Table of Contents  

Amarasinghe and Sifrim: Functional oesophageal disorders

Introduction

Physicians commonly encounter functional gastrointestinal disorders in their clinical practice. We discuss the prevalence, investigation and diagnosis of functional oesophageal disorders and their treatment in this review.

The Rome III group defined four specific functional oesophageal disorders: functional chest pain, functional heartburn, functional dysphagia and globus.

The recommended diagnostic criteria are shown in Table 1. Patients should fulfil diagnostic criteria for the last 3 months with an onset at least 6 months prior to diagnosis. This timescale, although arbitrary, is useful for physicians to assess a patient.1

TABLE 1

Rome III diagnostic criteria for functional heartburn

Disorder Diagnostic criteria
A1
Functional heartburn
Burning retrosternal discomfort or pain, AND
Absence of evidence that gastro-oesophageal acid reflux is the cause of the symptom, AND
Absence of histopathology-based oesophageal motility disorders
A2
Functional chest pain of presumed oesophageal origin
Midline chest pain or discomfort that is not of burning quality, AND
Absence of evidence that gastro-oesophageal reflux is the cause of the symptom, AND
Absence of histopathology-based oesophageal motility disorders
A3
Functional dysphagia
Sense of solid and/or liquid foods sticking, lodging or passing abnormally through the oesophagus, AND
Absence of evidence that gastro-oesophageal reflux is the cause of the symptom, AND
Absence of histopathology-based oesophageal motility disorders
A4
Globus
Persistent or intermittent non-painful sensation of a lump or foreign body in the throat, AND
Occurrence of the sensation between meals, AND
Absence of dysphagia or odynophagia, AND
Absence of evidence that gastro-oesophageal reflux is the cause of the symptom, AND
Absence of histopathology-based oesophageal motility disorders

Modified from Galmiche JP, Clouse RE, Bálint A, et al. Functional esophageal disorders. Gastroenterology 2006; 130:1459–65.1

It is of note that, in the above diagnostic criteria, the absence of evidence that gastro-oesophageal reflux disease (GORD) is the cause of the symptoms experienced by the patient is paramount. This is because, apart from heartburn, GORD is known to cause symptoms such as chest pain, dysphagia and globus.2

A normal gastroscopy along with the exclusion of motility disturbances using manometry (preferably high-resolution manometry) are required to evaluate a patient with a potential functional oesophageal disorder. If these do not yield a diagnosis, either a proton pump inhibitor (PPI) trial or reflux monitoring with pH-metry or multichannel intraluminal impedance pH (MII-pH) studies is carried out as a means of excluding GORD. Response to a PPI trial of up to 4 weeks has not been shown to clearly diagnose GORD,3 although this is a common practice amongst clinicians.4 When using MII-pH, evidence of a positive symptom association between symptoms and reflux events, be they acid or non-acid (as is the case in the hypersensitive oesophagus), confers a diagnosis of reflux-related symptoms. Therefore, if there is no symptom association between reflux events and symptoms, when all other criteria are fulfilled, the disorder is termed ‘functional’. This definition by the Rome III group has facilitated a more ordered evaluation of this group of patients and also helps in the process of finding new therapeutic options.1

As our understanding of the pathophysiology of oesophageal disorders increases, the diagnostic criteria and types of functional oesophageal disorders are likely to change. The awaited Rome IV criteria will no doubt add a great deal to our approach to the diagnosis and treatment of patients with these functional disorders.

Incidence

The overall incidence of functional oesophageal disorders is not clear. The incidence of globus appears to be the highest, with up to 46% of healthy individuals admitting to having had symptoms of globus.5 The definition used in this survey was not as strict as that specified in the Rome III criteria. More accurate incidence data are less easy to come by because of the likelihood of patients not undergoing extended investigations as a result of the benign nature of the condition. Incidence rates of 8.5% have been quoted for functional heartburn.6,7 The incidence of functional chest pain is again unclear, although the rate of non-cardiac chest pain can be as high as 33%.8 Functional dysphagia is much more rare.

The pathophysiology of functional oesophageal disorders is complex and is currently the subject of extensive research. Current research, building on recent advances in the field of neurogastroenterology, has furthered our knowledge of the brain–gut axis, its function and its dysfunction.

Functional oesophageal disorders

Functional heartburn

Functional heartburn is described as a burning retrosternal discomfort or pain that is not caused by GORD, a hypersensitive oesophagus or a motility disorder.1

It is diagnosed in patients with continuing symptoms of typical heartburn despite PPI therapy. These patients have usually undergone a PPI trial, followed by gastroscopy, oesophageal manometry and 24-hour pH studies, with or without impedance.

As mentioned above in the Rome III diagnostic criteria, a negative pH study is required, and often it is the final step in the diagnostic process. Currently, an episode of reflux within a 2-minute window prior to an episode of heartburn is taken to mean that the reflux event and the episode of heartburn are related.9

In clinical trials on functional heartburn, most patients have undergone investigations consistent with Rome III criteria.10 The requirement for the absence of eosinophilic oesophagitis is often the only point that is missed when reviewing current clinical trials in the field of functional heartburn. By having this requirement highlighted by the Rome III criteria, patients who may have symptoms of heartburn caused by eosinophilic oesophagitis are excluded. In addition, there is evidence that a lack of microscopic oesophagitis in distal oesophageal biopsies may indicate functional heartburn as well. Certainly, patients with GORD and non-oesophageal reflux disease can be distinguished from patients with functional heartburn by looking for microscopic oesophagitis.11 Therefore, these patients would correctly be excluded when oesophageal biopsies are reviewed.

Functional chest pain

Functional chest pain was initially evaluated in the context of non-cardiac chest pain. Patients presenting to emergency departments and to cardiologists with chest pain and subsequently having entirely negative cardiac investigations were presumed to have ‘non-cardiac’ chest pain. Their chest pain was thought to be mostly oesophageal in origin and several studies have shown that, of patients who are deemed to have ‘non-cardiac’ chest pain, most have chest pain due to GORD or motility disorders. Only a proportion of these patients are subsequently diagnosed with functional chest pain.12

The diagnosis and pharmacological therapy of functional chest pain has been evaluated more than the other three functional oesophageal disorders, probably because of the drive to improve rapid diagnosis and therapy for cardiac chest pain as well as to reduce unnecessary investigations and burden on already stretched cardiology services.

Functional dysphagia

Functional dysphagia is described in the Rome III consensus as a sense of solid and/or liquid foods sticking, lodging or passing abnormally through the oesophagus. There should be an absence of GORD and histopathology-based oesophageal motility disorders. Functional dysphagia is uncommon, although prevalence is difficult to estimate at present because of the degree of investigations required for what is considered to be a benign condition.1

Globus

Globus is described in the Rome III classification as a persistent or intermittent, non-painful sensation of a lump or foreign body in the throat in the context of no structural lesion identified on physical exam or endoscopy. The sensation must occur between meals. Dysphagia, odynophagia, GORD and histopathology-based oesophageal motility disorders (such as eosinophilic oesophagitis) must be excluded.1

Patients with globus are often referred to ear, nose and throat and gastroenterology clinics. The prevalence is between 0.1% and 21%.1 This vast variation is because of the different understanding of the definition of globus.

The Rome III criteria for globus are specific and only a proportion of patients presenting with symptoms will fall into this category. Patients who fall outside the Rome III definition of globus probably represent a significant number. It is therefore more useful to look at the patient presenting with globus initially, and then work through a logical algorithm of evaluation and treatment.

Despite the high prevalence of globus, the aetiology is still unclear. GORD, laryngeal and pharyngeal dysfunction, motility disorders, including upper oesophageal sphincter dysfunction, visceral hypersensitivity and psychological factors, have been suggested as causes for globus, although the evidence for each of these is not robust. It is being increasingly recognized that globus is likely to be caused by a combination of the above factors. This realization has implications for future research into the aetiology of globus and also its evaluation and treatment.13

Diagnosis of functional oesophageal disorders

Diagnosis of functional oesophageal disorders is dependent on negative standard investigations for histopathology-based oesophageal motility disorders, structural disorders and reflux (Figures 1, 2, 3 and 4).

FIGURE 1

An algorithm based on current evidence for the diagnosis and treatment of functional heartburn.

8-3-9-fig1.jpg
FIGURE 2

An algorithm based on current evidence for the diagnosis and treatment of functional chest pain. Therapies marked with an asterisk (*) are those that have evidence for use in non-cardiac chest pain. SSRI, selective serotonin reuptake inhibitor.

8-3-9-fig2.jpg
FIGURE 3

An algorithm for the diagnosis and treatment of functional dysphagia. There are no clinical trials for treatments for functional dysphagia, so therapies used for other functional oesophageal disorders are often used because of presumed similar pathophysiological mechanisms. Note: pregabalin (Lyrica®, Pfizer, Surrey, UK).

8-3-9-fig3.jpg
FIGURE 4

An algorithm based on current evidence for the diagnosis and treatment of globus. UES, upper oesophageal sphincter.

8-3-9-fig4.jpg

Often the first investigation performed is an oesophagogastroduodenoscopy (OGD). Most OGD examinations show a macroscopically normal upper gastrointestinal tract. Oesophageal biopsies for eosinophilic oesophagitis or microscopic oesophagitis can be taken at the same time.

Following a negative OGD, patients are usually referred for high-resolution manometry, which is often performed at the same time as reflux studies. High-resolution manometry involves insertion of a catheter via a nostril into the upper gastrointestinal tract. The catheter is often a size 12 French (4.2 mm diameter) and has numerous (often 36) pressure sensors along its length. Insertion is performed with or without topical anaesthetic spray and after baseline oesophageal pressure readings usually 10 small water swallows are performed, allowing for the diagnosis of oesophageal motility disorders. A high-resolution manometry tracing and a conventional manometry tracing of a normal swallow are shown in Figure 5.

FIGURE 5

Conventional and high-resolution oesophageal manometry.

8-3-9-fig5.jpg

Reflux studies are most often catheter based, involving either pH sensors alone or impedance and pH sensors (Figures 6 and 7). Recently, the length of pH studies has come under scrutiny. Sweis et al.14 examined 38 patients who had a negative 24-hour catheter-based pH study and who continued to have symptoms. They then performed prolonged wireless pH studies (up to 96 hours, with a median of 72 hours). Average versus worst day analysis demonstrated that oesophageal acid exposure was 37% versus 47%. More strikingly, when the symptom association probability (SAP) was calculated, average versus worst day analysis showed a positive SAP in 34% versus 63%. Overall, using average and worst day analyses, 61% and 76% of these patients were diagnosed with GORD, respectively. This highlights not only the increased tolerability of wireless pH studies, but also that a negative SAP would confer a diagnosis of functional heartburn. The concern is that these patients may be erroneously diagnosed as having functional heartburn and not GORD, limiting their access to potentially helpful treatments.

FIGURE 6

Normal multichannel impedance pH study with physiological oesophageal pH levels seen in the oesophageal pH channel and predominantly acidic pH levels seen in the gastric pH channel. This patient had an oesophageal pH of less than 4 for only 0.5% of the total study. In addition, as shown in the event markers, the patient had very few symptoms.

8-3-9-fig6.jpg
FIGURE 7

Abnormal multichannel impedance pH study with high oesophageal pH levels seen in the oesophageal pH channel and predominantly acidic pH levels seen in the gastric pH channel. This patient had an oesophageal pH of less than 4 for 13.2% of the total study. The patient had many symptoms and many reflux events.

8-3-9-fig7.jpg

Another area of debate is the reliability of calculating symptom association using either symptom index (SI) or SAP. SI and SAP are used as a means of reconciling the probability of a reflux event and an episode of heartburn. Currently, both are used to assess symptom association. Both these statistical methods of calculating symptom association are more useful when patients experience higher rates of reflux. Slaughter et al.15 concluded that SI and SAP were less reliable in those patients with low numbers of reflux events (less than 10% of the physiologically accepted number of reflux episodes), and SI and SAP were also less reliable in those who responded poorly to PPI therapy, with the effect of overestimating symptom association. Therefore, it is clear that exclusion of GORD using pH metry is not as straightforward as would be desired.

Functional heartburn

Following a diagnosis of functional heartburn, there are very few adequate evidence-based treatment options. Treatments used for functional chest pain empirically may give some symptomatic relief, but there is no evidence to back this up.

Functional chest pain

The diagnosis of functional chest pain starts with exclusion of cardiac causes. Patients presenting to their general practitioner or to an emergency department will initially have an electrocardiogram to look for ischaemic changes. If such changes are absent, an exercise stress test or coronary angiography may be organized.16

Once a cardiac cause has been excluded, oesophageal causes of chest pain should be reviewed. Often a PPI trial is commenced and, if there is no response, a gastroscopy is performed. A gastroscopy excludes the possibility of chest pain due to a malignancy or oesophageal injury (oesophagitis). Biopsies taken at gastroscopy are needed to exclude eosinophilic oesophagitis, which is another cause of chest pain. If no cause is found, high-resolution manometry and 24-hour MII-pH studies are performed. Functional chest pain is diagnosed if all these investigations are negative.1

Functional dysphagia

Dysphagia is investigated with a gastroscopy (with biopsies to exclude possible eosinophilic oesophagitis or micro-oesophagitis), barium swallow (or video fluoroscopic swallow study if high dysphagia is present) and oesophageal manometry (preferably high-resolution manometry). If an extrinsic cause is suspected, endoscopic ultrasound and/or cross-sectional imaging may be of value. In the absence of positive findings, a diagnosis of functional dysphagia may be made.

Globus

The evaluation of a patient with a persistent or intermittent, non-painful sensation of a lump or foreign body in the throat should be carried out in a systematic manner, excluding structural and motility causes for the patient’s symptoms. A nasopharyngoscopy (and possibly gastroscopy if indicated) will exclude a malignancy. If no diagnosis is evident, GORD may be the cause, and a PPI trial may be appropriate in the first instance. If this does not help, it is reasonable to consider high-resolution manometry and oesophageal pH testing with multichannel intraluminal impedance to exclude motility abnormalities as well as GORD, so that these conditions may be treated accordingly. If these tests are negative, then the diagnosis is probably globus.

Treatment options for functional oesophageal disorders

Functional heartburn

Tricyclic antidepressants (TCAs). The results from a phase III clinical trial (ClinicalTrials.gov Identifier: NCT01753128) looking at the effect of imipramine on functional heartburn and oesophageal hypersensitivity may lend some weight to the use of TCAs for functional heartburn. Other TCAs have not been studied in the context of functional heartburn but have been looked at with respect to functional chest pain and oesophageal hypersensitivity. For example, amitriptyline has been shown to improve symptoms in patients with functional chest pain.2 It seems sensible to use pain modulators in view of our current poor understanding of the pathophysiology of functional heartburn.

Tegaserod (Zelnorm®/Zelmac®, Novartis, Basel, Switzerland) is a 5-hydroxytryptamine-4 receptor partial agonist that was used for irritable bowel syndrome and constipation. It had been shown to also improve heartburn symptoms in patients with functional heartburn and functional dyspepsia in a small population of patients recruited based on Rome II criteria (may have included patients with hypersensitive oesophagus).17,18 However, tegaserod was withdrawn from the market because of increased risk of heart attack, stroke and unstable angina.

Fluoxetine. Ostovaneh et al.19 showed that fluoxetine was superior to omeprazole in improving the percentage of heartburn-free days in patients who were endoscopy negative with a negative impedance pH study. The patients in this study were not strictly characterized as having ‘functional heartburn’, as motility disorders and eosinophilic oesophagitis were not excluded. Confirmation of these results in a larger group of well-characterized functional heartburn patients may lend more weight to the use of fluoxetine in patients with functional heartburn.

Functional chest pain

Several pharmacological agents have been evaluated in the treatment of functional chest pain. These include TCAs, serotonin–noradrenaline reuptake inhibitors (SNRIs), SSRIs and non-pharmacological interventions.

Amitriptyline. A recent study by Park et al.20 looked at low-dose amitriptyline combined with rabeprazole for the treatment of functional chest pain. The study was a randomized open-label trial comparing patients with functional chest pain (based on Rome III) on standard-dose rabeprazole (20 mg once daily) plus amitriptyline 10 mg at night versus high-dose rabeprazole (20 mg twice daily), over a period of 8 weeks. The primary endpoint was an improvement in global symptom scores of > 50%. Improvements in global symptom scores were seen towards the end of the study period and, overall, the rabeprazole + amitriptyline group fared better, with the improvement being statistically significant. Prior to this, the only review on the use of amitriptyline for chest pain refractory to PPI therapy (pre-Rome III) was a retrospective long-term outcome review by Prakash et al.21 over a 2.7-year period, which showed that 75% of such patients felt that amitriptyline was effective for the treatment of their chest pain.

Venlafaxine, an SNRI, has recently been shown to reduce symptoms of functional chest pain in young adult patients. Lee et al.22 assessed 43 young men, aged 23.5 years ± 1.9 years, with a diagnosis of functional chest pain. They were treated with either venlafaxine 75 mg or a placebo over a 4-week period. Symptom scores for venlafaxine were significantly better than placebo, suggesting that this may be a valuable option for the treatment of functional chest pain.22

Imipramine has been shown to reduce episodes of non-cardiac chest pain by Cannon et al.23 They studied 60 patients with chest pain and negative cardiac investigations. Imipramine, clonidine and a placebo were compared over a period of 3 weeks, with a statistically significant improvement in symptoms seen in the imipramine group. A similar pattern was shown by Cox et al.24 when they looked at 18 patients with chest pain with negative cardiac investigations and no response to antiangina therapy. No trials have yet been carried out to look at functional chest pain.

Selective serotonin reuptake inhibitors. In clinical trials, SSRIs have been shown to be useful for the treatment of non-cardiac chest pain. Keefe et al.25 randomized 115 patients with non-cardiac chest pain (oesophageal causes were not investigated) to one of four treatment arms: placebo, sertraline, placebo + coping skills training (CST) or sertraline + CST. Sertraline was shown to reduce non-cardiac chest pain alone as well as in combination with CST.25 Paroxetine has also been shown to help patients with non-cardiac chest pain in a randomized placebo-controlled trial.26 Because of the use of SSRIs for non-cardiac chest pain as well as for oesophageal hypersensitivity,27 clinicians empirically may use SSRIs to treat patients with functional chest pain.

Biofeedback therapy has been reported as useful for the treatment of functional chest pain, although the same effect was not seen with functional heartburn.28 In a study by Shapiro et al.28 functional chest pain and functional heartburn were classified using Rome II criteria and 4 out of the 13 patients classed as having functional heartburn had a positive SI (hypersensitive oesophagus using Rome III criteria). A similar issue was observed in the patients classed as having functional chest pain, where one of these nine patients with functional chest pain had a positive SI. Six patients in each group were randomized to have a course of 8 to 10 weekly biofeedback therapy sessions over a period of 1 to 4 years. Despite use of the less stringent Rome II criteria, the patients with functional chest pain who had biofeedback therapy did better in terms of symptom scores than those who did not receive the therapy. There was no difference in the functional heartburn group.28

Biofeedback therapy has been shown to be useful in other functional gastrointestinal disorders such as constipation, incontinence29 and dyspepsia,30 so further work on the effectiveness of biofeedback therapy on functional oesophageal disorders is needed.

Cognitive behavioural therapy (CBT) has been used to treat non-cardiac chest pain. Jonsbu et al.31 assessed 40 patients complaining of persistent chest pain after cardiac causes had been ruled out. Oesophageal causes did not appear to be addressed in these patients. Patients were randomized to receive three sessions of CBT versus usual primary medical care. Follow-up at 3 and 12 months showed significant symptom improvement in the CBT arm.31 There are no current trials looking specifically at CBT and functional chest pain.

Other therapies

  • Johrei is a therapy involving the transfer of healing energy, and it is similar to the more popular therapy reiki. Gasiorowska et al.32 studied 39 patients who fulfilled criteria for functional chest pain. Twenty-one were randomized to 6 weeks of treatment with johrei and 18 did not receive treatment. Symptom intensity scores were significantly better in the johrei treatment arm, although the mechanism of this effect was not explored in the study. Further studies using sham therapy or a support treatment would be useful to explore johrei as a treatment for functional chest pain.32

  • Rao et al.33 assessed the use of theophylline in patients with oesophageal hypersensitivity who experienced non-cardiac chest pain. Patients were randomized to receive intravenous theophylline or a placebo. They also assessed oral theophylline.34 Overall, they showed that the number of chest pain episodes and their duration and severity improved with theophylline.33,34 Side-effects are an issue, however, and there have not been any further studies assessing theophylline in the context of functional oesophageal disorders.

  • Hypnotherapy has also been shown to be effective in the treatment of non-cardiac chest pain.35 In this study, oesophageal causes were not assessed and sample sizes were small.

  • Trazodone has been shown to improve symptoms such as chest pain in patients with oesophageal contractile disorders, although manometric changes were not influenced by treatment.36

Functional dysphagia

Clinical trials for therapeutic measures to treat functional dysphagia are currently lacking. Physicians tend to use a pragmatic approach, treating patients with pain modulators and antidepressants. The evidence for this is extrapolated from the treatment for oesophageal hypersensitivity and also from work showing that acute stress is able to alter oesophageal function.37

Functional dysphagia is a benign condition. Patients are reassured and given advice to avoid foods that trigger symptoms and advice to masticate food well.38

Empirical dilatation, smooth muscle relaxants and pneumatic dilatation have been tried in patients who have incomplete lower oesophageal relaxation or delay in distal oesophageal emptying.1 With advances in the diagnosis of achalasia and advances in high-resolution manometry, it is difficult to say if these patients may now be diagnosed with early achalasia and therefore may not fall within the diagnostic criteria of functional dysphagia.

Globus

Treatment options are based on the presumed possible pathophysiological mechanisms mentioned above. The evidence for a proportion of these mechanisms and treatments is in the form of case reviews and case series and not from randomized clinical trials. The randomized clinical trials that have focused on pathophysiology and treatments for globus have suffered from variations in the definitions of globus and in techniques used and therefore are not entirely comparable. This makes it difficult to formulate definite guidance strategies for treatment.

In the context of GORD, there is evidence that PPI therapy is an effective treatment for laryngopharyngeal reflux in patients who also have typical symptoms. The extrapolation here is that globus is caused by laryngopharyngeal reflux and therefore treating this may improve symptoms. A 4-month trial of high-dose PPI therapy is reasonable.39

Kirch et al.40 looked at patients with globus and their response to PPI + gabapentin. Of the 87 patients included, 67% responded either partially or completely to PPI therapy. Of those who had a trial of gabapentin, 66% reported an improvement, with a proportion unresponsive to PPI therapy reporting an improvement with gabapentin.40

Hypnotically assisted relaxation therapy may be used as a treatment for globus.41 Although only 1 out of the 10 patients had a diagnosis of functional globus, good levels of improvement were reported overall suggesting that, irrespective of the cause, this treatment may be useful.

Low-dose amitriptyline was investigated by You et al.42 A total of 34 patients with globus, who fulfilled Rome III criteria, were given conventional therapy of pantoprazole 40 mg once daily and the treatment arm consisted of amitriptyline 25 mg at night. The study was over a 4-week period and quality of life and symptom scores were significantly better in the amitriptyline arm. Previous work carried out using higher doses was unsuccessful because of significant side-effects,43 but the tolerability of the side-effects in this study (constipation, dry mouth, sleepiness and dizziness) improved over the course of the 4 weeks.

A Japanese study showed that a herbal remedy, rikkunshito, improved symptoms of globus.44 The study was relatively small, and the improvement was seen with rikkunshito alone as well as with rikkunshito + PPI over a 4-week period.44 This remedy has been used to treat other functional gastrointestinal disorders as well and is thought to work by stimulating gastric emptying and enhancing ghrelin secretion in the stomach whilst also increasing ghrelin receptor sensitivity.45

Symptoms of globus may improve with attention and reassurance based on interventions by speech and language therapists and psychologists.46,47

What is the outlook for the future of functional oesophageal disorders?

The main difficulties in evaluating therapies for functional oesophageal disorders are the wide variety of definitions of functional disorders, the range of specialties dealing with the same or similar disorders, differing diagnostic criteria and small sample sizes. For the future, more streamlined trials with comparable patient populations using Rome diagnostic criteria are likely to yield comparable trials which, as well as being more useful for clinicians, also allow for the issue of small sample sizes. The Rome IV diagnostic criteria are eagerly awaited. With better defined populations, larger trials are possible and the hope would be that this will bring forth more promising treatment options faster.

An anticipated issue is the re-evaluation of functional oesophageal disorders based on our ever increasing understanding of the pathophysiology of these disorders. As in the case for oesophageal hypersensitivity, it is likely that in time, as more knowledge is gained, some disorders classed as functional may be redefined. There is also the possibility that the very nature of a ‘functional disorder’ may also be redefined.

Progress in the field of functional gastrointestinal disorders is encouraging, with the ever increasing acceptance of the Rome process. This plays a major role in the facilitation of research into pathophysiology and therapies. Much more definitive diagnostic criteria, as well as collating current knowledge, is reaping benefits, although there is still a great deal more to be achieved.

References

1. 

Galmiche JP, Clouse RE, Bálint A, et al. Functional esophageal disorders. Gastroenterology 2006; 130:1459–65. http://dx.doi.org/10.1053/j.gastro.2005.08.060

2. 

Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R, Group GC. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006; 101:1900–20; quiz 43.

3. 

Numans ME, Lau J, de Wit NJ, Bonis PA. Short-term treatment with proton-pump inhibitors as a test for gastroesophageal reflux disease: a meta-analysis of diagnostic test characteristics. Ann Intern Med 2004; 140:518–27. http://dx.doi.org/10.7326/0003-4819-140-7-200404060-00011

4. 

Vakil N. Review article: how valuable are proton-pump inhibitors in establishing a diagnosis of gastro-oesophageal reflux disease? Aliment Pharmacol Ther 2005; 22 (Suppl. 1):64–9. http://dx.doi.org/10.1111/j.1365-2036.2005.02612.x

5. 

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; 38:1569–80. http://dx.doi.org/10.1007/BF01303162

6. 

Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Non-erosive reflux disease (NERD)—acid reflux and symptom patterns. Aliment Pharmacol Ther 2003; 17:537–45. http://dx.doi.org/10.1046/j.1365-2036.2003.01423.x

7. 

Surdea Blaga T, Dumitrascu D, Galmiche JP, Bruley des Varannes S. Functional heartburn: clinical characteristics and outcome. Eur J Gastroenterol Hepatol 2013; 25:282–90. http://dx.doi.org/10.1097/MEG.0b013e32835b108f

8. 

Eslick GD, Jones MP, Talley NJ. Non-cardiac chest pain: prevalence, risk factors, impact and consulting—a population-based study. Aliment Pharmacol Ther 2003; 17:1115–24. http://dx.doi.org/10.1046/j.1365-2036.2003.01557.x

9. 

Zerbib F, Bruley des Varannes S, Simon M, Galmiche JP. Functional heartburn: definition and management strategies. Current Gastroenterol Rep 2012; 14:181–8. http://dx.doi.org/10.1007/s11894-012-0255-7

10. 

Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 2009; 58:295–309. http://dx.doi.org/10.1136/gut.2007.145581

11. 

Savarino E, Zentilin P, Mastracci L, et al. Microscopic esophagitis distinguishes patients with non-erosive reflux disease from those with functional heartburn. J Gastroenterol 2013; 48:473–82. http://dx.doi.org/10.1007/s00535-012-0672-2

12. 

Fass R, Achem SR. Noncardiac chest pain: epidemiology, natural course and pathogenesis. J Neurogastroenterol Motil 2011; 17:110–23. http://dx.doi.org/10.5056/jnm.2011.17.2.110

13. 

Selleslagh M, van Oudenhove L, Pauwels A, Tack J, Rommel N. The complexity of globus: a multidisciplinary perspective. Nat Rev Gastroenterol Hepatol 2014; 11:220–33. http://dx.doi.org/10.1038/nrgastro.2013.221

14. 

Sweis R, Fox M, Anggiansah A, Wong T. Prolonged, wireless pH-studies have a high diagnostic yield in patients with reflux symptoms and negative 24-h catheter-based pH-studies. Neurogastroenterol Motil 2011; 23:419–26. http://dx.doi.org/10.1111/j.1365-2982.2010.01663.x

15. 

Slaughter JC, Goutte M, Rymer JA, et al. Caution about overinterpretation of symptom indexes in reflux monitoring for refractory gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2011; 9:868–74. http://dx.doi.org/10.1016/j.cgh.2011.07.009

16. 

Fenster PE. Evaluation of chest pain: a cardiology perspective for gastroenterologists. Gastroenterol Clin North Am 2004; 33:35–40. http://dx.doi.org/10.1016/S0889-8553(03)00128-6

17. 

Miner PB Jr, Rodriguez-Stanley S, Proskin HM, Kianifard F, Bottoli I. Tegaserod in patients with mechanical sensitivity and overlapping symptoms of functional heartburn and functional dyspepsia. Curr Med Res Opin 2008; 24:2159–72. http://dx.doi.org/10.1185/03007990802222832

18. 

Rodriguez-Stanley S, Zubaidi S, Proskin HM, Kralstein JR, Shetzline MA, Miner PB Jr. Effect of tegaserod on esophageal pain threshold, regurgitation, and symptom relief in patients with functional heartburn and mechanical sensitivity. Clin Gastroenterol Hepatol 2006; 4:442–50. http://dx.doi.org/10.1016/j.cgh.2006.01.014

19. 

Ostovaneh MR, Saeidi B, Hajifathalian K, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial. Neurogastroenterol Motil 2014; 26:670–8. http://dx.doi.org/10.1111/nmo.12313

20. 

Park SW, Lee H, Lee HJ, et al. Low-dose amitriptyline combined with proton pump inhibitor for functional chest pain. World J Gastroenterol 2013; 19:4958–65. http://dx.doi.org/10.3748/wjg.v19.i30.4958

21. 

Prakash C, Clouse RE. Long-term outcome from tricyclic antidepressant treatment of functional chest pain. Dig Dis Sci 1999; 44:2373–9. http://dx.doi.org/10.1023/A:1026645914933

22. 

Lee H, Kim JH, Min BH, et al. Efficacy of venlafaxine for symptomatic relief in young adult patients with functional chest pain: a randomized, double-blind, placebo-controlled, crossover trial. Am J Gastroenterol 2010; 105:1504–12. http://dx.doi.org/10.1038/ajg.2010.82

23. 

Cannon RO, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. New Engl J Med 1994; 330:1411–17. http://dx.doi.org/10.1056/NEJM199405193302003

24. 

Cox ID, Hann CM, Kaski JC. Low dose imipramine improves chest pain but not quality of life in patients with angina and normal coronary angiograms. Eur Heart J 1998; 19:250–4. http://dx.doi.org/10.1053/euhj.1997.0615

25. 

Keefe FJ, Shelby RA, Somers TJ, et al. Effects of coping skills training and sertraline in patients with non-cardiac chest pain: a randomized controlled study. Pain 2011; 152:730–41. http://dx.doi.org/10.1016/j.pain.2010.08.040

26. 

Doraiswamy PM, Varia I, Hellegers C, et al. A randomized controlled trial of paroxetine for noncardiac chest pain. Psychopharmacol Bull 2006; 39:15–24.

27. 

Broekaert D, Fischler B, Sifrim D, Janssens J, Tack J. Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study. Aliment Pharmacol Ther 2006; 23:365–70. http://dx.doi.org/10.1111/j.1365-2036.2006.02772.x

28. 

Shapiro M, Shanani R, Taback H, Abramowich D, Scapa E, Broide E. Functional chest pain responds to biofeedback treatment but functional heartburn does not: what is the difference? Eur J Gastroenterol Hepatol 2012; 24:708–14. http://dx.doi.org/10.1097/MEG.0b013e3283525a0c

29. 

Chiarioni G, Whitehead WE. The role of biofeedback in the treatment of gastrointestinal disorders. Nat Clin Pract Gastroenterol Hepatol 2008; 5:371–82. http://dx.doi.org/10.1038/ncpgasthep1150

30. 

Hjelland IE, Svebak S, Berstad A, Flatabo G, Hausken T. Breathing exercises with vagal biofeedback may benefit patients with functional dyspepsia. Scand J Gastroenterol 2007; 42:1054–62. http://dx.doi.org/10.1080/00365520701259208

31. 

Jonsbu E, Dammen T, Morken G, Moum T, Martinsen EW. Short-term cognitive behavioral therapy for non-cardiac chest pain and benign palpitations: a randomized controlled trial. J Psychosom Res 2011; 70:117–23. http://dx.doi.org/10.1016/j.jpsychores.2010.09.013

32. 

Gasiorowska A, Navarro-Rodriguez T, Dickman R, et al. Clinical trial: the effect of Johrei on symptoms of patients with functional chest pain. Aliment Pharmacol Ther 2009; 29:126–34. http://dx.doi.org/10.1111/j.1365-2036.2008.03859.x

33. 

Rao SS, Mudipalli RS, Mujica V, Utech CL, Zhao X, Conklin JL. An open-label trial of theophylline for functional chest pain. Dig Dis Sci 2002; 47:2763–8. http://dx.doi.org/10.1023/A:1021017524660

34. 

Rao SS, Mudipalli RS, Remes-Troche JM, Utech CL, Zimmerman B. Theophylline improves esophageal chest pain – a randomized, placebo-controlled study. Am J Gastroenterol 2007; 102:930–8. http://dx.doi.org/10.1111/j.1572-0241.2007.01112.x

35. 

Jones H, Cooper P, Miller V, Brooks N, Whorwell PJ. Treatment of non-cardiac chest pain: a controlled trial of hypnotherapy. Gut 2006; 55:1403–8. http://dx.doi.org/10.1136/gut.2005.086694

36. 

Clouse RE, Lustman PJ, Eckert TC, Ferney DM, Griffith LS. Low-dose trazodone for symptomatic patients with esophageal contraction abnormalities. A double-blind, placebo-controlled trial. Gastroenterology 1987; 92:1027–36.

37. 

Cook IJ, Dent J, Shannon S, Collins SM. Measurement of upper esophageal sphincter pressure. Effect of acute emotional stress. Gastroenterology 1987; 93:526–32.

38. 

Kumar AR, Katz PO. Functional esophageal disorders: a review of diagnosis and management. Expert Rev Gastroenterol Hepatol 2013; 7:453–61. http://dx.doi.org/10.1586/17474124.2013.811028

39. 

Jeon HK, Kim GH, Choi MK, et al. Clinical predictors for response to proton pump inhibitor treatment in patients with globus. J Neurogastroenterol Motil 2013; 19:47–53. http://dx.doi.org/10.5056/jnm.2013.19.1.47

40. 

Kirch S, Gegg R, Johns MM, Rubin AD. Globus pharyngeus: effectiveness of treatment with proton pump inhibitors and gabapentin. Ann Otol Rhinol Laryngol 2013; 122:492–5. http://dx.doi.org/10.1177/000348941312200803

41. 

Kiebles JL, Kwiatek MA, Pandolfino JE, Kahrilas PJ, Keefer L. Do patients with globus sensation respond to hypnotically assisted relaxation therapy? A case series report. Dis Esophagus 2010; 23:545–53. http://dx.doi.org/10.1111/j.1442-2050.2010.01064.x

42. 

You LQ, Liu J, Jia L, Jiang SM, Wang GQ. Effect of low-dose amitriptyline on globus pharyngeus and its side effects. World J Gastroenterol 2013; 19:7455–60. http://dx.doi.org/10.3748/wjg.v19.i42.7455

43. 

Deary IJ, Wilson JA. Problems in treating globus pharyngis. Clin Otolaryngol Allied Sci 1994; 19:55–60. http://dx.doi.org/10.1111/j.1365-2273.1994.tb01148.x

44. 

Tokashiki R, Okamoto I, Funato N, Suzuki M. Rikkunshito improves globus sensation in patients with proton-pump inhibitor-refractory laryngopharyngeal reflux. World J Gastroenterol 2013; 19:5118–24. http://dx.doi.org/10.3748/wjg.v19.i31.5118

45. 

Nahata M, Muto S, Oridate N, et al. Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease. Am J Physiol Gastrointest Liver Physiol 2012; 303:G42–53. http://dx.doi.org/10.1152/ajpgi.00462.2011

46. 

Khalil HS, Reddy VM, Bos-Clark M, et al. Speech therapy in the treatment of globus pharyngeus: how we do it. Clin Otolaryngol 2011; 36:388–92. http://dx.doi.org/10.1111/j.1749-4486.2011.02326.x

47. 

Millichap F, Lee M, Pring T. A lump in the throat: should speech and language therapists treat globus pharyngeus? Disabil Rehabil 2005; 27:124–30. http://dx.doi.org/10.1080/09638280400007448




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