follow-up
Symptom
assessment
Outcomes


Author,
year
Surgery
type
Study
size (N)
Follow-up
Brown
201124
Laparascopic Nissen
fundoplication
57
7 years
Symptom score
(severity 9
frequency) using
Likert scale (score
05) and Visual
analogue scale
7678% patients with chest

pain improvement/resolution
(pre-op chest pain intensity
score: 2.96 0.44 vs. post-op
0.71 0.22; P < 0.0001)
Cough, wheezing and
hoarseness symptoms
improved as often as typical
oesophageal symptoms
(P = 0.4)
Oesophageal hypomotility dis
orders with least improvement
in atypical symptoms (22%
improvement) vs. normal
motility (72% improvement)
vs. spastic features (84%);
P = 0.04
Hamdy
20148
Laparascopic Nissen
fundoplication
(LNF)
370
80% PPI
responders
(n = 296)
PPI failure
(n = 74) more
atypical
symptoms
(asthma, cough,
NCCP)
1 year
Symptoms
recorded in
standardised
manner, reux
symptoms graded
by DeMeester
score
Post-op outcomes
scored as
excellent, good,
fair, poor
Patients who responded poorly

post fundoplication tended to
have more atypical reux
symptoms compared to good
responders (37% vs. 7.4%;
(P = 0.006)
Typical symptoms of reux had
best outcomes
Atypical symptoms (asthma,
chest pain and cough) had
improvement in symptoms
(P = 0.002)
PPI responders had better out
comes for heartburn
(P = 0.01) and regurgitation
(P = 0.04) compared to PPI
failure patients
94% of PPI responders had
excellent to satisfactory scores
post-op vs. 84% in PPI failures
Farrell
200125
Laparascopic Nissen
fundoplication
62, stratied by
reux and
atypical
symptoms
(including chest
pain, asthma,
cough,
hoarseness)
13 months
Chest pain score

(04)
90% chest pain symptom

improvement, 50% symptom
resolution
Heartburn only patients did
better than those with heart
burn and atypical symptoms
(heartburn only: 99% symptom
improvement, 87% symptom
resolution vs. heartburn +
atypical symptoms: 95%
symptom improvement, 76%
symptom resolution; P < 0.05)
cebo on oesophageal motility in both healthy volunteers

(n = 8) and patients with nutcracker oesophagus who
reported chest pain symptoms (n = 5/9). The results
showed a signicant decrease in the LES resting pressure
and amplitude contractions at 1 h post-infusion of sildenal into the stomach.37 There were no side effects
Symptom
assessment
Outcomes
reported in this study. However, other trials have

reported side effects such as sleep disturbances, chest
tightness, dizziness and headache, which led to the discontinuation of the drug during follow-up visits in some
patients.38 Table 3 summarises studies of smooth muscle
relaxant therapies for NCCP.
221
N. George et al.
Botulinum toxin A: Studies evaluating the role of botulinum toxin A as a therapeutic modality in non-achalasia
spastic disorders of the oesophagus have shown varying
results. In an open label trial, that included 29 patients
with NCCP, Miller et al. have demonstrated a 62%
decrease in chest pain scores (scale 04) pre- and postinjections of botulinum toxin A (3.4 vs. 1.3; P < 0.0001)
above the lower oesophageal sphincter.39 The mean
duration of response for chest pain was 6 months
(5.8 4.8 months). There was no difference in symptomatic response among patients with different oesophageal dysmotility patterns, which included diffuse
oesophageal spasm, hypertensive lower oesophageal
sphincter, and ineffective oesophageal motor disorder.39
A smaller cohort of patients with diffuse oesophageal
spasm were treated with botulinum toxin A injections
demonstrated a signicant improvement in chest pain
symptoms scores (scale 03) from pre-injection (3.0) to
day 1 (1.0; P < 0.01), 1 month (1.0; P < 0.01) and
6 month post injection (0.0; P < 0.01). At 6-month follow-up, 89% of patients (n = 8/9) remained in clinical
remission. A total of four (50%) patients returned for
retreatment due to recurrence of symptoms at 8, 12, 15
and 24 months after initial treatment. Patients who were
re-treated with botulinum toxin A demonstrated treatment response for at least 6 months. NCCP scores
before reinjection (3.0) were signicantly better at day 1
(0; P < 0.01), 1 month (0; P < 0.01) and at 6-month
post-injection (1.0; P < 0.01).40
In contrast, a recent study with botulinum toxin A
injection in 22 non-achalasia patients showed an overall decrease in total symptom score for dysphagia
(P = 0.04) and chest pain (P = 0.03) on post hoc analysis. However, there was no statistical difference in
individual chest pain scores compared to saline injections.41 There is controversy regarding proper location
of the botulinum toxin A injections in NCCP patients
with non-achalasia oesophageal motor disorders. It still
has to be determined if the botulinum injections
should all occur just above the LES, or at differing
intervals above the LES. One study showed that multiple injections along the posterior wall of the oesophagus in 11.5 cm intervals proximally and into
endoscopically visible contraction rings, resulted in
improved chest pain, dysphagia, and regurgitation
symptom scores in eight of nine patients, thirty days
to 6 months post-treatment.40 Table 4 highlights summary data regarding usage of botulinum toxin A injection in NCCP.
222
Balloon and pneumatic dilation

There have been few studies evaluating balloon and
pneumatic dilation as therapeutic modalities for NCCP
due to spastic motor disorders of the oesophagus. In a
randomised, prospective trial with crossover design, the
authors compared dilation with a 54 fr bougie to 24 fr
bougie (placebo) in eight patients with nutcracker
oesophagus. Chest pain scores were documented daily
on a severity scale of 110. Mean chest pain scores from
pre- and post-treatment for both interventions (pretreatment: 4.2 1.0 vs. post-treatment: 3.2 0.8;
P = N.S.) and placebo (pre-treatment: 4.1 1.0 vs.
post-treatment: 3.1 0.0; P = N.S.) were not statistically
signicant between the two dilators. However, overall
chest pain scores at completion of the study were signicantly better (mean score at baseline: 4.7 1.0 vs. posttreatment with either placebo or intervention: 2.3 0.5;
P < 0.05) for both dilators, suggesting a signicant placebo response to the intervention.42
In a study that evaluated pneumatic dilation as a therapeutic modality for diffuse oesophageal spasm, symptom relief after pneumatic dilation was recorded on a
scale of 110 (0, indicating complete relief, and 10
dened as no relief at all). In this study that included 20
patients undergoing pneumatic dilation, the authors
found 70% (14/20) of patients reporting symptom
improvement (n = 6) or resolution (n = 8). Of those
who did not respond to dilation, 80% were found to
have positive pH testing for acid reux, compared to
only one patient with positive pH testing in the successfully dilated patients (P = 0.0105).43 While these data
imply that the presence of reux may impact response to
pneumatic dilation, the numbers were too small to draw
meaningful conclusions.
Peroral endoscopic myotomy (POEM)
Multiple case series evaluating POEM for the treatment
of spastic oesophageal motility disorders (diffuse oesophageal spasm, jackhammer oesophagus, nutcracker
oesophagus and hypertensive LES) have shown symptomatic improvement in chest pain symptoms reaching
91%.44 Some controversy exists on whether a longer
myotomy extending into the full length of the spastic
oesophageal muscle or short segment myotomy should
be pursued in patients with spastic oesophageal motor
disorders.45 It appears that patients with achalasia
demonstrate better symptom response to POEM compared to patients with spastic oesophageal motor disorders. However, larger trials are needed to further


Table 3 | Smooth muscle relaxant treatment for NCCP
Author, year
Type of trial
Study size (N)
Medication
name
Dose, schedule
Richter
198726
20 nutcracker
Double-blind,
patients
placebocontrolled
with crossover
Total
Symptom assessment
Outcome
Nifedipine
1030 mg, 3
times daily vs.
placebo
14 weeks with
crossover
design
Chest pain
index:
(severity 9
frequency)
Decreased amplitude and duration

of contraction as well as LES pres
sure compared to placebo
No difference in mean chest pain
frequency, severity or chest pain
index scores compared to placebo
at 6 weeks
16.6 month mean follow-up, over
all improved chest pain index
scores with both placebo and
nifedipine (pre-treatment:
10.3 2.0, during treatment
5.4 1.9. follow-up: 3.2 0.8;
p < 0.005)
Davies 198728 Double-blind,

8 DES patients
placebocontrolled
with crossover
Nifedipine
1030 mg
t.d.s. vs.
placebo
48 weeks with
active
treatment,
with crossover
to placebo in
4 weeks
Diaries of
frequency of
pain,
number of
attacks
weekly and
severity of
pain (daily
score)
No difference in chest pain or

dysphagia frequency and severity
compared to placebo
Nasrallah
198529
Nifedipine
10 mg t.d.s.
2 weeks, with
crossover to
placebo for
2 weeks
Symptom
improvement
(scale 010)
based on
frequency,
duration,
intensity of
pain,
dysphagia
All patients improved with

treatment
Hypertensive LES patients with
improved symptoms of chest pain
(P < 0.01) compared to placebo
No change in manometry with
treatment compared to placebo
Double-blind,
10 hypertensive
placeboLES
controlled
4 DES
with crossover
3 vigorous
achalasia
2 nutcracker
oesophagus
Drenth 199031 Double-blind,

placebocontrolled
with placebo
8 DES patients
Diltiazem
60 mg, t.d.s.
10 weeks, with
crossover to
placebo
Symptom
diaries using
visual
analogue
scales
Chest pain
index
75% improved chest pain

symptoms
No change in chest pain index
Richter
198432
Open-label
10 nutcracker
5
asymptomatic
normal
volunteers
Diltiazem
90150 mg,
q.d.s.
Chronic drug
study:
8 weeks
Average
frequency and
intensity of
chest pain per
week
recorded
using bar
graph
Chest pain
index-weekly
Dosage 90 mg and 150 mg

decreased amplitude (P < 0.01)
and mean duration of contraction
in nutcracker oesophagus patients
(P < 0.05)
Normal volunteers had no change
in manometry on treatment
86% of patients with improved
chest pain and dysphagia with
treatment (P < 0.01)
Cattau 199133
Double-blind,
placebocontrolled
with placebo
Total 14
-9 nutcracker
oesophagus
Diltiazem
6090 mg,
q.d.s.
8 week, with
crossover to
placebo for 8
weeks
Average fre
quency and
intensity of
recorded
chest pain per
week using
bar graph
Chest pain
index-weekly
Decreased distal amplitude con

tractions on treatment vs. placebo
(P < 0.05)
Decreased chest pain index and
intensity on treatment vs. placebo
(P < 0.05)

223
N. George et al.
Author, year
Type of trial
Study size (N)
Konturek
199534
Nonrandomized,
placebocontrolled
Mellow
198235
Swamy
197736
Total
Symptom assessment
Outcome
5 DES, 2/5 with Glyceryl

NCCP
trinitrate
infusion at a
dose of
200 mcg/kg/h
vs. saline
2 days
No formal
questionnaire or
symptom diary
Improved symptoms of chest pain

during swallowing
Decreased duration of amplitude
contractions (5.4 0.8 s vs.
saline, mean 11.2 4.8 s)
Prolonged latency (7.3 0.5 s vs.
saline, 1.8 0.3 s)
Reduced mean LES resting
pressure (11.6 8.2 vs. saline,
27.8 6.2 mmHg)
No side effects noted
Open-label
5 painful
oesophageal
dysmotility
2/5 DES
Isosorbide
20 mg vs.
hydralazine
10 mg IM and
25 mg oral
b.d. on
pre-treatment
for
bethanechol
challenge
2 days
Chest pain diary

(frequency and
severity)
1 in 5 patients pre-treated with

hydralazine experienced pain after
bethanechol vs. 3 in 5 patients
pre-treated with isosorbide
Pre-treatment with hydralazine
mean duration of contractions
12.7 1.8 s vs. bethanechol alone
31.4 4.8 s; P < 0.0005
Improved chest pain symptoms
with oral hydralazine, no
improvement or change in
manometry with isosorbide
No side effects noted with
treatment
Open-label
12 DES, 8
normal
12/12 pts on
short acting
nitrates
(sublingual
nitroglycerin)
8/12 patients
received long
acting
nitrates:
Isorbide
dinitrate 10
30 mg q.d.s.
or erythrityl
tetranitrate
q.d.s.
Sidenal 50 mg
dissolved in
20 mL of
water infused
into stomach
vs. saline
infusion
Sildenal
50 mg vs.
placebo
Short acting =
<6 months
Long acting =
6 months to
4 years
Lee. 200337
Eherer
200238
224
Medication
name
Dose, schedule
Double-blind,
randomized,
placebocontrolled
with normal,
open-label
with
oesophageal
dysmotility
patients
Eight normal
patients
nine
nutcracker
(n = 5/9
patients with
chest pain)
Six normal
patients
11
oesophageal
dysmotility
patients
N = 4/11
nutcracker
N = 3/11
achalasia
N = 2/11
hypertensive
LES
N = 1/11 DES
GERD positive patients

unpredictable response to nitrates
for NCCP symptoms
GERD negative patients had good
long-term nitrate response at
4 years for NCCP symptoms
2 days
No symptoms were
assessed during
treatment
In nutcracker patients: decreased

resting LES pressure over 1 h
compared to control (P < 0.05)
In nutcracker patients: prolonged
duration of swallow induced LES
relaxation at 30 min (P < 0.05)
2 days
Symptom
diary for
treatment and
side effects
82% (n = 9/11) of oesophageal

dysmotility patients showed
improvements on manometry
44% (n = 4/9, no patients
with achalasia) improved
symptom of dysphagia and
heartburn treated with as
needed sildenal
Side effects: sleep
disturbances, chest
tightness, dizziness, headache


determine the value of POEM in NCCP patients with
oesophageal hypercontractility.44
Surgery
Small case series have shown that minimally invasive
oesophagomyotomy (Heller myotomy) may be an effective
treatment modality for NCCP patients. Resolution of chest
pain after myotomy, in conjunction with fundoplication,
has been shown to be as high as 94% in open-label trials.46, 47 Given the high incidence of gastro-oesophageal
reux, post-myotomy due to LES disruption, one study
focused on evaluating the various fundoplication techniques, including standard Belsey procedure, partial fundoplication gastroplasty (PFG), total fundoplication
gastroplasty (TFG) and modied short Nissen fundoplication in 65 chest pain patients with diffuse oesophageal
spasm with chest pain undergoing extended myotomy.
Treatment success was classied based on the following
categories: (i) no imaging ndings of reux or residual
symptoms of reux, dysphagia or chest pain, (ii) only
imaging ndings of reux on water siphon barium studies
or (iii) both imaging ndings of reux and residual symptoms of chest pain, dysphagia and reux. Results of this
retrospective trial found Nissen fundoplication be the
most effective adjunct to esophagomyotomy, with 87% of
patients without symptoms or ndings of residual reux
(13/15), and 13% (2/15) with no symptoms but ndings of
residual reux on imaging studies post operatively. The
other surgical modalities had the following ndings: Belsey
procedure (n = 20): 10% with trace reux, 50% with residual symptoms, PFG (n = 9): 22% with trace reux, 11%
with residual symptoms, and TFG (n = 19): 32% with
trace reux and 5% with residual symptoms.47 A recent
retrospective trial of 20 patients with diffuse oesophageal
spasm who underwent myotomy and anterior fundoplication demonstrated signicant improvement in overall
post-operative clinical course in 80% of patients (Eckhart
scores, pre- 6, post-operatively- 1; P < 0.01), post-op surgical chest pain scores (pre- 2, post-operatively- 0;
P < 0.01) and post-op surgical dysphagia scores (pre-op3, post-operatively- 0; P < 0.01). Importantly, 100% of the
patients reported complete resolution of chest pain postoperatively at 36 months.48
Oesophageal hypersensitivity
Medical therapy. Tricyclic antidepressants: The only
tricyclic antidepressant that has been studied in a randomised double-blind, placebo-controlled trial is imipramine. In one study, 60 NCCP patients were divided into

three groups and treated with either imipramine 50 mg,

clonidine 0.1 mg or placebo daily. Treatment with imipramine, clonidine and placebo showed a mean reduction in chest pain frequency (s.d.) compared to the
placebo phase of 52% ( 25%), 39% ( 51%) and 1%
( 86%) respectively. Only impramine treatment showed
signicant reduction in chest pain frequency
(approximately 50%) compared to the placebo phase
(P = 0.03), as well as decreased right ventricular sensitivity to pain. Both imipramine and clonidine had
improved symptoms of chest pain intensity compared to
placebo, (P = 0.001 and 0.002 respectively). There was
no difference in treatment effect when patients with normal and those with abnormal oesophageal motility studies were compared. There was no change in oesophageal
sensitivity to balloon distension during treatment as
compared to baseline. Fifteen patients treated with imipramine had a slight but signicant prolongation of the
corrected QT interval (P = 0.02). No patients reported
symptoms suggestive of a pro-arrhythmic effect.49 Cox
et al. performed a randomised, double-blind, cross-over
trial of imipramine vs. placebo in 18 women with chest
pain and normal coronary angiograms who were suffering anginal episodes despite conventional anti-anginal
medication.50 All patients were randomised to treatment
with either imipramine 50 mg or placebo daily for a
period of 5 weeks, followed by a 2 week washout period.
Patients were then crossed over to the other arm for an
additional 5 weeks. The total number of chest pain episodes was signicantly less with imipramine compared
to placebo (11 vs. 21, respectively; P = 001). However,
no signicant improvement was detected in any of the
six quality of life domains when imipramine was
compared to placebo. This was most likely due to the
high incidence of side effects with imipramine compared to placebo (83% vs. 44% respectively; P = 001).
Furthermore, three patients were withdrawn from the
study due to side effects. The most common side effects
reported were dry mouth and dizziness.
Park et al. conducted a randomised, open-label trial in
functional chest pain patients refractory to standard dose
PPI.51 The study compared treatment outcomes between
standard dose PPI (rabeprazole 20 mg daily) plus lowdose amitriptyline (10 mg at bedtime) (n = 17) vs. double-dose PPI therapy alone (rabeprazole 20 mg b.d.)
(n = 19). Patients, who had both negative pH testing for
GERD and less than 50% improvement in global symptoms scores after treatment with standard dose rabeprazole for 1 month, were enrolled into the study. Daily
225
N. George et al.
Table 4 | Botulinum toxin therapy for NCCP
Author,
year
Symptom
assessment
Type of trial
Study size (N)
Dose, schedule
Duration
Miller
200239
Open-label
29
-13 DES
-3
hypertensive
LES
-4 IEM
Botulinum injection
at LES
018 months
Chest pain
score (04)
62% decrease in chest pain

score
Mean response duration
5.8 4.8 months
72% patients with at least
50% reduction in chest pain
scores
Storr.
200140
Open-label
9 DES
Botulinum toxin
injected
proximally in
multiple sites into
visible contraction
rings
6 months
Total
symptom
score
(Eckardt
score)
At 6 month follow-up, 89%

decreased total symptom
score, including chest pain as
individual score
Mean duration of treatment
effect at 6 months (P < 0.01)
Repeat injections required in 4
patients at 6 months, with
treatment response with rein
jection for additional 6 months
(P < 0.01)
Vanuytsel
201341
Double-blind,
randomized,
placebocontrolled,
with
cross-over
22 DES and
nutcracker
Botulinum toxin to
LES
12 months
Symptom
frequency
(score 04)
Modied Vantrappen criteria

for achalasia used to evaluate
effectiveness of treatment
Total symptom scores
improved for dysphagia
(P = 0.04) and chest pain
(P = 0.03) on post hoc analysis
No improvement on individual
chest pain scores
50% patients had response on
treatment after 1 month, com
pared to 10% on placebo
(P = 0.04)
symptom diaries were used to evaluate global symptom

scores each week. Mean global symptom scores were not
statistically signicant between the two treatment groups
(3.75 0.31 vs. 4.35 0.29, P = 0.172); however,
within the groups differences in global symptom scores
were signicant at week 8 (P < 0.001). After 8 weeks,
71% of patients treated with both amitriptyline and standard dose rabeprazole had greater than 50% global
symptom improvement, whereas only 26% of patients
treated with double-dose rabeprazole had a similar
degree of symptom improvement (P = 0.008). In addition, those patients who received both amitriptyline and
standard dose rabeprazole were noted to have signicant
improvement in scores of body pain and general health
perception, compared with those receiving double-dose
rabeprazole (P = 0.031 and 0.01 respectively).51 Other
new TCAs known to have fewer anti-cholinergic side
effects, such as nortriptyline, are attractive treatment
options due to more favourable side effect proles, but
have not been formally studied in NCCP. Table 5 highlights the studies evaluating pain modulatory therapy in
NCCP.
226
Outcome
Trazadone: Trazadone, dosed between 100 and 150 mg,

was evaluated in 29 patients with contraction abnormalities and non-cardiac chest pain using a double-blind placebo-controlled trial for 6 weeks. Questionnaires that
were used to evaluate symptom improvement with treatment, included the Oesophageal Distress Symptom Score,
Symptom Checklist 90-Revised (SCL-90), global symptom index, positive symptom index, and the Montgomery-Asberg Depression Rating Scale (MADRS). All
patients underwent the Bernstein test with acid perfusion
into the oesophagus at the time of oesophageal manometry. Those patients with positive acid perfusion testing,
ndings of oesophagitis on upper endoscopy or barium
studies were excluded. Trazadone treated patients
reported a signicantly greater global improvement (per
visual analogue scale) compared to placebo at 6 weeks
post-treatment (trazadone: 48% vs. placebo: 11%;
P = 0.02), despite no effect on oesophageal motility. In
addition, patients treated with trazadone had a statistically signicant reduction in oesophageal distress symptom scores (including NCCP) compared to placebo
(P = 0.03). However, there was no signicant difference

in chest pain intensity or frequency in patients treated
with trazadone vs. placebo. Side effects were generally
mild and consisted of dry mouth in two patients and
dizziness, drowsiness, and fatigue in ve patients receiving trazadone.52
Serotonin-norepinephrine reuptake inhibitors: Venlafaxine 75 mg/day was compared with placebo for the treatment of 43 patients with functional chest pain. Symptom
diaries documented scores of frequency and severity of
chest pain. Symptom intensity scores were calculated by
adding daily severity for the week multiplied by daily
frequency. Additional questionnaires included Short
Form 36 (SF-36) and the Becks Depression Inventory
(BDI). Symptom score improvement of greater than 50%
was considered to be treatment success. On the intention-to-treat analysis, more than 50% improvement in
symptoms was seen in 52% of patients treated with venlafaxine vs. 4% treated with placebo (OR 26.0; 95%
CI = 5.7118.8; P < 0.001). Furthermore, patients in the
venlafaxine group had a signicantly greater improvement in body pain and emotional state compared with
the placebo group (P = 0.002 and 0.002 respectively).53
Overall, the side effects were minimal and primarily consisted of sleep disturbances.
Selective serotonin reuptake inhibitors: A double-blind,
randomised placebo-controlled trial evaluating paroxetine in dosages ranging from 550 mg was performed
in 43 NCCP patients. Patients were evaluated by the
physician-rated scales (Clinical Global Impression of Illness Severity and Clinical Global Impression of
Improvements), Beck Depression Inventory (BDI), Short
Form McGill Pain Questionnaire, Medical Outcomes
Study Short Form 36 (SF-36) and a patient-rated scale
of symptom severity (visual analogue scale) to assess
symptoms throughout the study period. No gastrointestinal evaluation had been performed before or during
enrolment into the study. Only on Clinical Global
Impression of Improvements questionnaire did paroxetine treatment show superiority to placebo
(P < 0.05).54
Sertraline was evaluated as a treatment for NCCP in
a single-site, double-blind placebo-controlled study consisting of 30 patients.55 The sertraline group received
50 mg at the beginning of the study, with titration of
the dose to 200 mg based on clinical response. Patients
were evaluated with daily pain diaries (visual analogue
scales), Short Form (SF) 36 Health Survey Manuel and
the Beck Depression Inventory (BDI) at enrollment.
Patients treated with sertraline had greater reduction in

chest pain scores (week 0: 3.94, week 9: 1.49) compared
to those treated with placebo (week 0: 3.50, week 9:
2.96; 95% CI 3.49, 0.36; P = 0.02), with pain scores
decreasing by approximately 0.2 units for each week of
the study. The SF-36 subscore for general health had
signicantly improved at the end of treatment compared
to placebo. Side effects were generally mild and reported
as restlessness, nausea, decreased libido and delayed
ejaculation.55
Adenosine antagonists: A few studies have evaluated the

role of theophylline in the treatment of oesophageal
chest pain. Rao et al. rst conducted a 3-month openlabel trial of theophylline infusion in 21 patients with
functional chest pain.56 Patients underwent impedance
planimetry as well as balloon distension of the oesophagus, with oesophageal hypersensivity being dened as
reproduction of chest pain symptoms with balloon distension 55 cm H2O pressure. Chest pain intensity and
improvement in chest pain symptoms were measured by
visual analogue scales. Sensory responses to balloon distension were graded on a scale of 13 (0no pain, 1fullness/distension, 2discomfort, 3pain). Of those who
demonstrated reproducible chest pain with graded balloon distension (16/21), 12 (75%) had increased chest
pain thresholds (P < 0.05). The median threshold for
discomfort increased to 45 cm H2O (vs. pre-treatment:
20 cm H2O; P < 0.05) and for chest pain to greater than
65 cm H2O (vs. pre-treatment: 40 cm H2O; P < 0.05).
Eight of the twelve patients who received oral theophylline (6 mg/kg/day) completed the second portion of
the study. Six of eight patients (75%) had greater than
50% reduction in chest pain frequency and intensity
(P < 0.05) with intravenous theophylline compared to
baseline scores (P < 0.05). These six patients were subsequently transitioned to the oral theophylline phase of the
trial.
Adverse effects were noted in four patients including
transient insomnia, nausea, palpitations, and tremor.
Two patients who were transitioned to oral theophylline,
discontinued treatment due to symptoms of nausea,
transient insomnia and palpitations.56
Rao et al. also performed two randomised placebocontrolled trials in a single cohort of NCCP patients several years later involving intravenous and oral theophylline.57 The rst trial with intravenous administration
of theophylline treatment in 16 NCCP patients demonstrated increased chest pain thresholds (P = 0.027),
increased oesophageal cross-sectional area (P = 0.03),
227
N. George et al.
Table 5 | Pain modulators in NCCP
Author,
year
Type of trial
Study
size (N)
Medication
name,
Dose, schedule
Duration
Symptom assessment
Outcome
Cannon
199449
Double-blind,
placebocontrolled
with crossover
60
Clonidine
0.1 mg b.d.
vs. Imipramine
50 m at
bedtime vs.
placebo b.d.
10 weeks
Symptom diary of
chest pain fre
quency, intensity,
and magnitude of
pain per week
41% (n = 22/54) had

provocative oesopha
geal testing with
chest pain symptoms
Mean reduction in
chest pain frequencyimipramine: 52 25%,
clonidine: 39 51%
placebo: 1 86%
Imipramine with reduced
chest pain frequency
vs. placebo (P = 0.03)
Chest pain intensity
lower with imipramine
(P = 0.001) and clonidine
(P = 0.002) vs. placebo
No central nervous system
side effects reported
Cox
199850
Randomized,
Double-blind
placebocontrolled
with crossover
18 women
Imipramine
50 mg daily
vs. placebo
12 weeks:
5 weeks of
treatment or
placebo with
2 week
washout,
then
crossover to
for 5 weeks
Chest pain diaries

(onset, duration,
severity)
Chest pain severity
using visual ana
logue scale (VAS)
Nottingham Health
Prole questionnaire
Decreased median
total number of chest
pain episodes with
imipramine vs. pla
cebo (11 vs. 21; P = 0.01)
Decreased number of
moderate severity of
chest pain episodes with
imipramine vs. placebo
(5 vs. 12; P = 0.05)
No difference in max
imal duration of chest
pain episodes
Dry mouth and dizzi
ness most common
side effects
Park
201351
Randomized,
open-label
36
Amitriptyline
10 mg with
rabeprazole
20 mg once
daily vs.
raperazole
20 mg b.d.
8 weeks
Daily symptom
diary
Global symptom
score (visual ana
logue scale)
SF-36
Beck Depression
Inventory (BDI)
Mean difference in
global symptoms
scores not statistically
signicant between
two groups
Between group differ
ence in global symp
tom scores were sig
nicant (P < 0.001)
Amitriptyline + stan
dard dose PPI had
greater symptom
improvement vs. dou
ble-dose PPI (71% vs.
26%, with greater
than 50% symptom
improvement;
P = 0.008)
228


Author,
year
Type of trial
Study
size (N)
Medication
name,
Dose, schedule
Duration
Symptom assessment
Outcome
Clouse
198752
Double-blind,
placebocontrolled
with crossover
29
Trazadone 50
150 mg daily
vs. placebo
6 weeks
Rating of oesopha
geal distress
Oesophageal symp
tom index
SCL-90R
Global symptom
index
Symptom index
(MontgomeryAsberg Depression
Rating Scale)
Global change
(VAS)
Improved global
symptoms at 6 weeks
(trazadone: 48% vs.
placebo 11%;
P = 0.02)
Decreased oesopha
geal distress scores
with trazadone com
pared to placebo
(P = 0.03)
No change in chest
pain intensity or fre
quency between pla
cebo and trazadone
No change on oeso
phageal manometry
seen
Side effects: dry
mouth, dizziness,
drowsiness, fatigue
Rao
200256
Open-label
12
-IV theophylline
infusion
-Theophylline
150250 mg
b.d.
12 weeks
Chest pain fre

quency and inten
sity scored by visual
analogue scales
Balloon distension
sensation (grade 0
3)
75% (n = 12/16) of
patients had
increased chest pain
threshold
Median threshold for
discomfort increased
to 45 cm H2O vs.
20 cm H2O; P < 0.05
Increased pain
threshold to >65 cm
H2O (vs. 40 cm
H2O); P < 0.05
75% (n = 6/8)
improved chest pain
frequency and inten
sity with oral theo
phylline (P < 0.05)

229
N. George et al.
Author,
year
Type of trial
Study
size (N)
Medication
name,
Dose, schedule
Duration
Symptom assessment
Outcome
Rao
200757
Double-blind,
placebocontrolled
16 (IV infusion
study)
19 (oral (PO)
study)
-IV theophylline
vs. 0.9%
NaCl solution
placebo
-Theophylline
200 mg b.d.
vs. placebo 9
8 weeks
8 weeks
Chest pain fre

quency and inten
sity (scores 04)
Balloon distension
sensation (grade 03)
Increased oesopha
geal cross-sectional
area and wall tension
with IV theophylline
infusion (P = 0.03,
P = 0.04) vs. placebo
Less median number
of painful days with
PO theophylline (5
vs. 10 placebo;
P = 0.03)
Decreased median
chest pain episodes
with PO theophylline
(8 vs. 16 placebo;
P = 0.025)
Decreased chest pain
severity compared to
PO placebo (2 vs. 3;
P = 0.031)
40% pain severity
score >3 with PO
theophylline com
pared to placebo
(60%; P = 0.047)
Median difference of
2 min less of chest
pain with PO theo
phylline compared to
placebo (mean dura
tion 8.5 vs. 6.5 min;
P = 0.002)
58% improved symp
toms with PO theo
phylline vs. 6% pla
cebo (p < 0.02)
Lee 201053
Double-blind,
placebocontrolled
53
Venlafaxine
75 mg at
bedtime vs.
placebo
Initial 4 week
treatment
period,
followed by 2
week washout,
then followed by
4 week crossover
Short form 36 and

Becks Depression
Inventory
Symptom intensity
scores (daily severity
X daily frequency)
Greater than 50%
improvement in 52%
of patients given
treatment compared
to 4% in placebo (OR
26.0; 95% CI = 5.7
118.8; P < 0.001)
Bodily pain and emo
tional state improved
with treatment
(P = 0.002)
230


Author,
year
Type of trial
Study
size (N)
Medication
name,
Dose, schedule
Duration
Symptom assessment
Outcome
Doraiswamy
200654
Double-blind,
placebocontrolled
43
Paroxetine 10
50 mg daily
vs. placebo
8 week trial with

crossover
Clinical Global
Impression (CGI) of
severity (CGI-S),
and improvement
(CGI-I)
Daily pain scores
(visual analogue
scale)
Beck Depression
Inventory (BDI)
Short form McGill
Pain Questionnaire
Medical Outcome
Study Short Form
36 (SF 36)
Improved chest pain

symptoms on CGI-I
with paroxetine com
pared to placebo (P
< 0.01)
No improvement of
chest pain on patient
reported scores
Varia
200055
Double-blind,
placebocontrolled
30
Sertraline 50
200 mg
8 weeks
Chest pain scores

(visual analogue
scale)
Beck Depression
Inventory (BDI)
SF36 Health Survey
Manual
Improved chest pain

scores with sertraline
vs. placebo
(P = 0.02)
Higher SF-36 scores
with sertraline
(P = 0.02)
and a more distensible oesophageal wall (P = 0.04) after

treatment, as compared with placebo, suggesting a more
relaxed oesophagus after theophylline infusion. The second trial evaluated oral theophylline treatment response
in 19 NCCP patients compared to placebo. Patients treated with oral theophylline (200 mg capsules b.d. for
4 weeks) had a 58% reduction in symptoms, compared
to 6% on placebo (P < 0.02). Patients were noted to have
less chest pain episodes (P = 0.025) as well as decreased
duration (P = 0.002) and severity (P = 0.031) of symptoms (Table 5). Theophylline was reasonably tolerated,
with reported side effects of nausea, insomnia, tremor
and light-headedness.57
Alternative medicine
Johrei therapy. Johrei therapy is a technique by which a
healer transmits healing energy to the patient. Gasiorowska et al. conducted a randomised, controlled pilot
study evaluating the effect of Johrei vs. wait list (no
intervention) in controlling symptoms of 39 patients
with functional chest pain. All patients enrolled had normal ambulatory oesophageal pH testing, upper endoscopy, and oesophageal manometry. Patients were
evaluated by the Short Form-36, Symptom Check list
90R (SCL-90R), Perceived Stress Scale (PSS) and Hospital Anxiety and Depression (HAD) scale. Symptom
intensity scores were calculated by adding the reported
daily symptom severity multiplied by frequency. Eighteen

Johrei sessions delivered by the same certied practitioner were conducted over a 6-week period. The study
demonstrated a signicant post-treatment reduction in
symptom intensity scores (7.0) in the Johrei group as
compared to baseline (20.28; P = 0.0023). In contrast,
the wait list group demonstrated no difference in symptom intensity scores compared to baseline (23.06) and
post-treatment (20.69; P = N.S.) scores.58 Johrei was well
tolerated with no side effects reported.
Psychological treatment. Cognitive behavioural therapy: Cognitive behavioural therapy (CBT) emphasises
cognitive methods by which patients examine beliefs
regarding symptoms and undergo a process of adjustment of these beliefs (Table 6). The role of CBT in the
treatment of NCCP has been evaluated in several randomised controlled trials.5965 One of the earliest studies
was conducted in 31 patients with NCCP who were randomised to either immediate CBT (n = 14) or assessment only (n = 17). Gastroenterology evaluation was not
performed prior to enrolment into the study. Questionnaires used in the study included the State-Trait Anxiety
Inventory (STAI-T), Beck Depression Inventory (BDI),
Symptom Rating Test (SRT) and 5-point avoidance
checklist (from prior 3 months). Mental state was
assessed using the Present State Examination interview.
231
N. George et al.
Chest pain diaries were kept by patients. Within the
CBT group, there were signicant reductions in the
number of days with chest pain (2.47 1.72; P < 0.01),
psychological distress (3.03 1.42; P < 0.001), avoidance of activity due to pain (0.45 0.31; P < 0.01), and
depressed mood (5.31 3.4 l; P < 0.01) compared to
the controls.59 These ndings were also supported in a
later study that included 72 patients who underwent
CBT therapy. In this study, symptoms were evaluated
using the Anxiety Disorder Interview Schedule (ADISR), chest pain diary (measuring intensity and duration
weekly), Hospital Anxiety and Depression Scale (HADS)
and Short Form Health Survey (SF-36). Forty-seven per
cent (n = 15/32) of patients having undergone CBT were
chest pain free at 12 month follow-up compared to 12%
(n = 4/33) of the cohort receiving usual care during the
same interval (P < 0.001).60
Mayou et al. evaluated 37 patients with NCCP by
comparing CBT with standard clinical management and
advice.61 Of those who completed 6-month treatment,
there was a statistically signicant difference between
CBT and standard treatment in terms of severity of
symptoms (CBT: 1.75 1.07 vs. standard treatment:
2.65 0.93; P = 0.05). At 6 months, severity scores
improved with CBT treatment compared to standard
treatment (CBT: 1.95 1.32 vs. standard treatment:
2.35 1.54; P < 0.05), but not NCCP frequency scores
(CBT 2.75 1.59 vs. standard treatment: 2.71 1.80;
P = N.S.). Of those who completed treatment (n = 16),
43% (n = 7/16) reported major reductions in frequency
and severity of symptoms as well as concern about
symptoms, and were more likely to demonstrate return
to normal activities at 6 month follow-up. The control
group experienced only modest improvement in symptoms and associated distress and less change in everyday
activity and beliefs.61
Jonsbu et al. conducted two studies evaluating the
role of CBT in NCCP. The rst study included 40
NCCP patients who were randomised to CBT, which
included exposure to physical activity as a key element
in treatment, and usual care. Patients were not evaluated
by a gastroenterologist prior to enrollment into the
study. Patients completed questionnaires that included:
Body Sensations Questionnaire (BSQ), Beck Depression
Inventory (BDI), Short Form Health Survey 36 (SF-36),
frequency of chest pain symptoms (scale 14), avoidance
of physical activity (scale 14), and impact of cardiac
symptoms on various social domains (scale 14). The
CBT group experienced greater improvement in fear of
bodily sensations, avoidance of physical activity, depres232
sion and other quality of life measures after treatment at

various time points during the study as compared with
the control group. However, there was no change in
chest pain symptom frequency between the groups.62
The second study that was done with the same cohort
of patients, aimed to compare change and impact of illness perception in NCCP patients treated with three-session CBT intervention (n = 21) and compared to a
usual care (n = 19). Illness perception between the
groups was evaluated using the eight-item Brief Illness
Perception Questionnaire (BIPQ). Mean differences in
change at end of CBT treatment and long-term followup (3 months and 12 months) were notable for signicant change in chest pain frequency from pre- to postintervention (baseline mean score: 4.3 1.4 vs. end of
treatment: 1.52, 95% CI: 0.482.56, at 3 months: 1.72,
95% CI: 0.692.7 and at 12 months: 1.77, 95% CI: 0.74
2.80). In addition, 50% (4/8) of the items on the BIPQ
were signicantly better with CBT compared with usual
care on long-term follow-up at 3 and 12 month followup as compared to the end of treatment (3/8). These
ndings demonstrate that maintenance of physical activity and experience after treatment intervention (i.e.
CBT) is required to change perceptions regarding an illness (i.e. chest pain) in order to sustain the effect of
treatment.63
Cott et al. also used cognitive behavioural therapy (individual CBT, group CBT, self-monitoring attention control or wait-control setting) in 104 patients with NCCP.
Patients were subdivided into two groups, normal coronary angiograms (n = 14) and those with history of
mitral valve prolapse (MVP) without other known cardiac conditions other than benign arrhythmias
(n = 90).64 Questionnaires were used to quantify treatment outcomes using the Body Sensation Questionnaire
(BSQ), Becks Depression Index (BDI), Short Form
Health Survey 36 (SF-36) and visual analogue scales to
quantify functional status. A total of 69 patients completed pre-intervention measures (cardiac testing, resolution of psychiatric issues for at least 6 months, and
compliance with self-monitoring of symptoms for
2 weeks) were randomised into the different treatment
groups (individual CBT19, group CBT28, self-monitoring attention control7 and wait list control settings
15). Patients were not evaluated by a gastroenterologist
prior to the study. There were more women than men in
the MVP group (P < 0.01). No statistically signicant
differences were found between the normal coronary
angiogram patient group and the MVP group. Therefore,
data from both groups were pooled for analysis. The

Table 6 | Cognitive behavioural therapy
Author, year
Type of trial
Study size (N)
Randomized
controlled
31
van-PeskiOosterbaan
199960
Randomized
controlled
Mayou 199761
Jonsbu 201162
Klimes 1990
59
Group sizes,
schedule
Duration
Symptom assessment
Outcome
CBT (n = 14), vs.

control for
assessment
(n = 17)
46 months
State-Trait Anxiety
Inventory (STAI-T)
Beck Depression
Inventory (BDI)
Symptom Rating
Test (SRT)
5-point avoidance
checklist
(3 months prior)
Present State
Examination inter
view
Chest pain diaries
CBT group reduced

number of chest
pain days (mean
difference 95%
CI) 2.47 1.7;
P < 0.01, avoid
ance of activity
due to pain
(0.45 0.31;
P < 0.01), com
pared to controls
72
CBT (n = 33), usual

care (n = 33), 7
patient drop out
12 months
Anxiety Disorder
Interview Schedule
(ADIS-R)
Chest pain diary
(intensity, duration
weekly)
Hospital Anxiety
and Depression
Scale (HAD)
RAND-36 Health
Survey (SF-36)
47% treated with CBT

were chest pain
free vs. 12% at
12 months;
p < 0.001
Randomized
controlled
37
CBT vs. standard

clinical
management and
advice
3 months
Chest pain diary

Detailed question
naire regarding
limitation and
avoidance of spec
ied
Activities scored
on a 03 scale of
difculty
Structured Clinical
Interview for
DSMIII-R for anxi
ety and depression
and somatoform
disorders
6 months: CBT
group improved in
change in severity
of NCCP symp
toms vs. standard
care (1.75 1.07
vs. 2.65 0.93;
P = 0.05)
CBT group
Improved severity
scores at
6 months vs. stan
dard care
(1.95 1.32 vs.
2.35 1.54;
P < 0.05)
No change in
chest pain fre
quency between
the two groups
Randomized
controlled
40
CBT with physical

activity exposure
vs. usual care
12 months
Body Sensations
Questionnaire
(BSQ)
Beck Depression
Inventory (BDI)
Short Form Health
Survey 36 (SF-36)
Frequency of chest
pain
Avoidance of
physical activity
Impact of cardiac
symptoms on
social domains
CBT improved
sentiments regard
ing fear of bodily
sensations, avoid
ance of physical
activity, depression
and other quality
of life measures
No change in
chest pain fre
quency with CBT
compared to usual
care

233
N. George et al.
Author, year
Type of trial
Study size (N)
Randomized
controlled
40
Cott 199264
Randomised
controlled
Spinhoven
201065
Double-blind,
placebocontrolled
Jonsbu 2013
234
63
Group sizes,
schedule
Duration
Symptom assessment
Outcome
CBT with physical

activity exposure
vs. usual care
12 months
Brief Illness Per

ception Question
naire (BIPQ)
Higher mean
change in frequency of chest
pain symptoms
(BIPQ #5 item)
with CBT com
pared to usual
care at the end of
treatment: 1.52,
95% CI: 0.48,
2.56, at 3 months:
1.72, 95% CI:
0.69, 2.76, at
12 months: 1.77,
95% CI: 0.74,
2.80
104
Normal
coronary
angiograms
(n = 14), history of
mitral valve
prolapse
(n = 90)
69 completed
interventions
4 groups:
Group CBT vs.
Individual CBT vs.
Self-monitoring vs.
attention control
vs.
Wait-control
setting
16 months
Body Sensation
Questionnaire
(BSQ)
Becks Depression
Index (BDI)
Short Form 36
Health Survey (SF
36)
Assessment of
functional status
using visual ana
logue scales
No difference
between normal
coronary angio
gram patients and
mitral valve pro
lapse group
Group and individ
ual CBT interven
tions improved
short and longterm functional
status at 6
16 months,
P < 0.001 vs. con
trol groups
58
Paroxetine 10
50 mg daily vs.
placebo vs. CBT
12 weeks
Chest pain index

(duration 9 inten
sity)
Hospital Anxiety
and Depression
Scale (HAD)
Cardiac Anxiety
Questionnaire
(CAQ)
M.I.N.I Plus
Higher treatment
response in CBT
(47.8%),
compared to
paroxetine
(21.7%) and pla
cebo (13%)
Improved chest
pain index scores
at post-treatment
with CBT com
pared to placebo
and paroxetine
(P = 0.04,
P = 0.03 respec
tively)
CBT or paroxetine
improved CAQ
scores compared
to placebo at mid
treatment
(P = 0.04,
P = 0.02 respec
tively), and posttreatment
(P = 0.03,
P = 0.02 respec
tively)
Paroxetine was
noted to be no
more effective
than placebo in
the short term


researchers found that group or individual interdisciplinary intervention was successful for improving shortterm and long-term (616 months) functional status,
(both P < 0.001) compared to the wait list control
group.64
Lastly, a study by Spinhoven et al. randomised 58
NCCP patients to 12 weeks of either outpatient treatment with CBT, paroxetine or placebo.65 The comparison between placebo and paroxetine was carried out in
a double-blind fashion. Intensity and duration of chest
pain were rated on two visual analogue scales, with subsequent calculation of daily chest pain index. Three measurements were obtained based on these scores and
included pre-treatment score (3 weeks prior to treatment), mid treatment score (week 46), post-treatment
score (weeks 1012). The questionnaires that were used
in evaluation of symptoms included the Hospital Anxiety
and Depression Scale (HADS), Cardiac Anxiety Questionnaire (CAQ), and the MINI-Plus. Intent-to-treat
analysis showed signicantly higher treatment response
in patients treated with CBT (47.8%, n = 11) compared
to paroxetine (21.7%, n = 5) and placebo (13%, n = 3).
Patients treated with CBT had improved chest pain
index scores post-treatment compared to placebo
(P = 0.04) and paroxetine (P = 0.03). However, with
respect to CAQ scores, patients treated with either CBT
or paroxetine had improved scores compared to placebo
at mid treatment (P = 0.04 and 0.02 respectively) and
post-treatment (P = 0.03 and 0.02 respectively). Interestingly, paroxetine was noted to be no more effective than
placebo in the short term.65
Hypnotherapy: Jones et al. conducted a single blinded,

randomised controlled trial of hypnotherapy in 28
patients with NCCP.66 The patients received 12 sessions
of hypnotherapy or supportive therapy plus placebo
medication over a 17-week period. Patients answered
questions regarding global assessment of wellbeing, pain
severity (scale 0100), frequency of pain (episodes per
month) and completed the Hospital Anxiety Depression
Scale Questionnaire (HADS). All patients in the study
had prior negative pH testing for acid reux. Of the
patients treated with hypnotherapy, 80% experienced
global improvement in chest pain (vs. 23% treated with
supportive therapy; P = 0.008) and reduced chest pain
intensity scores (13.31 18.44 vs. supportive therapy
59.7 25.31; P = 0.046). However, there was no
change in pain frequency scores between hypnotherapy
and supportive therapy plus placebo medication
(P = 0.02).66
Group psychological treatment. Potts et al. conducted a

randomised study using a psychological treatment package consisting of education, relaxation, breathing training, graded exposure to activity exercise and challenging
automatic thoughts about heart disease in groups of up
to six patients.67 Fifty-six patients completed the Hospital Anxiety and Depression Scale Questionnaire (HADS),
Nijmegen hyperventilation scale, Sickness Impact Prole
(SIP), The Nottingham Health Prole (NHP) and chest
pain diaries (frequency, duration and severity, as well as
frequency of nitrate use to relieve pain). The treatment
was delivered in six sessions over 8 weeks. Group treatment was shown to reduce chest pain episodes per week
(median 6.5 vs. 2.5; P < 0.01), improve anxiety (8 vs. 6;
P = 0.001) and depression scores (6 vs. 3; P = 0.001),
disability rating on the SIP (15.3 vs. 5.9; P = 0.0001) and
exercise tolerance (7.4 vs. 9.3; P = 0.001) when compared to the control group. All of these improvements
were maintained at 6-month follow-up.67
Coping skills. Keefe et al. randomised 116 NCCP
patients to a combination of coping skills plus sertraline, sertraline alone, coping skills plus placebo or placebo.68 Patients recorded chest pain intensity and
unpleasantness scores using visual analogue scales (0
100) and completed the State Trait Anxiety Inventory
(STAI), Pain Catastrophizing Scale (PCS), Beck Depression Inventory (BDI), Sickness Impact Prole (SIP),
Stone and Neales Coping Inventory and Coping Strategies Questionnaire. The rate of change in chest pain
intensity and unpleasantness with coping skills and sertraline either alone or in combination, was statistically
signicant compared to those treated with placebo
alone. Of note, patients treated with coping skills plus
sertraline also had a signicant improvement in catastrophising of pain symptoms and anxiety compared to
the other groups (P = 0.02).68
CONCLUSIONS
Current treatment of NCCP aims to target underlying
pathophysiological mechanisms, including GERD, oesophageal dysmotility, oesophageal hypersensitivity and
psychological comorbidity (Figure 1). GERD is the most
common cause of NCCP and is commonly treated with
double-dose PPI.35 However, there have been only a
few randomised clinical trials that substantiated the role
of double-dose PPI in patients with GERD-related
NCCP. In addition, few studies of PPI therapy formally
excluded oesophageal dysmotility or assessed psychiatric
comorbidities at screening. Furthermore, the duration of
235
N. George et al.
NCCP
Alarm
symptoms
PPI test (1-2 weeks)

or
PPI empirical trial (2 months)
Upper endoscopy
Treat mucosal abnormality

pH/impedance test on PPI
treatment
Taper down PPI to lowest dose

that controls patients
symptoms
Maintenance PPI or other

GERD-related therapeutic
modalities
TLESR reducer
Endoscopic/surgical
therapy
Pain modulators
High resolution
esophageal manometry
Hypercontractile motility disorder
Functional chest pain
Pain modulators
Psychological treatments
Hypnotherapy
Complimentary medicine
Muscle relaxants
Botulinum toxin A
Balloon/pneumatic dilation
Peroral esophageal
myotomy (POEM)
Surgery
Figure 1 | Management algorithm of patients with noncardiac chest pain (NCCP). NCCP, noncardiac chest pain; PPI,
proton pump inhibitor; GERD, gastroesophageal reux disease; TLESR, transient lower esophageal sphincter relaxant.
initial treatment with double-dose PPI remains to be elucidated. Moreover, there have been varying treatment
responses to placebo (1068%) and PPI (739%) in those
without gastro-oesophageal reux. Thus, far, there is
only one open-label study evaluating endoscopic treatment for GERD-related NCCP. NCCP patients with proven acid reux and typical reux symptoms preoperatively, who underwent complete or partial fundoplication in open-label trials, tended to have better treatment outcomes. Studies evaluating the value of medical
236
therapy for oesophageal dysmotility-related NCCP, such

as calcium channel blockers (nifedipine, diltiazem),
nitrates and sildenal, demonstrated equivocal data
regarding efcacy in improving chest pain symptoms,
despite some improvement seen on oesophageal manometry in a subset of patients. Botulinum toxin injection
into the LES in patients with NCCP and spastic oesophageal motor disorders demonstrated improved chest
pain symptoms only for the short term (6 months), with
approximately half of the patients requiring re-treatment.


An important limitation of some of the studies evaluating botulinum toxin include lack of standardised
injection technique as well as injection protocol. Few
studies have evaluated balloon and pneumatic dilation as
treatment modalities for NCCP-related oesophageal dysmotility, with the former demonstrating a high placebo
response rate. Peroral endoscopic myotomy is an attractive endoscopic modality primarily used to treat achalasia patients. Its role in NCCP-related spastic motor
disorders remains to be determined. Esophagomyotomy
has shown to improve symptoms (94100%) in carefully
selected NCCP patients with oesophageal dysmotility.
Treatment for oesophageal hypersensitivity in NCCP
includes, visceral pain modulators such as TCAs, trazadone, adenosine antagonists, SNRIs and SSRIs. Although
most trials evaluating pain modulators are small and
many are not placebo-controlled, these medications
remain the cornerstone of therapy for oesophageal
hypersensitivity in NCCP. Venlafaxine and sertraline
show the most encouraging data for pain modulation in
NCCP. Jorhei therapy has been studied with varied treat-
ment outcomes. CBT has been extensively evaluated in

patients with functional chest pain with good results,
although characterisation of the patient for GERD or
coexisting oesophageal dysmotility was not done in most
studies. The other psychological techniques such as hypnotherapy, group therapy or coping skills have been
scarcely studied in NCCP patients. Further longitudinal
studies are required to compare therapy vs. treatment
based on diagnostic evaluation in order to determine
which intervention provides better treatment outcome.
AUTHORSHIP
Guarantor of the article: Ronnie Fass.
Author contributions: N George and J Abdullah - literature search,
writing manuscript; C Maradey-Romero -reviewing manuscript; L
Gerson and R. Fass - writing manuscript; All authors approved the
nal version of the manuscript.
ACKNOWLEDGEMENTS
Declaration of personal interests: Ronnie Fass: Speaker Takeda,
Mederi Therapeutics and Dr. Reddys Advisor Vecta, Torax, Mederi Therapeutics, Pzer, Ironwood and Medtronics.
Declaration of funding interests: None.
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Alimentary Pharmacology and Therapeutics

Review article: the current treatment of non-cardiac chest pain

*Division of Gastroenterology and

2015 John Wiley & Sons Ltd

41% (n = 22/54) had

Chest pain diaries

Aliment Pharmacol Ther 2016; 43: 213239

Week 1: GERD positive has

40% overall symptom

63% NCCP patients were

Aliment Pharmacol Ther 2016; 43: 213239

Review: non-cardiac chest pain

NCCP. Trials evaluating omeprazole 20 mg b.d., 40 mg

RabeprazoleRabeprazole in a dosage of 20 mg b.d.,

LansoprazoleVarying dosages of lansoprazole have

EsomeprazoleA single randomised placebo-controlled

Review: non-cardiac chest pain

NCCP due to oesophageal dysmotility

Signicant adverse events of facial ushing, headache,

Diltiazem: Three randomised placebo-controlled trials

39, 46% with

72% improvement of chest

11, all GERD

Chest pain score

91% patients had improved

165, 34% with

Chest pain score

96% of patients with >40%

Chest pain score

81% NCCP with excellent/good

Previous medical therapy with

Aliment Pharmacol Ther 2016; 43: 213239

Review: non-cardiac chest pain

7678% patients with chest

Patients who responded poorly

Chest pain score

90% chest pain symptom

cebo on oesophageal motility in both healthy volunteers

reported in this study. However, other trials have

Balloon and pneumatic dilation

Aliment Pharmacol Ther 2016; 43: 213239

Review: non-cardiac chest pain

Study size (N)

Decreased amplitude and duration

Davies 198728 Double-blind,

No difference in chest pain or

All patients improved with

Drenth 199031 Double-blind,

75% improved chest pain

Dosage 90 mg and 150 mg

Decreased distal amplitude con

Aliment Pharmacol Ther 2016; 43: 213239

Study size (N)

5 DES, 2/5 with Glyceryl

Improved symptoms of chest pain

Chest pain diary

1 in 5 patients pre-treated with

GERD positive patients

In nutcracker patients: decreased

82% (n = 9/11) of oesophageal

Aliment Pharmacol Ther 2016; 43: 213239

Review: non-cardiac chest pain

Aliment Pharmacol Ther 2016; 43: 213239