Nonc ardiac Chest Pain ^ Treatment Approaches Sami R. Achem, MD, FACP, FACG, AGAF KEYWORDS  Noncardiac chest pain  Reflux  Treatment

Noncardiac chest pain (NCCP) is a very common disorder of international proportions. In the United States, nearly 70 million patients (23% of the population) suffer from NCCP.1 Population-based studies have also reported similar figures in: Australia, 33%;2 South China, 21%;3 Argentina, 24%;4 and Spain, 8% to 28%.5 Patients with NCCP represent a significant economic impact. They account for 2% to 5% of all emergency room evaluations and are one of the most frequent causes of hospital admission in the western world.6 A United States household survey of functional gastrointestinal disorders found that NCCP patients are usually gainfully employed and lose an average of 13 days of work each year.7 The pathophysiology of NCCP is complex and poorly understood. Several mechanisms have been identified as possible sources of pain, including gastroesophageal reflux (GER), visceral hyperalgesia, esophageal motility disorders, psychiatric dysfunction, abnormal biomechanical properties of the esophageal wall, sustained esophageal contractions, abnormal cerebral processing of visceral stimulation, and disrupted autonomic activity.8–11 Treatment of NCCP is challenging due to the heterogeneous nature of this disorder. It is also possible that many patients suffer from more than one condition. Selection of therapy is frequently aimed at the suspected underlying process. The purpose of this article is to provide a focused review of available treatment modalities for this challenging disorder. GASTROESOPHAGEAL REFLUX

GER is the most common cause of NCCP, and the best studied.12 The benefits of acid inhibition in NCCP have been demonstrated during short- (1 day–2 weeks) and longterm (6–8 weeks) trials. Tables 1 and 213–24 summarize the studies that have examined the impact of acid-inhibitory therapy in NCCP. These trials underscore the favorable effect of acid suppression in NCCP. Table 1 shows that for long-term therapy, only two studies were double blind and placebo controlled; and one is available only as an abstract. Table 2 shows that for short-term therapy, five studies were placebo controlled and two studies (available only as an abstract) were not. Overall, sample size is Mayo College of Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA E-mail address: [email protected] Gastroenterol Clin N Am 37 (2008) 859–878 doi:10.1016/j.gtc.2008.09.013 0889-8553/08/$ – see front matter ª 2008 Published by Elsevier Inc.

gastro.theclinics.com

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Table 1 Long-term medical trial with acid inhibition in noncardiac chest pain Author, Reference,Year

Number of Cases

Type of Trial

Medication and Dosage

Achem et al,13 1993

12 (Nutcracker and GER)

Open-label

High-dose ranitidine, 150 mg/qid, or omeprazole 20 mg bid for 8 weeks

80% improved

Stahl et al,14 1994

13

Open-label

Ranitidine, 150 mg/qid for 8 weeks

100% improved

Achem et al,15 1997

36

Double-blind, placebocontrolled

Omeprazole, 20 mg/bid for 8 weeks

81% improved on omeprazole, 6% on placebo

Chambers et al,16 1998

23

Open-label

Omeprazole, 40 mg bedtime for 6 weeks

Improvement, but complete resolution in only 30%

Flook et al,17 2007 (abstract only)

599 (Intention to treat)

Double-blind placebocontrolled

Esomeprazole, 40 mg/bid versus placebo for 4 weeks

Post-hoc analysis, esomeprazole improvement was 33.1% versus 24.9% for placebo (P 5 .035)

Outcome

small: 12 to 36 subjects for long-term studies (with the exception of Flook’s17 study, an abstract containing 599 subjects) and 17 to 68 subjects in short-term trials. In contrast to the robust data available comparing medical to surgical therapies for the treatment of typical forms of GER, there is limited information regarding the surgical outcome for extra-esophageal GER, particularly NCCP. Furthermore, there are no randomized surgical trials. Six studies have addressed the effects of anti-reflux surgery on NCCP (Table 3).25–30 All are retrospective, uncontrolled studies. The results of these investigations found that between 41% and 100% of these patients obtain symptom relief. Patient selection has not been described, though it is likely to be highly selective. Complications were uncommon, but when they occurred, some were serious. All studies come from academic centers experienced in esophageal surgery, thus it is unknown how these results apply to community centers. Well-designed, prospective, controlled trials are needed to determine the efficacy of anti-reflux surgery in patients with GER related NCCP. These studies suggest that in approaching patients with NCCP, an initial medical trial of acid suppression provides effective chest pain relief in the majority of the patients. Furthermore, the data from short-term therapeutic trials (Table 2) indicate that a brief course of high-dose proton pump inhibitor (PPI) therapy has the potential to serve as both a diagnostic and therapeutic approach to identify patients with GER-related chest pain. VISCERAL HYPERALGESIA

Patients with NCCP show a heightened sensitivity to a variety of experimental esophageal stimuli such as pharmacologic provocation with cholinergic agonists,

Table 2 Short-course PPI trials as a diagnostic test in noncardiac chest pain Author, Reference, Year

Number of Cases

Medication and Dosage

Sensitivity (%)

Specificity (%)

PPV (%)

Young et al,18 1992 (abstract)

30

Omeprazole, 80 mg/d for 1 day

90

80

NA

NA

Squillace et al,19 1993 (abstract)

17

Omeprazole, 80 mg/d for 1 day

69

75

90

43

Fass et al,20 1998

37

Omeprazole, 40 mg/AM 20 mg/PM versus placebo for 7 days

78

86

90

71

Pandak et al,21 2002

37

Omeprazole, 40 mg/bid versus placebo for 2 weeks

90

67

73

92

Xia et al,22 2003

68

Lansoprazole, 30 mg/d versus placebo for 4 weeks

92

67

58

94

Bautista et al,23 2004

40

Lansoprazole, 60 mg/AM 30 mg/PM versus placebo for 7 days

78

80

88

83

Dickman et al,24 2005

35

Rabeprazole, 20 mg/bid versus placebo for 7 days

75

90

83

75

Noncardiac Chest Pain–Treatment

Abbreviations: NA, not available; NPV, negative predictive value; PPV, positive predictive value. Data from Achem SR. Treatment of noncardiac chest pain. Dis Month 2008;54:642–70.

NPV (%)

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Table 3 Anti-reflux surgery outcome in noncardiac chest pain Author, Reference, Year

Number of Cases

Improvement

Follow-up Time

Comments

DeMeester et al,25 1982

11

100%

2–3 years

Symptom index at pH predicted improvement

So et al,26 1998

12

48%

Median 22 months (12–36)

Previous improvement with histamine 2 receptor antagonists blockers or PPI predicted improvement

Chen et al,27 2000

11

13% symptom free, 41% some improvement, 46% no improvement

1–5 years

Patients with atypical symptoms had less response than those with typical GER

Farrell et al,28 2001

62

55% improved, 45% resolved

13 months

More improvement seen in patients with typical than atypical symptoms

Patti et al,29 2002

165

65% (of those with no SI correlation), 79% of those with % 40% SI correlation, 96% with R 40 SI correlation

13 months

Highest improvement based on symptom index correlation

Rakita et al,30 2006

158

81%

50 months  83 months

Data from Achem SR. Treatment of noncardiac chest pain. Dis Month 2008;54:642–70.

hydrochloric acid, and intraesophageal balloon distension.31 Studies have shown that 60% of patients with NCCP have an increased perception to esophageal distension, a phenomenon observed in only 20% of healthy controls.32 This increased reactivity has been termed visceral hyperalgesia and has also been described in subjects with irritable bowel syndrome during rectal balloon distension studies. Although the mechanisms responsible for visceral hyperalgesia remains unclear, several pharmacologic agents that reduce chest pain are believed to act by diminishing visceral sensitivity or inducing ‘‘visceral analgesia.’’33 For instance, imipramine, when compared with baseline, was found to be effective in improving chest pain threshold induced during esophageal balloon distension studies in healthy males.34 In addition to tryciclic antidepressants (TCA), imipramine and trazodone, recent information suggests that the serotonin-uptake inhibitors (SSRIs) may also play an important role in visceral pain. The SSRIs, sertraline and paroxetine, have been studied in NCCP and compared with placebo showing favorable effects. The clinical trials that have examined the outcome of these therapeutic compounds (TCA and SSRI), on NCCP are summarized in Table 4.35–39 These studies suggest that visceral analgesics are effective in the

Noncardiac Chest Pain–Treatment

Table 4 Visceral analgesics in noncardiac chest pain Author, Reference, Year

Number of Cases

Type of Trial

Medication and Dosage

Outcome

Clouse et al,35 1987

30 (15 received trazodone and 15 placebo)

Placebocontrolled for 6 weeks

Trazone, 100–150 mg

Trazodone improved chest pain

Cannon et al,36 1994

60 (20 patients in each arm of trial)

Double-blind, placebocontrolled for 3 weeks

Imipramine, 50 mg at night time; Clonidine, 0.2 mg or placebo

Imipramine induced significant improvement

Prakash and Clouse,37 1999

21

Open-label, long-term up to 3 years

Several tricyclic antidepressant

Tricyclic antidepressant produced 75% improvement at 3 years

Varia et al,38 2000

25

Single-blind, placebocontrolled for 9 weeks

Sertaline, 50–200 mg adjusted dose to response

Sertraline improved chest pain

Doraiswamy et al,39 2006

50 (27 paroxetine and 23 placebo)

Double-blind, placebocontrolled

Paroxetine induced 10 mg for 1 wk improvement and titrated on a physicianupward weekly rated scale, but not on up to 50 mg; self- rated pain scores median dose was 30 mg (range 5–50 mg)

treatment of NCCP when compared with placebo. Interestingly, all these trials are of relatively small sample size, a problem similar to that observed with antisecretory therapy trials. There are no head-to-head comparative studies. Potential side effects such as drowsiness, prostatic retention, and arrhythmias may limit the use of the TCAs, imipramine, and trazodone. Trazodone has also been associated with priapism. Decreased libido or ejaculation dysfunction may limit the use of SSRIs, sertraline, and paroxetine. PSYCHIATRIC DISORDERS

Psychiatric conditions are common in NCCP. Several studies have noted a variable prevalence of panic disorders (24%–70%),40–42 anxiety (33%–50%),43–45 and major depression (11%–22%).46,47 Management of these patients is difficult because physicians may not critically screen for these conditions. Treatment is further complicated by the patient’s unwillingness to accept their psychiatric comorbidity and the lack of timely referral. The treatment may also be hampered by insufficient access to or availability of specially trained or interested therapists. Finally, it is unknown what therapeutic options are best suited to treat NCCP; whether pharmacologic intervention, cognitive therapy or other forms of intervention combined or alone yield the best treatment outcomes.

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A typical approach has been to offer patients reassurance and education about the ‘‘benign nature’’ of NCCP and good prognosis in comparison to the prognosis of patients with chest pain and coronary artery disease. Despite a favorable medical prognosis,48 patients with NCCP continue to experience chest pain symptoms (50%–70%), occupational (19%–51%) and functional impairment (46%–100%), and high levels of chest pain–related medical use; including hospitalization and use of inappropriately prescribed cardiac medications (27%–79%).49–52 The goals of therapy should be to reduce unnecessary use of emergency services and other medical resources, to decrease the incidence and severity of chest pain symptoms, and improve patients’ quality of life. A number of psychologic techniques have been employed for the treatment of NCCP. Cognitive therapy (CT) is based on the model of attribution approach. After cardiac tests deem chest pain as noncardiac, patients undergo several treatment sessions (7–16 sessions, 8–38 hours). The goal of treatment is to correct the misattributions regarding physical symptoms (ie, chest pain) as being harmful. Patients must adopt the belief that psychologic factors cause chest pain; and attribute the chest pain to panic attacks, anxiety, and psychologic factors. Three general principles are used during CT : (1) offer an alternative, noncardiac, explanation for the patient’s symptoms by addressing the problem as a combination of physical, cognitive, and behavioral factors, while challenging any catastrophic interpretation of patient’s symptoms; (2) teach patients how to cope with their symptoms using behavioral interventions such as relaxation and controlled breathing; and (3) address the potential problems that perpetuate symptoms such as stress, family, work, or other personal issues. Randomized, controlled trials of these treatments for NCCP demonstrate that these relatively lengthy treatments are effective in reducing psychologic distress, chest pain episodes, and decreasing functional impairment (Cott and colleagues, unpublished, 1990). Table 553–61 summarizes several trials of CT in NCCP and their outcomes. Overall, most published studies have shown a favorable outcome for CT. In a Cochrane analysis that involved eight studies of CT, Kisely and colleagues62 reported a significant benefit on chest pain parameters with CT. Esler and Bock60 provide persuasive arguments to consider alternative psychologic management strategies to CT for NCCP, such as the biopsychosocial model. This approach is based on the following principles: (1) most illness, whether physical or psychiatric, is influenced and determined by biological, psychologic, and social phenomena; (2) biological, psychologic, and social variables influence the predisposition, onset, course, and outcome of most illnesses; and (3) better patient outcomes are achieved when therapeutic interventions are based on evaluation of the relationship between biological, psychologic, and social variables. Even if there is not a clinically-significant psychiatric disorder present, evaluating and managing psychologic and social variables is still critical.63 The biopsychosocial model allows the physician to admit uncertainty and retain the possibility of cardiac etiology, while still recognizing and treating psychiatric problems such as anxiety. The biopsychosocial model does not force an ‘‘either-or’’ view of the patient’s condition: medical versus psychologic. This model allows for the co-occurrence of biological, psychologic, and social factors, which influence the course, and outcome of distressing symptoms.60 This model has been used in the treatment of other chronic pain syndromes. Its proponents believe that because it requires shorter intervention time (such as one session in hospital while patient is having structural studies and two or three telephone follow-up sessions), it is more practical and faster, while also allowing for continued medical evaluation. It also allows for additional forms of treatment such as pharmacologic intervention. Controlled clinical trials are needed to evaluate the results of this type of therapy.

Noncardiac Chest Pain–Treatment

OTHER INTERVENTIONS Hypnotherapy

A recent study examined the effects of hypnotherapy in NCCP. During a small trial, 28 patients were assigned to receive hypnotherapy (12 sessions) or supportive therapy plus placebo medication for a 17-week period. The hypnotherapy group experienced significantly more chest pain reduction (global and intensity, but not frequency). Hypnotherapy did not affect anxiety or depression scores.64

Biofeedback

Biofeedback has been used in a small trial of 70 patients with a variety of functional disorders, including NCCP (the precise number of patients with NCCP was not specified). Thirty patients were randomized to a control period, and 40 to active therapy. The authors reported symptom reduction and lowered costs for the treatment group compared with the control.65 Clearly, more studies are needed to determine whether this technique is effective in the treatment of NCCP.

Transcutaneous Nerve Stimulation

Transcutaneous nerve stimulation (TENS) has been used to treat diverse types of pain,66 including pain resulting from gastrointestinal tract distension.67 TENS has also been shown to exert important effects on esophageal motility parameters in achalasia and sphincter of Oddi dysfunction.68 During acute esophageal balloon distension studies in 18 patients with NCCP, TENS resulted in decreased perception of pain evoked by acute esophageal stimulation.69 This was not a blinded study with respect to the treatment given, and the patients could differentiate between the two TENS modes offered. However, the patients were not aware which of the stimulation sites was supposed to be active. It is unclear whether the use of TENS may have systemic effects (such as those potentially induced by placebo application). In a recent nonblinded, small trial of 24 patients with NCCP using either TENS or spinal cord stimulation, de Vries and colleagues70 found a greater than 50% improvement in pain parameters and nitroglycerin consumption during a mean follow-up time of five years. Thus, it appears that further research is warranted to evaluate the potential role of TENS in the treatment of NCCP.

Anxiolytics

The high prevalence of anxiety disorders in NCCP suggests that anxiety may amplify, trigger, or perpetuate NCCP. Although it is not known whether anxiety is a cause or an effect in NCCP, effective management of anxiety may have a favorable impact on chest pain. Benzodiazepines reduce the levels of peripheral catecholamines. Two small studies have suggested the potential benefit of anxiolytic agents in NCCP. In one nonblinded trial of 20 patients with NCCP and panic disorder, Beitman and colleagues71 showed that Alprazolan improved panic frequency but had no substantive benefit on chest pain parameters. In a second study, Clonazepan, at dosages of 1 to 4 mg/d for 6 weeks, was compared with placebo in 27 patients with NCCP and panic disorder. There was a significant reduction in panic attacks in the treated group compared with the control. However, the effects on chest pain were not described.72 Concern with drug dependence mandates caution in the use of these agents, particularly for patients with chronic chest pain.

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Table 5 Cognitive therapy trials in noncardiac chest pain Author, Reference,Year

Type of Trial

Number and Type of Cases

Outcome

Comments

Klimes et al,53 1990

Cognitive therapy: controlled, clinical trial; randomized to immediate treatment or wait control; then control was crossed over

31 NCCP

Significant reductions in chest pain, disruption of daily life, autonomic symptoms, distress and psychologic morbidity in the treated group. The assessment-only group were treated subsequently showing similar improvement.

Improvements maintained by both treated groups at four–six months follow-up

Cott et al,54 1992

Cognitive therapy: individual, group, self-monitoring or wait control

14 NCCP versus 90 with mitral valve prolapse

Group or individual treatment in NCCP and mitral valve prolapse improved short and long-term follow-up (6–12 months).

Functional improvement was independent of reduction of symptoms

De Guire et al,55 1996

Paced diaphragmatic breathing

10 NCCP

Decrease in frequency of pain at 3 year follow up

Improvement in respiratory rates and end-tidal carbon dioxide levels

Mayou et al,56 1997

Cognitive therapy: treatment or assessment only control group.

37 NCCP

At 3 months, significant differences between the treatment group and the control on key outcome measures of symptoms, mood, and activity

At 6 months, there were fewer differences but significant advantages of treatment in terms of limitation of activities and worry about physical symptoms.

Cognitive therapy

10 NCCP

Significant improvement in intensity and duration of chest pain, anxiety, and functional limitations

Significant reduction of scores for fear of bodily sensations and of credibility ratings of idiosyncratic disease-related, negative, automatic thoughts; changes in scores for the inclination to interpret bodily sensations catastrophically almost reached the level of significance

van Peski-Oosterbaan et al,58 1999

Cognitive therapy: patients randomized to active treatment or wait control

72 NCCP (37 to therapy, 35 control); 65 completed trial

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 control group (P 5 .002)

—

Potts et al,59 1999

Cognitive therapy: comparing active group to waiting list control

56 NCCP

Treatment significantly reduced chest pain scores; anxiety and depression maintained for 6 months

—

Esler et al,60 2001

Cognitive therapy: randomized controlled trial; controls received education and usual medications

36 NCCP with complete follow up (of 59 randomized)

Study did not find significant chest pain improvement compared with control

High attrition rate, which may bias study results

Tyni-Lenne et al,61 2002

Cognitive therapy: single-blinded, randomized to 3 groups: (1) physical training, (2) relaxaton and (3) control.

24 female patients with Syndrome X

Patients benefited from physical training in terms of exercise capacity and quality of life and from relaxation therapy in terms of quality of life

No comments regarding impact on chest pain parameters

Noncardiac Chest Pain–Treatment

van Peski-Oosterbaan et al,57 1997

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ESOPHAGEAL MOTILITY DISORDER

Esophageal motility disorders such as diffuse esophageal spasm (DES), nutcracker esophagus, and hypertensive lower-esophageal sphincter may be found in 28% to 30% of patients with NCCP.73,74 Although it is not clear whether these motility disorders are the cause of NCCP or an epiphenomenon,75,76 several pharmacologic trials aimed at reducing the abnormal esophageal motility in these patients have produced mixed results.77 Unfortunately, most of these trials have considerable flaws including small sample size (1–22 patients) and open-label, uncontrolled study designs. The few studies with a placebo control are hampered by small sample size (14 was the largest) and fail to provide convincing evidence that improvement in esophageal motility parameters results in symptom reduction.78 A number of pharmacologic agents have been employed to treat NCCP in the setting of abnormal esophageal motility. Despite inconsistent outcomes and the concerns mentioned above, clinicians continue to use many of these pharmacologic agents. Nitrates and calcium blockers are the most commonly employed agents to treat patients with NCCP and abnormal esophageal motility, with variable degrees of success. Clearly, better-designed, placebocontrolled investigations of appropriate sample size are needed to better understand the role of these agents in the treatment of spastic esophageal disorders. The available studies and their outcome using these compounds are summarized in Tables 6–8.79–95 Of note, GER may coexist in patients with spastic motility disorders.96 This is important since treatment of acid reflux in patients with nutcracker esophagus and DES coexisting with GER has resulted in chest pain reduction;13,80 and nitrates and calcium blockers are better avoided in these individuals for fear they may worsen coexisting GER.80 Nitric Oxide

Nitric oxide (NO) is a major inhibitory nonadrenergic and noncholinergic neurotransmitter in the gastrointestinal tract.97 NO is synthesized by the activation of neuronal synthase (nNOS) in the myenteric plexus. Abundant concentrations of nNOS

Table 6 Studies showing symptomatic improvement with nitrates Author, Reference

Year

Number of Cases

Trial

Medication and Dosage

Orlando and Bozymski79

1973

1

Open

Erythyityl tetra nitrate, 10 mg tid

Swamy80

1977

12

Open

Isosorbate dinitrate (Isordil), 15–30 mg qid

Shafran et al81

1979

5

Open

Nitroglycerin, 0.4 mg (sublingual)

Parker and Mackinon82

1981

1

Open

Isosorbate dinitrate (Isordil), 5 mg before meals

Mellow83

1982

5

Open

Isosorbide 20 mg tid dose

Millaire et al84

1989

22

Open

Nitroglycerin spray, 0.8 mg

Konturek85

1995

5

Open

Glyceryl trinitrate, 100 to 200 micrograms/kg/h intravenously

Data from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol Clin North Am 2004;33(1):107–24.

Noncardiac Chest Pain–Treatment

Table 7 Nifedipine trials in diffuse esophageal spasm Author, Reference

Year

Study Design

Number of Cases Dosage

Outcome

Blackwell et al86

1981 Open-label

6

20 mg tid

3/6 improved

Davies et al87

1982 Double-blind, placebo

10

10–40 mg tid

Short-term improvement

Nasrallah et al88

1982 Open-label

1

10 mg tid

Improved

Nasrallah et al89

1985 Open-label

4

10 mg tid

Improved

Thomas et al90 1986 Open-label

6

10–20 mg tid

Improvement of dysphagia

Davies et al91

1987 Placebo-controlled 8 (a single- and a double-blinded phase)

Banciu et al92

1990 Open-label

12a

10–30 mg tid No response (mean 64 mg) (treatment for up to 3 months) 10–20 mg

Acute ‘‘improvement of radiologic appearance’’

a

Patients defined radiologically. Data from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol Clin North Am 2004;33(1):107–24.

containing neurons have been identified in the human esophagus.98 In the smooth circular muscle of the human esophagus it regulates the latency and contraction amplitude of esophageal peristalsis.99 Murray and colleagues100 and Konturek and colleagues85,101 have shown that the experimental removal of NO in humans induces a pattern of simultaneous contractions similar to DES. Therefore, pharmacologic agents that result in the augmentation of NO may improve the clinical and manometric patterns of patients with diffuse esophageal spasm. At present time there are no available NO compounds for clinical use, but there is ongoing research to synthesize these agents. Phosphodiestarease 5 (PD-5) inhibitors are important regulator of smooth muscle contraction that increase the availability of NO. Recent preliminary studies in small number of patients offer promising results for the treatment of spastic motility disorders. These studies suggest that the commercially available PD-5 inhibitors: sildenafil, vardenafil and tadalafil may be of potential therapeutic value.102–107 Certainly large, placebo-controlled, dose-finding clinical trials are needed before recommending the use of these agents.

Botulinum Toxin

Botulinum toxin (Botox) has been used successfully to treat achalasia, although its effects are temporary.108,109 Botox binds irreversibly to cholinergic nerve terminals blocking acetylcholine-mediated neuromuscular transmission, reducing LES pressures in animal models and humans.110 Several studies in patients with motility disorders have shown beneficial effects of Botox. Table 9111–117summarizes the published experience with Botox in patients with diverse nonachalasia esophageal motility

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Table 8 Diltiazem trials Author, Reference

Year

Study Design

Numer of Cases

Richter et al93

1984

Dosage

Outcome

Open-label, 8 weeks

10 (NE)

90 mg tid

Improved

Cattau et al94

1991

Double-blind, placebocontrolled, 8 weeks

14 (NE)

60–90 mg tid

Improved

Drenth et al95

1990

Double-blind, cross-over, 10 weeks

8 (DES)

60 mg tid

No significant improvement

Abbreviations: DES, diffuse esophageal spasm; NE, nutcracker esophagus. Data from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol Clin North Am 2004;33(1):107–24.

disorders (mostly DES and hypertensive lower esophageal sphincter). These trials have shown positive benefits in approximately 72% of the patients treated. Unfortunately, these studies are also hampered by small sample, lack of placebo control and some are available only as an abstract. The short-lived duration of the benefits of Botox injection remains problematic. Properly designed, controlled trials are sorely needed to determine whether Botox is effective in the treatment of NCCP. RECENT PHARMACOLOGIC DEVELOPMENTS

Treatment of NCCP remains difficult. The multi-factorial nature of the disorder and the insufficient understanding of the putative sensory mechanism (s) are some of the factors challenging us in finding an ideal therapeutic modality. Recent studies suggest that adenosine plays a role in esophageal sensory processing.118 Infusion of adenosine induces chest pain in patients with chest pain and coronary artery disease as well as in healthy controls and in patients with NCCP (without triggering ischemic or EKG changes in the later two groups).119 However, there is an enhanced pharmacologic reactivity to adenosine in NCCP when compared with the other two groups.

Table 9 Summary trials: treatment of spastic disorders with botulinum toxin Author, Reference

Year

Number and Type of Cases

Publication Type

Miller111

1996

15 DES and other spastic disorders

Full paper

Cassidy112

1996

10 DES

Abstract

Jones113

1996

1 HLES

Letter to the editor

Nebendahl114

1999

9 DES

Abstract

Storr115

2001

9 DES

Full paper

Miller116

2002

29 DES and other Spastic disorders

Full paper

Lacy117

2002

1 HLES

Case report

Abbreviations: DES, diffuse esophageal spasm; HLES, hypertensive lower-esophageal sphincter. Data from Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol Clin North Am 2004;33(1):107–24.

Noncardiac Chest Pain–Treatment

Patients with NCCP developed chest pain at much lower doses of adenosine than the other two groups.120 Melcher and Sylven121 triggered chest pain after acute infusion of adenosine, but failed to identify significant effects of adenosine infusion on esophageal peristalsis in healthy controls, suggesting that the effects of this drug on visceral pain are not mediated by esophageal spasm. Theophylline (a nonselective adenosine receptor antagonist) reduces chest pain significantly, suggesting that pain triggered by adenosine is, at least to some degree, dependant on activation of theophylline-sensitive receptors. Rao and colleagues,122 reported data from consecutive patients with recurrent NCCP who failed an eight-week therapeutic trial of double-dose PPI, or had a negative 24-hour pH testing. They found that intravenous infusion of theophylline, an adenosine receptor antagonist, but not placebo, improved 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, twice a day, for 4 weeks in a crossover design, experienced significant improvement in pain parameters when compared with placebo. Unfortunately, theophylline has significant toxicity. Thus, it is unlikely that it will used for the treatment of NCCP.123 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.

SUMMARY

Treatment of NCCP remains difficult. In great part, this is due to the heterogeneous nature of the disorder. Available information indicates that GER is a very common problem in these patients and that PPI therapy is effective in reducing chest pain for the majority of patients with GER-related NCCP. Furthermore, a short trial of highdose PPI may help identify those patients with GER-related NCCP. On the other hand, the widespread use of PPI therapy has led to the recognition of a group of patients with persistent NCCP who fail to respond to PPI therapy. For these patients, therapeutic approaches are frequently directed at improving suspected visceral hyperalgesia with the aid of TCAs or SSRIs. Esophageal motility testing should also be considered to exclude the occasional patient with achalasia presenting with NCCP, since specific therapy for this condition is readily available. For patients without achalasia and non-GER–related NCCP who do not respond to visceral analgesics, psychiatric evaluation and treatment should be considered. Depression, anxiety, or somatization may amplify or contribute to NCCP. Cognitive therapy and appropriate management of potential associated psychologic disorders may be very valuable in reducing chest pain for patients refractory to other pharmacologic interventions and those who have coexisting psychologic morbidity. Nitrates and calcium blockers, and even Botox, are commonly used in the treatment of patients with non-GER–related esophageal motility disorders. However, the outcome of treatment with these compounds is inconsistent and there is a lack of randomized, controlled trials to support the use of this approach. New research into additional mechanisms involved in visceral pain, such as adenosine receptors, appears promising. Future studies using improved selective adenosine receptor antagonists and other therapeutic interventions are needed. Further studies should take into account that the goals of therapy are to identify better strategies to decrease pain, diminish recurrent diagnostic evaluations and health care use, improve quality of life, and attenuate the disability of this challenging condition.

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REFERENCES

1. Locke G III, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmstead County, Minnesota. Gastroenterologist 1997;112:1448–56. 2. Eslick GD, Jones MP, Talley NJ. Non-cardiac chest pain: prevalence, risk factors, impact and consulting—a population-based study. Aliment Pharmacol Ther 2003;17(9):1115–24. 3. Wong Wai Man, Lam Kwok Fai, Cheng, et al. Population based study of noncardiac chest pain in southern Chinese: prevalence, psychosocial factors, and health care utilization. World J Gastroenterol 2004;10(5):707–12. 4. Chiocca JC, Olmos JA, Salis GB, et al. Prevalence, clinical spectrum and atypical symptoms of gastro-oesophageal reflux in Argentina: a nationwide population-based study. Aliment Pharmacol Ther 2005;22:331–42. 5. Rey E, Elola-Olaso CM, Rodriguez-Artalejo F. Prevalence of atypical symptoms and their association with typical symptoms of gastroesophageal reflux in Spain. Eur J Gastroenterol Hepatol 2006;18:969–75. 6. Eslick GD, Talley NJ. Non-cardiac chest pain: squeezing the life out of the Australian healthcare system? Med J Aust 2000;173:223–4. 7. Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38(9):1569–80. 8. Achem SR, DeVault KR. Recent developments in chest pain of undetermined origin. Curr Gastroenterol Rep 2000;2(3):201–9. 9. Fass R, Hyun JG, Sewel JL. Pathophysiology of noncardiac chest pain. In: Fass R, Eslick GD, editors. Noncardiac chest pain: a growing problem. San Diego, (CA): Plural Publishing; 2007. p. 29–37. 10. Van Handel D, Fass R. The pathophysiology of non-cardiac chest pain. J Gastroenterol Hepatol 2005;20(Suppl):S6–13. 11. Katz PO. Noncardiac chest pain. Rev Cardiovasc Med 2005;6(Suppl 4):S32–9. 12. Faybush EM, Fass R. Gastroesophageal reflux disease in noncardiac chest pain. Gastroenterol Clin North Am 2004;33(1):41–54. 13. Achem SR, Kolts BE, Wears R, et al. Chest pain associated with nutcracker esophagus: a preliminary study of the role of gastroesophageal reflux. Am J Gastroenterol 1993;88(2):187–92. 14. Stahl WG, Beton RR, Johnson CS, et al. Diagnosis and treatment of patients with gastroesophageal reflux and noncardiac chest pain. Southampt Med J 1994; 87(7):739–42. 15. Achem SR, Kolts BE, MacMath T, et al. Effects of omeprazole versus placebo in treatment of noncardiac chest pain and gastroesophageal reflux. Dig Dis Sci 1997;42(10):2138–45. 16. Chambers J, Cooke R, Anggiansah A, et al. Effect of omeprazole in patients with chest pain and normal coronary anatomy: initial experience. Int J Cardiol 1998; 65(1):51–5. 17. Flook N, Moayyedi P, Dent J, et al. Esomeprazole for treatment of unexplained chest pain in primary care: a prospective, randomized, double-blind, placebo-controlled multicenter study. Gastroenterology 2007;132(No. 4- Suppl 2):A-480 (T1163). 18. Young M, Sanowski R, Talbert G, et al. Omeprazole administration as a test for gastroesophageal reflux [abstract]. Gastroenterol 1992;102:192. 19. Squillace S, Young M, Sanowski R. Single dose omeprazole as a test for noncardiac chest pain [abstract]. Gastroenterol 1993;107:A197.

Noncardiac Chest Pain–Treatment

20. Fass R, Fennerty B, Ofman J, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterol 1998;115:42–9. 21. Pandak WM, Arezo S, Everett S, et al. Short course of omeprazole: a better first diagnostic approach to noncardiac chest pain than endoscopy, manometry, or 24-hour esophageal pH monitoring. J Clin Gastroenterol 2002;35(4): 307–14. 22. Xia HH, Lai KC, Lam SK, et al. Symptomatic response to lansoprazole predicts abnormal acid reflux in endoscopy-negative patients with non-cardiac chest pain. Aliment Pharmacol Ther 2003;17(3):369–77. 23. Bautista J, Fullerton H, Briseno M, et al. The effect of an empirical trial of highdose lansoprazole on symptom response of patients with non-cardiac chest pain— a randomized, double-blind, placebo-controlled, crossover trial. Aliment Pharmacol Ther 2004;19(10):1123–30. 24. Dickman R, Emmons S, Cui H, et al. The effect of a therapeutic trial of high-dose rabeprazole on symptom response of patients with non-cardiac chest pain: a randomized, double-blind, placebo-controlled, crossover trial. Aliment Pharmacol Ther 2005;22(6):547–55. 25. DeMeester TR, O’Sullivan GC, Bermudez G, et al. Esophageal function in patients with angina-type chest pain and normal coronary angiograms. Ann Surg 1982;196(4):488–98. 26. So JB, Zeitels SM, Rattner DW. Outcomes of atypical symptoms attributed to gastroesophageal reflux treated by laparoscopic fundoplication. Surgery 1998;124(1):28–32. 27. Chen RY, Thomas RJ. Results of laparoscopic fundoplication where atypical symptoms coexist with oesophageal reflux. Aust N Z J Surg 2000;70(12):840–2. 28. Farrell TM, Richardson WS, Trus TL, et al. Response of atypical symptoms of gastro-oesophageal reflux to antireflux surgery. Br J Surg 2001;88(12):1649–52. 29. Patti MG, Molena D, Fisichella PM, et al. Gastroesophageal reflux disease (GERD) and chest pain: results of laparoscopic antireflux surgery. Surg Endosc 2002;16(4):563–6. 30. Rakita S, Villadolid D, Thomas A, et al. A Laparoscopic Nissen fundoplication offers high patient satisfaction with relief of extra-esophageal symptoms of gastroesophageal reflux disease. Am Surg 2006;72(3):207–12. 31. DeVault KR, Achem SR. Sensory testing. In: Schuster M, Crowel M, Koch K, editors. Schuster atlas of gastrointestinal motility in health and disease. 2nd edition. Hamilton, London, Ontario: BC Decker, Inc; 2002. p. 87–95. 32. Richter JE, Barish CF, Castell DO. Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 1986;91(4):845–52. 33. Egbunike IG, Chaffee BJ. Antidepressants in the management of chronic pain syndromes. Pharmacotherapy 1990;10(4):262–70. 34. Peghini PI, Katz PO, Castell DO. Imipramine decreases esophageal pain perception in human healthy volunteers. Gut 1998;42(6):807–13. 35. Clouse RE, Lustman PJ, Eckert TC, et al. Low-dose trazodone for symptomatic patients with esophageal contraction abnormalities: a double-blind, placebocontrolled trial. Gastroenterology 1987;92:1027–36. 36. Cannon RO III, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med 1994;330: 1411–7. 37. Prakash C, Clouse RE. Long-term outcome from tricyclic antidepressant treatment of functional chest pain. Dig Dis Sci 1999;44:2373–9.

873

874

Achem

38. Varia I, Logue E, O’connor C, et al. Randomized trial of sertraline in patients with unexplained chest pain of noncardiac origin. Am Heart J 2000;140:367–72. 39. Doraiswamy PM, Varia I, Hellegers C, et al. A randomized controlled trial of paroxetine for noncardiac chest pain. Pharmacology Bulletin Vol. 39. No. 1. 15–24. 40. Cormier LE, Katon W, Russo J, et al. Chest pain with negative cardiac diagnostic studies: relationship to diagnostic illness. J Nerv Ment Dis 1988;176:351–8. 41. Wulsin LR, Yingling K. Psychiatric aspects of chest pain in the emergency department. Med Clin North Am 1991;75:1175–88. 42. Beitman BD, Basha I, Flaker G, et al. Atypical or nonanginal chest pain: panic disorder or coronary artery disease? Arch Intern Med 1987;147:1548–52. 43. Carter C, Maddock R, Zoglio M, et al. Panic disorder and chest pain: a study of cardiac stress scintigraphy patients. Am J Cardiol 1994;74:296–8. 44. Fleet RP, Dupuis G, Marchand A, et al. Panic disorder in emergency department chest pain patients: prevalence, comorbidity, suicidal ideation, and physician recognition. Am J Med 1996;101:371–80. 45. Carter C, Maddock RJ. Chest pain in generalized anxiety disorder. Int J Psychiatry Med 1992;22:291–8. 46. Cormier LE, Carter C, Maddock RJ, et al. Panic disorder and chest pain in the coronary care unit. Psychosomatics 1992;33:302–9. 47. Dammen T, Arnesen H, Ekeberg O, et al. Panic disorder in chest pain patients referred for cardiological outpatient investigation. J Intern Med 1999;245:497–507. 48. Ockene IS, Shay MJ, Alpert JS, et al. Unexplained chest pain in patients with normal coronary angiograms: a follow-up study of functional status. N Engl J Med 1980;30:1249–52. 49. Papanicolaou MN, Califf RM, Hlatky MA, et al. Prognostic implications of angiographically normal and insignificantly narrowed coronary arteries. Am J Cardiol 1986;58:1181–7. 50. Beitman BD, Kushner MG, Basha I, et al. Follow-up status of patients with angiographically normal coronary arteries and panic disorder. JAMA 1991;265: 1545–9. 51. Channer KS, James MA, Papouchado M, et al. Failure of a negative exercise test to reassure patients with chest pain. QJM 1987;63:315–22. 52. Kemp HG, Kronmal RA, Vlietstra RE, et al. Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. J Am Coll Cardiol 1986;7:479–83. 53. Klimes, Mayou RA, Pearce MJ, et al. Psychological treatment for atypical noncardiac chest pain: a controlled evaluation. Psychol Med 1990;20:605–11. 54. Cott A, McCully J, Goldberg WM, et al. Interdisciplinary treatment of morbidity in benign chest pain. Angiology 1992;43:195–202. 55. DeGuire S, Gevirtz R, Hawkinson D, et al. Breathing retraining: a three-year follow-up study of treatment for hyperventilation syndrome and associated functional cardiac symptoms. Biofeedback Self Regul 1996;21(2):191–8. 56. Mayou RA, Bryant BM, Sanders D, et al. A controlled trial of cognitive behavioural therapy for non-cardiac chest pain. Psychol Med 1997;27:1021–31. 57. van Peski-Oosterbaan AS, Spinhoven P, van Rood Y, et al. Cognitive behavioural therapy for unexplained non-cardiac chest pain: a pilot study. Behav Cogn Psychother 1997;25:339–50. 58. van Peski-Oosterbaan AS, Spinhoven P, van Rood Y, et al. Cognitive-behavioral therapy for noncardiac chest pain: a randomized trial. Am J Med 1999;106:424–9. 59. Potts SG, Lewin R, Fox KA. Group psychological treatment for chest pain with normal coronary arteries. QJM 1999;92(2):81–6.

Noncardiac Chest Pain–Treatment

60. Esler JL, Bock BC. Psychological treatments for noncardiac chest pain: recommendations for a new approach. J Psychosom Res 2004;56(3):263–9. 61. Tyni-Lenne R, Stryjan S, Eriksson B, et al. Beneficial therapeutic effects of physical training and relaxation therapy in women with coronary syndrome X. Physiother Res Int 2002;7(1):35–43. 62. Kisely S, Campbell LA, Skerritt P. Psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy. Cochrane Database Syst Rev 2005:CD004101. 63. Cohen-Cole SA, Levinson RM. The biopsychosocial model in medical practice. In: Stoudemire A, editor. Human behavior: an introduction for medical students. Philadelphia: J.B. Lippincott; 1994. p. 22–63. 64. Jones H, Cooper P, Miller V, et al. Treatment of non-cardiac chest pain: a controlled trial of hypnotherapy. Gut 2006;55(10):1403–8. 65. Ryan M, Gevirtz R. Biofeedback-based psycho physiological treatment in a primary care setting: an initial feasibility study. Appl Psychophysiol Biofeedback 2004;29(2):79–93. 66. Johnson MI, Ashton CH, Thompson JW. An in-depth study of long-term users of transcutaneous electrical nerve stimulation (TENS). Implications for clinical use of TENS. Pain 1991;44:221–9. 67. Coffin B, Azpiroz F, Malagelada JR. Somatic stimulation reduces perception of gut distention in humans. Gastroenterology 1994;107:1636–42. 68. Guelrud M, Rossiter A, Souney PF, Mendoza S, Mujica V. The effect of transcutaneous nerve stimulation on sphincter of Oddi pressure in patients with biliary dyskinesia. Am J Gastroenterol 1991;86(5):581–5. 69. Bo¨rjesson M, Pilhall M, Eliasson T, et al. Esophageal visceral pain sensitivity: effects of TENS and correlation with manometric findings. Dig Dis Sci 1998;43(8):1621–8. 70. de Vries J, Dejongste MJ, Durenkamp A, et al. The sustained benefits of longterm neurostimulation in patients with refractory chest pain and normal coronary arteries. Eur J Pain 2007;11(3):360–5. 71. Beitman BD, Basha IM, Trombka LH, et al. Alprazolam in the treatment of cardiology patients with atypical chest pain and panic disorder. J Clin Psychopharmacol 1988;8(2):127–30. 72. Wulsin LR, Maddock R, Beitman B, et al. Clonazepam treatment of panic disorder in patients with recurrent chest pain and normal coronary arteries. Int J Psychiatry Med 1999;29(1):97–105. 73. Katz PO, Dalton CB, Richter JE, et al. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years’ experience with 1161 patients. Ann Intern Med 1987;106:593–7. 74. Dekel R, Pearson T, Wendel C, et al. Assessment of oesophageal motor function in patients with dysphagia or chest pain—the Clinical Outcomes Research Initiative experience. Aliment Pharmacol Ther 2003;18(11–12):1083–9. 75. Achem SR, Benjamin S. Esophageal dysmotility (Spastic Dysmotility). In: Castell DO, editor. The esophagus. 2nd edition. New York: Little, Brown and Company; 1995. p. 247–68. 76. Kahrilas PJ. Nutcracker esophagus: an idea whose time has gone? Am J Gastroenterol 1993;88(2):167–9. 77. Achem SR. Treatment of spastic esophageal motility disorders. Gastroenterol Clin North Am 2004;33(1):107–24. 78. Richter JE, Dalton CB, Bradley LA, et al. Oral nifedipine in the treatment of noncardiac chest pain in patients with the nutcracker esophagus. Gastroenterology 1987;93(1):21–8.

875

876

Achem

79. Orlando RC, Bozymski EM. Clinical and manometric effects of nitroglycerin in diffuse esophageal spasm. N Engl J Med 1973;289:23–5. 80. Swamy N. Esophageal spasm: clinical and manometric response to nitroglycerine and long acting nitrites. Gastroenterology 1977;72(1):23–7. 81. Shafran Drug treatment of esophageal spasm. Gastroenterology 1982;83:134–5. 82. Parker WA, MacKinnon GL. Nitrites in the treatment of diffuse esophageal spasm. Drug Intell Clin Pharm 1981;15:806–7. 83. Mellow MH. Effect of isosorbide and hydralazine in painful primary esophageal motility disorders. Gastroenterology 1982;83:364–70. 84. Millaire A, Ducloux G, Marquand A, et al. Nitroglycerin and angina with angiographically normal coronary vessels. Clinical effects and effects on esophageal motility. Arch Mal Coeur Vaiss 1989;82:63–8. 85. Konturek JW, Gillessen A, Domschke W. Diffuse esophageal spasm: a malfunction that involves nitric oxide? Scand J Gastroenterol 1995;30:1041–5. 86. Blackwell JN, Holt S, Heading RC. Effect of nifedipine on oesophageal motility and gastric emptying. Digestion 1981;21:50–6. 87. Davies HA, Lewis M, Rhodes J, et al. Nifedipine for relief of esophageal chest pain? N Engl J Med 1982;307:1274. 88. Nasrallah SM. Nifedipine in the treatment of diffuse oesophageal spasm. Lancet 1982;2:1285. 89. Nasrallah SM, Tommaso CL, Singleton RT, et al. Primary esophageal motor disorders: clinical response to nifedipine. Southampt Med J 1985;78:312–5. 90. Thomas E, Witt P, Willis M, et al. Nifedipine therapy for diffuse esophageal spasm. Southampt Med J 1986;79:847–9. 91. Davies HA, Lewis MJ, Rhodes J, et al. Trial of nifedipine for prevention of oesophageal spasm. Digestion 1987;36(2):81–3. 92. Banciu T, Iova M, Biroasiu G, et al. The diagnostic and therapeutic contribution of calcium channel inhibitors (nifedipine) in esophageal spasm. Med Interne 1990;28:69–71. 93. Richter JE, Spurling TJ, Cordova CM, et al. Effects of oral calcium blocker, diltiazem, on esophageal contractions: studies in volunteers and patients with nutcracker esophagus. Dig Dis Sci 1984;29:649–56. 94. Cattau EL Jr, Castell DO, Johnson DA, et al. Diltiazem therapy for symptoms associated with nutcracker esophagus. Am J Gastroenterol 1991;86:272–6. 95. Drenth JP, Bos LP, Engels LG. Efficacy of diltiazem in the treatment of diffuse oesophageal spasm. Aliment Pharmacol Ther 1990;4:411–6. 96. Achem SR. Treatment of noncardiac chest pain. Dis Mon 2008;54:642–70. 97. Takahashi T. Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. J Gastroenterol 2003;38(5):421–30. 98. Singaram C, Sengupta A, Sweet MA, et al. Nitrinergic and peptidergic innervation of the human esophagus. Gut 1994;35:1690–6. 99. Anand N, Paterson WG. Role of nitric oxide in esophageal peristalsis. Am J Phys 1994;266:G123–31. 100. Murray JA, Ledlow A, Launspach J, et al. The effects of recombinant human hemoglobin on esophageal motor functions in humans. Gastroenterology 1995; 109:1241–8. 101. Konturek JW, Thor P, Lukaszyk A, et al. Endogenous nitric oxide in the control of esophageal motility in humans. J Physiol Pharmacol 1997;48:201–9. 102. Rhee P-L, Hyun JG, Lee JH, et al. The effect of sildenafil on lower esophageal sphincter and body motility in normal male adults. Am J Gastroenterol 2001;96:3251–7.

Noncardiac Chest Pain–Treatment

103. Agrawal A, Tutuian R, Hila A, et al. Successful use of phosphodiesterase type 5 inhibitors to control symptomatic esophageal hypercontractility: a case report. Dig Dis Sci 2005;50(11):2059–62. 104. Bortolotti M, Pandolfo N, Giovannini M, et al. Effect of sildenafil on hypertensive lower oesophageal sphincter. Eur J Clin Invest 2002;32(9):682–5. 105. Kim HS, Conklin JL, Park H. The effect of sildenafil on segmental oesophageal motility and gastro-esophageal reflux. Aliment Pharmacol Ther 2006;24(7): 1029–36. 106. Fox M, Sweis R, Wong T, et al. Sildenafil relieves symptoms and normalizes motility in patients with oesophageal spasm: a report of two cases. Neurogastroenterol Motil 2007;19(10):798–803. 107. Eherer AJ, Schwetz I, Hammer HF, et al. Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders. Gut 2002;50:758–64. 108. Birgisson S, Richter JE. Achalasia: what’s new in diagnosis and treatment? Dig Dis 1997;15:1–27. 109. Vela MF, Richter JE, Wachsberger D, et al. Efficacy of botulinum toxin injection before pneumatic dilatation in patients with idiopathic achalasia. Dis Esophagus 2004;17(3):213–7. 110. Brisinda G, Civello IM, Albanese A, et al. Gastrointestinal smooth muscles and sphincters spasms: treatment with botulinum neurotoxin. Curr Med Chem 2003; 10(7):603–23. 111. Miller LS, Parkman HP, Schiano TD, et al. Treatment of symptomatic nonachalasia esophageal motor disorders with botulinum toxin injection at the lower esophageal sphincter. Dig Dis Sci 1996;41:2025–31. 112. Cassidy MJ, Schiano TD, Adrain AL, et al. Botulinum toxin injection for the treatment of symptomatic diffuse esophageal spasm. Am J Gastroenterol 1996;91:1884 [abstract]. 113. Jones MP. Botulinum toxin in hypertensive lower esophageal sphincter [letter]. Am J Gastroenterol 1996;91:1283–4. 114. Nebendahl JC, Brand B, von Schrenck T, et al. Treatment of diffuse esophageal spasm with botulinum toxin: a prospective study with 6 months follow up. Gastrointest Endosc 1999;49:A302. 115. Storr M, Allescher HD, Rosch T, et al. Treatment of symptomatic diffuse esophageal spasm by endoscopic injections of botulinum toxin: a prospective study with long-term follow-up. Gastrointest Endosc 2001;54:754–9. 116. Miller LS, Pullela SV, Parkman HP, et al. Treatment of chest pain in patients with noncardiac, nonreflux, nonachalasia spastic esophageal motor disorders using botulinum toxin injection into the gastroesophageal. Am J Gastroenterol 2002; 97:1640–6. 117. Lacy Brian E, Zayat Estephan N, Crowell Michael D. Case report: botulinum toxin in hypertensive lower esophageal sphincter: a manometric case study. Dysphagia 2002;17(1):75–80. 118. Remes-Troche JM, Chahal P, Mudipalli R, et al. Adenosine modulates oesophageal sensorimotor function in humans. Gut 2008. 119. Sylven C, Jonzon B, Edlund A. Angina pectoris-like pain provoked by intravenous infusion of adenosine. Br Med J Clin Res Ed 1986;293(6556):1240. 120. Lagerqvist B, Sylven C, Waldenstrom A. Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary angiograms. Br Heart J 1992;68(3):282–5.

877

878

Achem

n C. Chest pain and oesophageal pressure relationships in 121. Melcher A, Sylve man following an intravenous bolus of adenosine. Clin Physiol 1989;9(5):441–8. 122. Rao SS, Mudipalli RS, Remes-Troche JM, et al. Theophylline improves esophageal chest pain—a randomized, placebo-controlled study. Am J Gastroenterol 2007;102(5):930–8. 123. Achem SR. New frontiers for the treatment of noncardiac chest pain: the adenosine receptors. Am J Gastroenterol 2007;102(5):939–41.