Treatment of Non-Cardiac Chest Pain

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Treatment of Non-Cardiac Chest Pain

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

ntroductionhe treatment of noncardiac chest pain (NCCP) is challenging due to theeterogeneous nature of the disorder. NCCP may be caused or associatedith a spectrum of clinical conditions, including gastroesophageal reflux,isceral hyperalgesia, esophageal motility disorders, and psychiatriconditions. It is also possible that many patients may suffer from morehan one source of pain, although this has not been critically studied.election of therapy is frequently aimed at the suspected underlyingisorder. The purpose of this paper is to provide a comprehensive reviewf available treatment modalities for NCCP.

astroesophageal Reflux: The Role of Acidnhibition Therapy (“Long-Term” Studies)By far, gastroesophageal reflux (GER) is the most common cause ofCCP and the better studied. In 1982, DeMeester and coworkers1

eported the association of GER with NCCP and the success of anti-refluxherapy. In 50 patients with NCCP, they noted that 23 (46%) had refluxy pH testing. Twelve were treated with medical therapy (antacids;imetidine, unreported dose; and postural measures) and 11 by a surgicalnti-reflux procedure (10 Nissen and 1 esophagomyotomy with a Belsey),nd all were followed for 2 to 3 years. Ten (91%) of the 11 surgicallyreated patients became chest pain-free compared with 5 (42%) of the 12edically treated patients.Following this observation, the importance of GER was underscoreduring an open label trial of acid suppressive medications in patients withCCP, abnormal esophageal motility (nutcracker esophagus), and coex-

sting GER on pH testing. In a study by Achem and coworkers,2 patientseceived high dose ranitidine (300 mg qid) or omeprazole (20 mg bid) forweeks. Drug selection was based on market availability for omeprazole

t the time of the trial. Treatment with acid-suppressive agents resulted insignificant improvement in chest pain in the majority of patients (80%).

is Mon 2008;54:642-670
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espite symptomatic improvement, there was no consistent improvementn esophageal motility.In a subsequent open label study involving 13 patients with NCCP and

vidence of GER, Stahl and coworkers3 found that intensive anti-refluxherapy for 8 weeks improved chest pain in all patients. Anti-refluxherapy consisted of ranitidine 150 mg four times a day in 10 patients andhree times a day in 3 patients. None of the 3 above-cited studies werelacebo-controlled, and all involved relatively few patients.The ubiquitous nature of GER in the population and the lack oflacebo-controlled trials raised the possibility that reflux could be aoincidental disorder rather than the cause of chest pain. To address thisoncern, the first double-blind, placebo-controlled trial of acid suppres-ion versus placebo in patients with chest pain was published in 1997 bychem and coworkers.4 In this study, 36 patients with chest pain andER documented on pH testing were randomized in a parallel trial tomeprazole (20 mg po twice daily) or placebo for 8 weeks. A significantlinical response was noted in 81% of the patients receiving omeprazolen comparison with 6% of the placebo group.A year later, Chambers and coworkers,5 in an open-label trial of 23atients with NCCP, showed that omeprazole 40 mg at bedtime for 6eeks induced considerable symptomatic improvement from baseline.owever, complete resolution of symptoms occurred in only 30% of theatients.A recent preliminary communication in abstract form evaluated the

ffects of esomeprazole 40 mg twice daily for 4 weeks compared withlacebo in primary care patients with NCCP. The subjects were stratifiedccording to the frequency of heartburn or acid regurgitation: group 1, �2ays/week; group 2, �2 days/week. The intention-to-treat populationncluded 599 patients: 297 patients received esomeprazole (group 1, n �53; group 2, n � 144) and 302 received placebo (group 1, n � 161;roup 2, n � 141). Esomeprazole induced significantly more chest painelief than placebo in group 1 (38.7% versus 25.5%, P � 0.018);owever, the difference was not significant in group 2 (27.2% versus4.2%). In a post hoc analysis, esomeprazole was more effective thanlacebo when the 2 groups where combined (33.1% versus 24.9%; P �.035).6

In summary, the above studies suggest that acid-inhibition therapy isffective in the long-term treatment of NCCP (up to 8 weeks). A recenttudy found that patients with NCCP who have more pronouncedsophageal acid exposure appear to have a greater response to anti-reflux
reatment.7 Published information is lacking regarding the pharmacolog-
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cal efficacy of proton pump inhibitor (PPI) agents, other than omeprazolend esomeprazole in the long-term treatment of GER-related NCCP (ie,eyond 8 weeks).4 Although the long-term efficacy of other PPIs has noteen studied, it is likely to be as effective as that of omperazole. Studiesuggest that PPI therapy is in wide use by most practitioners.8 At ourertiary center, we found that as many as 60% of patients referred forreatment of NCCP have already received at least one PPI trial and andditional 20% had two previous trials prior to referral.9 It is unknownhether patients benefit from a gradual step-down program or whether

brupt cessation of therapy is possible without symptom relapse. Whetherifestyle modifications for GER or different dose/duration/schedule ofcid inhibition benefit these patients providing sustained relief alsoemains undetermined.

hort Course of High-Dose PPIA short course of a high-dose PPI trial has been proposed as aiagnostic tool to identify patients with GER-related NCCP.10 In 1992nd 1993, preliminary studies in abstract form suggested that thispproach provided a favorable response in GER-related NCCP. Youngnd coworkers11 communicated their experience with 30 patients withCCP in whom omeprazole 80 mg daily for 1 day induced symptomatic

mprovement in 75% of patients. Squillace and coworkers,12 from theame group, found that omeprazole at 80 mg also for 1 day producedymptomatic improvement in 17 patients (diagnostic sensitivity 69%,pecificity 75%). Unfortunately, neither abstract was published as a fullaper.In 1998, Fass and coworkers13 were the first to show the beneficial

ffects of a high-dose PPI trial in a randomized, placebo-controlled trial.sing omeprazole (40 mg a.m. and 20 mg p.m.) for 7 days, they evaluated7 patients with NCCP. Twenty-three (62.2%) were classified as GER-ositive and 14 as GER-negative. Eighteen (78%) GER-positive patientsnd 2 (14%) GER-negative patients had a positive response (P � 0.01).

placebo response was seen in 23% of patients in the GER-positiveroup and 7% in the GER-negative group.13 Following this seminaltudy, other investigators have confirmed similar findings using otherPIs, as described in the subsequent section.Pandak and coworkers14 evaluated the effects of omeprazole in NCCP

n a prospective, double-blinded, placebo-controlled, crossover trial.atients were randomly assigned to either placebo or omeprazole (40g/day orally twice daily) for 14 days, washed out for 21 days, and then

rossed over. Thirty-seven patients completed both arms of the trial.


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indings were compared with those of endoscopy, manometry, andmbulatory 24-hour esophageal pH monitoring. Seventy-one percent ofatients in the omeprazole arm reported improved chest pain, comparedith only 18% in the placebo arm. Abnormal results on endoscopy,anometry, or pH testing were less sensitive than the PPI trial in the

iagnosis of GER-related NCCP. Omeprazole induced a 95% responseate in patients with GER-related NCCP compared with a placeboesponse of only 10% in the GER-positive patients. The false-positiveesponse rate of NCCP GER-negative patients to omeprazole was 39%.Xia and coworkers15 evaluated the effects of lansoprazole 30 mg daily

ompared with placebo in a Chinese population. Patients with NCCPere asked to undergo upper endoscopy (EGD). Those with negativeGD had 24-hour ambulatory esophageal pH monitoring and were

andomly given lansoprazole 30 mg or placebo daily for 4 weeks.ymptom improvement was defined as �50% reduction in symptomcore. A total of 68 patients (36 on lansoprazole and 32 on placebo)ompleted the trial. In the lansoprazole group, more patients with thanithout abnormal reflux showed symptom improvement [92% versus3%; odds ratio � 22; 95% confidence interval (CI), 2.3-201.8; �2 �0.9; P � 0.001]. In the placebo group, the rates of symptom improve-ent were similar between those with and without abnormal reflux (33%

ersus 35%, P � nonsignificant).15

Bautista and coworkers16 also evaluated the effects of lansoprazole inCCP. Patients were randomized to either placebo or lansoprazole 60 mg

.m. and 30 mg p.m. for 7 days. After a washout period of 1 week,atients crossed over to the other arm of the study for an additional 7ays. The lansoprazole empirical trial was considered diagnostic if chestain score improved �50% than baseline. Of the 40 patients with NCCPhat were enrolled, 18 (45%) had erosive esophagitis and/or abnormal pHest (GER-positive) and 22 (55%) had both tests negative (GER-egative). Of the GER-positive patients, 14 (78%) had significantlyigher symptom improvement on lansoprazole than on placebo (22%;� 0.0143). Of the GER-negative group, 2 (9.1%) improved on the

edication and 8 (36.3%) on placebo (P � 0.75).16

Dickman and coworkers17 completed a double-blind, randomized,lacebo-controlled, crossover study of patients with NCCP. Patients wereandomized to placebo or rabeprazole 20 mg a.m. and 20 mg p.m. for 7ays. After a washout period of 1 week, patients crossed over to the otherrm of the study for an additional 7 days. The rabeprazole trial wasonsidered as a diagnostic if chest pain scores improved �50% from
aseline. Of the 35 patients enrolled, 16 (46%) were diagnosed as

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ER-positive and 19 (54%) as GER-negative. Of the GER-positiveatients, 12 of 16 (75%) had a significant symptom improvement onherapy when compared with 3 of 16 (19%) on placebo (P � 0.029). Ofhe GER-negative group, only 2 of 19 (11%) improved on the medicationnd 4 of 19 (21%) on placebo (P � 0.6599).17

In summary, 7 studies have evaluated the impact of a short trial ofigh-dose PPI (“PPI test”) (Table 1). The 2 initial trials were published inbstract form only. Sample size varied from 17 to 68 patients (a singletudy). These investigations indicate that the diagnostic sensitivity variesrom 75% to 92% and the specificity from 67% to 90%. Positiveredictive value varies from 58% to 90% and negative predictive valuerom 43% to 94%. Three studies were crossover design,14,16,17 and theemaining were parallel trials. Overall, these studies found that aigh-dose, short trial of a PPI is an effective means of diagnosingER-related NCCP. There is also a small placebo response rate13,14,16

hat is important to recognize when interpreting these observations.

ost Analysis Strategies for GER-Related NCCPThe cost benefits of a PPI trial, compared with a diagnostic evaluation,

ABLE 1. Short-course PPI trials in NCCP

Author, Year (Ref.) NMedication and

DoseSensitivity

(%)Specificity

(%)PPV(%)

NPV(%)

oung et al., 1992 (11) 30 Omep 80 mg/dayfor 1 day

90 80 NA NA

quillace et al., 1993 (12) 17 Omep 80 mg/dayfor 1 day

69 75 90 43

ass et al., 1998 (13) 37 Omep 40 mga.m./20 mgp.m. for 7 days

78 86 90 71

andak et al., 2002 (14) 37 Omep 40 mg bidfor 2 weeks

90 67 73 92

ia et al., 2003 (15) 68 Lansoprazole 30mg/day for 4weeks

92 67 58 94

autista et al., 2004 (16) 40 Lansoprazole 60mg a.m./30mg p.m. for 7days

78 80 88 83

ickman et al., 2005 (17) 35 Rabeprazole 20mg bid for 7days

75 90 83 75

bbreviations: PPV, positive predictive value; NPV, negative predictive value; Omep, omepra-ole; NA, not available.

ave also been the subject of several studies. Fass showed that the PPI


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herapeutic trial resulted in savings of nearly $600 dollars/patient (aver-ge). Using a PPI trial, nearly 80% of patients would avoid a pH test and1% an EGD.13

Using decision analysis, Offman and coworkers18 examined the clinicalnd economic outcomes of two diagnostic strategies. One involvedmeprazole test (60 mg daily for 7 days) followed sequentially bynvasive testing using endoscopy (EGD), ambulatory 24-hour esophagealH monitoring, and esophageal manometry as necessary, compared withwo traditional strategies involving sequential invasive diagnostic tests.trategies using the initial omeprazole test resulted in 84% of patientseing symptom-free at 1 year, compared with 73% to 74% for thetrategies that began with invasive tests. The strategy of the omeprazoleest, followed if necessary by ambulatory pH monitoring, then manome-ry, and then EGD, was both most effective and least expensive. It led ton 11% improvement in diagnostic accuracy and a 43% reduction in these of invasive diagnostic tests. It provided an average cost savings of454 per patient, compared with the strategy of beginning with EGD, thenH monitoring, and then manometry. Similar findings were confirmed bysubsequent study that also employed decision analysis.19

eta-Analysis of PPI Therapy in NCCPCremonini and coworkers20 performed a meta-analysis to evaluate the

mpact of PPI therapy in NCCP. Eight studies were included in the PPIfficacy analysis. The pooled risk ratio for continued chest pain after PPIherapy was 0.54 (95% CI 0.41-0.71). The overall number needed to treatas 3 (95% CI 2-4). The pooled sensitivity, specificity, and diagnosticdds ratio for the PPI test versus 24-hour pH monitoring and endoscopeere 80%, 74%, and 13.83 (95% CI 5.48-34.91), respectively. All studies

nvolved in this analysis were small, and there was evidence of publica-ion bias or other small study effects.20 Unfortunately, the quality of thistudy is affected by the inclusion of studies with different end points,bstract form, and studies that varied in clinical aspects.A meta-analysis by Wang and coworkers21 included six studies that

valuated the efficacy of the PPI short course in the diagnosis of GER inatients with NCCP. A summary diagnostic odds ratio and summaryeceiver operating characteristic curve analysis were used to estimate theverall accuracy and to explore any contributing factors. The overallensitivity and specificity of a PPI test were 80% (95% CI 71%-87%) and4% (95% CI 64%-83%), respectively, compared with 19% (95% CI2%-29%) and 77% (95% CI 62%-87%), respectively, in the placebo
roup. The PPI test showed a significant higher discriminative power,

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ith a summary diagnostic odds ratio of 19.35 (95% CI 8.54-43.84)ompared with 0.61 (95% CI, 0.20-1.86) in the placebo group.21

ndoscopic Therapies for GER-Related NCCPEndoscopic therapies have been used for the treatment of GER withariable success rates.22,23 Liu and coworkers24 recently completed anpen label trial of patients with extra-esophageal forms of GER. After 3onths of anti-secretory therapy, they treated patients with persistent

xtra-esophageal forms of GER (19 dysphonia, 19 cough, 9 wheezing,nd 18 chest pain) with endoscopic luminal gastroplication (ELGP). Ofhe 18 patients with chest pain, 13 (72%) had short-term (6 month)ymptomatic response; during long-term follow-up (18 months), 3 of the

patients with continued chest pain at 6-month follow-up becameymptom-free; 4 patients who were symptom free during short-termollow-up developed recurrence of chest pain, and 3 additional patientsere lost to follow-up. Clearly, more studies involving a larger sample

ize are needed to determine the role of endoscopic therapies, if any, inhe treatment on GER-related NCCP.

nti-Reflux SurgeryThe efficacy of anti-reflux surgery has been established for patients with

ypical forms of GER25,26 during randomized controlled trials and,ecently, even for patients with non-erosive GER.27 In contrast to theobust data available comparing medical wit surgical therapies for thereatment of typical forms of GER, there is more limited informationegarding the surgical outcome for extra-esophageal GER, particularlyCCP.In the first uncontrolled study aimed at acid control by anti-reflux

urgery in NCCP, DeMeester and coworkers obtained improvement in1% of 11 patients.1 They also found that patients who showed aorrelation between acid reflux episodes and pH testing had a uniform00% success rate. Two (18%) of the operated patients had complica-ions: 1 developed postoperative dysphagia requiring esophageal resec-ion and colon interposition, and 1 had failure of the surgery withecurrent postoperative GER documented on pH testing.So and coworkers28 described their experience with fundoplication in5 patients with extra-esophageal forms of GER, including 12 withCCP. Sixteen patients had pulmonary complications of GER, 12 had

pigastric and chest pain, and 9 had pharyngolaryngeal complications (2atients had both intractable cough and chest pain, and 1 patient had
sthma and chest/epigastric pain). The median follow-up was 22 months

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range 12 to 36 months). The response rates of pharyngolaryngealymptoms, chest or epigastric pain, and pulmonary symptoms were 78%,8%, and 48%, respectively. Improvement of the atypical symptoms withmeprazole or H2-blockers before operation was significantly associatedith successful surgical outcome.Chen and Thomas29 reported a retrospective study on the effects of

aparoscopic anti-reflux surgery (LARS) in 90 patients: 97% had typicalymptoms, and 56% had concurrent atypical symptoms. From the atypicalymptoms, 15 (17%) patients had cough and only 11 (12%) had chestain. The remaining had other atypical symptoms (“indigestion, choking,omiting, belching, burping, dysphagia and chest tightness”). Eighty-hree of 90 patients were available for follow-up; typical reflux symptomsmproved in 95% of patients, whereas atypical symptoms improved innly 54% (13% symptom-free, 41% “some improvement”). The fol-ow-up “in all patients was between 1-5 years.” Patients with atypicalymptoms had a lower satisfaction score versus patients with only typicalymptoms (P � 0.05).Farrell and coworkers30 reported on a retrospective study the impact ofARS (types of fundoplication not described) in patients with typical andxtra-esophageal forms of GER. Patients were stratified based on preop-rative symptoms into three groups: group 1, severe heartburn/minimaltypical symptoms; group 2, severe heartburn/severe atypical symptoms;nd group 3, minimal heartburn/severe atypical symptoms. In group 1n � 173), heartburn improved in 99% and resolved in 87%. In group 2n � 95), heartburn improved in 95% and resolved in 76%, and atypicalymptoms improved in 94 % and resolved in 42%. In group 3 (n � 56),typical symptoms improved in 93% and resolved in 48 %. Although allymptoms were improved by fundoplication, resolution was more likelyor heartburn than for atypical symptoms. Specifically examining theroup of patients with atypical GER, there were 62 patients with chestain; approximately 45% resolved their pain and 55% improved.30

election criteria for surgery were not described.In 2002, Patti and coworkers31 published data in NCCP patientsndergoing LARS for chest pain. The clinical outcome was comparedgainst the pH test results. A total of 165 patients underwent LARS (51%ad a Nissen fundoplicaton and 49% a partial fundoplication). Selectionor the type of surgery was based on the presence of intact peristalsis forhe former and weak peristalsis (�40 mm Hg distal esophagus) for theatter. Mean postoperative follow-up was 13 months. The patients wererouped as follows: 39 patients (group A) experienced no chest pain
uring pH testing; in 28 patients (group B), chest pain correlated with

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eflux in �40% of instances; in 98 patients (group C), chest painorrelated with reflux in �40% of the events. Chest pain improvedostoperatively in 65% of group A patients, 79% of group B patients, and6% of group C patients (group C versus A and B: P � 0.05). Heartburnnd regurgitation resolved or improved in 97% and 95% of patients,espectively. These data show that pH monitoring helped to identify aelationship between chest pain and reflux. Nevertheless, several obser-ations deserve to be made. This was a retrospective study of patientsho had received previous medical therapy (80% had a PPI), and it is not

lear which selection criteria were used to operate on these patients.ubjects in the study did not have chest pain as the only complaint; indeed6% suffered from heartburn and 78% from regurgitation. Thus, it isnclear whether the favorable effects observed in this study are applicableo patients with chest pain alone. This was also a unique population in that0 of the patients had visible erosive esophagitis at endoscopy, an unusualeature in patients with NCCP.Recently (2006), Rakita and coworkers32 described their experienceuring a retrospective review of a large number of patients withxtra-esophageal forms of GER undergoing LARS (n � 722). Of these,58 specifically had chest pain. They report a mean follow-up period of0 � 83 months. A total of 81% improved postoperatively. It is unclearow patient selection for this study took place. Complications occurred ineveral patients: cardiac arrest in 2, death (from sepsis) in 1, and 4equired re-operation.In summary, 6 studies have addressed the impact of anti-reflux surgeryn NCCP (Table 2). All are retrospective, uncontrolled studies. Theumber of patients is variable ranging from 11-12 (3 series) to 165 in theargest study. The results of these studies suggest that between 48% and00% of these patients obtain symptom relief. Most studies found thatatients with atypical forms of GER fare less well when compared withatients with typical GER. Some studies have shown that there is aorrelation between a high symptom index during pH test and favorableutcome. Patient selection has not been described, although it is likely toe highly selected. Follow-up period has varied from 1 year to slightlyver 5 years. Complications are uncommon, but when they occurred somef those reported were serious. All studies come from academic centersxperienced in esophageal surgery, thus it is unknown how these resultspply to community centers. Carefully designed, prospective, controlledrials are needed to determine the efficacy of anti-reflux surgery in
atients with GER-related NCCP.

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sophagaeal Motility DisordersEvaluation of large number of patients with NCCP reveals that 28% to0% have an esophageal motility disorder.33,34 Esophageal motilityisorders noted in these patients include nutcracker esophagus (NE),iffuse esophageal spasm (DES), nonspecific motility disorder (NEMD),ypertensive and hypotensive lower esophageal sphincter (LES), ineffec-ive peristalsis, and achalasia.33-35

Treatment of patients with NCCP and esophageal motility disorders ishallenging. This is due, in large part, to our insufficient understanding ofhe relationship between abnormal motility and chest pain. It is alsoelated to the lack of understanding of the etiology, pathophysiology, andatural history of esophageal motility disorders. In addition, therapeuticttempts aimed at improvement of the abnormal motility (ie, reduction ofsophageal amplitude in NE) have not resulted in parallel improvement inain.36 Despite the fact that there are a variety of pharmacologic agents

ABLE 2. Anti-reflux surgery outcome in NCCP

Author, Year (Ref.) n Improved % Follow-Up Time Comments

eMeester et al.,1992 (1)

11 100% 2-3 years SI at pH predictedimprovement.

o et al.,1998 (28)

12 48% Median 22 months(12-36)

Previous improvementwith H2 blockers orPPI predictedimprovement.

hen et al.,2000 (29)

11 13% symptom-free;41% someimprovement;46% noimprovement

1-5 years Patients with “atypical”symptoms had lessresponse than thosewith typical GER.

arrell et al.,2001 (30)

62 55% improved;45% resolved

13 months More improvementseen in patients withtypical than atypicalsymptoms.

atti et al.,2002 (31)

165 65% (of those withno SIcorrelation); 79%of those with�40% SIcorrelation; 96%with �40 SIcorrelation

13 months Highest improvementbased on SIcorrelation.

akita et al.,2006 (32)

158 81% 50 months � 83

bbreviation: SI, symptom index.

hat have been used to treat spastic motility disorders, most studies are of


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mall sample size and few are placebo-controlled. No single agent hasmerged as the treatment of choice.37 It is also not clear whether there areifferences in outcome based on symptoms: ie, chest pain or dysphagia oroth. There is scarcity of data regarding whether the type of symptomarrants a different tailored approach. Therefore, these limitations need

o be taken into account when examining the literature on this subject inhe subsequent section.Since our last review of the topic in 2004,37 there have been a few

dvances in the field. Using our former review as a frame of reference, inhe next section we provide an update in areas where there has been andvance. We focus only on spastic motility disorders other than achalasia.

ER in Patients with DismotilityEarlier studies by Crozier have shown that acid can induce esophageal

pasm.38 Swamy and coworkers39 have also shown a different clinicalesponse between patients with GER and DES and those without GER.he potential role of acid in esophageal dismotility was further stressedith the use of high-frequency ultrasound. Pehlivanov and coworkers40

oted sustained esophageal contractions induced by GER. Recently, weound in a preliminary communication that GER occurs in more than 35%f patients with DES.41 In patients with NE and coexisting GERdocumented by 24-hour ambulatory pH test), acid suppression results inymptomatic improvement despite lack of resolution of the esophagealotility abnormalities.2 These observations suggest that, in patients with

pastic motility disorders, such as DES and NE, treatment with aciduppressive therapy is warranted prior to initiation of muscle relaxantsince muscle relaxants, such as calcium-channel blockers, nitrates, andnticholinergic agents, may decrease the LES pressures and thus increaseeflux.42,43 Thus, these agents may be used in patients with spasticisorders only after GER has been excluded.

harmacologic Treatment for Non-GER-Relatedsophageal Motility DisordersFor patients with spastic motility disorders without GER, severaluscle-relaxing agents have been used in the treatment of symptoms such

s NCCP and dysphagia. These medications include nitrates, nitric oxideNO) donors, phosphodiesterase-5 inhibitors (PD-5), anticholinergic
gents, and calcium blockers.

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itratesNitrates are one of the earliest agents used to treat esophageal spasm.hese medications are potent relaxants of gastrointestinal smooth muscle

hrough the stimulation of cyclic guanosine monophosphate-dependentathway.44 In 1973, Orlando and Bozymski45 showed that nitratesffectively reduced manometric findings and symptoms in a patientuffering from DES. Since that original observation, several trials haveddressed the efficacy of nitrates in the treatment of DES. Table 3ummarizes the published data.The published experience with these agents is limited to 51 patients. Nolacebo-controlled trials have been completed (studies were all openabel). However, most authors describe symptomatic improvement afterrimarily short-term studies, and, in some trials, long-term use. Thesencontrolled clinical observations suggest that nitrates induce chest painelief in selected patients with DES. However, side effects such aseadaches and hypotension may limit their use. It is also possible thatachyphilaxis may develop. Administration every 6-12 hours may de-rease the likelihood of this problem.44 There is no available informationegarding the effect of these compounds in patients with motilityisorders, other than DES.

he Role of NONO is an inhibitory neurotransmitter in the gastrointestinal tract.51 In

he smooth circular muscle of the human esophagus, it regulates theatency gradient and the contraction amplitude of esophageal peristalsis.52

legant studies by Murray and coworkers53 and Konturek and cowork-rs50,54 have shown that the experimental removal of NO in humans

ABLE 3. Nitrates and esophageal motility*

Author (Ref.) Year n Trial Medication

rlando and Bozymski (44) 1973 1 Open Erythyityl tetra nitrate 10 mg tidwamy (39) 1977 12 Open Isosorbate dinitrate (Isordil) 15-30 mg qidhafran et al. (46) 1979 5 Open Nitroglycerin 0.4 mg (sublingual)arker and Mackinon (47) 1981 1 Open Isosorbate dinitrate (Isordil) 5 mg prior to

mealsellow (48) 1982 5 Open Isosorbide 20 mg po before meals.

Unsatisfactory responseillaire et al. (49) 1989 22 Open Nitroglycerin spray, 0.8 mgonturek (50) 1995 5 Open Glyceryl trinitrate 100-200 �g/kg-h IV

Modified from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterollin North Am 2004;33(1):107-24.37

nduces a pattern of simultaneous contractions similar to DES. Therefore,


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harmacologic agents that result in the augmentation of NO may improvehe clinical and manometric patterns of patients with diffuse esophagealpasm.Glyceryl trinitrate (GTN) is a donor of NO.55 Acute (intravenous

dministration in humans) of GTN produced a dose-dependent elon-ation of peristalsis and duration of esophageal contractions accom-anied by a significant improvement in symptoms in DES.50 L-rginine is a basic, semi-essential amino acid that acts as a substrateor the synthesis of NO. Bortolotti and coworkers56 found that-arginine IV did not affect esophageal peristalsis or LES parameters.owever, during a small, double-blind, crossover trial with each phase

placebo or drug) lasting 6 weeks, oral administration (30 mL of a 10%-arginine solution tid versus placebo) induced chest pain improve-ent in eight patients with spastic esophageal motility (DES, n � 3;E, n � 5). No side effects were reported. These observations suggest

hat spastic disorders of the esophagus that may cause NCCP, such asES, may be due to either a dysfunctional L-arginine/NO system or aeficient nitrergic system.

hosphodiesterase InhibitorsPhosphodiesterase-5 (PD-5) is an important modulator of smoothuscle contraction. Both human and animal studies show that it regulates

sophageal contraction amplitude by increasing the availability ofO.52-54 There are three commercially available PD-5 inhibitors: silde-afil, vardenafil, and tadalafil.Several investigators have studied the effects of sildenafil in humans.verall, these studies indicate that sildenafil markedly inhibits the motor

ctivity of the esophageal musculature by decreasing LES pressure, wavemplitude, and propagation velocity and increasing the onset latency ofressure waves.57 It has also been shown to decrease esophageal bolusransit and esophageal amplitude but have no effect on gastro-esophagealeflux parameters.58,59 These studies suggest that this and related com-ounds may have a beneficial effect in patients with spastic motilityisorders.In a study of 11 patients with a variety of spastic motility disorders [NE,� 4; DES, n � 1; hypertensive LES (HLES), n � 3; achalasia, n � 3],

ildenafil improved the manometric pattern in 9 of 11 patients withypercontractile esophageal motility; however, only 4 of these patientseported symptomatic improvement, and 2 of these 4 discontinued drugherapy due to side effects.60 Agrawal and coworkers61 reported a case of
patient with NCCP who at manometry showed simultaneous features of

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E and DES. The patient’s symptoms and motility pattern improved withhe use of all 3 available PD-5 inhibitors. Following acute administrationf sildenafil 50 mg versus placebo in a random, double-blinded trial,ildenafil inhibited the LES tone and pressure wave amplitude of 7atients with symptomatic HLES.62 No long-term or controlled trials arevailable. These observations suggest that these agents deserve furthertudy in patients with NCCP.

nticholinergic AgentsCholinergic (muscarinic) innervation plays an important role in esoph-

geal peristalsis and LES activity.63 Using cimetropium bromide (10 mgV)63 in a single-blind design, eight patients with NE and similar controlubjects had significant reduction of distal esophageal amplitude and LESressures. However, the effects of this agent on clinical symptoms haveot been studied. There are no other clinical trials supporting the use ofuscarinic blocking agents for the treatment of patients with painful

sophageal motility. Side effects, such as dry mouth and tachycardia, mayimit their use. The role of new muscarinic receptor antagonist withpecific selectivity remains to be evaluated.

alcium BlockersCalcium is a mediator of esophageal muscle contraction.64 In animal

tudies, interference with calcium entry at the cellular level leads toecreased LES pressure and esophageal contractions.65,66

ifedipineNifedipine has been shown to decrease the frequency and amplitude ofonperistaltic esophageal contraction in healthy subjects.67 Clinicalxperience in the treatment of esophageal motility remains limited. Table 4rovides a summary of therapeutic trials in patients with DES.In contrast to achalasia, where several investigators have examined the

ffects of nifedipine, there is more limited information about the effectsf this drug in non-achalasia-related motility disorders other than DES.raube and coworkers74 studied the esophageal effects of nifedipine inine patients with high-amplitude peristaltic esophageal contractions (NE,0 mg orally). Nifedipine decreased LES pressure by approximately 50%nd contraction amplitude in the body of the esophagus by approximately5%. The effects of the drug on symptoms were not evaluated. Richternd coworkers36 completed the only controlled trial of nifedipine inatients with NE. Twenty patients received oral nifedipine (10-30 mg tid)
r placebo during a 14-week crossover study. Despite a statistically

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ignificant improvement in esophageal amplitude, no symptomatic ben-fits were observed.

iltiazemRichter and coworkers75 examined the effects of diltiazem (90, 120, or50 mg orally) in healthy controls and found no effect on distalsophageal contractions. The clinical effects of this calcium blocker haveeen examined in two clinical studies in patients with NE and in a smalltudy of patients with DES (Table 5). These studies show that, despitemprovement in NE, studies involved very small number of patients. Noeneficial effects were observed in the few patients (n � 8) with DESTable 5).

ABLE 4. Nifedipine trials in diffuse esophageal spasm*

Author (Ref.) Year Study Design N Dose Outcome

lackwell et al. (67) 1981 Open label 6 20 mg tid 3/6 improvedavies et al. (68) 1982 Double-blind,

placebo10 10-40 mg tid Short-term improvement

asrallah et al. (69) 1982 Open-label 1 10 mg tid Improvedasrallah et al. (70) 1985 Open-label 4 10 mg tid Improvedhomas et al. (71) 1986 Open-label 6 10-20 mg tid Improvement of

dysphagiaavies et al. (72) 1987 Placebo-controlled

(a single and adouble-blindedphase)

8 10-30 mg tid(mean 64mg)

No response (treatmentfor up to 3 months)

anciu et al. (73) 1990 Open-label 12† 10-20 mg Acute “improvement ofradiologicappearance”


Patients defined radiologically.

ABLE 5. Diltiazem trials*

Author (Ref.) Year Study Design N Dose Outcome

ichter et al. (75) 1990 Open-label, 8 weeks 10 (NE) 90 mg tid Improvedattau et al. (76) 1991 Double-blind, placebo-

controlled, 8 weeks14 (NE) 60-90 mg tid Improved

renth et al. (77) 1990 Double-blind,crossover, 10weeks

8 (DES) 60 mg tid No significantimprovement

Reprinted with permission.37


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erapamilVerapamil decreases LES pressures and the amplitude of esophagealeristalsis in animal studies,78,79 but results in humans have not beenonsistent.80 No studies have been done with this agent in patients withpastic esophageal motility disorders.In summary, studies with calcium blockers include small sample size

nd most are open, uncontrolled trials. Although many report improve-ent, we lack long-term studies. Side effects such as constipation,

ypotension, and edema may limit the use of these compounds.

isceral Hyperalgesia: The Role of Painodulators

Visceral hyperalgesia (increased perception to esophageal balloonistension) has been recognized as a feature in NCCP. Tricyclic antide-ressants (TCA) such as imipramine, desipramine, clomipramine,mytryptiline, and trazodone have been used for years to treat varioushronic pain syndromes.81 In healthy volunteers, imipramine decreasesain thresholds to experimental somatic pain81 and to intra-esophagealalloon distension.82 The mechanism of action of these compounds is notnown. However, these medications block serotonin and norepinephrine.erotonin and norepinephrine are thought to mediate endogenous anal-esic mechanisms through the descending pain inhibitory pathways in therain and spinal cord.83 Antidepressant medications that enhance seroto-in and norepinephrine neurotransmission may therefore reduce pain inatients with NCCP. It is also possible that they act through N-methyl--aspartate antagonism and ion-channel blocking activity that may alsoediate antinociceptive effects.84,85

Clouse and coworkers86 examined the effects of trazodone in patientsith nonspecific esophageal motility disorders. During a controlled trial,atients treated with 100 to 150 mg/day of trazodone (n � 15) obtained

significant symptomatic improvement after 6 weeks of treatmentompared with placebo (n � 14). Manometric parameters did not changeespite symptom improvement. Prakash and Clouse87 also reportedong-term effects of TCA in NCCP. In a retrospective analysis of 21atients treated with a variety of TCA after incomplete response tonti-reflux therapy, they found that 75% of patients with chest painontinued to experience symptomatic relief during long-term use of up toyears.Another TCA, imipramine, has been found effective for the treatment of
atients with NCCP regardless of the esophageal motility findings.

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annon and coworkers,88 during a double-blind, placebo-controlled trialf 60 patients with chest pain, compared the effects of imipramine (50 mgs; n � 20 patients) with clonidine (0.2 mg daily; n � 20 patients) orlacebo (n � 20 patients) for 3 weeks.88 They found that only imipramineesulted in a significant reduction (52%) in chest pain episodes. Anncontrolled study from Japan found that a combination of psychotherapynd trazodone (50 mg) orally or clomipramine (25 mg IV daily) for 1onth produced clinical and radiologic improvement in 9 patients withES.89 There is paucity of data regarding the therapeutic efficacy of other

ricyclic compounds.TCA should be administered at bedtime in a low dose (10-25 mg) and

itrated up to 50-75 mg/day based on symptom response or side effects.90

otential side effects include priapism for trazodone; all other TCA maynduce constipation, hypotension, arrhythmias, drowsiness, urinary reten-ion, and changes in intraocular pressure. Thus, caution should bexercised in patients with glaucoma or prostate retention. Concerns withrug interactions should also be taken into consideration.

elective Serotonin Reuptake Inhibitors (SSRIs)Recent studies have suggested that serotonin is an important mediator

or esophageal pain. Varia and coworkers91 evaluated the effects ofertraline (Zoloft) in patients with NCCP. During a single-blinded,lacebo-controlled trial, 25 subjects with NCCP were randomized toeceive sertraline or placebo for 8 weeks. Doses started at 50 mg and weredjusted to a maximum of 200 mg on the basis of each subject’s clinicalesponse. Sertraline induced significantly more reduction in pain scoreshan placebo. No data were provided regarding esophageal testing. Sideffects occurred in 27% of the patients, including delayed ejaculation,ecreased libido, and restlessness.Citalopram (Celexa; 20 mg IV) in healthy volunteers produced signif-

cant reduction in esophageal pain perception to chemical and mechanicaltimulation when compared with placebo, but it did not affect esophagealotility parameters.92

Tegaserod, a 5-hydroxytryptamine subtype-4 (5-HT4) receptor partialgonist (recently withdrawn from the US market), improves esophagealain threshold following esophageal mechanical distension in patientsith functional heartburn.93

A recent trial examined the effects of another SSRI, paroxetine (Paxil),n 50 patients with NCCP. During a double-blind, placebo-controllednvestigation, patients were randomized to the medication versus placebo
n � 27 paroxetine and n � 23 placebo) for 8 weeks. Paroxetine-treated

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atients showed a greater improvement on a physician-rated scale (Thelinical Global Impression scale), but not on self-rated pain scores.94

hese above studies highlight the role of serotonin in visceral painransmission and suggest that further trials are needed to evaluate theotential role of the serotonin pathway in NCCP.95

otulinum toxin (Botox)Botulinum toxin (Botox) binds irreversibly to cholinergic nerve termi-als blocking acetylcholine-mediated neuromuscular transmission, reduc-ng LES pressures in animal model and humans.96 In 1996, Miller andoworkers97 treated 15 patients with spastic motility disorders (DES,EMD, and lower esophageal dysfunction) unresponsive to previousedical therapy with intraesophageal injection of Botox (80 U). A

atisfactory outcome was noted in up to 67% of the patients, but a secondnjection was required to sustain remission. In 2002, Miller and cowork-rs98 amplified their observations during an open-label trial of Botox in9 patients with spastic motility disorders other than achalasia. A total of2% of the patients experienced symptomatic improvement; 6 of 9esponders required a third dose to maintain remission. No informationas provided regarding the effects of Botox on esophageal manometry.torr and coworkers99 treated 9 patients with DES with Botox (100 U atultiple sites in the distal esophagus, 1- to 1.5-cm intervals). After 6onths, 8 patients remained improved, but a repeat injection was required

n 4 of these subjects to maintain remission. Several preliminary reportsn abstract form or Letters to the Editor have also indicated a beneficialesponse with Botox in a variety of patients with spastic disorders.100-102

able 6 summarizes the published experience with Botox. Placebo-

ABLE 6. Summary trials: Treatment of spastic disorders with Botox*

Author (Ref.) Year N Publication Type

iller (97) 1996 15 Full Paperassidy (101) 1996 10 Abstractones (103) 1996 1 Letter to the Editorebendahl (100) 1999 9 Abstracttorr (99) 2001 9 Full Paperiller (98) 2002 29 Full Paper

acy (104) 2002 1 Case Report


ontrolled trials are needed to confirm these observations.


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ranscutaneous Electrical Nerve StimulationTranscutaneous electrical nerve stimulation (TENS) has been found

ffective in the treatment of diverse types of pain.104 Borjesson andoworkers105 found that TENS reduced esophageal symptoms induceduring esophageal balloon distension and decreased peristaltic velocity.ncreased visceral perception was positively correlated to the amplitudend duration of the esophageal peristalsis. The impact of this therapy onong-term clinical remission has not been evaluated.

ypnotherapyTwenty-eight patients with NCCP were randomized to receive either 12

essions of hypnotherapy or supportive therapy plus placebo medicationver a 17-week period. The primary outcome measure was globalssessment of chest pain improvement. Twelve of 15 (80%) hypnotherapyatients compared with 3 of 13 (23%) controls experienced a globalmprovement in pain (P � 0.008), which was associated with a signifi-antly greater reduction in pain intensity (P � 0.046) although notrequency. Hypnotherapy also resulted in a significantly greater improve-ent in overall well being in addition to a reduction in medication usage.here were no differences favoring hypnotherapy with respect to anxietyr depression scores.106

sychological InterventionSeveral studies have noted a high prevalence of psychiatric disorders inatients with NCCP.107,108 Therefore, a number of psychological trialsave been conducted to manage patients with NCCP and several areeviewed here.A postal survey of 1053 patients with unexplained chest pain was done

o evaluate interest in psychotherapy.109 This study showed no associa-ion between duration of chest pain and interest in treatment. Youngerale patients were more interested in treatment. A limitation in activities

ather than frequency or intensity of pain was the most importantredictor of interest in treatment.Cognitive therapy has been reported effective for the treatment ofCCP in 2 separate trials. In one study, cognitive-behavior therapy (n �7) was compared with “usual care” (n � 35). Intervention patientsmproved significantly with regard to frequency and intensity of chestain: 15 (48%) of the 31 patients in the treatment group were pain free at
2-month follow-up compared with 4 (13%) of the 33 patients in the

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ontrol group (P � 0.002).110 In a second study, 31 patients with NCCPere treated in a controlled trial of cognitive-behavioral therapy. Patientsere randomized to either immediate treatment or as a control to

ssessment only. The average number of sessions given was 7.2. Thereere significant reductions in chest pain, limitations and disruption ofaily life, autonomic symptoms, distress and psychological morbidity inhe treated group as compared with the control group. The assessment-nly group was treated subsequently with cognitive therapy and showedomparable benefit. Improvements were sustained by both treated groupst 4- to 6-month follow-up.111

Kisley and coworkers112 conducted a Cochrane analysis of studiesnvolving psychological intervention in NCCP. They included 8 studiesnvolving 403 randomized participants. They found a significant reduc-ion in reports of chest pain in the first 3 months following thentervention; fixed effects relative risk � 0.68 (95% CI 0.57-0.81). Thisas maintained from 3 to 9 months afterwards; relative risk � 0.58 (95%I 0.45-0.76). There was also a significant increase in the number of chestain-free days up to 3 months following the intervention; the standardizedean difference � 0.85 (95% CI 0.38-1.31).A recent study proposed that psychological interventions that take place

n the emergency room and use a Bio-Psychosocial Model may be moreffective for treatment of NCCP.113 Taken together these studies supporthe role of psychological intervention in selected patients with NCCP.

ore work needs to be done to identify which type of patient benefits bestrom these interventions, timing, length, and type of therapy.

enzodiazepinesBenzodiazepines amplify gamma-aminobutyric acid throughout the

entral nervous system and act more peripherally to reduce cat-cholamines. Huffman and Stern suggest that these agents could be usedn the emergency room setting to treat NCCP, provided they are used on

short-term basis in order to decrease the rate of dependency.114 Fewtudies and of very small sample size have been done with thesegents.115 In a non-blind, 8-week trial of alprazolam in patients present-ng with chest pain and panic disorder, 15 of 20 improved by 50% orreater reduction in panic frequency. However, patients experienced onlymodest drop in episodes of chest pain or discomfort.116

A small, placebo-controlled, double-blind, flexible-dose (1-4 mg/day),-week trial of clonazepam was completed by Wuslim and coworkers.117

n 27 patients with NCCP and coexisting panic disorder, they found a


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ignificant reduction in the 50% reduction in anxiety scores, in therug-treated group compared with placebo.117

Unfortunately, concerns with dependency make it unlikely that theseedications will be used in the daily treatment of patients with recurrent

hest pain.

he Role of Adenosine Receptors in NCCPMice lacking functional adenosine receptor activity show signs of

ncreased hyperalgesia and anxiety.118 In healthy volunteers, bolusdenosine infusion induces angina-like pain shortly after infusion. The-phylline (a nonselective adenosine receptor antagonist) reduces this painignificantly, suggesting that pain triggered by adenosine is, at least toome degree, dependent on activation of theophylline-sensitive recep-ors.119 Rao and coworkers120 reported data from consecutive patientsith recurrent NCCP who failed an 8-week therapeutic trial of doubleose PPI, and “various empirical trials” (not specified), or lackedvidence of GER on 24-hour pH testing. They found that intravenousnfusion of theophylline (an adenosine receptor antagonist), but notlacebo, improves the biomechanical and sensory properties of thesophageal wall. In a long-term study, 19 patients with esophagealypersensitivity, randomized to receive oral theophylline 200 mg bid forweeks in a crossover design, experienced significant improvement in

ain parameters when compared with placebo. It is unlikely that theoph-lline will become in use for the treatment of NCCP due to its potentialoxicity. However, the findings of the above study suggest that researchnvolving newer selective adenosine receptor agents may offer newpportunities for the treatment of NCCP.121

ummaryTreatment of NCCP remains a difficult problem due to the heteroge-eous nature of the disorder. GER is the best studied condition contrib-ting to NCCP. Pharmacological trials of acid inhibition show a robustesponse rate for patients with NCCP-related GER. More rigorouslyxecuted studies are needed to understand the role of endoscopicherapies (if any) and surgery in patients with NCCP and coexisting GER.or patients with spastic disorders without GER, most therapeutic trials

nvolve small, uncontrolled studies with variable outcome. Although aumber of therapeutic options have been used to treat spastic dysmotilityn these patients, no one agent has emerged as the drug of choice. Botoxs a promising agent for the treatment of selected patients due to its rapid
eneficial effect and relative simplicity (though invasive) of administra-

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ion. However, placebo-controlled trials are lacking to validate itsfficacy. NO donors and phosphodiesterase inhibitors are attractiveompounds that warrant further testing since they seem to influence thentimate mechanism involved in the pathogenesis of DES (simultaneousontractions). Two TCA (imipramine and trazondone) remain valuablerugs in NCCP since small, randomized, placebo-controlled trials supportheir beneficial effect. The role of serotonin and the newly reporteddenosine receptor pathway opens another opportunity for further re-earch to better understand the neurotransmitters involved in the genesisf visceral chest pain. Finally, the high prevalence of psychiatricisorders in patients with NCCP is concerning. It begs for a combinedultidisciplinary approach to study the interaction between the esophagus

nd the brain and better define the role, timing, and forms of psycholog-cal intervention in these patients.

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Treatment of Non-Cardiac Chest Pain

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