Treatment of noncardiac chest pain is often difficult because of the heterogeneous nature of the disorder. This condition can stem from gastroesophageal reflux, visceral hyperalgesia, esophageal motility disorders, psychiatric dysfunction, abnormal biomechanical properties of the esophageal wall, sustained esophageal contractions, abnormal cerebral processing of visceral stimulation, or disrupted autonomic activity. For a treatment to be successful, diagnosis of the underlying cause is essential. This article examines three decades of studies from around the world. It concludes that new research into additional mechanisms involved in visceral pain appears promising; but that future studies using improved selective adenosine receptor antagonists and other therapeutic interventions are needed.
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. Population-based studies have also reported similar figures in: Australia, 33%; South China, 21%; Argentina, 24%; and Spain, 8% to 28%. 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. 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.
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. 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. The benefits of acid inhibition in NCCP have been demonstrated during short- (1 day–2 weeks) and long-term (6–8 weeks) trials. Tables 1 and 2 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 small: 12 to 36 subjects for long-term studies (with the exception of Flook’s study, an abstract containing 599 subjects) and 17 to 68 subjects in short-term trials.
| Author, Reference, Year | Number of Cases | Type of Trial | Medication and Dosage | Outcome |
|---|---|---|---|---|
| Achem et al, 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, 1994 | 13 | Open-label | Ranitidine, 150 mg/qid for 8 weeks | 100% improved |
| Achem et al, 1997 | 36 | Double-blind, placebo-controlled | Omeprazole, 20 mg/bid for 8 weeks | 81% improved on omeprazole, 6% on placebo |
| Chambers et al, 1998 | 23 | Open-label | Omeprazole, 40 mg bedtime for 6 weeks | Improvement, but complete resolution in only 30% |
| Flook et al, 2007 (abstract only) | 599 (Intention to treat) | Double-blind placebo-controlled | Esomeprazole, 40 mg/bid versus placebo for 4 weeks | Post-hoc analysis, esomeprazole improvement was 33.1% versus 24.9% for placebo ( P = .035) |
| Author, Reference, Year | Number of Cases | Medication and Dosage | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) |
|---|---|---|---|---|---|---|
| Young et al, 1992 (abstract) | 30 | Omeprazole, 80 mg/d for 1 day | 90 | 80 | NA | NA |
| Squillace et al, 1993 (abstract) | 17 | Omeprazole, 80 mg/d for 1 day | 69 | 75 | 90 | 43 |
| Fass et al, 1998 | 37 | Omeprazole, 40 mg/ am 20 mg/ pm versus placebo for 7 days | 78 | 86 | 90 | 71 |
| Pandak et al, 2002 | 37 | Omeprazole, 40 mg/bid versus placebo for 2 weeks | 90 | 67 | 73 | 92 |
| Xia et al, 2003 | 68 | Lansoprazole, 30 mg/d versus placebo for 4 weeks | 92 | 67 | 58 | 94 |
| Bautista et al, 2004 | 40 | Lansoprazole, 60 mg/ am 30 mg/ pm versus placebo for 7 days | 78 | 80 | 88 | 83 |
| Dickman et al, 2005 | 35 | Rabeprazole, 20 mg/bid versus placebo for 7 days | 75 | 90 | 83 | 75 |
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 ). 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.
| Author, Reference, Year | Number of Cases | Improvement | Follow-up Time | Comments |
|---|---|---|---|---|
| DeMeester et al, 1982 | 11 | 100% | 2–3 years | Symptom index at pH predicted improvement |
| So et al, 1998 | 12 | 48% | Median 22 months (12–36) | Previous improvement with histamine 2 receptor antagonists blockers or PPI predicted improvement |
| Chen et al, 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, 2001 | 62 | 55% improved, 45% resolved | 13 months | More improvement seen in patients with typical than atypical symptoms |
| Patti et al, 2002 | 165 | 65% (of those with no SI correlation), 79% of those with ≤ 40% SI correlation, 96% with ≥ 40 SI correlation | 13 months | Highest improvement based on symptom index correlation |
| Rakita et al, 2006 | 158 | 81% | 50 months ± 83 months |
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, hydrochloric acid, and intraesophageal balloon distension. 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. 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.” 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. 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 . These studies suggest that visceral analgesics are effective in the 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.
| Author, Reference, Year | Number of Cases | Type of Trial | Medication and Dosage | Outcome |
|---|---|---|---|---|
| Clouse et al, 1987 | 30 (15 received trazodone and 15 placebo) | Placebo-controlled for 6 weeks | Trazone, 100–150 mg | Trazodone improved chest pain |
| Cannon et al, 1994 | 60 (20 patients in each arm of trial) | Double-blind, placebo-controlled for 3 weeks | Imipramine, 50 mg at night time; Clonidine, 0.2 mg or placebo | Imipramine induced significant improvement |
| Prakash and Clouse, 1999 | 21 | Open-label, long-term up to 3 years | Several tricyclic antidepressant | Tricyclic antidepressant produced 75% improvement at 3 years |
| Varia et al, 2000 | 25 | Single-blind, placebo-controlled for 9 weeks | Sertaline, 50–200 mg adjusted dose to response | Sertraline improved chest pain |
| Doraiswamy et al, 2006 | 50 (27 paroxetine and 23 placebo) | Double-blind, placebo-controlled | 10 mg for 1 wk and titrated upward weekly up to 50 mg; median dose was 30 mg (range 5–50 mg) | Paroxetine induced improvement on a physician- rated scale, but not on self- rated pain scores |
Visceral hyperalgesia
Patients with NCCP show a heightened sensitivity to a variety of experimental esophageal stimuli such as pharmacologic provocation with cholinergic agonists, hydrochloric acid, and intraesophageal balloon distension. 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. 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.” 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. 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 . These studies suggest that visceral analgesics are effective in the 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.
| Author, Reference, Year | Number of Cases | Type of Trial | Medication and Dosage | Outcome |
|---|---|---|---|---|
| Clouse et al, 1987 | 30 (15 received trazodone and 15 placebo) | Placebo-controlled for 6 weeks | Trazone, 100–150 mg | Trazodone improved chest pain |
| Cannon et al, 1994 | 60 (20 patients in each arm of trial) | Double-blind, placebo-controlled for 3 weeks | Imipramine, 50 mg at night time; Clonidine, 0.2 mg or placebo | Imipramine induced significant improvement |
| Prakash and Clouse, 1999 | 21 | Open-label, long-term up to 3 years | Several tricyclic antidepressant | Tricyclic antidepressant produced 75% improvement at 3 years |
| Varia et al, 2000 | 25 | Single-blind, placebo-controlled for 9 weeks | Sertaline, 50–200 mg adjusted dose to response | Sertraline improved chest pain |
| Doraiswamy et al, 2006 | 50 (27 paroxetine and 23 placebo) | Double-blind, placebo-controlled | 10 mg for 1 wk and titrated upward weekly up to 50 mg; median dose was 30 mg (range 5–50 mg) | Paroxetine induced improvement on a physician- rated scale, but not on self- rated pain scores |
Psychiatric disorders
Psychiatric conditions are common in NCCP. Several studies have noted a variable prevalence of panic disorders (24%–70%), anxiety (33%–50%), and major depression (11%–22%). 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.
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, 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%). 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 5 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 colleagues reported a significant benefit on chest pain parameters with CT.
| Author, Reference, Year | Type of Trial | Number and Type of Cases | Outcome | Comments |
|---|---|---|---|---|
| Klimes et al, 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, 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, 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, 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. |
| van Peski-Oosterbaan et al, 1997 | 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, 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 = .002) | — |
| Potts et al, 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, 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, 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 |
Esler and Bock 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. 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. 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.
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.
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. 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, including pain resulting from gastrointestinal tract distension. TENS has also been shown to exert important effects on esophageal motility parameters in achalasia and sphincter of Oddi dysfunction. During acute esophageal balloon distension studies in 18 patients with NCCP, TENS resulted in decreased perception of pain evoked by acute esophageal stimulation. 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 colleagues 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 colleagues 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. Concern with drug dependence mandates caution in the use of these agents, particularly for patients with chronic chest pain.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
