Gut Check: Andree Koop, MD, on Noncardiac Chest Pain

In the latest Gut Check podcast, Drs. Brian Lacy and Andree Koop talk about noncardiac chest pain, a common condition that often send patients to emergency departments or primary care and from there to the care of gastroenterologists. 

Brian Lacy, MD, is a professor of medicine at Mayo Clinic-Florida in Jacksonville, Florida. Andree Koop, MD, is an assistant professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic in Jacksonville, Florida.

Noncardiac Chest Pain: Diagnostic Approach, Common Etiologies, and Management Strategies

• Noncardiac chest pain (NCCP) is defined as recurrent retrosternal chest pain/discomfort after cardiac causes have been excluded. NCCP is common, accounting for up to 5% of emergency department visits, up to 6% of primary care visits, with an estimated 13% community prevalence; among patients presenting to the emergency department with chest pain, ≥60% may have a noncardiac etiology. Patient history and pain descriptors alone do not reliably distinguish cardiac from esophageal chest pain, necessitating objective cardiac evaluation before gastrointestinal testing.

• Gastroesophageal reflux disease (GERD) is the most common esophageal cause of NCCP, affecting 30%–60% of patients, followed by functional chest pain (approximately one-third of cases) and esophageal motility disorders such as distal esophageal spasm and hypercontractile (“jackhammer”) esophagus (≤10%). Initial management typically includes a 4–8 week proton pump inhibitor (PPI) trial (eg, omeprazole or esomeprazole 40 mg daily), with response defined as ≥50% reduction in pain severity or frequency.

• For persistent symptoms, a structured evaluation includes upper endoscopy, ambulatory pH monitoring (catheter-based or wireless capsule), and high-resolution esophageal manometry. Management may involve smooth muscle relaxants (calcium channel blockers, nitrates) for spastic disorders and neuromodulators (eg, nortriptyline, imipramine, trazodone, sertraline, venlafaxine) targeting visceral hypersensitivity. Psychiatric comorbidities, including anxiety, depression, and panic disorder, occur in up to 50% of patients; cognitive behavioral therapy, gut-directed hypnotherapy, relaxation training, and diaphragmatic breathing may provide additional benefit.

Any views and opinions expressed are those of the authors and/or participants and do not necessarily reflect the views, policies, or position of the Gastroenterology Learning Network or H&P Global, its employees and affiliates.

Dr Lacy:

Welcome to GutCheck, a podcast from the Gastroenterology Learning Network.  My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida. I am absolutely delighted to be speaking today with Dr. Andree Koop, assistant professor of medicine in the division of gastroenterology and hepatology at the Mayo Clinic in Jacksonville, Florida. Dr. Koop is an expert in the field of esophageal disorders and one of his areas of research is noncardiac chest pain, a common reason why patients are referred to gastroenterologists for evaluation and treatment. Dr. Koop, welcome. Let's begin simply. How do you define noncardiac chest pain?

Dr Koop:

Dr. Lacy, to start, I want to thank you for inviting me on this podcast. I'm really excited for this discussion today and this really important topic. It's something that greatly affects the quality of life of our patients and also is associated with significant healthcare utilization. And yet to start, how do we define noncardiac chest pain? This is typically defined as a recurring retrosternal chest pain or discomfort of noncardiac etiology. It's a pain that can vary in intensity. In some patients it's a discomfort and may be a stabbing or sharp pain and it can vary in frequency from daily to several times per week, but typically a retrosternal pain or discomfort.

Dr Lacy:

So perfect. So following up on that, when we think about this retrosternal chest pain or discomfort, are there any specific descriptors that help distinguish a cardiac cause of chest pain from a noncardiac cause of chest pain? For example, is burning pain more likely to represent a noncardiac cause as opposed to a squeezing type of pain?

Dr Koop:

This is an excellent and important point. Patient history and pain descriptors alone do not reliably distinguish cardiac ischemia from esophageal chest pain because both share visceral AFR innervation and they can present similarly. We do think about features like postprandial timing, relief with antacids or heartburn and regurgitation and perhaps those may suggest an esophageal source, but they're not specific enough to be diagnostic so that's really important. This is particularly important with patients with diabetes or women or older adults who may have atypical or they may present with more atypical symptoms as well. So we cannot rely on history and physical examination and this is where we rely on our objective cardiac testing to rule out cardiac etiology.

Dr Lacy:

Andre, this is something that you see all the time. I see all the time, but to put this in perspective for our listeners, how common is this problem?

Dr Koop:

Yeah, this is really common and this is something that a practicing emergency department physician, a primary care physician, or a gastroenterologist may see daily or at least several times per week in their clinic or their other practice setting. Noncardiac chest pain, it's estimated to account for up to 5% of emergency department visits. It may account for up to 6% of primary care visits and there's an estimated community prevalence of 13%. Of all patients who present to the emergency department for chest pain, it's thought that at least 60% may have a noncardiac etiology. So this is something that is really common.

I like to also point out that as common as this is something that greatly impacts the quality of life of our patients. There have been studies that have shown to patients with noncardiac chest pain compared to cardiac chest pain, or which has a higher mortality that patients with noncardiac chest pain have greater symptom severity. It may impact their functioning at work more and overall they have worse quality of life.

Dr Lacy:

So a lot of great teaching points here. One, we learned symptoms are nonspecific. We learned that this is an incredibly common problem with a huge impact on quality of life. Let's shift gears just a little bit and let's think about a patient with chest pain, maybe a 30-year-old woman with 2 to 3 episodes of chest pain per week. What's the first step in the evaluation of this patient?

Dr Koop:

Great. Yeah, the first step is really a good history and physical examination. And really for a patient coming with chest pain, the history first focuses on excluding life-threatening causes or other cardiac etiologies. And so again, most of the time when patients have seen us in GI clinic, they've previously had stress testing or cardiac etiology ruled out. That's been by an emergency medicine physician or by their cardiologist. And if not, we often feel comfortable ordering a cardiac stress testing ourselves. But once a cardiac etiology has been rolled out, that's where with the history we focus on other signs or symptoms. We do ask about heartburn, regurgitation, that may suggest an esophageal cause.

It's very important early on to focus on red flag signs or symptoms. Those are things such as weight loss, blood in the stool, family history of esophageal or GI malignancy, because if those are present, we may have a lower threshold to proceed directly to an upper endoscopy as the next step. So those are important factors.

Another important thing is the physical exam. We call this noncardiac chest pain. There are other noncardiac causes, things like costochondritis, as patients will typically have reproducible pain on physical examinations. Those are some other things that we think about as well.

Dr Lacy:

So great, you've touched on a few common causes such as acid reflux disease, maybe costochondritis, a musculoskeletal problem. What are some of the other common causes of noncardiac chest pain?

Dr Koop:

So overall, by and far, gastroesophageal reflux disease is the most common cause and can affect anywhere from 30 to 60% of patients. This is next followed by functional chest pain, which is a disorder of gut-brain interaction and accounts for approximately one-third of these patients and is driven largely by visceral hypersensitivity. Then the third esophageal cause that we think about are esophageal motility disorders, particularly those of esophageal spasm. That's distal esophageous spasm and hypercontractile esophagus, which is often commonly referred to as jackhammer esophagus. And overall, these are less common again in 10% or less of our patients. While we're talking about other causes, I think this is a good time to point out that these patients frequently have psychiatric comorbidities. There's a very high percentage of anxiety, depression, and panic disorder. These comorbidities occur in up to 50% of our patients.

Dr Lacy:

Wow. So recognizing that ongoing or concomitant psychological distress may play a role a little bit later when we talk about treatment. So let's go back. Patients are always worried about pain. They're always fearful that pain means something bad, but kind of what's the underlying pathophysiology that causes this noncardiac chest pain?

Dr Koop:

The pathophysiology is complex and may vary per patient to patient, but it can involve a combination of impaired esophageal integrity. That's something that we may see in our patients with reflux disease. Again, they can have esophageal motor abnormalities in our patients who have esophageal spasm. But most importantly—and I think this is the driving cause in most patients—there's visceral hypersensitivity with altered central pain processing. Essentially, these patients have a high sensitivity to esophageal stimuli and that's what drives the pain in these patients. There have been a number of studies that have looked at this. There have been older studies where they've done balloon distension testing where a balloon is inflated within the esophagus to try and reproduce this pain. And in most of these patients, the pain is reproducible with the balloon and at least 40% have lower thresholds to inducing pain, so evidence of visceral hypersensitivity.

They've also done studies where they will infuse acid into the esophagus, in essence, almost reproducing reflux. And these patients will develop pain at lower thresholds or lower amounts of acid. So multiple findings that implicate visceral hypersensitivity as the underlying pathophysiology of this disorder.

Dr Lacy:

Wonderful. Great explanation. We recognize that there are millions of nerves, sensory nerves in the esophagus and many of these patients, they just sense things differently at a lower threshold. So let's get back to our patient. She's 38. She's lean, not obese. She does not have a big hiatal hernia. Because of the concerns about a cardiac cause, she went to see a cardiologist. Unfortunately, all the tests were normal. Now you mentioned that gastroesophageal reflux is really the most common cause of noncardiac chest pain. So what do you do in a patient like this? Do you treat empirically? Let's just put you on a medicine to suppress acid reflux and treat that, or does this type of patient require objective testing?

Dr Koop:

Agree. Yeah. Most of the time, given the high pretest probability and the higher proportion of patients with noncardiac chest pain who have reflux, our first step is usually a PPI trial. And we usually start with a good potent once daily PBI, such as omeprazole or esomeprazole 40 milligrams once daily. And we try that for 4 to 8 weeks and see if there's improvement in pain symptoms. We typically define improvement as at least a 50% reduction in the pain severity or frequency.

It's important to note that some patients with reflux as a cause of pain, they may respond within just a couple of days of this PPI trial, whereas others, it may take a few weeks. So that's typically our first step and that's typically what most primary care physicians will do prior to referral of these patients to GI clinic.

Dr Lacy:

Wonderful. So we're really kind of working with a real world scenario because this is so common. So let's say you take that patient, you put them on a once a day PPI, reminding our listeners that not all PPIs are created equally. Some are more potent, some are less potent, but you put on this patient on a high potency PPI. She's very good about taking her medicine correctly on an empty stomach, does it for 8 weeks, but then calls you back and says, "You know what? This has done nothing. I'm still having my 2 to 3 episodes per week. Now what do you do?

Dr Koop:

So this is also a very common scenario in clinical practice and I’d like to point out that as much as 60% of our patients do not respond to PPI trials. And so this is where, if you have someone who you have a high suspicion for reflux disease, we can proceed with objective testing for reflux. There's 2 ways to do this. There's catheter-based testing, in which patients are monitored for 24 hours, and there's a wireless pH capsule testing, in which a capsule is placed during upper endoscopy and that allows for prolonged monitoring from 48 to 96 hours, but these tests can be performed to truly exclude reflux.

I skipped a step. Actually, the next step is to proceed with a diagnostic upper endoscopy. And for our patients with persistent pain, this is really important. We look for things like erosive esophagitis. We look for mucosal changes of EoE. Patients can have underlying pathophysiology like eosinophilic esophagitis or lymphocytic esophagitis, even with a normal appearing esophagus. So we often biopsy in these scenarios as well. But typically the next step is an upper endoscopy to exclude other mucosal disease and then we may consider objective reflux testing as well. And if that is negative, our test after that is high-resolution esophageal manometry, and that's how we'll assess for motor disorders of the esophagus.

Dr Lacy:

Wonderful. Great explanation. So let's say that in this patient and she was a lean patient without a hiatal hernia. So although acid reflux disease is the most common cause, you pursue testing, you do the endoscopy. Fortunately, things look normal. A 48-hour wireless pH capsule test was normal off of PPI therapy, but then you do the manometry, esophageal manometry, high-resolution esophageal manometry, and you identify a spastic disorder of the esophagus. So how is that treated?

Dr Koop:

So there's a number of ways that we can go for treatment of spastic orders of the esophagus, but we typically do a step-up approach. When you think about esophageal spasm, there can be two flavors of symptoms that patients may have. In this case, it's chest pain, but other patients may have more dysphasia-predominant symptoms. And this is important to differentiate because as we discussed, patients with chest pain that's driven primarily by visceral hypersensitivity, even though there are these spastic changes of esophagus that receive…There have been studies that show even with medications in reversal of spastic changes on manometer, chest pain may still persist in these patients, again, suggesting a role of visceral hypersensitivity.

But different options, we can use smooth muscle relaxers. These are things like calcium channel blockers, nitrates. And then we also use neuromodulator medications for these patients targeting visceral hypersensitivity. These are medications like nortriptyline, imipramine, tricyclic amines, or trazodone to try and decrease pain in that standpoint. And then there'll be other things that I'm sure we will get into like cognitive behavioral therapy, relaxation therapy. These are other complimentary ways to root pain as well.

Dr Lacy:

Andree, perfect segue. So let's think about that patient with noncardiac chest pain where PPIs didn't work and the pH testing was negative or normal off of PPI therapy and the esophageal motility study was actually normal. It wasn't a spastic disorder. Are there other medications we can try? And can you also touch on maybe some of those other things you mentioned in terms of behavioral therapy or hypnotherapy or CBT?

Dr Koop:

Yeah, these are all very important points. So again, we do use neuromodulator medications to treat these patients and studies have shown that these medications are helpful for pain. Most of these studies have been smaller anywhere from 20 to a hundred patients, but medications like imipramine, sertraline, venlafaxine, they've all shown benefit in chest pain, whereas some of these other neuromodulators have shown improvement in overall quality of life.

It's important to note again that there's a really high prevalence of anxiety, depression, panic disorder in these patients. And so these medications may also be helpful in this regard. That's kind of interesting. Studies have actually shown how these medications may improve pain. For example, there was a study with intravenous infusion of citalopram and that actually decreased the threshold during balloon distension testing by which patients felt the balloon. So it may help reduce the overall pain thresholds.

These patients can be very hypervigilant. They can be very focused on symptoms and they can have what we call symptom specific anxiety and that focus on symptoms can in turn make symptoms worse. These patients may have pervasive negative thought patterns and these are where things like cognitive behavioral therapy where you target these maladaptive thoughts can be really helpful and other things may be gut-directed hypnotherapy. We do relaxation training with diaphragmatic breeding. Diaphragmatic breathing can be very helpful for those patients and brings the body from this heightened state to a more rest and digest state.

Dr Lacy:

Wonderful. I like the way you said that because for many of these patients, it can become a vicious cycle where they have some chest pain, but they're also anxious. They start to worry about will they have an episode of chest pain at some event, makes them a little bit more anxious, they're more hypervigilant and this old thing becomes this kind of vicious cycle and vicious circle of this overlapping psychological distress with visceral hypersensitivity. So employing these other techniques, as you mentioned, behavioral therapy, CBT, hypnotherapy with medications such as neuromodulators, can be perfect. So Andree, this has been a wonderful conversation. Any last thoughts for our listeners and do you want to cue us in on any of your cutting edge research?

Dr Koop:

Yeah, Dr. Lacy, I want to thank you again for having me on this podcast. This has been really fun today. Just a couple take home points. One, noncardiac chest pain means that a cardiac etiology has to have been ruled out. So I would not proceed with any esophageal testing until that patient has had testing or seen a cardiologist to truly exclude a cardiac etiology. The second point, it's good to have a structured evaluation for these patients. We talked about the 3 most common esophageal causes—that's gastroesophageal reflux disease, functional chest pain and esophageal motor disorders. And we do really a structured evaluation and treatment pathway where we may consider a PPI trial endoscopy with or without ambulatory pH monitoring and then high resolution esophageal manometry. And then the last point which you really brought up as a lot of these patients can be quite anxious or have hypervigilance, they may be really worried that they have esophagus cancer.

And so doing this evaluation, but then giving these patients reassurance that they do not have a condition that's life-threatening, they do not have cancer, that can go a really long way as well. And note with Dr. Lacy, here at Mayo Clinic- Florida, we have an exciting study where we have been looking at virtual reality with a treatment of noncardiac chest pain. And the goal of this study has been to incorporate other nonmedicine type treatments where again, we focus on this hypervigilance and using virtual reality as a different treatment paradigm to help these patients' mind symptom improve.

Dr Lacy:

Wonderful. So Dr. Koop, once again, thank you so very much for lending your expertise on this important and common and sometimes frustrating topic. To our listeners on Apple, Spotify, and other streaming networks, I'm Brian Lacy, a professor of medicine for Mayo Clinic in Jacksonville, Florida. You have been listening to Gut Check, a podcast from the Gastroenterology Learning Network. Our guest today was Dr. Andree Koop from the Mayo Clinic in Jacksonville, Florida. I hope you found this just as enjoyable as I did and I look forward to having you join us for future Gut Check podcasts. Stay well.