Treatment of Non-Cardiac Chest Pain

Sami R. Achem, MD, FACP, FACG, AGAF

Introduction
The treatment of noncardiac chest pain (NCCP) is challenging due to the
heterogeneous nature of the disorder. NCCP may be caused or associated
with a spectrum of clinical conditions, including gastroesophageal reflux,
visceral hyperalgesia, esophageal motility disorders, and psychiatric
conditions. It is also possible that many patients may suffer from more
than one source of pain, although this has not been critically studied.
Selection of therapy is frequently aimed at the suspected underlying
disorder. The purpose of this paper is to provide a comprehensive review
of available treatment modalities for NCCP.
Gastroesophageal Reflux: The Role of Acid
Inhibition Therapy (“Long-Term” Studies)
By far, gastroesophageal reflux (GER) is the most common cause of
NCCP and the better studied. In 1982, DeMeester and coworkers1
reported the association of GER with NCCP and the success of anti-reflux
therapy. In 50 patients with NCCP, they noted that 23 (46%) had reflux
by pH testing. Twelve were treated with medical therapy (antacids;
cimetidine, unreported dose; and postural measures) and 11 by a surgical
anti-reflux procedure (10 Nissen and 1 esophagomyotomy with a Belsey),
and all were followed for 2 to 3 years. Ten (91%) of the 11 surgically
treated patients became chest pain-free compared with 5 (42%) of the 12
medically treated patients.
Following this observation, the importance of GER was underscored
during an open label trial of acid suppressive medications in patients with
NCCP, abnormal esophageal motility (nutcracker esophagus), and coex-
isting GER on pH testing. In a study by Achem and coworkers,2 patients
received high dose ranitidine (300 mg qid) or omeprazole (20 mg bid) for
8 weeks. Drug selection was based on market availability for omeprazole
at the time of the trial. Treatment with acid-suppressive agents resulted in
a significant improvement in chest pain in the majority of patients (80%).

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Despite symptomatic improvement, there was no consistent improvement
in esophageal motility.
In a subsequent open label study involving 13 patients with NCCP and
evidence of GER, Stahl and coworkers3 found that intensive anti-reflux
therapy for 8 weeks improved chest pain in all patients. Anti-reflux
therapy consisted of ranitidine 150 mg four times a day in 10 patients and
three times a day in 3 patients. None of the 3 above-cited studies were
placebo-controlled, and all involved relatively few patients.
The ubiquitous nature of GER in the population and the lack of
placebo-controlled trials raised the possibility that reflux could be a
coincidental disorder rather than the cause of chest pain. To address this
concern, the first double-blind, placebo-controlled trial of acid suppres-
sion versus placebo in patients with chest pain was published in 1997 by
Achem and coworkers.4 In this study, 36 patients with chest pain and
GER documented on pH testing were randomized in a parallel trial to
omeprazole (20 mg po twice daily) or placebo for 8 weeks. A significant
clinical response was noted in 81% of the patients receiving omeprazole
in comparison with 6% of the placebo group.
A year later, Chambers and coworkers,5 in an open-label trial of 23
patients with NCCP, showed that omeprazole 40 mg at bedtime for 6
weeks induced considerable symptomatic improvement from baseline.
However, complete resolution of symptoms occurred in only 30% of the
patients.
A recent preliminary communication in abstract form evaluated the
effects of esomeprazole 40 mg twice daily for 4 weeks compared with
placebo in primary care patients with NCCP. The subjects were stratified
according to the frequency of heartburn or acid regurgitation: group 1, ⬍2
days/week; group 2, ⬎2 days/week. The intention-to-treat population
included 599 patients: 297 patients received esomeprazole (group 1, n ⫽
153; group 2, n ⫽ 144) and 302 received placebo (group 1, n ⫽ 161;
group 2, n ⫽ 141). Esomeprazole induced significantly more chest pain
relief than placebo in group 1 (38.7% versus 25.5%, P ⫽ 0.018);
however, the difference was not significant in group 2 (27.2% versus
24.2%). In a post hoc analysis, esomeprazole was more effective than
placebo when the 2 groups where combined (33.1% versus 24.9%; P ⫽
0.035).6
In summary, the above studies suggest that acid-inhibition therapy is
effective in the long-term treatment of NCCP (up to 8 weeks). A recent
study found that patients with NCCP who have more pronounced
esophageal acid exposure appear to have a greater response to anti-reflux
treatment.7 Published information is lacking regarding the pharmacolog-
DM, September 2008 643
ical efficacy of proton pump inhibitor (PPI) agents, other than omeprazole
and esomeprazole in the long-term treatment of GER-related NCCP (ie,
beyond 8 weeks).4 Although the long-term efficacy of other PPIs has not
been studied, it is likely to be as effective as that of omperazole. Studies
suggest that PPI therapy is in wide use by most practitioners.8 At our
tertiary center, we found that as many as 60% of patients referred for
treatment of NCCP have already received at least one PPI trial and an
additional 20% had two previous trials prior to referral.9 It is unknown
whether patients benefit from a gradual step-down program or whether
abrupt cessation of therapy is possible without symptom relapse. Whether
lifestyle modifications for GER or different dose/duration/schedule of
acid inhibition benefit these patients providing sustained relief also
remains undetermined.

Short Course of High-Dose PPI

A short course of a high-dose PPI trial has been proposed as a
diagnostic tool to identify patients with GER-related NCCP.10 In 1992
and 1993, preliminary studies in abstract form suggested that this
approach provided a favorable response in GER-related NCCP. Young
and coworkers11 communicated their experience with 30 patients with
NCCP in whom omeprazole 80 mg daily for 1 day induced symptomatic
improvement in 75% of patients. Squillace and coworkers,12 from the
same group, found that omeprazole at 80 mg also for 1 day produced
symptomatic improvement in 17 patients (diagnostic sensitivity 69%,
specificity 75%). Unfortunately, neither abstract was published as a full
paper.
In 1998, Fass and coworkers13 were the first to show the beneficial
effects of a high-dose PPI trial in a randomized, placebo-controlled trial.
Using omeprazole (40 mg a.m. and 20 mg p.m.) for 7 days, they evaluated
37 patients with NCCP. Twenty-three (62.2%) were classified as GER-
positive and 14 as GER-negative. Eighteen (78%) GER-positive patients
and 2 (14%) GER-negative patients had a positive response (P ⬍ 0.01).
A placebo response was seen in 23% of patients in the GER-positive
group and 7% in the GER-negative group.13 Following this seminal
study, other investigators have confirmed similar findings using other
PPIs, as described in the subsequent section.
Pandak and coworkers14 evaluated the effects of omeprazole in NCCP
in a prospective, double-blinded, placebo-controlled, crossover trial.
Patients were randomly assigned to either placebo or omeprazole (40
mg/day orally twice daily) for 14 days, washed out for 21 days, and then
crossed over. Thirty-seven patients completed both arms of the trial.
644 DM, September 2008
Findings were compared with those of endoscopy, manometry, and
ambulatory 24-hour esophageal pH monitoring. Seventy-one percent of
patients in the omeprazole arm reported improved chest pain, compared
with only 18% in the placebo arm. Abnormal results on endoscopy,
manometry, or pH testing were less sensitive than the PPI trial in the
diagnosis of GER-related NCCP. Omeprazole induced a 95% response
rate in patients with GER-related NCCP compared with a placebo
response of only 10% in the GER-positive patients. The false-positive
response rate of NCCP GER-negative patients to omeprazole was 39%.
Xia and coworkers15 evaluated the effects of lansoprazole 30 mg daily
compared with placebo in a Chinese population. Patients with NCCP
were asked to undergo upper endoscopy (EGD). Those with negative
EGD had 24-hour ambulatory esophageal pH monitoring and were
randomly given lansoprazole 30 mg or placebo daily for 4 weeks.
Symptom improvement was defined as ⬎50% reduction in symptom
score. A total of 68 patients (36 on lansoprazole and 32 on placebo)
completed the trial. In the lansoprazole group, more patients with than
without abnormal reflux showed symptom improvement [92% versus
33%; odds ratio ⫽ 22; 95% confidence interval (CI), 2.3-201.8; ␹2 ⫽
10.9; P ⫽ 0.001]. In the placebo group, the rates of symptom improve-
ment were similar between those with and without abnormal reflux (33%
versus 35%, P ⫽ nonsignificant).15
Bautista and coworkers16 also evaluated the effects of lansoprazole in
NCCP. Patients were randomized to either placebo or lansoprazole 60 mg
a.m. and 30 mg p.m. for 7 days. After a washout period of 1 week,
patients crossed over to the other arm of the study for an additional 7
days. The lansoprazole empirical trial was considered diagnostic if chest
pain score improved ⱖ50% than baseline. Of the 40 patients with NCCP
that were enrolled, 18 (45%) had erosive esophagitis and/or abnormal pH
test (GER-positive) and 22 (55%) had both tests negative (GER-
negative). Of the GER-positive patients, 14 (78%) had significantly
higher symptom improvement on lansoprazole than on placebo (22%;
P ⫽ 0.0143). Of the GER-negative group, 2 (9.1%) improved on the
medication and 8 (36.3%) on placebo (P ⫽ 0.75).16
Dickman and coworkers17 completed a double-blind, randomized,
placebo-controlled, crossover study of patients with NCCP. Patients were
randomized to placebo or rabeprazole 20 mg a.m. and 20 mg p.m. for 7
days. After a washout period of 1 week, patients crossed over to the other
arm of the study for an additional 7 days. The rabeprazole trial was
considered as a diagnostic if chest pain scores improved ⱖ50% from
baseline. Of the 35 patients enrolled, 16 (46%) were diagnosed as
DM, September 2008 645
TABLE 1. Short-course PPI trials in NCCP
Medication and Sensitivity Specificity PPV NPV
Author, Year (Ref.) N
Dose (%) (%) (%) (%)
Young et al., 1992 (11) 30 Omep 80 mg/day 90 80 NA NA
for 1 day
Squillace et al., 1993 (12) 17 Omep 80 mg/day 69 75 90 43
for 1 day
Fass et al., 1998 (13) 37 Omep 40 mg 78 86 90 71
a.m./20 mg
p.m. for 7 days
Pandak et al., 2002 (14) 37 Omep 40 mg bid 90 67 73 92
for 2 weeks
Xia et al., 2003 (15) 68 Lansoprazole 30 92 67 58 94
mg/day for 4
weeks
Bautista et al., 2004 (16) 40 Lansoprazole 60 78 80 88 83
mg a.m./30
mg p.m. for 7
days
Dickman et al., 2005 (17) 35 Rabeprazole 20 75 90 83 75
mg bid for 7
days
Abbreviations: PPV, positive predictive value; NPV, negative predictive value; Omep, omepra-
zole; NA, not available.

GER-positive and 19 (54%) as GER-negative. Of the GER-positive

patients, 12 of 16 (75%) had a significant symptom improvement on
therapy when compared with 3 of 16 (19%) on placebo (P ⫽ 0.029). Of
the GER-negative group, only 2 of 19 (11%) improved on the medication
and 4 of 19 (21%) on placebo (P ⫽ 0.6599).17
In summary, 7 studies have evaluated the impact of a short trial of
high-dose PPI (“PPI test”) (Table 1). The 2 initial trials were published in
abstract form only. Sample size varied from 17 to 68 patients (a single
study). These investigations indicate that the diagnostic sensitivity varies
from 75% to 92% and the specificity from 67% to 90%. Positive
predictive value varies from 58% to 90% and negative predictive value
from 43% to 94%. Three studies were crossover design,14,16,17 and the
remaining were parallel trials. Overall, these studies found that a
high-dose, short trial of a PPI is an effective means of diagnosing
GER-related NCCP. There is also a small placebo response rate13,14,16
that is important to recognize when interpreting these observations.
Cost Analysis Strategies for GER-Related NCCP
The cost benefits of a PPI trial, compared with a diagnostic evaluation,
have also been the subject of several studies. Fass showed that the PPI
646 DM, September 2008
therapeutic trial resulted in savings of nearly $600 dollars/patient (aver-
age). Using a PPI trial, nearly 80% of patients would avoid a pH test and
81% an EGD.13
Using decision analysis, Offman and coworkers18 examined the clinical
and economic outcomes of two diagnostic strategies. One involved
omeprazole test (60 mg daily for 7 days) followed sequentially by
invasive testing using endoscopy (EGD), ambulatory 24-hour esophageal
pH monitoring, and esophageal manometry as necessary, compared with
two traditional strategies involving sequential invasive diagnostic tests.
Strategies using the initial omeprazole test resulted in 84% of patients
being symptom-free at 1 year, compared with 73% to 74% for the
strategies that began with invasive tests. The strategy of the omeprazole
test, followed if necessary by ambulatory pH monitoring, then manome-
try, and then EGD, was both most effective and least expensive. It led to
an 11% improvement in diagnostic accuracy and a 43% reduction in the
use of invasive diagnostic tests. It provided an average cost savings of
$454 per patient, compared with the strategy of beginning with EGD, then
pH monitoring, and then manometry. Similar findings were confirmed by
a subsequent study that also employed decision analysis.19

Meta-Analysis of PPI Therapy in NCCP

Cremonini and coworkers20 performed a meta-analysis to evaluate the
impact of PPI therapy in NCCP. Eight studies were included in the PPI
efficacy analysis. The pooled risk ratio for continued chest pain after PPI
therapy was 0.54 (95% CI 0.41-0.71). The overall number needed to treat
was 3 (95% CI 2-4). The pooled sensitivity, specificity, and diagnostic
odds ratio for the PPI test versus 24-hour pH monitoring and endoscope
were 80%, 74%, and 13.83 (95% CI 5.48-34.91), respectively. All studies
involved in this analysis were small, and there was evidence of publica-
tion bias or other small study effects.20 Unfortunately, the quality of this
study is affected by the inclusion of studies with different end points,
abstract form, and studies that varied in clinical aspects.
A meta-analysis by Wang and coworkers21 included six studies that
evaluated the efficacy of the PPI short course in the diagnosis of GER in
patients with NCCP. A summary diagnostic odds ratio and summary
receiver operating characteristic curve analysis were used to estimate the
overall accuracy and to explore any contributing factors. The overall
sensitivity and specificity of a PPI test were 80% (95% CI 71%-87%) and
74% (95% CI 64%-83%), respectively, compared with 19% (95% CI
12%-29%) and 77% (95% CI 62%-87%), respectively, in the placebo
group. The PPI test showed a significant higher discriminative power,
DM, September 2008 647
with a summary diagnostic odds ratio of 19.35 (95% CI 8.54-43.84)
compared with 0.61 (95% CI, 0.20-1.86) in the placebo group.21

Endoscopic Therapies for GER-Related NCCP

Endoscopic therapies have been used for the treatment of GER with
variable success rates.22,23 Liu and coworkers24 recently completed an
open label trial of patients with extra-esophageal forms of GER. After 3
months of anti-secretory therapy, they treated patients with persistent
extra-esophageal forms of GER (19 dysphonia, 19 cough, 9 wheezing,
and 18 chest pain) with endoscopic luminal gastroplication (ELGP). Of
the 18 patients with chest pain, 13 (72%) had short-term (6 month)
symptomatic response; during long-term follow-up (18 months), 3 of the
4 patients with continued chest pain at 6-month follow-up became
symptom-free; 4 patients who were symptom free during short-term
follow-up developed recurrence of chest pain, and 3 additional patients
were lost to follow-up. Clearly, more studies involving a larger sample
size are needed to determine the role of endoscopic therapies, if any, in
the treatment on GER-related NCCP.
Anti-Reflux Surgery
The efficacy of anti-reflux surgery has been established for patients with
typical forms of GER25,26 during randomized controlled trials and,
recently, even for patients with non-erosive GER.27 In contrast to the
robust data available comparing medical wit surgical therapies for the
treatment of typical forms of GER, there is more limited information
regarding the surgical outcome for extra-esophageal GER, particularly
NCCP.
In the first uncontrolled study aimed at acid control by anti-reflux
surgery in NCCP, DeMeester and coworkers obtained improvement in
91% of 11 patients.1 They also found that patients who showed a
correlation between acid reflux episodes and pH testing had a uniform
100% success rate. Two (18%) of the operated patients had complica-
tions: 1 developed postoperative dysphagia requiring esophageal resec-
tion and colon interposition, and 1 had failure of the surgery with
recurrent postoperative GER documented on pH testing.
So and coworkers28 described their experience with fundoplication in
35 patients with extra-esophageal forms of GER, including 12 with
NCCP. Sixteen patients had pulmonary complications of GER, 12 had
epigastric and chest pain, and 9 had pharyngolaryngeal complications (2
patients had both intractable cough and chest pain, and 1 patient had
asthma and chest/epigastric pain). The median follow-up was 22 months
648 DM, September 2008
(range 12 to 36 months). The response rates of pharyngolaryngeal
symptoms, chest or epigastric pain, and pulmonary symptoms were 78%,
58%, and 48%, respectively. Improvement of the atypical symptoms with
omeprazole or H2-blockers before operation was significantly associated
with successful surgical outcome.
Chen and Thomas29 reported a retrospective study on the effects of
laparoscopic anti-reflux surgery (LARS) in 90 patients: 97% had typical
symptoms, and 56% had concurrent atypical symptoms. From the atypical
symptoms, 15 (17%) patients had cough and only 11 (12%) had chest
pain. The remaining had other atypical symptoms (“indigestion, choking,
vomiting, belching, burping, dysphagia and chest tightness”). Eighty-
three of 90 patients were available for follow-up; typical reflux symptoms
improved in 95% of patients, whereas atypical symptoms improved in
only 54% (13% symptom-free, 41% “some improvement”). The fol-
low-up “in all patients was between 1-5 years.” Patients with atypical
symptoms had a lower satisfaction score versus patients with only typical
symptoms (P ⬍ 0.05).
Farrell and coworkers30 reported on a retrospective study the impact of
LARS (types of fundoplication not described) in patients with typical and
extra-esophageal forms of GER. Patients were stratified based on preop-
erative symptoms into three groups: group 1, severe heartburn/minimal
atypical symptoms; group 2, severe heartburn/severe atypical symptoms;
and group 3, minimal heartburn/severe atypical symptoms. In group 1
(n ⫽ 173), heartburn improved in 99% and resolved in 87%. In group 2
(n ⫽ 95), heartburn improved in 95% and resolved in 76%, and atypical
symptoms improved in 94 % and resolved in 42%. In group 3 (n ⫽ 56),
atypical symptoms improved in 93% and resolved in 48 %. Although all
symptoms were improved by fundoplication, resolution was more likely
for heartburn than for atypical symptoms. Specifically examining the
group of patients with atypical GER, there were 62 patients with chest
pain; approximately 45% resolved their pain and 55% improved.30
Selection criteria for surgery were not described.
In 2002, Patti and coworkers31 published data in NCCP patients
undergoing LARS for chest pain. The clinical outcome was compared
against the pH test results. A total of 165 patients underwent LARS (51%
had a Nissen fundoplicaton and 49% a partial fundoplication). Selection
for the type of surgery was based on the presence of intact peristalsis for
the former and weak peristalsis (⬍40 mm Hg distal esophagus) for the
latter. Mean postoperative follow-up was 13 months. The patients were
grouped as follows: 39 patients (group A) experienced no chest pain
during pH testing; in 28 patients (group B), chest pain correlated with
DM, September 2008 649
reflux in ⬍40% of instances; in 98 patients (group C), chest pain
correlated with reflux in ⱖ40% of the events. Chest pain improved
postoperatively in 65% of group A patients, 79% of group B patients, and
96% of group C patients (group C versus A and B: P ⬍ 0.05). Heartburn
and regurgitation resolved or improved in 97% and 95% of patients,
respectively. These data show that pH monitoring helped to identify a
relationship between chest pain and reflux. Nevertheless, several obser-
vations deserve to be made. This was a retrospective study of patients
who had received previous medical therapy (80% had a PPI), and it is not
clear which selection criteria were used to operate on these patients.
Subjects in the study did not have chest pain as the only complaint; indeed
96% suffered from heartburn and 78% from regurgitation. Thus, it is
unclear whether the favorable effects observed in this study are applicable
to patients with chest pain alone. This was also a unique population in that
60 of the patients had visible erosive esophagitis at endoscopy, an unusual
feature in patients with NCCP.
Recently (2006), Rakita and coworkers32 described their experience
during a retrospective review of a large number of patients with
extra-esophageal forms of GER undergoing LARS (n ⫽ 722). Of these,
158 specifically had chest pain. They report a mean follow-up period of
50 ⫾ 83 months. A total of 81% improved postoperatively. It is unclear
how patient selection for this study took place. Complications occurred in
several patients: cardiac arrest in 2, death (from sepsis) in 1, and 4
required re-operation.
In summary, 6 studies have addressed the impact of anti-reflux surgery
on NCCP (Table 2). All are retrospective, uncontrolled studies. The
number of patients is variable ranging from 11-12 (3 series) to 165 in the
largest study. The results of these studies suggest that between 48% and
100% of these patients obtain symptom relief. Most studies found that
patients with atypical forms of GER fare less well when compared with
patients with typical GER. Some studies have shown that there is a
correlation between a high symptom index during pH test and favorable
outcome. Patient selection has not been described, although it is likely to
be highly selected. Follow-up period has varied from 1 year to slightly
over 5 years. Complications are uncommon, but when they occurred some
of those reported were serious. All studies come from academic centers
experienced in esophageal surgery, thus it is unknown how these results
apply to community centers. Carefully designed, prospective, controlled
trials are needed to determine the efficacy of anti-reflux surgery in
patients with GER-related NCCP.
650 DM, September 2008
TABLE 2. Anti-reflux surgery outcome in NCCP
Author, Year (Ref.) n Improved % Follow-Up Time Comments
DeMeester et al., 11 100% 2-3 years SI at pH predicted
1992 (1) improvement.
So et al., 12 48% Median 22 months Previous improvement
1998 (28) (12-36) with H2 blockers or
PPI predicted
improvement.
Chen et al., 11 13% symptom-free; 1-5 years Patients with “atypical”
2000 (29) 41% some symptoms had less
improvement; response than those
46% no with typical GER.
improvement
Farrell et al., 62 55% improved; 13 months More improvement
2001 (30) 45% resolved seen in patients with
typical than atypical
symptoms.
Patti et al., 165 65% (of those with 13 months Highest improvement
2002 (31) no SI based on SI
correlation); 79% correlation.
of those with
ⱕ40% SI
correlation; 96%
with ⱖ40 SI
correlation
Rakita et al., 158 81% 50 months ⫾ 83
2006 (32)
Abbreviation: SI, symptom index.

Esophagaeal Motility Disorders

Evaluation of large number of patients with NCCP reveals that 28% to
30% have an esophageal motility disorder.33,34 Esophageal motility
disorders noted in these patients include nutcracker esophagus (NE),
diffuse esophageal spasm (DES), nonspecific motility disorder (NEMD),
hypertensive and hypotensive lower esophageal sphincter (LES), ineffec-
tive peristalsis, and achalasia.33-35
Treatment of patients with NCCP and esophageal motility disorders is
challenging. This is due, in large part, to our insufficient understanding of
the relationship between abnormal motility and chest pain. It is also
related to the lack of understanding of the etiology, pathophysiology, and
natural history of esophageal motility disorders. In addition, therapeutic
attempts aimed at improvement of the abnormal motility (ie, reduction of
esophageal amplitude in NE) have not resulted in parallel improvement in
pain.36 Despite the fact that there are a variety of pharmacologic agents
that have been used to treat spastic motility disorders, most studies are of
DM, September 2008 651
small sample size and few are placebo-controlled. No single agent has
emerged as the treatment of choice.37 It is also not clear whether there are
differences in outcome based on symptoms: ie, chest pain or dysphagia or
both. There is scarcity of data regarding whether the type of symptom
warrants a different tailored approach. Therefore, these limitations need
to be taken into account when examining the literature on this subject in
the subsequent section.
Since our last review of the topic in 2004,37 there have been a few
advances in the field. Using our former review as a frame of reference, in
the next section we provide an update in areas where there has been an
advance. We focus only on spastic motility disorders other than achalasia.

GER in Patients with Dismotility

Earlier studies by Crozier have shown that acid can induce esophageal
spasm.38 Swamy and coworkers39 have also shown a different clinical
response between patients with GER and DES and those without GER.
The potential role of acid in esophageal dismotility was further stressed
with the use of high-frequency ultrasound. Pehlivanov and coworkers40
noted sustained esophageal contractions induced by GER. Recently, we
found in a preliminary communication that GER occurs in more than 35%
of patients with DES.41 In patients with NE and coexisting GER
(documented by 24-hour ambulatory pH test), acid suppression results in
symptomatic improvement despite lack of resolution of the esophageal
motility abnormalities.2 These observations suggest that, in patients with
spastic motility disorders, such as DES and NE, treatment with acid
suppressive therapy is warranted prior to initiation of muscle relaxants
since muscle relaxants, such as calcium-channel blockers, nitrates, and
anticholinergic agents, may decrease the LES pressures and thus increase
reflux.42,43 Thus, these agents may be used in patients with spastic
disorders only after GER has been excluded.

Pharmacologic Treatment for Non-GER-Related

Esophageal Motility Disorders
For patients with spastic motility disorders without GER, several
muscle-relaxing agents have been used in the treatment of symptoms such
as NCCP and dysphagia. These medications include nitrates, nitric oxide
(NO) donors, phosphodiesterase-5 inhibitors (PD-5), anticholinergic
agents, and calcium blockers.
652 DM, September 2008
TABLE 3. Nitrates and esophageal motility*
Author (Ref.) Year n Trial Medication
Orlando and Bozymski (44) 1973 1 Open Erythyityl tetra nitrate 10 mg tid
Swamy (39) 1977 12 Open Isosorbate dinitrate (Isordil) 15-30 mg qid
Shafran et al. (46) 1979 5 Open Nitroglycerin 0.4 mg (sublingual)
Parker and Mackinon (47) 1981 1 Open Isosorbate dinitrate (Isordil) 5 mg prior to
meals
Mellow (48) 1982 5 Open Isosorbide 20 mg po before meals.
Unsatisfactory response
Millaire et al. (49) 1989 22 Open Nitroglycerin spray, 0.8 mg
Konturek (50) 1995 5 Open Glyceryl trinitrate 100-200 ␮g/kg-h IV
*Modified from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol
Clin North Am 2004;33(1):107-24.37

Nitrates
Nitrates are one of the earliest agents used to treat esophageal spasm.
These medications are potent relaxants of gastrointestinal smooth muscle
through the stimulation of cyclic guanosine monophosphate-dependent
pathway.44 In 1973, Orlando and Bozymski45 showed that nitrates
effectively reduced manometric findings and symptoms in a patient
suffering from DES. Since that original observation, several trials have
addressed the efficacy of nitrates in the treatment of DES. Table 3
summarizes the published data.
The published experience with these agents is limited to 51 patients. No
placebo-controlled trials have been completed (studies were all open
label). However, most authors describe symptomatic improvement after
primarily short-term studies, and, in some trials, long-term use. These
uncontrolled clinical observations suggest that nitrates induce chest pain
relief in selected patients with DES. However, side effects such as
headaches and hypotension may limit their use. It is also possible that
tachyphilaxis may develop. Administration every 6-12 hours may de-
crease the likelihood of this problem.44 There is no available information
regarding the effect of these compounds in patients with motility
disorders, other than DES.
The Role of NO
NO is an inhibitory neurotransmitter in the gastrointestinal tract.51 In
the smooth circular muscle of the human esophagus, it regulates the
latency gradient and the contraction amplitude of esophageal peristalsis.52
Elegant studies by Murray and coworkers53 and Konturek and cowork-
ers50,54 have shown that the experimental removal of NO in humans
induces a pattern of simultaneous contractions similar to DES. Therefore,
DM, September 2008 653
pharmacologic agents that result in the augmentation of NO may improve
the clinical and manometric patterns of patients with diffuse esophageal
spasm.
Glyceryl trinitrate (GTN) is a donor of NO.55 Acute (intravenous
administration in humans) of GTN produced a dose-dependent elon-
gation of peristalsis and duration of esophageal contractions accom-
panied by a significant improvement in symptoms in DES.50 L-
arginine is a basic, semi-essential amino acid that acts as a substrate
for the synthesis of NO. Bortolotti and coworkers56 found that
L-arginine IV did not affect esophageal peristalsis or LES parameters.
However, during a small, double-blind, crossover trial with each phase
(placebo or drug) lasting 6 weeks, oral administration (30 mL of a 10%
L-arginine solution tid versus placebo) induced chest pain improve-
ment in eight patients with spastic esophageal motility (DES, n ⫽ 3;
NE, n ⫽ 5). No side effects were reported. These observations suggest
that spastic disorders of the esophagus that may cause NCCP, such as
DES, may be due to either a dysfunctional L-arginine/NO system or a
deficient nitrergic system.

Phosphodiesterase Inhibitors
Phosphodiesterase-5 (PD-5) is an important modulator of smooth
muscle contraction. Both human and animal studies show that it regulates
esophageal contraction amplitude by increasing the availability of
NO.52-54 There are three commercially available PD-5 inhibitors: silde-
nafil, vardenafil, and tadalafil.
Several investigators have studied the effects of sildenafil in humans.
Overall, these studies indicate that sildenafil markedly inhibits the motor
activity of the esophageal musculature by decreasing LES pressure, wave
amplitude, and propagation velocity and increasing the onset latency of
pressure waves.57 It has also been shown to decrease esophageal bolus
transit and esophageal amplitude but have no effect on gastro-esophageal
reflux parameters.58,59 These studies suggest that this and related com-
pounds may have a beneficial effect in patients with spastic motility
disorders.
In a study of 11 patients with a variety of spastic motility disorders [NE,
n ⫽ 4; DES, n ⫽ 1; hypertensive LES (HLES), n ⫽ 3; achalasia, n ⫽ 3],
sildenafil improved the manometric pattern in 9 of 11 patients with
hypercontractile esophageal motility; however, only 4 of these patients
reported symptomatic improvement, and 2 of these 4 discontinued drug
therapy due to side effects.60 Agrawal and coworkers61 reported a case of
a patient with NCCP who at manometry showed simultaneous features of
654 DM, September 2008
NE and DES. The patient’s symptoms and motility pattern improved with
the use of all 3 available PD-5 inhibitors. Following acute administration
of sildenafil 50 mg versus placebo in a random, double-blinded trial,
sildenafil inhibited the LES tone and pressure wave amplitude of 7
patients with symptomatic HLES.62 No long-term or controlled trials are
available. These observations suggest that these agents deserve further
study in patients with NCCP.

Anticholinergic Agents
Cholinergic (muscarinic) innervation plays an important role in esoph-
ageal peristalsis and LES activity.63 Using cimetropium bromide (10 mg
IV)63 in a single-blind design, eight patients with NE and similar control
subjects had significant reduction of distal esophageal amplitude and LES
pressures. However, the effects of this agent on clinical symptoms have
not been studied. There are no other clinical trials supporting the use of
muscarinic blocking agents for the treatment of patients with painful
esophageal motility. Side effects, such as dry mouth and tachycardia, may
limit their use. The role of new muscarinic receptor antagonist with
specific selectivity remains to be evaluated.

Calcium Blockers
Calcium is a mediator of esophageal muscle contraction.64 In animal
studies, interference with calcium entry at the cellular level leads to
decreased LES pressure and esophageal contractions.65,66

Nifedipine
Nifedipine has been shown to decrease the frequency and amplitude of
nonperistaltic esophageal contraction in healthy subjects.67 Clinical
experience in the treatment of esophageal motility remains limited. Table 4
provides a summary of therapeutic trials in patients with DES.
In contrast to achalasia, where several investigators have examined the
effects of nifedipine, there is more limited information about the effects
of this drug in non-achalasia-related motility disorders other than DES.
Traube and coworkers74 studied the esophageal effects of nifedipine in
nine patients with high-amplitude peristaltic esophageal contractions (NE,
20 mg orally). Nifedipine decreased LES pressure by approximately 50%
and contraction amplitude in the body of the esophagus by approximately
25%. The effects of the drug on symptoms were not evaluated. Richter
and coworkers36 completed the only controlled trial of nifedipine in
patients with NE. Twenty patients received oral nifedipine (10-30 mg tid)
or placebo during a 14-week crossover study. Despite a statistically
DM, September 2008 655
TABLE 4. Nifedipine trials in diffuse esophageal spasm*
Author (Ref.) Year Study Design N Dose Outcome
Blackwell et al. (67) 1981 Open label 6 20 mg tid 3/6 improved
Davies et al. (68) 1982 Double-blind, 10 10-40 mg tid Short-term improvement
placebo
Nasrallah et al. (69) 1982 Open-label 1 10 mg tid Improved
Nasrallah et al. (70) 1985 Open-label 4 10 mg tid Improved
Thomas et al. (71) 1986 Open-label 6 10-20 mg tid Improvement of
dysphagia
Davies et al. (72) 1987 Placebo-controlled 8 10-30 mg tid No response (treatment
(a single and a (mean 64 for up to 3 months)
double-blinded mg)
phase)
Banciu et al. (73) 1990 Open-label 12† 10-20 mg Acute “improvement of
radiologic
appearance”
*Modified from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol
Clin North Am 2004;33(1):107-24.37
†Patients defined radiologically.

TABLE 5. Diltiazem trials*

Author (Ref.) Year Study Design N Dose Outcome
Richter et al. (75) 1990 Open-label, 8 weeks 10 (NE) 90 mg tid Improved
Cattau et al. (76) 1991 Double-blind, placebo- 14 (NE) 60-90 mg tid Improved
controlled, 8 weeks
Drenth et al. (77) 1990 Double-blind, 8 (DES) 60 mg tid No significant
crossover, 10 improvement
weeks
*Reprinted with permission.37

significant improvement in esophageal amplitude, no symptomatic ben-

efits were observed.

Diltiazem
Richter and coworkers75 examined the effects of diltiazem (90, 120, or
150 mg orally) in healthy controls and found no effect on distal
esophageal contractions. The clinical effects of this calcium blocker have
been examined in two clinical studies in patients with NE and in a small
study of patients with DES (Table 5). These studies show that, despite
improvement in NE, studies involved very small number of patients. No
beneficial effects were observed in the few patients (n ⫽ 8) with DES
(Table 5).

656 DM, September 2008

Verapamil
Verapamil decreases LES pressures and the amplitude of esophageal
peristalsis in animal studies,78,79 but results in humans have not been
consistent.80 No studies have been done with this agent in patients with
spastic esophageal motility disorders.
In summary, studies with calcium blockers include small sample size
and most are open, uncontrolled trials. Although many report improve-
ment, we lack long-term studies. Side effects such as constipation,
hypotension, and edema may limit the use of these compounds.

Visceral Hyperalgesia: The Role of Pain

Modulators
Visceral hyperalgesia (increased perception to esophageal balloon
distension) has been recognized as a feature in NCCP. Tricyclic antide-
pressants (TCA) such as imipramine, desipramine, clomipramine,
amytryptiline, and trazodone have been used for years to treat various
chronic pain syndromes.81 In healthy volunteers, imipramine decreases
pain thresholds to experimental somatic pain81 and to intra-esophageal
balloon distension.82 The mechanism of action of these compounds is not
known. However, these medications block serotonin and norepinephrine.
Serotonin and norepinephrine are thought to mediate endogenous anal-
gesic mechanisms through the descending pain inhibitory pathways in the
brain and spinal cord.83 Antidepressant medications that enhance seroto-
nin and norepinephrine neurotransmission may therefore reduce pain in
patients with NCCP. It is also possible that they act through N-methyl-
D-aspartate antagonism and ion-channel blocking activity that may also
mediate antinociceptive effects.84,85
Clouse and coworkers86 examined the effects of trazodone in patients
with nonspecific esophageal motility disorders. During a controlled trial,
patients treated with 100 to 150 mg/day of trazodone (n ⫽ 15) obtained
a significant symptomatic improvement after 6 weeks of treatment
compared with placebo (n ⫽ 14). Manometric parameters did not change
despite symptom improvement. Prakash and Clouse87 also reported
long-term effects of TCA in NCCP. In a retrospective analysis of 21
patients treated with a variety of TCA after incomplete response to
anti-reflux therapy, they found that 75% of patients with chest pain
continued to experience symptomatic relief during long-term use of up to
3 years.
Another TCA, imipramine, has been found effective for the treatment of
patients with NCCP regardless of the esophageal motility findings.
DM, September 2008 657
Cannon and coworkers,88 during a double-blind, placebo-controlled trial
of 60 patients with chest pain, compared the effects of imipramine (50 mg
Hs; n ⫽ 20 patients) with clonidine (0.2 mg daily; n ⫽ 20 patients) or
placebo (n ⫽ 20 patients) for 3 weeks.88 They found that only imipramine
resulted in a significant reduction (52%) in chest pain episodes. An
uncontrolled study from Japan found that a combination of psychotherapy
and trazodone (50 mg) orally or clomipramine (25 mg IV daily) for 1
month produced clinical and radiologic improvement in 9 patients with
DES.89 There is paucity of data regarding the therapeutic efficacy of other
tricyclic compounds.
TCA should be administered at bedtime in a low dose (10-25 mg) and
titrated up to 50-75 mg/day based on symptom response or side effects.90
Potential side effects include priapism for trazodone; all other TCA may
induce constipation, hypotension, arrhythmias, drowsiness, urinary reten-
tion, and changes in intraocular pressure. Thus, caution should be
exercised in patients with glaucoma or prostate retention. Concerns with
drug interactions should also be taken into consideration.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Recent studies have suggested that serotonin is an important mediator
for esophageal pain. Varia and coworkers91 evaluated the effects of
sertraline (Zoloft) in patients with NCCP. During a single-blinded,
placebo-controlled trial, 25 subjects with NCCP were randomized to
receive sertraline or placebo for 8 weeks. Doses started at 50 mg and were
adjusted to a maximum of 200 mg on the basis of each subject’s clinical
response. Sertraline induced significantly more reduction in pain scores
than placebo. No data were provided regarding esophageal testing. Side
effects occurred in 27% of the patients, including delayed ejaculation,
decreased libido, and restlessness.
Citalopram (Celexa; 20 mg IV) in healthy volunteers produced signif-
icant reduction in esophageal pain perception to chemical and mechanical
stimulation when compared with placebo, but it did not affect esophageal
motility parameters.92
Tegaserod, a 5-hydroxytryptamine subtype-4 (5-HT4) receptor partial
agonist (recently withdrawn from the US market), improves esophageal
pain threshold following esophageal mechanical distension in patients
with functional heartburn.93
A recent trial examined the effects of another SSRI, paroxetine (Paxil),
in 50 patients with NCCP. During a double-blind, placebo-controlled
investigation, patients were randomized to the medication versus placebo
(n ⫽ 27 paroxetine and n ⫽ 23 placebo) for 8 weeks. Paroxetine-treated
658 DM, September 2008
TABLE 6. Summary trials: Treatment of spastic disorders with Botox*
Author (Ref.) Year N Publication Type
Miller (97) 1996 15 Full Paper
Cassidy (101) 1996 10 Abstract
Jones (103) 1996 1 Letter to the Editor
Nebendahl (100) 1999 9 Abstract
Storr (99) 2001 9 Full Paper
Miller (98) 2002 29 Full Paper
Lacy (104) 2002 1 Case Report
*Modified from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol
Clin North Am 2004;33(1):107-24.37

patients showed a greater improvement on a physician-rated scale (The

Clinical Global Impression scale), but not on self-rated pain scores.94
These above studies highlight the role of serotonin in visceral pain
transmission and suggest that further trials are needed to evaluate the
potential role of the serotonin pathway in NCCP.95

Botulinum toxin (Botox)

Botulinum toxin (Botox) binds irreversibly to cholinergic nerve termi-
nals blocking acetylcholine-mediated neuromuscular transmission, reduc-
ing LES pressures in animal model and humans.96 In 1996, Miller and
coworkers97 treated 15 patients with spastic motility disorders (DES,
NEMD, and lower esophageal dysfunction) unresponsive to previous
medical therapy with intraesophageal injection of Botox (80 U). A
satisfactory outcome was noted in up to 67% of the patients, but a second
injection was required to sustain remission. In 2002, Miller and cowork-
ers98 amplified their observations during an open-label trial of Botox in
29 patients with spastic motility disorders other than achalasia. A total of
72% of the patients experienced symptomatic improvement; 6 of 9
responders required a third dose to maintain remission. No information
was provided regarding the effects of Botox on esophageal manometry.
Storr and coworkers99 treated 9 patients with DES with Botox (100 U at
multiple sites in the distal esophagus, 1- to 1.5-cm intervals). After 6
months, 8 patients remained improved, but a repeat injection was required
in 4 of these subjects to maintain remission. Several preliminary reports
in abstract form or Letters to the Editor have also indicated a beneficial
response with Botox in a variety of patients with spastic disorders.100-102
Table 6 summarizes the published experience with Botox. Placebo-
controlled trials are needed to confirm these observations.
DM, September 2008 659
Other Therapies
Transcutaneous Electrical Nerve Stimulation
Transcutaneous electrical nerve stimulation (TENS) has been found
effective in the treatment of diverse types of pain.104 Borjesson and
coworkers105 found that TENS reduced esophageal symptoms induced
during esophageal balloon distension and decreased peristaltic velocity.
Increased visceral perception was positively correlated to the amplitude
and duration of the esophageal peristalsis. The impact of this therapy on
long-term clinical remission has not been evaluated.
Hypnotherapy
Twenty-eight patients with NCCP were randomized to receive either 12
sessions of hypnotherapy or supportive therapy plus placebo medication
over a 17-week period. The primary outcome measure was global
assessment of chest pain improvement. Twelve of 15 (80%) hypnotherapy
patients compared with 3 of 13 (23%) controls experienced a global
improvement in pain (P ⫽ 0.008), which was associated with a signifi-
cantly greater reduction in pain intensity (P ⫽ 0.046) although not
frequency. Hypnotherapy also resulted in a significantly greater improve-
ment in overall well being in addition to a reduction in medication usage.
There were no differences favoring hypnotherapy with respect to anxiety
or depression scores.106
Psychological Intervention
Several studies have noted a high prevalence of psychiatric disorders in
patients with NCCP.107,108 Therefore, a number of psychological trials
have been conducted to manage patients with NCCP and several are
reviewed here.
A postal survey of 1053 patients with unexplained chest pain was done
to evaluate interest in psychotherapy.109 This study showed no associa-
tion between duration of chest pain and interest in treatment. Younger
male patients were more interested in treatment. A limitation in activities
rather than frequency or intensity of pain was the most important
predictor of interest in treatment.
Cognitive therapy has been reported effective for the treatment of
NCCP in 2 separate trials. In one study, cognitive-behavior therapy (n ⫽
37) was compared with “usual care” (n ⫽ 35). Intervention patients
improved significantly with regard to frequency and intensity of chest
pain: 15 (48%) of the 31 patients in the treatment group were pain free at
12-month follow-up compared with 4 (13%) of the 33 patients in the
660 DM, September 2008
control group (P ⫽ 0.002).110 In a second study, 31 patients with NCCP
were treated in a controlled trial of cognitive-behavioral therapy. Patients
were randomized to either immediate treatment or as a control to
assessment only. The average number of sessions given was 7.2. There
were significant reductions in chest pain, limitations and disruption of
daily life, autonomic symptoms, distress and psychological morbidity in
the treated group as compared with the control group. The assessment-
only group was treated subsequently with cognitive therapy and showed
comparable benefit. Improvements were sustained by both treated groups
at 4- to 6-month follow-up.111
Kisley and coworkers112 conducted a Cochrane analysis of studies
involving psychological intervention in NCCP. They included 8 studies
involving 403 randomized participants. They found a significant reduc-
tion in reports of chest pain in the first 3 months following the
intervention; fixed effects relative risk ⫽ 0.68 (95% CI 0.57-0.81). This
was maintained from 3 to 9 months afterwards; relative risk ⫽ 0.58 (95%
CI 0.45-0.76). There was also a significant increase in the number of chest
pain-free days up to 3 months following the intervention; the standardized
mean difference ⫽ 0.85 (95% CI 0.38-1.31).
A recent study proposed that psychological interventions that take place
in the emergency room and use a Bio-Psychosocial Model may be more
effective for treatment of NCCP.113 Taken together these studies support
the role of psychological intervention in selected patients with NCCP.
More work needs to be done to identify which type of patient benefits best
from these interventions, timing, length, and type of therapy.

Benzodiazepines
Benzodiazepines amplify gamma-aminobutyric acid throughout the
central nervous system and act more peripherally to reduce cat-
echolamines. Huffman and Stern suggest that these agents could be used
in the emergency room setting to treat NCCP, provided they are used on
a short-term basis in order to decrease the rate of dependency.114 Few
studies and of very small sample size have been done with these
agents.115 In a non-blind, 8-week trial of alprazolam in patients present-
ing with chest pain and panic disorder, 15 of 20 improved by 50% or
greater reduction in panic frequency. However, patients experienced only
a modest drop in episodes of chest pain or discomfort.116
A small, placebo-controlled, double-blind, flexible-dose (1-4 mg/day),
6-week trial of clonazepam was completed by Wuslim and coworkers.117
In 27 patients with NCCP and coexisting panic disorder, they found a
DM, September 2008 661
significant reduction in the 50% reduction in anxiety scores, in the
drug-treated group compared with placebo.117
Unfortunately, concerns with dependency make it unlikely that these
medications will be used in the daily treatment of patients with recurrent
chest pain.
The Role of Adenosine Receptors in NCCP
Mice lacking functional adenosine receptor activity show signs of
increased hyperalgesia and anxiety.118 In healthy volunteers, bolus
adenosine infusion induces angina-like pain shortly after infusion. The-
ophylline (a nonselective adenosine receptor antagonist) reduces this pain
significantly, suggesting that pain triggered by adenosine is, at least to
some degree, dependent on activation of theophylline-sensitive recep-
tors.119 Rao and coworkers120 reported data from consecutive patients
with recurrent NCCP who failed an 8-week therapeutic trial of double
dose PPI, and “various empirical trials” (not specified), or lacked
evidence of GER on 24-hour pH testing. They found that intravenous
infusion of theophylline (an adenosine receptor antagonist), but not
placebo, improves the biomechanical and sensory properties of the
esophageal wall. In a long-term study, 19 patients with esophageal
hypersensitivity, randomized to receive oral theophylline 200 mg bid for
4 weeks in a crossover design, experienced significant improvement in
pain parameters when compared with placebo. It is unlikely that theoph-
ylline will become in use for the treatment of NCCP due to its potential
toxicity. However, the findings of the above study suggest that research
involving newer selective adenosine receptor agents may offer new
opportunities for the treatment of NCCP.121

Summary
Treatment of NCCP remains a difficult problem due to the heteroge-
neous nature of the disorder. GER is the best studied condition contrib-
uting to NCCP. Pharmacological trials of acid inhibition show a robust
response rate for patients with NCCP-related GER. More rigorously
executed studies are needed to understand the role of endoscopic
therapies (if any) and surgery in patients with NCCP and coexisting GER.
For patients with spastic disorders without GER, most therapeutic trials
involve small, uncontrolled studies with variable outcome. Although a
number of therapeutic options have been used to treat spastic dysmotility
in these patients, no one agent has emerged as the drug of choice. Botox
is a promising agent for the treatment of selected patients due to its rapid
beneficial effect and relative simplicity (though invasive) of administra-
662 DM, September 2008
tion. However, placebo-controlled trials are lacking to validate its
efficacy. NO donors and phosphodiesterase inhibitors are attractive
compounds that warrant further testing since they seem to influence the
intimate mechanism involved in the pathogenesis of DES (simultaneous
contractions). Two TCA (imipramine and trazondone) remain valuable
drugs in NCCP since small, randomized, placebo-controlled trials support
their beneficial effect. The role of serotonin and the newly reported
adenosine receptor pathway opens another opportunity for further re-
search to better understand the neurotransmitters involved in the genesis
of visceral chest pain. Finally, the high prevalence of psychiatric
disorders in patients with NCCP is concerning. It begs for a combined
multidisciplinary approach to study the interaction between the esophagus
and the brain and better define the role, timing, and forms of psycholog-
ical intervention in these patients.

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