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Pain in the Gut
Klaus Bielefeldt, MD, PhD
Intestinal failure, while rare, constitutes a severe chronic problem that often requires complex medical interventions—from insertion of feeding or decompression tubes to initiation of parenteral nutrition, or even intestinal transplantation. These therapies can sustain life. However, once on these therapies many patients continue to have symptoms and problems with nausea, bloating, discomfort, and pain. My goal is to discuss our current understanding of visceral pain (pain that originates in the inner organs, like the stomach) and visceral pain management.
Acute vs. Chronic Pain
We all have experienced pain and know that it is more than a mere sensation, such as seeing a light or noticing a touch. Instead, pain is alarming; it forces us to pay attention and to react. For acute pain, these characteristics closely match our understanding of its physiologic role, as it is typically triggered by a potential injury (e.g., heat) and quick action is required to prevent harm.
The perception of threat or danger exists when pain originates in the inner organs as well. Further, this visceral pain is often accompanied by other sensations, such as shortness of breath or nausea. Thus, it may not be surprising that it is typically judged as more unpleasant than similar pain from other sites of the body and that it is also associated with a stronger emotional reaction. Moreover, you may be able to move your hand away from heat, but you certainly cannot move your stomach away from anything when it hurts from inside. Thus, visceral pain has unique aspects that overall make it more difficult to deal with.
Things get even more complicated when pain becomes chronic. Chronic pain is often as alarming as acute pain. Thus, physicians and patients deal with it as they do acute pain and ask for tests to address the fear that there may be some new or different problem. But chronic pain has often lost its “physiologic relevance” as a red flag, as a warning about impending danger. More often than not, there is no truly alarming or acute problem that can or needs to be fixed. Under such circumstances, chronic pain has become its own problem.
Sensory Mechanisms within the GI Tract
We typically think about pain as a complex experience triggered by some potentially harmful stimulus. This concept requires a sensor to register the stimulus and send the information to higher centers in the nervous system. In our skin, we have many specialized sensors. These inform us about a light touch, a sharp prick, and contact with a cold or hot object. With increasing stimulus intensity, we start feeling pain. Does this also apply for the gut?
Detailed physiologic experiments tell us that much sensing is going on in the gastrointestinal (GI) tract. Sensors register the temperature, flow or chemical composition of intestinal contents, and filling of hollow viscera. However, most of this information never reaches our consciousness. We can feel some signals, such as those related to filling (distension), tone or contractions of GI muscles, or some chemicals, most notably acid. The more intense the stimulus, the more it is felt; eventually it may exceed the threshold for discomfort and is perceived as pain.
Over the last few decades, we have learned about specific pathways that are important for the normal function of these sensors and that may play a role in the steps that ultimately lead to pain. The following example may show the importance of this research: More than ten years ago, researchers at Johns Hopkins University identified a protein that is present in the membrane of specialized nerve cells and that may contribute to pain sensation. This protein forms a channel (a type of pore) that can open and allow the flow of ions across the cell membrane of these nerves. The regulated flow of such ions constitutes a signal that can then be sent “upward” and may ultimately reach the brain. What is unique about this ion channel is that it can be activated by extracts of hot and spicy peppers.
If you have eaten a habanero pepper, you know it truly burns. If you go a step further and inject the extract of this pepper under the skin, you would experience a severe burning pain. This ion channel, later named TRPV1, appears to be a good candidate for a pain sensor. Indeed, animals lacking this receptor show different pain behavior in specially designed experiments. In humans, we find increased nerve endings with this ion channel in the GI tract of patients with problems such as acid reflux, inflammatory bowel disease, or diverticulitis, all conditions associated with pain.
Several other molecules that send painful signals to the central nervous system have subsequently been identified. These may also play a role in the initial steps of pain sensation. Why is this important? Because if we learn about some of the mechanisms involved in pain signaling, we can work on treatments that target these molecules. In the case of TRPV1, blockers have been developed and are currently in early phases of clinical testing.
Illness May Increase Pain Sensation
Let’s go back to the observation that the more intense a stimulus, the more severe the pain it may cause. This relationship between stimulus strength and perceived pain is not static. For example, illnesses “sensitize” the system, transforming a moderate touch into a painful experience. Most clinicians refer to such states as hyperalgesia, a term you may have heard. We have learned how our sensory system may be up-regulated during illnesses and how this can contribute to pain.
Take inflammation as an example. During colitis flares, many different mediators are produced and released. These substances include prostaglandins, interleukins, chemokines, and different growth factors, to mention just a few classes of molecules. Many of these signaling molecules affect the nerve endings, making them more excitable. A standard stimulus may now elicit a stronger response, which may even lead to the perception of pain while it was barely noticed beforehand.
Non-steroidal anti-inflammatory agents (NSAIDS) like ibuprofen or naproxen may partially reverse this process. These two “pain killers” are part of a class of agents that block the production of prostaglandins, important mediators of inflammation. The limited effectiveness of these medications and their serious side effects have led to the search for more specific medications. Ideally such medication would only influence pain-sensing nerve cells. Recent studies have identified nerve growth factor as a possible specific pain-sensing mediator and clinical investigations show some promise with medications affecting this signaling pathway in patients with chronic pain syndromes.
From Sensation to Perception
Each and every second, a barrage of sensory information floods your brain, informing it—oddly enough, not “you”—about the expansion of your lungs, the beating of your heart, the distension of your stomach, the contraction of your bladder, and much more. Very little of this information ever reaches the point of conscious perception.
Using modern technology with sophisticated imaging techniques, such as functional MRI, researchers have been able to take a “look” into the functioning brain. Stimulation of internal organs typically activates brain structures that are linked to pain, to regulation of the internal bodily “environment,” and to emotion. This may explain the strong link between visceral pain and emotion. Moreover, these centers are activated more or less independently of stimulus intensity. This may provide the basis for the observation that, with the exception of hunger, satiation, and urgency, most feelings we experience from our internal organs are unpleasant, such as bloating, palpitations, shortness of breath, nausea—the list could span several lines. In addition, it may also explain why even mild symptoms from our gut have a significant negative impact on our emotional sense of well-being.
When I talked about stimulus intensity and its effect on responses we can record, I mentioned the dynamic nature of this relationship. The brain can play an important role in tuning this stimulus up or down. Selective attention (vigilance or—when deemed abnormal—hypervigilance) may increase the pain, while distraction may decrease it. Past associations may give similar symptoms different relevance. Moving to a common example not associated with pain, I may experience rectal filling as a harmless sensation that gets me out of my chair to go to the bathroom. A patient with fistulizing Crohn’s disease and impaired closing muscle function may experience the very same stimulation with a sense of panic.
Perception without Sensation
All of the examples I have used to this point describe a link between a stimulus, such as rectal distension in the last paragraph, and a response. However, things are more complicated. Many patients with chronic pain repeatedly hear judgmental statements that it is “all in their heads.” Ironically, modern science confirms this view as much as it debunks it. Let me explain this apparent paradox.
A group of investigators gave patients uncomfortable visceral distension and examined the responses in the brain with functional MRI. They then linked the painful stimulus to a warning signal, a bit like how the physiologist Pavlov rang a bell before feeding his dog in his classic conditioning experiments. After repeated trials, patients actually reported discomfort soon after the warning signal, even if there was no visceral stimulus. Interestingly, the brain activation, during real distension and with anticipation only, was quite similar. So, yes it is in the head, but it may still feel real!
We are also learning that chronic pain changes brain structure, leaving its physical imprint. This imprint may not be permanent, but it clearly shows the strength of the mind-body connection. These findings may help explain why the removal of the organ where chronic pain originates, or a nerve block that prevents transmission of pain, have only limited success in curing or alleviating chronic pain.
Pain and Intestinal Failure
Intestinal failure can be due to many different disorders, such as massive bowel resections for ischemia or Crohn’s disease or pseudo-obstruction caused by impaired gut motility. While the endpoint, the inability of the gut to meet nutritional needs through absorption of nutrients, is similar, the clinical manifestations may differ, and so do the presence, character, cause, and severity of pain.
For example, chronic intestinal pseudo-obstruction maybe due to mitochondrial dysfunction, which often leads to a secondary nerve dysfunction, which in turn may contribute to pain in these patients. Patients with systemic sclerosis, where muscle is replaced by non-contracting fibrous tissue, may also develop pseudo-obstruction. If pain develops, it is mostly due to the progressive intestinal distension that results from lack of intestinal motility. Contrast this to the experience of patients with Crohn’s disease, who may have had many surgeries, with extensive adhesions and intestinal strictures causing intermittent obstruction, which also leads to pain.
The message is clear: since there is no simple and single explanation for pain, we need to individualize our diagnostic and therapeutic approach. What are the options that I as a physician choose from and you as a patient may consider?
Pain and Gut Muscle
Powerful muscle contractions or changes in tone can contribute to symptoms, often described as cramps or spasms. We use a variety of strategies to interfere with intestinal muscle activity. The most commonly used “spasmolytics” are anticholinergics (e.g., hyoscyamine or dicyclomine, commonly sold as Levsin® or Bentyl®, respectively), which are relatively safe but can cause side effects from constipation to dry mouth or even somnolence. Acutely, nitroglycerin, which we use to help patients with chest pain, may also blunt abdominal cramps. However, what you win on one side (less of a spasm), you may loose on the other side, as nitroglycerin often causes headaches.
Small studies also report potential benefit from clonidine (sold as Catapres®) or buspirone (BuSpar®), but the number of patients treated this way is small and side effects or interactions with other medications may limit the utility of these agents. Outside of the spectrum of traditional medicine, we have herbal remedies. Here, peppermint oil is probably the most promising, either as a single agent or in combination remedies.
Targeting the Nerves
Some of the newer strategies that are being developed to influence nerves sensing or mediating painful sensations are not yet routinely available. We can however block all nerve activity by using local anesthetics. Some studies suggest a benefit of mucosal lidocaine application (e.g., enemas with lidocaine).
In the section about sensors that produce painful stimuli, I brought up TRPV1, the molecule that senses the heat of spicy peppers. Capsaicin, the molecule responsible for this spiciness, is actually a mixed blessing. Acutely, it burns. But over time, it chemically depletes or even destroys the nerve endings that produce the sensation of burning pain. Thus, we successfully use capsaicin cream to treat chronic pain after shingles. Obviously, this strategy will not work in the gut. But two small studies packaged the capsaicin into gel capsules and reported some benefit over time. Be aware, it will burn at least initially! Cinnamon may actually be a more user-friendly alternative. This spice affects another molecule, TRPA1, that is also preferentially found on pain-sensing nerve endings. Interestingly, cinnamon oil has long been used to treat dyspeptic symptoms.
Some like to be more radical and cut or block the whole bundle of nerves as they travel from the gut to the brain. I have previously described why such approaches have only limited success. They also come with a set of problems and side effects. For those of us who do not want to cut connections but still try to influence information flow to the brain, anticonvulsants may be an option. The use of agents such as gabapentin (sold as Neurontin®) and pregabalin (sold as Lyrica®) has been advocated for neuropathic bowel pain and other pain syndromes. The jury on true efficacy for GI pain is still out. Some studies on GI pain show some acute, but limited lasting effects.
As mentioned earlier, a small group of patients with primary chronic intestinal pseudo-obstruction may have underlying mitochondrial disorders. These patients often suffer from neuropathic pain, as well as pain from bowel obstruction, and they may benefit from high doses of L-carnitine or coenzyme Q10, both of which are available over the counter.
Targeting Pain Processing
Moving from peripheral sensation to central processing and perception of pain, we can employ strategies that work centrally. For centuries, opioids (narcotics) have been used to treat pain. They are certainly the most effective pain medication we have to ease severe acute pain. Opioids may also work to improve chronic pain. However, they at times fall short of expectations as they seem to influence how well people feel, but not how well they function. Moreover, narcotics come with their own set of problems, from side effects to dependence and addiction. Not surprisingly, researchers and clinicians are looking for alternatives.
I already mentioned anticonvulsive agents, which also affect the brain. Many patients will hear about the potential use of antidepressants. There are many theories about their potential mechanism of action in chronic pain, and there are many studies investigating the effects. Despite this plethora of information, the overall impact still remains unclear. Tricyclic antidepressants (e.g., amitriptyline, commonly sold as Elavil®) seem to be effective in nerve pain and may help in organ pain, if patients can tolerate their common side effects (which range from somnolence to constipation). Selective serotonin reuptake inhibitors (e.g., citalopram, commonly sold as Celexa®) are now preferred for the treatment of mood disorders, but they have an uncertain track record once it comes to pain. However, remember the bidirectional linkage between mood and pain. So, affecting mood as a cause for or consequence of chronic pain could still be helpful. Lastly, there are serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, sold as Cymbalta®), which have shown benefit in some chronic pain syndromes, but which have not yet been studied in patients with GI pain.
The reciprocal relationship between pain and emotion opens up opportunities for psychologically based treatments. Stress-reduction techniques such as progressive relaxation, biofeedback, cognitive behavioral therapy, and hypnotherapy have all been used in chronic GI disorders. They show promise on scales that measure the patients’ overall sense of well-being, which after all is what matters most. As we are learning about these approaches, we are still not sure whether they truly improve pain or primarily alter the tolerance for distress and pain.
Beyond the Belly
When patients or physicians face abdominal pain, they both typically look for a problem originating in one or several of the organs within the abdominal cavity. The previous sections already demonstrated that such a causal linkage is not always present. Beyond the points I made before, I have to keep in mind that the abdominal viscera are surrounded by other structures, which may also play a role in clinical presentations. Abdominal wall pain is common, can be quite severe, and will be missed if we do not consider it. Shingles can erupt over the abdomen and trigger persistent nerve pain. Spinal compression fractures typically hurt in the back; however, they may radiate to the front, and may become so dominant that patients present with severe abdominal pain. I mention these examples not to confuse things even more, but to show that an open and inquisitive mind may identify problems with a more treatable origin.
Chronic pain affects mind and body. Thus treatment needs to go beyond pain medication only. Our armamentarium has expanded and comes with more options that target different levels, from the initial sensation of a painful stimulus to the cognitive processing of such information. All of us, whether patient or physician, have to remember that chronic pain has often lost its physiologic role as an alarm signal, yet it still alarms us.
This knowledge should guide us as we consider diagnostic testing. The reassurance of yet one more unchanged or negative test comes at a price measured not only in economic terms but also in the context of potential medical harm. An example is the cumulative radiation exposure through repeated CT scans. In many cases, it may be better to shift the paradigm and view pain as a disease in its own rights. We may not be able to “fix” it, but we have more options for treating it.
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