Definition: Non-cardiac chest pain (NCCP) refers to recurrent retrosternal pain excluding cardiac factors, and usually refers exclusively to chest pain of esophageal origin or presumed to be of esophageal origin. 1, the etiology and pathogenesis of NCCP 1, gastroesophageal reflux disease and NCCP in the Western population, the most common cause of NCCP is gastroesophageal reflux disease (GERD), accounting for about 4O% to 60%. The results reported about the Chinese population vary, with GERD accounting for about 30% to 80%. The prevalence of NCCP is higher in patients with typical reflux symptoms. Studies have reported 37% NCCP in patients with frequent (at least 1 time per week) heartburn, compared to 7.9% NCCP in those without reflux symptoms. A recent study from South America reported similar results, and the association between GERD and NCCP does not suggest a causal relationship. Patients presenting with acid reflux are not often associated with chest pain. However, the study showed that more than 80% of patients with NCCP who had erosive esophagitis or abnormal pH monitoring had a significant effect of anti-reflux treatment (chest pain disappeared or was significantly reduced. The mechanism of GERD-induced chest pain is not fully understood. It may be related to acid reflux stimulating the esophagus or causing esophageal injury, secondary power abnormalities and esophageal hypersensitivity to acid. Some esophageal motility disorder (esophageal motility disorder, esophageal dysmotility), such as diffuse esophageal spasm and cardia failure, can have symptoms of chest pain. In patients with NCCP, however, esophageal motility disorders are relatively rare, and a significant proportion of patients with abnormal esophageal motility on manometry also have GERD. studies have shown that 30% of patients with NCCP without dysphagia have abnormal esophageal motility, increasing to 45% in patients with dysphagia. common esophageal motility abnormalities in NCCP include nutcracker esophagus (nutcrackeresophagus), nonspecific esophageal dysmotility, low or high LES pressure, diffuse esophageal spasm, and cardia achalasia. The relationship between esophageal motility disorders and NCCP is still controversial, mainly because patients undergoing esophageal manometry with motility abnormalities do not often present with chest pain, and chest pain may improve even if esophageal motility is not normalized. 3.Functional chest pain presumed to be of esophageal origin in the Rome III diagnostic criteria for functional gastrointestinal disease. Functional chest pain of presumed esophageal origin (functional chest pain of presumed esophageal origin) is defined as recurrent episodes of unexplained chest pain. The pain is often located in the middle and characterized by visceral pain. The diagnosis must include all of the following: 1) non-burning retrosternal pain or discomfort; 2) no evidence of gastroesophageal reflux causing the symptom; 3) no histopathologic basis for esophageal dysmotility disorders; and 4) symptoms present for at least 6 months prior to diagnosis, with the above criteria being met in the last 3 months. Functional chest pain presumed to be of esophageal origin is an important etiology of NCCP. After exclusion of GERD. A significant proportion of NCCP can be classified in this category. Current studies have found the following pathophysiological manifestations of the disease: visceral hypersensitivity, abnormal esophageal dynamics and psychosomatic abnormalities. Most scholars believe that visceral hypersensitivity is the main pathogenesis of functional chest pain. 4.Visceral hypersensitivity is a phenomenon of enhanced sensation to visceral stimuli. This enhancement is not dependent on the intensity of the stimulus. Visceral hypersensitivity in NCCP patients can exist both peripherally (sensitization of esophageal sensory afferents) and centrally (increased excitability of spinal cord neurons or enhanced cortical signal processing), and the exact mechanism remains to be clarified. Esophageal hypersensitivity persists even after the initial stimulation ends and the mucosa heals. It has been demonstrated that patients with NCCP have a reduced esophageal pain threshold (pain threshold). Some NCCP patients with GERD have an increased esophageal pain threshold after high-dose PPI therapy. The enhanced sensation to esophageal stimuli may also be due to enhanced signal processing of visceral sensory afferents by the cerebral cortex. Not only the hypersensitive response of the visceral sensory afferent pathway . A recent study found that. NCCP patients with esophageal hypersensitivity may be divided into different subgroups according to their sensory responses and neurophysiological characteristics. It is estimated that 17% to 43% of NCCP patients have some kind of psychosomatic abnormality. Chest pain is also one of the manifestations of panic attack. Studies have reported that the prevalence of panic disorder, anxiety and depression is high in NCCP. Psychosomatic factors are related to functional chest pain. However, their potential roles are complex, and psychiatric disorders may be the reason for patients to seek medical attention. They may not be the direct cause of chest pain. In addition, esophageal cardiac inhibitory reflex (esophagocardiac inhibitory re-flex), prolonged and sustained contraction of longitudinal smooth muscle of the esophagus and autonomic dysfunction may also be the pathogenesis of NCCP. Second, the diagnosis of NCCP excludes cardiac factors and non-esophageal diseases such as pulmonary pleural diseases, musculoskeletal diseases, abdominal lesions (cholelithiasis, cholecystitis, peptic ulcer) and other causes of chest pain, relevant diagnostic tests are needed to clarify whether NCCP is caused by GERD or other esophageal factors. The value of upper gastrointestinal endoscopy and x-ray examination in the diagnosis of NCCP is limited. It is estimated that no more than 25% of patients can be seen with mucosal involvement of the esophagus. However, endoscopy is an important tool to rule out malignant lesions and peptic ulcers, and to know the presence of erosive esophagitis and Barrett’s esophagus in patients with GERD-related NCCP. Barium swallow x-ray of the esophagus is less sensitive, but it has some advantages for the diagnosis of esophageal hiatal hernia and cardia incontinentia. 2.Esophageal pH monitoring 24 hours can confirm the presence of pathological acid reflux and understand the relationship between chest pain and acid reflux, but at present, its sensitivity for GERD diagnosis is only 50%~80%. In the last lO years. With the development of protonpump inhibitor (PPI) therapy trials, the status of 24-hour esophageal pH monitoring in the evaluation of NCCP has changed significantly. Currently. This monitoring is recommended for NCCP patients who have failed empirical PPI therapy. A new study using a wireless esophageal pH monitoring system found that extending the monitoring time to 48 hours increased the detection rate of GERD in NCCP patients. 3.PPI therapeutic test PPl test is easy to perform, has high sensitivity and specificity, and is a valuable diagnostic test for NCCP. In some major studies, the sensitivity of the PPl test for diagnosing GERD-related NCCP is 78%-92%. The specificity ranged from 67% to 86% (see Table 1). Two recent meta-analyses have evaluated PPI tests: PPI treatment has been shown to reduce NCCP symptoms and is a valuable diagnostic test for identifying abnormal acid reflux in the esophagus. However, the authors also noted that most of the published studies had small sample sizes and were potentially biased (several studies were actually from the same group). Therefore, it can be concluded that the PPI test has an acceptable sensitivity and specificity as a diagnostic test for GERD in patients with NCCP and can be the first method used to diagnose GERD-related NCCP. 4.Esophageal manometry esophageal standard manometry, provocation test and 24-hour dynamic manometry have been widely used in the research and clinical diagnosis of NCCP. However, in recent years, it is believed that esophageal manometry is only considered in patients who do not respond to acid suppression therapy (negative PPl test) or negative esophageal pH monitoring, and its significance in NCCP may be limited to excluding cardia achalasia, which is uncommon in patients with NCCP without concomitant symptoms such as dysphagia. Diagnosis of other esophageal motility disorders such as nutcracker esophagus, LES hypertension, and diffuse esophageal spasm does not affect the choice of treatment options. Because these patients can be tried with both smooth muscle relaxants and pain modifiers, or a combination of both. 5, other esophageal stimulation test, such as balloon dilation test, Tensilon test, acid drip test (Bemstein test), etc. because of the low sensitivity and side effects. They are rarely used nowadays. The value of intracavitary multichannel impedance and functional brain imaging in NCCP needs to be further investigated. Due to the high prevalence of psychiatric disorders in patients with NCCP, the prevalence of psychiatric disorders in patients with NCCP is high. Patients who respond poorly to treatment or present with psychosomatic abnormalities should perhaps undergo psychosomatic evaluation by a specialist. Most experts now believe that after excluding cardiac and non-esophageal disease. A positive PPI test should be considered as GERD-associated NCCP and may require long-term acid suppression therapy. Further 24-hour esophageal pH monitoring is required if there is no response to the PPI test, and if the pH monitoring is abnormal. Long-term treatment with acid-suppressing drugs at higher doses is indicated. If pH monitoring is negative, esophageal manometry can be performed to detect dysmotility disorders. Third, the treatment of GERD-related NCCP 1, general treatment changes in lifestyle and dietary habits may help to reduce reflux symptoms. However, the benefits in GERD-related NCCP have not been evaluated and are usually used as an adjunctive treatment in addition to drugs. 2. The acid-suppressing drug PPI is a landmark drug in the treatment of GERD-related NCCP. In a randomized double-blind controlled trial [2Ol, patients with NCCP showed significant improvement in symptoms after 8 weeks of omeprazole 2O mgbid compared with placebo. Most patients with GERD-related NCCP had significantly reduced or even disappeared chest pain after treatment with PPl. In the treatment of NCCP, it is advisable to double the dose of PPI until the symptoms are relieved. A major PPI trial for non-cardiogenic chest pain is often required to be taken for more than 2 months. Research on maintenance therapy for GERD-related NCCP is lacking. However, patients are generally advised to take long-term maintenance therapy to reduce symptom recurrence. 3. anti-reflux surgery There are few studies about fundoplication for GERD-related NCCP. Follow-up of patients with chest pain and other GERD symptoms who underwent anti-reflux surgery found that 65% of patients who did not have chest pain present on preoperative pH monitoring had improved symptoms after surgery, compared with 65% of patients whose preoperative pH monitoring showed chest pain associated with acid reflux events. Postoperatively, 96% of symptoms improved. Although studies have shown a high success rate of anti-reflux surgery for GERD-related NCCP, their study population is usually carefully selected. IV. Treatment of non-GERD-related NCCP 1. Smooth muscle relaxants The treatment of abnormal esophageal dynamics in patients with NCCP is more controversial. There is growing evidence that, in addition to cardia incontinentia, patients with NCCP and spastic esophageal motility disorder (spastic esophageal motility disorder) do not respond as well to muscle relaxants as pain modifiers. There is insufficient evidence that nitrates are effective for chest pain in esophageal dysmotility disorders. Calcium channel blockers, although commonly used in I clinics, have limited effect on NCCP other than cardia incontinentia and are not effective in relieving symptoms. 2, lower esophageal sphincter injection In recent years, some uncontrolled studies have shown that. Miller et al. showed that endoscopic injection of botulinum toxin (Btulinum toxin) into the lower esophageal sphincter (LES) has some promise in the treatment of spastic esophageal motility disorders. Miller et al. injected botulinum toxin into the gastroesophageal junction in NCCP patients with non-reflux-related spastic esophageal motility abnormalities. Each 100-point 5-point cricoid injection of 20 u each was administered. 72% of patients had more than 50% reduction in chest pain after treatment. The average chest pain score was reduced by 79% compared to the previous one, and the average time without chest pain was 7.3 months. Botulinum toxin injection appears to result in short-term symptomatic improvement in patients with NCCP who have spastic esophageal motility abnormalities. However, controlled studies are needed to confirm this. 3, pain modulator (pain modulator) or visceral analgesic (visceralanalgesic) antidepressants have been used to treat chest pain caused by esophageal disease for nearly 20 years, and studies have confirmed that such drugs can improve symptoms. It is presumed to be functional chest pain of esophageal origin. The treatment options are limited, but the efficacy of antidepressants is encouraging. Pain modifiers for NCCP include tricyclic an-tidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin reuptake inhibitors (SSRIs). The mechanism by which TCA reduces visceral pain has not been elucidated, with some studies suggesting a central and others suggesting a peripheral effect. Promethazine (imipramine) can increase the esophageal pain threshold in normal subjects. Varia et al. conducted a randomized double-blind placebo-controlled study to evaluate the SSRI sertraline in the treatment of NC-CP. Patients in the sertraline group were given 50-200 mg/d for 8 weeks, and compared with the placebo group. Chest pain was significantly reduced. It is suggested that SSRI has the potential to treat NCCP. Low doses of trazodone (100-150 mg/d) did not affect the contraction of esophageal increase, but improved the symptoms of patients with abnormal esophageal dynamics NCCP. Some individual studies have shown that octreotide and theophylline can increase the esophageal pain threshold in patients with NCCP. Some patients with NCCP have varying degrees of psychiatric or psychological disorders. This may be a cause or consequence of chest pain, and their relationship with NCCP is more complex. Alprazolam (Alprazolam) and clonazepam (Clonazepam) help to reduce panic attacks, chest pain and anxiety score. Behavioral treatments such as education, controlled breathing, relaxation training, and distraction from pain may have some effect. Further in-depth research into the pathogenesis of pain and the search for new therapeutic measures are expected to improve the efficacy of NCCP. Some drugs used in functional gastrointestinal disorders will also be tried in the treatment of NCCP. Novel 5-monohydroxytryptamine. receptor antagonists as well as 5-monohydroxytryptamine. receptor partial agonists (e.g., tegaserod) in NCCP need to be further investigated. the K-opioid receptor antagonist fidotoxine (fedo-tozine) has shown a peripheral antisensory injury (antinociceptive) effect in patients with irritable bowel syndrome, reducing gastrointestinal dilatation sensation and relieving pain; neurokinin ( neurokinin (NK) receptor antagonists type l and type 2, which reduce gastrointestinal motility and pain. These drugs have the potential to become new options for the treatment of NCCP.