Unlocking the keys to chronic visceral pain

Most physicians view pain the way firefighters view smoke, as an urgent alarm that signals an underlying problem. Find and treat the underlying problem and the pain should go away. (That’s why there’s an understandable caution in medicine about anything that might mask pain and make it harder to recognize an underlying problem.)

But chronic pain presents a different challenge. It causes great suffering, and increases the risk for additional harm, including depression and fatigue. But because pain is invisible to everyone except the person who experiences it, chronic pain can be difficult to diagnose and treat effectively. Such is the case with chronic abdominal pain in IBD. Unfortunately, the problem is not rare. As Dr. Andres Hurtado-Lorenzo, the Crohn’s & Colitis Foundation’s Vice President of Translational Research, highlighted in his opening remarks at last year’s Pain in IBD conference, studies show that 20-50% of IBD patients report chronic visceral (abdominal) pain lasting at least three months or longer even in the absence of inflammation or during periods of remission.

In 2019, the Foundation identified chronic visceral pain as one of their top research priorities. The next step was to strategically identify innovative research pathways that hold the potential to significantly advance our understanding of the biology of chronic pain and to identify better clinical management approaches. Towards that end, the Foundation convened a two-day virtual workshop on November 12-13, 2020 to focus on Pain in IBD: From Biological Mechanisms to Clinical Management. The conference agenda, as defined by Dr. Hurtado-Lorenzo, was both visionary and action-oriented. Key questions addressed throughout the conference included:

• What are the key gaps in our current knowledge about the biological drivers of chronic pain?
• What are top priority areas of clinical need in diagnosing and treating chronic visceral pain?
• Are there known biological mechanisms, or targets, that could be translated into new therapeutic approaches?
• Are there existing chronic pain treatments in other medical areas that should be explored for use in IBD patients?  

Based on the deep analysis generated at this conference, the Foundation will issue requests for research proposals in 2021 in order to fund two new multi-year grants (each worth approximately one million dollars in total). One grant will focus on advancing our understanding of the biology of chronic pain while the second will focus on clinical management. In choosing to make these research investments, the Foundation considered many factors, including taking a patient-centric approach to fund pioneering research in areas critical for patients as well as the need to support under-funded critical or highly promising research areas.  

The scope of the discussion depends on who’s in the room

As they have in the past, the Foundation convened an impressively broad range of researchers and clinicians to shine light on this important but difficult area.  Participants included researchers and clinicians from all over the world representing many different fields, including gastroenterology, neurobiology, neurogastroenterology, immunology, cell and molecular biology, psychiatry, neuroimaging, and complementary health. The objective was not only to share and compare notes based on their different perspectives and expertise, but also to catalyze new ideas that might light the way towards innovative research and treatment approaches. As we all know from our own lives, the discussion changes depending on who’s in the room. The virtual conference room included many with years of experience with IBD issues as well as chronic pain researchers and clinicians who were relatively new to IBD. 

The first day featured presentations and discussions about the biological mechanisms of chronic visceral pain. The second day was dedicated to reviewing existing innovative chronic pain treatments. The program kicked off with two powerful keynote presentations which, together, captured both the promise and the urgency of the agenda. And, as always with Foundation events, the keynote presentations highlighted patient perspectives alongside cutting-edge research innovation.

Promising research findings and one patient’s journey

Dr. Stuart Brierley, Director of the Visceral Pain Research Institute at the South Australian Health and Medical Research Institute, gave an overview into several areas of brain-gut research. One key finding concerns how specific nerves signal pain from different areas of the gastrointestinal tract. Why does this matter? The goal of getting the right medicine to the right patient at the right time may depend on being able to identify specific pain patterns, including location. This new capacity to identify specific neural pathways depending on pain location (e.g., small intestine, proximal colon, distal colon, or rectum) opens the door to more targeted therapy. 
Dr. Brierly’s research also tracks the shift from short-term to chronic pain, showing how some pain messenger nerves, even once the inflammation has quieted, remain over-sensitized. His research suggests that chronic pain that has lasted for years may require different treatment approaches than pain of shorter durations (of weeks or months).

The second keynote speaker was Dee Dee Branchaud, a pharmacist who has Crohn’s disease and has endured chronic visceral pain for years. Dee Dee began by saying, “I was one of those pharmacists who judged people who refilled pain medications weekly and didn’t seem to get better.” But the intense chronic pain she has experienced since 2014 following major abdominal surgery (an emergency hemicolectomy) changed everything. Too often, she found that medical care providers either marginalized, dismissed, or misidentified her pain. With great honesty, she said, “I also didn’t do a good enough job communicating to my gastroenterologist just how much pain was limiting my activities. I think it was two years before he really understood.” Accustomed to working 13- and 14-hour days standing in a neighborhood pharmacy, Dee Dee now became easily fatigued, irritable, had trouble sleeping, and even (perhaps most surprising and difficult for her) stopped loving her job.  

After trying disability-related job adjustments without success, she went on full-time disability in 2017. Now Dee Dee is in remission - her endoscopic examination revealed no sign of intestinal inflammation. Like many patients, her subjective experience of pain isn’t recognized by current objective tools like endoscopy. She continues to experience chronic visceral pain for no medically identified reason. She takes several medications plus non-pharmacologic treatments to manage her pain. She works with a team including a pain management specialist. But as she told the workshop participants, “We’ve got to do better than this. My only goal is to have my symptoms better controlled so I can live my life.”

Right now, Dee Dee’s pain remains undetectable by current diagnostic tools used in clinical practice. For example, we don’t have any biomarkers (like a blood or saliva test) that could measure it. But as researchers discussed, there are some models that may explain what is happening with chronic visceral pain, even if it’s not yet visible. As Dr. Brierley discussed, one model suggests that nerves can become oversensitized from intense or traumatic experiences (remember, Dee Dee’s chronic pain started after major abdominal surgery, a traumatic experience). Like a fire alarm that goes off when someone lights a cigarette, oversensitized nerves are ready to cascade into full fledged ‘flashing red’ status at extremely low levels of stimulation. Another model focuses on gut barrier breakdown and suggests that perhaps a signal that would usually be stopped is getting through. “Every problem is an opportunity,” said one researcher, meaning that pain has to be signaled in some way, and every signal might be interrupted or toned down through some intervention.

If Rip Van Winkle had attended the workshop

Workshop presentations and discussions examined chronic visceral pain from many different perspectives, all with the goal of generating new knowledge that would improve patient care in the future. But I couldn’t help but think of how far we had traveled. Had Rip Van Winkle been a physician asleep for the past 20 years who awoke to find himself at this workshop, he would have been astonished by changes in the chronic pain landscape. A few examples:

• The integration of mind-body treatment models into conventional healthcare is becoming the norm and not the exception, including for the treatment of chronic visceral pain. As Dr. Brierly’s presentation made clear, the brain-gut axis is a two-way superhighway; we now recognize that the central nervous system (located in the brain and spinal cord) is constantly communicating with the messengers to and from the peripheral nervous system throughout the body. So, treatments that focus on the mind (including hypnosis, cognitive behavioral therapy, biofeedback, and mindfulness) are increasingly used to alter the way we process pain messages. Dr. Eva Szigethy, a psychiatrist who founded the Visceral Inflammation and Pain Center at the University of Pittsburgh, emphasized that this trend is likely to continue. According to Dr. Szigethy, integrated mind-body approaches for pain management seem to be more successful than relying only on single or combination pain medications. “Patients have been driving this, and we’re catching up with them,” she said.  
• The endocannabinoid system, which was first identified by name in the early 1990s, is now recognized as a major signaling system in the human body that helps to regulate biological processes including metabolism, pain sensation, neuronal activity, and immune function. Research has shown that some cannabinoid receptors are involved in managing pain and inflammation in the gut, making it a target of interest when it comes to chronic visceral pain.
• The microbiome (which one participant called “almost an organ in itself”) is now understood to affect many biological processes, including visceral pain. Using different probiotic strains can affect pain reduction in IBS patients, but we don’t yet understand its role in IBD. It, too, is a major research target.

Another takeaway from the Pain in IBD workshop: everyone recognized the need for much more detailed information about patterns of chronic pain in IBD patients. This was a topic in which both researchers and clinicians had many more questions than answers. Who develops chronic visceral pain, and are there any differences between them and IBD patients who don’t develop chronic pain? What other characteristics or features accompany the pain? For example, Dee Dee Branchaud gets blood pressure spikes and sweaty palms when she is in pain; another IBD patient feels pain around eating; another reports that pain is accompanied by depressive mood. Are there different triggers for different patients, and how might that guide treatment approaches? The history is also important. When do patients develop chronic pain? Can those patterns help identify earlier points of intervention that might ‘snap’ the cycle of chronic pain? Is there a way to identify patients more likely to develop chronic pain and intervene earlier? As several participants noted, creating large databases about chronic pain patterns in IBD is a critical priority. 

The meeting closed with a sharing of ideas about how to proceed with the development of research proposals. This workshop demonstrated the importance of cross-fertilization of ideas and perspectives. The discussion sparked new ideas and connections, which will find resonance in the strategic funding initiatives in 2021.

Stay tuned to this space. The Foundation will provide updates on chronic pain research, including clinical trials that might be a good fit for you.

Check out this profile of Dee Dee Branchaud for more coverage of the Pain in IBD workshop.