Non-cardiovascular chest pain (NCCP) leads to impaired quality of life and is associated with a high disease burden. Upon ruling out cardiovascular disease, only vague recommendations exist for further treatment.
Systematic review and meta-analysis. In July 2013, Medline, Web of Knowledge, Embase, EBSCOhost, Cochrane Reviews and Trials, and Scopus were searched. Hand and bibliography searches were also conducted. Randomized controlled trials (RCTs) evaluating non-surgical treatments in patients with NCCP were included. Exclusion criteria were poor study quality and small sample size (<10 patients per group).
Thirty eligible RCT’s were included. Most studies assessed PPI efficacy for gastroesophageal reflux disorders (GERD, n = 10). Two RCTs included musculoskeletal chest pain, seven psychotropic drugs, and eleven various psychological interventions. Study quality was high in five RCTs and acceptable in 25. PPI treatment in patients with GERD (5 RCTs, 192 patients) was more effective than placebo [pooled OR 11.7 (95% CI 5.5 to 25.0, heterogeneity I2 = 6.1%)]. The pooled OR in GERD negative patients (4 RCTs, 156 patients) was 0.8 (95% CI 0.2 to 2.8, heterogeneity I2 = 50.4%). In musculoskeletal NCCP (2 RCTs, 229 patients) manual therapy was more effective than usual care but not than home exercise [pooled mean difference 0.5 (95% CI −0.3 to 1.3, heterogeneity I2 = 46.2%)]. The findings for cognitive behavioral treatment, serotonin reuptake inhibitors, tricyclic antidepressants were mixed. Most evidence was available for cognitive behavioral treatment interventions.
Timely diagnostic evaluation and treatment of the disease underlying NCCP is important. For patients with suspected GERD, high-dose treatment with PPI is effective. Only limited evidence was available for most prevalent diseases manifesting with chest pain. In patients with idiopathic NCCP, treatments based on cognitive behavioral principles might be considered.
Citation: Burgstaller JM, Jenni BF, Steurer J, Held U, Wertli MM (2014) Treatment Efficacy for Non-Cardiovascular Chest Pain: A Systematic Review and Meta-Analysis. PLoS ONE 9(8): e104722. https://doi.org/10.1371/journal.pone.0104722
Editor: Sam Eldabe, The James Cook University Hospital, United Kingdom
Received: March 17, 2014; Accepted: July 12, 2014; Published: August 11, 2014
Copyright: © 2014 Burgstaller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
In the United States, 6 million patients present to emergency departments with chest pain each year, at an annual cost of $8 billion , . Sixty to ninety percent of the patients that present to emergency departments with chest pain have no underlying cardiovascular disease –. The proportion of patients with cardiovascular disease is higher in specialized units (cardiology emergency departments, CCU, ICU)  and lower in the primary care setting , –. After serious illnesses have been ruled out, physicians often assume that patients with non-cardiovascular chest pain (NCCP) have an excellent prognosis , . However, patients with NCCP have a high disease burden; many patients that seek care for NCCP complain of persisting symptoms in a 4-year follow-up . Furthermore, patients with non-cardiac chest pain experience an impaired quality of life and greater number of medical visits compared with patients with cardiac pain .
In patients with chest pain, the diagnostic work-up focuses primarily on cardiovascular disease and is often performed by cardiologists. Upon ruling out cardiovascular disease, only vague recommendations exist for further treatment, delaying appropriate treatment and causing uncertainty for patients . A recent systematic synthesis of diagnostic tests  showed that patients with gastroesophageal reflux disorder (GERD) can be identified by their response to proton pump inhibitor (PPI) treatment, and certain clinical findings can guide clinicians to the most appropriate treatments (e.g., pain increase with movement or decrease on medication were associated with musculoskeletal chest pain). However, limited data are available regarding the efficacy of treatments for patients with NCCP.
The present systematic review aimed to summarize the current evidence about the efficacy of different treatments based on randomized controlled trials (RCTs) for patients that seek care for NCCP.
Literature search and study selection
This search, conducted in July 2013, followed the PRISMA statement . We searched six databases: Medline (OvidSP), including In-Process & Other Non-Indexed Citations, Daily and OLDMEDLINE; Web of Knowledge, including Biosis and Web of Science; Embase (OvidSP); EBSCOhost, including CINAHL and PsycINFO; Cochrane Reviews and Trials; and Scopus. We used the following search terms as medical subject headings (MeSH terms) and other subject headings: ‘thoracic pain’, ‘chest pain’, ‘non-cardiac chest pain’, ‘atypical chest pain’, ‘musculoskeletal chest pain’, ‘esophageal chest pain’, and ‘thoracic spine pain’. The findings were limited to studies published in the last 20 years. We applied no limits regarding study setting or language. Table S1 depicts two detailed search strategies.
To ensure search completeness, one reviewer (BJ) conducted a thorough search of the bibliographies of all included studies. Potential eligible references were also included in the full text review.
Eligible studies were randomized controlled trials (RCTs) published in the last 20 years. Inclusion criteria were studies reporting on patients aged ≥18 years seeking care for NCCP. NCCP was defined as chest pain after cardiac or other vascular disease (e.g., cardiovascular disease, aortic dissection, pulmonary embolism) had been ruled out. Studies with less than 10 patients per group were excluded.
Study selection, data extraction, and synthesis
Two reviewers (MW and BJ) independently screened 5372 references by title and abstract. Both reviewers independently reviewed the full text of 62 studies that met the eligibility criteria. Disagreements were discussed and resolved by consensus or third party arbitration (JS). Researchers with specific language proficiencies reviewed non-English language references. When the same study was included in several publications without change in treatment, outcome, or follow-up, the most recent publication was chosen and missing information was added from previous publications.
All information regarding the treatment and control groups, treatment duration, follow-up duration, and patient population was extracted and grouped according to the disease investigated.
Study quality was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology checklist for RCTs . Overall bias risk and study quality were rated according to the SIGN recommendations. The ratings included high quality (++; the majority of criteria met; little or no risk of bias; results unlikely to be changed by further research.), acceptable quality (+; most criteria met; some flaws in the study with an associated risk of bias; conclusions may change in the light of further studies), and low quality (0; either most criteria not met, or significant flaws relating to key aspects of study design; conclusions likely to change in the light of further studies).
It was not possible to include all studies in the meta-analysis because data was missing for some outcomes. It may have happened that the studies originally considered several different outcome measures, but only reported the measures that provided significant results. Copas et al.  refer to this as outcome reporting bias, which is defined as outcome reporting driven by the significance and/or direction of the effect size. All studies that were not included in the meta-analyses were assessed for a potential outcome reporting bias using the 9-item outcome reporting in trails (ORBIT) tool . Risk of bias was rated from low (outcome of interest was not measured) to high [trial report states that outcome was analyzed, but only reports that the result was not significant (typically stating p>0.05)].
The outcome of primary interest was chest pain, including chest pain frequency and intensity.
We also assessed psychological outcome measures. In particular, we aimed to assess the efficacy of treatment interventions on anxiety, depression, and panic disorders. All measures were extracted, and validity of the outcome measure used was assessed.
Descriptive statistics were used to summarize findings across all groups of diagnostic studies. These included number of patients, mean patient age, and gender distribution.
In order to summarize findings across studies, different pain score scales were re-scaled to a 0- to 10-point scale where necessary. In addition, the frequency scores were homogenized to present results on a monthly basis. To present counted pain events in the treatment and control arms as odds ratios, we used number of events and number of patients in both groups, with a cut-off of >50% improvement. To present changes from baseline to follow-up in the treatment and control arms as mean differences, we used mean change, standard deviation of change, and number of patients in both groups. If the necessary information was not directly available from the original publication, we derived these quantities following instructions described in the Cochrane Handbook . We assumed a random effects model to obtain a pooled estimate of the effect if more than one trial was available in a subgroup. A restricted maximum-likelihood estimator was used to quantify the amount of heterogeneity.
Risk of bias was assessed using a funnel plot. Funnel plot asymmetry was assessed with the regression test proposed by Egger .
Figure 1 summarizes the search and inclusion process. Out of 5372 records, 62 were reviewed in full text, resulting in the exclusion of 5310 studies. In total, the analysis included 32 publications based on 30 RCTs. Reasons for the exclusion of 30 publications are provided in Figure 1.
Table 1 presents the study characteristics and included patients. Ten RCTs (33%) included patients with underlying gastrointestinal cause. Most RCTs (n = 8, 1037 patients) evaluated the treatment efficacy of a PPI in patients with NCCP –. Other treatments included baclofen  and hypnotherapy . Two RCTs included patients with musculoskeletal chest pain (7%, 229 patients): one compared the efficacy of manual therapy to acupuncture and sham intervention , while the other compared chiropractic treatment to self-management , . The efficacy of treatments based on cognitive behavioral principles was assessed in eleven RCTs (37%, 1370 patients) –. The use of psychotropic drugs compared with placebo was evaluated in seven RCTs (23%, 347 patients) –. Study quality was high in 5 RCTs (17%) and acceptable in 25 (83%; Table S2). No studies had to be excluded because of poor study quality. All studies included in the systematic review but not in the meta-analysis were rated to have low (n = 6) to no (n = 3) risk of outcome reporting bias.
Treatment efficacy for NCCP due to gastroesophageal reflux disease (GERD)
Only similar RCTs (n = 7, 771 patients) were included in the meta-analysis (Figure 2). A PPI was administered in most RCTs twice daily for 1 to 8 weeks. In two RCTs, GERD-positive and GERD-negative patients were not distinguished , ; in both of these studies, the efficacy of treatment was more effective than placebo. The pooled odds ratio for a reduction in chest pain of ≥50% was 4.2 (95% CI 2.7 to 6.7, heterogeneity I2 = 26.6%).
When patients with GERD [n = 5, 192 patients, GERD-positive: confirmed by upper endoscopy and/or 24-h pH manometry –, , ] were compared with patients without GERD [n = 4, 156 patients, GERD-negative , , , ] the treatment efficacy of the PPI treatment increased. The pooled OR for GERD-positive patients with NCCP was 11.7 (95% CI 5.5 to 25.0, heterogeneity I2 = 6.1%); in comparison, the pooled OR for patients without GERD was 0.8 (95% CI 0.2 to 2.8, heterogeneity I2 = 50.4%).
While the heterogeneity among GERD-positive patients was low and three of five RCTs emanated from the same center , , , there was some heterogeneity among the GERD-negative patients. Regarding GERD-negative patients, two RCTs found a trend toward more chest pain in the treatment group ,  while two RCTs found a trend toward less chest pain in the PPI group , . Funnel plots for the three groups (GERD-positive and GERD-negative mixed, GERD-positive alone, and GERD-negative alone) are depicted in Figure S1. There was no evidence for funnel plot asymmetry in the mixed group (GERD-positive and GERD-negative, p = 0.27) or in the GERD-negative group (p = 0.68); however, some evidence of funnel plot asymmetry was observed in the GERD-positive group (p = 0.04), as assessed using Egger’s regression test . We refrained from statistical adjustment for outcome reporting bias as proposed by Copas et al.  because only one PPI treatment study was not included in our meta-analysis . Dore et al. did not analyze the outcome of interest in our study and therefore the study was associated with a low risk of outcome reporting bias (Table S3). Jones et al. investigated the efficacy of hypnotherapy in patients with functional gastrointestinal symptoms (Figure 2) . Baclofen treatment was associated with more chest pain (Figure 3) at the 2-week follow-up . Detailed results for all studies are summarized in Table S4.
Treatment efficacy regarding the intensity and frequency of non-cardiac chest pain
Treating patients with NCCP without a specific diagnosis of psychiatric disease with the selective serotonin reuptake inhibitor sertraline was more effective after 2 months , but not after 8 months of follow-up for chest pain intensity (Figure 3) . Although use of the tricyclic antidepressant imipramine exhibited a trend towards less chest pain intensity, the effect was not statistically significant . Findings were mixed regarding treatments based on the principles of cognitive behavioral therapy (CBT). One study showed that CBT (4 to 12 60-min sessions) more effectively reduced chest pain intensity at 1 year than usual care at the cardiology department . Another study found that cognitive skill training (5 bi-weekly and 6 30-min monthly sessions), alone or supplemented with sertraline, was no more effective than placebo or sertraline alone in reducing chest pain intensity at 8 months of follow-up . A brief CBT intervention was not more effective in reducing chest pain intensity (Figure 3), but more effectively reduced chest pain frequency (Figure 3) at 3 months of follow-up . Two smaller RCTs found no  or only a trend towards  less frequent chest pain after CBT interventions (Figure 3). In a small pilot study Johrei, a process of transmission of healing energy, was compared to a waiting list . While the treatment group experienced a significant improvement in symptom intensity these findings need further validation. The heterogeneity of the study settings and treatments used prevented us from conducting a meta-analysis.
One study of patients with musculoskeletal NCCP found that manipulation reduced pain more effectively than acupuncture and usual care (Figure 3) . Another study found that chiropractic treatment and home exercise were similarly effective . The pooled mean difference for the manipulation therapy was 0.5 (95% CI −0.3 to 1.3, heterogeneity I2 = 46.2%).
Efficacy of treatment regarding anxiety and depression
Only similar studies were included in meta-analyses. CBT more effectively reduced anxiety scores in all studies (Figure 3). The pooled mean difference for CBT in two similar studies ,  was 4.4 (95% CI 0.5 to 8.4, heterogeneity I2 = 32.7%).
CBT treatment reduced depression scores more effectively than usual general practitioner (GP) care after 1 year , . The pooled mean difference for CBT was 3.1 (95% CI 0.5 to 5.7, heterogeneity I2 = 52.6%). A study with four arms compared CBT or no treatment and sertraline or placebo . While CBT with and without sertraline was more effective at reducing anxiety scores, they were no more effective at reducing depression scores than placebo. At baseline, depression scores were lower than anxiety scores in this study population (depression 8.9–10.2, range 0–63; anxiety 34–41, range 20–80).
The systematic analysis of 30 RCTs involving patients with NCCP demonstrated that PPI treatment was effective in patients with GERD. In NCCP patients without GERD, PPI treatment was no more effective than placebo. Treatment based on cognitive behavioral principles reduced chest pain frequency compared with ‘general practitioner treatment’ in three RCTs, while one study found no effect. Most studies that compared the efficacy of serotonin antagonists or tricyclic agents with placebo demonstrated no difference or only a trend towards less pain intensity in the treatment arms. Manipulative treatment interventions produced conflicting results for patients with musculoskeletal chest pain, and acupuncture was no more effective than usual care. For most prevalent diseases that manifested with chest pain, only a few studies were available.
Results in light of the existing literature
To our knowledge, this is the first comprehensive systematic review and meta-analysis to summarize the current evidence on treatment efficacy based on RCTs for various diseases presenting in patients with NCCP. Recently new therapies for NCCP of gastrointestinal origin were discussed . Treatment interventions including nitrates, Phosphodiesterase-5 inhibitors, anticholinergics, calcium channel blockers, and endoscopic injection of botulinum toxin may be effective in a subset of patients with gastrointestinal diseases. Most of these interventions have been studied in non-randomized trials or case series . This systematic review and meta-analysis confirms that limited RCTs are available for many interventions and highlights the need for further studies. Non-randomized trials tend to overestimate treatment effects . Further, this comprehensive overview addresses the need for interdisciplinary evaluation and care in patients with NCCP and summarizes the evidence for treatment interventions in underlying diseases oftentimes not considered. A recent systematic review found evidence that NCCP patients have similar levels of psychological morbidity than patients with cardiac chest pain and higher levels than healthy controls . While gastroesophageal diseases are common these findings indicate that other diseases might not be diagnosed.
Only limited evidence was available for most prevalent diseases that manifest with chest pain. Only two RCTs investigated treatment efficacy of manual therapy in patients with musculoskeletal chest pain , . The efficacy of psychotropic drugs on chest pain intensity, anxiety and depression scores were in line with a recently published meta-analysis that analyzed the efficacy of CBT compared with pharmacotherapy in adults with major depressive disorder (21 RCTs, 2027 patients) or anxiety disorder (21 RCTs, 1266 patients) . The authors found CBT to be equally effective as pharmacotherapy in patients with depression whereas CBT was somewhat more effective than pharmacotherapy in anxiety disorders . It has been shown that patients discharged from the emergency department with the diagnosis of NCCP had elevated anxiety levels compared to healthy individuals . Anxiety disorder might be an underlying disease for subjects with chest symptoms to seek evaluation in emergency departments. Interestingly, CBT was more effective in patients with panic disorders . This information may be relevant for further management of patients with unexplained chest pain. No study was identified that investigated panic disorders in patients with NCCP. However, in patients that present with NCCP to the emergency department, panic disorders are often not diagnosed , .
A recent meta-analysis using a hierarchical Bayesian model demonstrated the diagnostic value of the response to high-dose PPI treatment in patients with GERD [posterior mean sensitivity 0.89 and specificity of 0.88 ]. Together with the current findings in patients with NCCP, in which GERD is suspected, PPI treatment should be initiated early and PPI treatment response should be evaluated after 2 weeks . While the findings are in line with previous published meta-analyses on PPI treatment studies , , this is the first meta-analysis to assess study quality and the risk for outcome reporting bias. In comparison to Kahrilas et al. ,  and Cremonini et al. , , one additional study was included . Further, Cremonini et al. ,  included open-label studies and did not distinguish between GERD-positive and GERD-negative patients. We also used odds ratios as the effect measure for pooling because of its favorable mathematical properties over the relative risk. This includes that the odds ratio is unbounded regardless of the underlying event rate . Our study expands on a relevant aspect in the clinical setting where the PPI response is often used for the diagnosis of GERD. We showed that the effect in a mixed patient sample is smaller compared to patients where GERD was diagnosed by a reference test (e.g. 24-hour pH monitoring). Therefore, a lack of response to PPI treatment after 2 weeks should lead to discontinuation of PPI treatment, while a response indicates underlying GERD for which PPI treatment is effective.
Strengths and limitations
This review comprehensively evaluates the currently available studies. The search was inclusive; no language restrictions were applied, a thorough bibliographic search was conducted to identify all relevant studies, and rigorous methodology was applied. The extraction process was performed in accordance with current guidelines and supported by an experienced statistician. Potential factors influencing treatment efficacy were identified by a multidisciplinary team (an internist, general practitioner, statistician, and methodologist).
The main limitation of this systematic review and meta-analysis was the limited number of RCTs. Many interventions used in clinical practice in patients with NCCP were not assessed in RCTs. Of the included studies, many were only of moderate methodological quality. Furthermore, NCCP is a collective term with potentially different underlying diseases and therefore might present differently. Treatment efficacy in one population in which the prevalence for one disease is high might be entirely different for another population . In addition, the heterogeneity of the outcome measures used and follow-up durations reported prevented us from including most studies in our meta-analysis. The results of these studies should be interpreted on an individual study level within the context of the study population. We have tried to balance this by providing a thorough description of the studies inclusion and exclusion criteria and the study settings. This information will allow readers to judge to whom various study results apply.
Additional research should compare diagnostic indicators (e.g., pain increase with movement or decrease on medication were associated with musculoskeletal chest pain)  plus a corresponding treatment intervention to usual care alone in defined patient populations (e.g., emergency departments, primary care). Future research should also aim to contribute to our knowledge about diagnostic processes and treatment decisions for patients with NCCP. Although most patients with chest pain consult primary care physicians , few studies are performed in this setting. Additional research is needed to strengthen the evidence in a primary care setting. Screening questionnaires for panic and anxiety disorders could be used to identify patients that need further specialized assessment and would respond well to treatments based on cognitive behavioral principles. No such study was found in the current analysis.
Implication for practice
Patients with NCCP incur high healthcare costs owing to extensive and often invasive diagnostic testing, as well as the effect of NCCP on quality of life. Early identification of underlying diseases is essential to avoid delayed treatment and chronicity of complaints. Symptoms and clinical findings may provide important information to guide treatment of an underlying illness . In patients with typical GERD symptoms, twice-daily high-dose PPI treatment is the most efficient diagnostic and therapeutic approach. GERD is very likely if a positive treatment response occurs after 1 week, and is unlikely if there is no response after 4 weeks of PPI treatment . In patients that do not respond to PPI, PPI treatment should be stopped if an endoscopy reveals no pathological findings.
Panic and anxiety disorders are often missed in clinical practice . For patients with anxiety, treatments based on cognitive behavioral principles might be more effective than pharmacologic treatment. To date, evidence for the efficacy of serotonin antagonists or tricyclic agents in patients with NCCP is weak.
Timely diagnostic evaluation and treatment of the underlying disease is important for patients with NCCP. The current systematic review and meta-analysis showed a lack of RCTs for many diseases presenting with NCCP or treatment interventions proposed in the literature. Only limited evidence was available for prevalent diseases that manifest with chest pain. In addition, many treatment interventions that have been shown to be effective in non-randomized trials have not been studied in RCTs and might overestimate treatment efficacy. In patients suspected to have GERD high-dose treatment with a PPI is effective. In otherwise unexplained NCCP treatments based on cognitive behavioral principles might be considered. There is a need for further high quality studies addressing the gaps highlighted in this review.
Risk of bias assessment by using Funnel Plot.
Search Strategy July Week 28, 2013.
Summary of the SIGN quality assessment.
Risk for Outcome Reporting Bias in Trials (ORBIT) in studies excluded from Meta-analyses.
Conceived and designed the experiments: JB BJ UH MW JS. Performed the experiments: JB BJ MW. Analyzed the data: JB BJ UH MW JS. Contributed reagents/materials/analysis tools: JB BJ UH MW JS. Contributed to the writing of the manuscript: JB BJ UH MW JS.
- 1. Eslick GD, Coulshed DS, Talley NJ (2002) Review article: The burden of illness of non-cardiac chest pain. Alimentary Pharmacology and Therapeutics 16: 1217–1223.
- 2. Kahn SE (2000) The challenge of evaluating the patient with chest pain. Arch Pathol Lab Med 124: 1418–1419.
- 3. Cayley WE Jr (2005) Diagnosing the cause of chest pain. Am Fam Physician 72: 2012–2021.
- 4. Blatchford O, Capewell S, Murray S, Blatchford M (1999) Emergency medical admissions in Glasgow: General practices vary despite adjustment for age, sex, and deprivation. British Journal of General Practice 49: 551–554.
- 5. Rosengren A, Wilhelmsen L (1998) Respiratory symptoms and long-term risk of death from cardiovascular disease, cancer and other causes in Swedish men. Int J Epidemiol 27: 962–969.
- 6. Buntinx F, Knockaert D, Bruyninckx R, De Blaey N, Aerts M, et al. (2001) Chest pain in general practice or in the hospital emergency department: Is it the same? Fam Pract 18: 586–589.
- 7. Rosengren A, Wilhelmsen L, Hagman M, Wedel H (1998) Natural history of myocardial infarction and angina pectoris in a general population sample of middle-aged men: a 16-year follow-up of the Primary Prevention Study, Goteborg, Sweden. J Intern Med 244: 495–505.
- 8. Nilsson S, Scheike M, Engblom D, Karlsson LG, Molstad S, et al. (2003) Chest pain and ischaemic heart disease in primary care. British Journal of General Practice 53: 378–382.
- 9. Verdon F, Burnand B, Herzig L, Junod M, Pecoud A, et al. (2007) Chest wall syndrome among primary care patients: a cohort study. BMC Fam Pract 8: 51.
- 10. Svavarsdottir AE, Jonasson MR, Gudmundsson GH, Fjeldsted K (1996) Chest pain in family practice. Diagnosis and long-term outcome in a community setting. Can Fam Physician 42: 1122–1128.
- 11. Wilcox RG, Roland JM, Hampton JR (1981) Prognosis of patients with “chest pain ?cause”. Br Med J (Clin Res Ed) 282: 431–433.
- 12. Robertson N, Javed N, Samani NJ, Khunti K (2008) Psychological morbidity and illness appraisals of patients with cardiac and non-cardiac chest pain attending a rapid access chest pain clinic: a longitudinal cohort study. Heart 94: e12.
- 13. Eslick GD, Talley NJ (2008) Natural history and predictors of outcome for non-cardiac chest pain: a prospective 4-year cohort study. Neurogastroenterol Motil 20: 989–997.
- 14. Eslick GD, Talley NJ (2004) Non-cardiac chest pain: predictors of health care seeking, the types of health care professional consulted, work absenteeism and interruption of daily activities. Aliment Pharmacol Ther 20: 909–915.
- 15. Stochkendahl MJ, Christensen HW (2010) Chest pain in focal musculoskeletal disorders. Med Clin North Am 94: 259–273.
- 16. Wertli MM, Ruchti KB, Steurer J, Held U (2013) Diagnostic indicators of non-cardiovascular chest pain: a systematic review and meta-analysis. BMC Med 11: 239.
- 17. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6: e1000097.
- 18. Eslick GD, Talley NJ (2000) Non-cardiac chest pain: squeezing the life out of the Australian healthcare system? Med J Aust 173: 233–234.
- 19. Copas J, Dwan K, Kirkham J, Williamson P (2013) A model-based correction for outcome reporting bias in meta-analysis. Biostatistics.
- 20. Kirkham JJ, Dwan KM, Altman DG, Gamble C, Dodd S, et al. (2010) The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews. BMJ 340: c365.
- 21. Higgins JPT, Green S (2011) Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration.
- 22. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
- 23. R Development Core Team (2011) R: A language and environment for statistical computing. In: R Foundation for Statistical Computing V, Austria, editor. Vienna, Austria: R Foundation for Statistical Computing.
- 24. Viechtbauer W (2010) Conducting Meta-Analyses in R with the metafor Package. Journal of Statistical Software 36: 1–48.
- 25. Achem SR, Kolts BE, MacMath T, Richter J, Mohr D, et al. (1997) Effects of omeprazole versus placebo in treatment of noncardiac chest pain and gastroesophageal reflux. Dig Dis Sci 42: 2138–2145.
- 26. Bautista J, Fullerton H, Briseno M, Cui H, Fass R (2004) The effect of an empirical trial of high-dose lansoprazole on symptom response of patients with non-cardiac chest pain - A randomized, double-blind, placebo-controlled, crossover trial. Alimentary Pharmacology and Therapeutics 19: 1123–1130.
- 27. Dickman R, Emmons S, Cui H, Sewell J, Hernandez D, et al. (2005) 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. Alimentary Pharmacology and Therapeutics 22: 547–555.
- 28. Dore MP, Pedroni A, Pes GM, Maragkoudakis E, Tadeu V, et al. (2007) Effect of antisecretory therapy on atypical symptoms in gastroesophageal reflux disease. Digestive Diseases & Sciences 52: 463–468.
- 29. Fass R, Fennerty MB, Ofman JJ, Gralnek IM, Johnson C, et al. (1998) The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterology 115: 42–49.
- 30. Lind T, Havelund T, Carlsson R, Anker-Hansen O, Glise H, et al. (1997) Heartburn without oesophagitis: efficacy of omeprazole therapy and features determining therapeutic response. Scand J Gastroenterol 32: 974–979.
- 31. Pandak WM, Arezo S, Everett S, Jesse R, DeCosta G, et al. (2002) 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 35: 307–314.
- 32. Xia HHX, Lai KC, Lam SK, Hu WHC, Wong NYH, et al. (2003) Symptomatic response to lansoprazole predicts abnormal acid reflux in endoscopy-negative patients with non-cardiac chest pain. Alimentary Pharmacology and Therapeutics 17: 369–377.
- 33. Cossentino MJ, Mann K, Armbruster SP, Lake JM, Maydonovitch C, et al. (2012) Randomised clinical trial: the effect of baclofen in patients with gastro-oesophageal reflux - a randomised prospective study. Aliment Pharmacol Ther 35: 1036–1044.
- 34. Jones H, Cooper P, Miller V, Brooks N, Whorwell PJ (2006) Treatment of non-cardiac chest pain: a controlled trial of hypnotherapy. Gut 55: 1403–1408.
- 35. Lehtola V, Korhonen I, Airaksinen O (2010) A randomised, placebo-controlled, clinical trial for the short-term effectiveness of manipulative therapy and acupuncture on pain caused by mechanical thoracic spine dysfunction. International Musculoskeletal Medicine 32: 25–32.
- 36. Stochkendahl MJ, Christensen HW, Vach W, Hoilund-Carlsen PF, Haghfelt T, et al. (2012) Chiropractic treatment vs self-management in patients with acute chest pain: a randomized controlled trial of patients without acute coronary syndrome. J Manipulative Physiol Ther 35: 7–17.
- 37. Stochkendahl MJ, Christensen HW, Vach W, Hoilund-Carlsen PF, Haghfelt T, et al. (2012) A randomized clinical trial of chiropractic treatment and self-management in patients with acute musculoskeletal chest pain: 1-year follow-up. J Manipulative Physiol Ther 35: 254–262.
- 38. Arnold J, Goodacre S, Bath P, Price J (2009) Information sheets for patients with acute chest pain: randomised controlled trial. BMJ: British Medical Journal (Overseas & Retired Doctors Edition) 338: 700–702.
- 39. Esler JL, Barlow DH, Woolard RH, Nicholson RA, Nash JM, et al. (2003) A brief-cognitive behavioral intervention for patients with noncardiac chest pain. Behavior Therapy 34: 129–148.
- 40. Hess EP, Knoedler MA, Shah ND, Kline JA, Breslin M, et al. (2012) The chest pain choice decision aid: a randomized trial. Circulation Cardiovascular Quality & Outcomes 5: 251–259.
- 41. Jonsbu E, Dammen T, Morken G, Moum T, Martinsen EW (2011) Short-term cognitive behavioral therapy for non-cardiac chest pain and benign palpitations: a randomized controlled trial. J Psychosom Res 70: 117–123.
- 42. Lahmann C, Loew TH, Tritt K, Nickel M (2008) Efficacy of functional relaxation and patient education in the treatment of somatoform heart disorders: a randomized, controlled clinical investigation. Psychosomatics 49: 378–385.
- 43. Mayou R, Sprigings D, Birkhead J, Price J (2002) A randomized controlled trial of a brief educational and psychological intervention for patients presenting to a cardiac clinic with palpitation. Psychol Med 32: 699–706.
- 44. Mayou RA, Bryant BM, Sanders D, Bass C, Klimes I, et al. (1997) A controlled trial of cognitive behavioural therapy for non-cardiac chest pain. Psychol Med 27: 1021–1031.
- 45. Potts SG, Lewin R, Fox KA, Johnstone EC (1999) Group psychological treatment for chest pain with normal coronary arteries. QJM 92: 81–86.
- 46. Sanders D, Bass C, Mayou RA, Goodwin S, Bryant BM, et al. (1997) Non-cardiac chest pain: why was a brief intervention apparently ineffective? Psychol Med 27: 1033–1040.
- 47. Van Peski-Oosterbaan AS, Spinhoven P, Van der Does AJ, Bruschke AV, Rooijmans HG (1999) Cognitive change following cognitive behavioural therapy for non-cardiac chest pain. Psychotherapy & Psychosomatics 68: 214–220.
- 48. Van Peski-Oosterbaan AS, Spinhoven P, Van Rood Y, Van der Does JW, Bruschke AV, et al. (1999) Cognitive-behavioral therapy for noncardiac chest pain: A randomized trial. American Journal of Medicine 106: 424–429.
- 49. Cannon RO, Quyyumi AA, Mincemoyer R, Stine AM, Gracely RH, et al. (1994) Imipramine in Patients with Chest Pain Despite Normal Coronary Angiograms. New England Journal of Medicine 330: 1411–1417.
- 50. Cox ID, Hann CM, Kaski JC (1998) Low dose imipramine improves chest pain but not quality of life in patients with angina and normal coronary angiograms. Eur Heart J 19: 250–254.
- 51. Doraiswamy PM, Varia I, Hellegers C, Wagner HR, Clary GL, et al. (2006) A randomized controlled trial of paroxetine for noncardiac chest pain. Psychopharmacol Bull 39: 15–24.
- 52. Keefe FJ, Shelby RA, Somers TJ, Varia I, Blazing M, et al. (2011) Effects of coping skills training and sertraline in patients with non-cardiac chest pain: a randomized controlled study. Pain 152: 730–741.
- 53. Rao SS, Mudipalli RS, Remes-Troche JM, Utech CL, Zimmerman B (2007) Theophylline improves esophageal chest pain–a randomized, placebo-controlled study. American Journal of Gastroenterology 102: 930–938.
- 54. Varia I, Logue E, O’Connor C, Newby K, Wagner HR, et al. (2000) Randomized trial of sertraline in patients with unexplained chest pain of noncardiac origin. Am Heart J 140: 367–372.
- 55. Wulsin L, Liu T, Storrow A, Evans S, Dewan N, et al. (2002) A randomized, controlled trial of panic disorder treatment initiation in an emergency department chest pain center. Ann Emerg Med 39: 139–143.
- 56. Gasiorowska A, Navarro-Rodriguez T, Dickman R, Wendel C, Moty B, et al. (2009) Clinical trial: the effect of Johrei on symptoms of patients with functional chest pain. Aliment Pharmacol Ther 29: 126–134.
- 57. Maradey-Romero C, Fass R (2014) New therapies for non-cardiac chest pain. Curr Gastroenterol Rep 16: 390.
- 58. Hershcovici T, Achem SR, Jha LK, Fass R (2012) Systematic review: the treatment of noncardiac chest pain. Aliment Pharmacol Ther 35: 5–14.
- 59. Kunz R, Vist G, Oxman AD (2007) Randomisation to protect against selection bias in healthcare trials. Cochrane Database Syst Rev: MR000012.
- 60. Webster R, Norman P, Goodacre S, Thompson A (2012) The prevalence and correlates of psychological outcomes in patients with acute non-cardiac chest pain: a systematic review. Emergency Medicine Journal 29: 267–273.
- 61. Roshanaei-Moghaddam B, Pauly MC, Atkins DC, Baldwin SA, Stein MB, et al. (2011) Relative effects of CBT and pharmacotherapy in depression versus anxiety: is medication somewhat better for depression, and CBT somewhat better for anxiety? Depress Anxiety 28: 560–567.
- 62. Smeijers L, van de Pas H, Nyklicek I, Notten PJ, Pedersen SS, et al. (2014) The independent association of anxiety with non-cardiac chest pain. Psychol Health 29: 253–263.
- 63. White KS, Raffa SD, Jakle KR, Stoddard JA, Barlow DH, et al. (2008) Morbidity of DSM-IV Axis I disorders in patients with noncardiac chest pain: Psychiatric morbidity linked with increased pain and health care utilization. Journal of consulting and clinical psychology 76: 422.
- 64. Fleet RP, Dupuis G, Marchand A, Burelle D, Arsenault A, et al. (1996) Panic disorder in emergency department chest pain patients: prevalence, comorbidity, suicidal ideation, and physician recognition. The American journal of medicine 101: 371–380.
- 65. Cremonini F, Wise J, Moayyedi P, Talley NJ (2005) Diagnostic and therapeutic use of proton pump inhibitors in non-cardiac chest pain: A metaanalysis. American Journal of Gastroenterology 100: 1226–1232.
- 66. Kahrilas PJ, Hughes N, Howden CW (2011) Response of unexplained chest pain to proton pump inhibitor treatment in patients with and without objective evidence of gastro-oesophageal reflux disease. Gut 60: 1473–1478.
- 67. Egger M, Smith GD, Altman D (2008) Systematic reviews in health care: meta-analysis in context. Wiley. com.
- 68. Wilhelmsen L, Rosengren A, Hagman M, Lappas G (1998) “Nonspecific” chest pain associated with high long-term mortality: results from the primary prevention study in Goteborg, Sweden. Clin Cardiol 21: 477–482.
- 69. Bosner S, Becker A, Hani MA, Keller H, Sonnichsen AC, et al. (2010) Chest wall syndrome in primary care patients with chest pain: presentation, associated features and diagnosis. Fam Pract 27: 363–369.
- 70. Katerndahl DA, Trammell C (1997) Prevalence and recognition of panic states in STARNET patients presenting with chest pain. J Fam Pract 45: 54–63.