Introduction Not only acute but also chronic chest pain belongs to one complaint relatively commonly presented by patients to primary care physicians. Chronic chest pain is defined as pain within the thoracic region lasting more than 3 months.¹ Refractory chest pain is defined as chronic chest pain not reacting satisfactorily to routine pain medication and/or adjuvant chronic pain therapy. The main goal of any clinician is to distinguish between pain of cardiac and non-cardiac origin and also differentiate between potentially life-threatening conditions and relatively benign ones.

While the incidence of chest pain compared with other complaints in primary medical care is estimated between 7-24%, and in other sources even between 20-40%,² the incidence of chronic or refractory chest pain in the community is not well investigated. The approximate prevalence of chronic cardiac chest pain in a population older than 60 years is estimated between 10-15%.

Refractory angina Patients with diagnosed cardiac chest pain who are not suitable for percutaneous coronary intervention (PCI) or open surgical revascularization (CABG), and those not responding to standard conservative medical treatment get allocated a diagnosis of refractory angina. Chronic refractory angina is defined as any pain of cardiac origin associated with coronary vessel disease lasting for more than three months.³ Pathophysiologically, refractory angina can be described as reversible attacks of the cardiac muscle ischemia with concurrent anatomical changes of the coronary vasculature and with poor response to any conservative or interventional therapy. Refractory angina pain is present in approximately 5-10% of all subjects diagnosed with ischemic heart disease.⁴ Refractory angina is statistically associated with reduced quality of life, increased rate of hospital admissions, and also with increased financial burden for the healthcare system. Refractory angina may be divided into four phenotypes⁵: A – microvascular angina with minimum changes on coronary arteries (syndrome X), B – patients with localized narrowing or obstruction of coronary vessels, C – patients with diffuse atherosclerotic changes to the coronary arteries often affecting side branches or distal parts of the coronary vasculature, D – end-stage coronary artery disease with refractory angina pain even post PCI or CABG. The incidence of refractory angina on the European continent is reported to be as high as 30-50.000 patients yearly^{2 3} with 50.000 new patients diagnosed in the United States every year.³

Differential diagnosis It is clinically extremely important to differentiate cardiac chronic chest pain from pain of non-cardiac origin and subsequently, if cardiac chronic pain is confirmed, make its differential diagnosis and set up an appropriate pathway of medical and non-medical treatment.

During the differential diagnosis of chronic chest pain, the clinicians should start systematically with the detailed history obtained from the patient or his/her relatives, review of the previous medical charts, hospital admissions, and outpatient visits.² Subsequently, all methods of physical examination (inspection, palpation, percussion, auscultation) are used in the first instance. They should be followed by appropriate functional tests, laboratory methods, and evaluation using radiological examinations.

The presence or probability of chronic cardiac pain can be confirmed or excluded from underlying symptoms, the patient´s age, sex, family history factors, and from the presence or absence of risk factors for the development of atherosclerosis. Family history of myocardial infarction, coronary artery disease, sudden cardiac death, the presence of diabetes, poorly controlled hypertension, hyperlipidemia, and abuse of smoking increase the probability of cardiac origin of chronic chest pain.⁶ Essential information is also the identification of factors invoking, worsening, and alleviating chest pain. If provoking and worsening factors are associated with increased physical activity while reduction of intensity comes at rest, it is quite probable that the origin of pain is cardiac. Character and descriptors of pain can also help in the differential diagnosis of chronic chest pain. Sharp, exactly located pain is usually somatic in origin and may arise from subcutaneous tissue, muscles, ribs, or pleura. On the contrary, blunt, poorly located, or diffuse pain deep inside the chest is probably associated with myocardial ischemia or arises from the esophagus or stomach.

Vital signs such as heart rate, non-invasive blood pressure values, the character of the peripheral pulse wave, capillary refill time, respiratory rate, peripheral oxygen saturation using a pulse oximeter, and body temperature should be evaluated and recorded in every patient suffering from chest pain.² Twelve-lead electrocardiogram (ECG) should be carried out in all patients where the cardiac cause of chest pain could not be safely excluded. It must be mentioned that ECG without ischemic changes cannot always exclude the cardiac origin of pain. Other cardiac examinations such as treadmill test, bicycle ergometry, dobutamine stress echocardiography, or even mini-invasive coronarography are indicated if the cardiac origin of the pain is probable.

Other causes of chronic cardiac pain Vasospastic angina (Prinzmetal´s angina) – this type of angina pain is induced mainly by the coronary artery vasospasm at the level of epicardium.⁴ Concurrent obstructive coronary artery affliction may be either absent or present. Precipitating factors may be multifactorial and involve stress, cold, hyperinsulinemia, use of vasospasm-inducing drugs such as cocaine. This type of angina can present during exercise or as well at rest. Myocardial infarction may develop if the spasm is not terminated. Vasospastic angina is in most cases relieved by the sublingual use of glyceryl trinitrate and/or calcium channel blockers.

Pericarditis – pain in pericarditis is usually quite sharp, some patients describe it even as stabbing or stinging but a minority of affected persons may describe its character as pressure-like, dull, or astringent.² Pain is located mostly behind the sternum or inside of the left side of the chest but it can irradiate into the left shoulder, left arm, or neck. Its intensity decreases in the sitting position and worsens when supine, during deep breathing or coughing. Chronic constrictive pericarditis develops gradually and persists for more than 3 months. Diagnosis is confirmed with echocardiography.

Aortic stenosis – chest pain in aortic stenosis is similar to angina pain and is usually associated with physical activity. The presence of additional symptoms and findings such as shortness of breath, fatigue, palpitations, and long systolic murmur may help in differential diagnosis. Echocardiography confirms or excludes aortic stenosis.

Mitral valve prolapse – the character of pain in this condition mostly differs from angina pain. It is more sharp often similar to myofascial pain but may be very intense and cause major anxiety. Other symptoms associated with mitral valve prolapse include palpitation, arrhythmias, dizziness, or dyspnea. Mitral valve prolapse is confirmed with echocardiography.

Congenital heart defects and other anomalies – almost one-third of adult patients with congenital heart disease report chronic pain. The prevalence of pain increases with age and in individuals older than 65 years, the incidence of moderate or severe pain is reported at 47%.⁷ The highest incidence of pain has been reported in cyanotic congenital heart anomalies, Eisenmeger´s syndrome, and in those patients with a history of previous open heart surgery.

Pericardial effusion – chest pain is located directly behind the sternum or slightly on the left side from the sternal bone. Patients can also report the feeling of the full chest, tenderness, or pressure-like pain. Breathing difficulties and other symptoms usually improve when the affected persons sit up or stand up and worsen when lying flat. Transthoracic or transesophageal echocardiography is indicated if this diagnosis is suspected.

Causes of non-cardiac chronic chest pain Causes of non-cardiac (atypical) chronic chest pain include a relatively wide spectrum of diseases and conditions arising from pathologies or functional problems within the respiratory and gastrointestinal tracts, or from other organs of the thoracic cavity a chest wall.¹ The most important issue for the clinician is to distinguish between potentially life-threatening causes and relatively benign conditions. Any type of cancer should be always excluded. Other serious causes of chronic non-cardiac chest pain include almost all pulmonary diseases, GIT ulcers, and aneurysm/dissection of the intrathoracic aorta.

Pulmonary origin: pneumonia, pneumonitis, pulmonary embolism, pulmonary infarction, intrapulmonary abscess, pleuritis, pneumothorax, hemothorax, asthma, chronic pulmonary obstructive disease.

Pulmonary origin of chronic chest pain should be always confirmed or excluded using imaging methods (CT, MRI, ultrasound, bronchoscopy, EBUS).⁶ Pain in COPD is often related to mediastinal fascias.⁸

Origin from the gastrointestinal tract: esophagus inflammation, gastroesophageal reflux disease, esophageal spasm, esophageal cancer, gastritis, gastric or duodenal ulcer, Boerhave´s syndrome, less often cholecystitis (location predominantly right upper quadrant) or pancreatitis (location predominantly epigastrium, middle back or the entire abdomen).⁹

Most similar pain to chronic angina is that associated with the involvement of the esophagus.¹ While esophagitis, gastroesophageal reflux disease, and esophageal cancer may be quite easily diagnosed using upper gastrointestinal endoscopy, CT, MRI, or ultrasound, the diagnosis of esophageal spasms is often very difficult.¹⁰

Origin in mediastinum: dissection of the ascending aorta, aortic arch, descending aorta, aneurysms of the ascending aorta, aortic arch or thoraco-abdominal aorta, mediastinitis.

These diseases are excluded or confirmed usually with an MRI or CT scan if an MRI is not feasible or available.

Musculoskeletal origin: Costochondritis, trauma to the ribs, sternum, chest wall muscles, muscle spasms, fibromyalgia, post-procedural chronic pain (sternotomy, thoracotomy, breast surgery), referred pain from the thoracic spine (facet joint, nerve root compression, inflammation, discogenic pain), chest wall tumors (infiltration of the ribs, sternum, mesothelioma, sarcomas, lymphomas, thymoma).

Pathologies of the musculosceletal system and chest wall are confirmed by imaging methods, functional conditions are often difficult to diagnose.

Other origin: post-herpetic neuralgia, necrotizing fasciitis, panic attack disorders, psychiatric illness.

Conclusions Differential diagnosis of chronic or refractory chest pain includes as a first step exclusion of the cardiac origin of pain. Comprehensive differential diagnosis is based on the patient´s history, physical examination, and the judicious use of laboratory tests, functional evaluations, and imaging methods.

Appendix Suggested treatment algorithm for refractory angina pain

Based on our more than 15-year experience with patients suffering from refractory angina pain in our center, we would like to suggest the following treatment algorithm:

1. In the first step, we test the responsivity of the sympathetic nervous system in refractory angina pain. All patients undergo ultrasound–guided stellate ganglion block on the left side with 10 ml of 0.2% bupivacaine (levo–bupivacaine) twice in a two–week interval. The intensity of pain using a 0–10 visual analogue scale (VAS) of pain, the frequency of angina attacks, and the consumption of glyceryl trinitrate is evaluated and recorded daily for one month. All patients having at least a 50% reduction in two out of these three evaluated parameters are considered responders to sympathetic block and indicated for left–sided radiofrequency ablation of ympathetic chain at the level of T2 and T3.

2. Patients not responding to sympathetic block are offered a trial of transcutaneous electrical nerve stimulation (TENS) and if they have a positive response, they receive implantation of a spinal cord stimulator.

3. Patients in the terminal phase of their life may receive a tunneled high thoracic epidural catheter or systemic treatment with morphine.

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