As is true for all disorders associated with pain and discomfort, pain localization provides key information about the source of possible underlying problems. Peripheral visceral neural pathways reflect the embryologic origin or anatomical position of visceral structures, whereas the mapping of somatic pain is clearly organized along spinal segmental afferent pathways throughout the neuraxis. For example, pain from the proximal gastrointestinal tract tends to project to the upper abdomen (e.g., stomach), from the midgut (e.g., jejunum) to the periumbilical region, and from the hindgut (e.g., colon) to the lower abdomen. Processes involving the pelvic organs tend to trigger pain felt in the groin, suprapubic, or perineal area and often radiate toward the sacrum or genitals. Due to the retroperitoneal location of the pancreas, kidneys, and ureters, pain that arises from these structures projects more toward the flank, back, or groin. Yet, many patients experience the localization and quality of visceral pain in “atypical” ways. Experiments using a distension stimulus within the esophagus, stomach, small bowel, or colon triggered pain responses that fell within
predicted somatic areas in just more than half of participants.^4,5,6,7 In addition, the terms used to describe a perceived stimulus poorly correlated with the modality of the administered stimulus. For example, about one-third of subjects experienced a feeling of heartburn during esophageal luminal distension.⁸ Conversely, direct jejunal stimulation with capsaicin often was reported as a pressure sensation rather than an expected burning sensation.⁴ These observations could be explained by the fact that many visceral afferents are polymodal, meaning they can be activated by more than a single stimulus type.⁹

Sensory input from the viscera often is referred to distant sites within somatic structures, a phenomenon attributed to the convergence of primary visceral and somatic sensory input onto the same second-order neurons within the spinal cord.¹⁰ Although radiating pain is not always present or follows a consistent pattern, the pattern of radiating pain can provide important clinical clues to the true anatomical source of pain. For example, retrosternal pain radiating to the left shoulder or arm occurs during myocardial ischemia, right upper abdominal pain radiating to the right scapula in cases of cholecystitis, or flank pain radiating to the groin or genitals is a hallmark of a migrating kidney stone (Fig. 63.2).

The time course of more acute pain can provide important diagnostic clues about the source of the problem. For example, very sudden onset and intense pain suggests perforation, acute ischemia, or acute pancreatitis. In contrast, most inflammatory processes and obstructions tend to present with a more gradual and escalating intensity, may fluctuate in intensity over minutes, and, as already described earlier for appendicitis, change in character and location. Distension of the capsule of a parenchymal organ can trigger more constant discomfort, as can inflammation or infiltrative processes, such as pancreatic cancer. Constant pain also predicts a more significant impact on quality of life and is associated with increased health care resource utilization.¹¹ Recurring, intermittent pain is more common and characterized by a regular pattern of waxing and waning, often referred to as “colicky” in nature, and is frequently related to the obstruction of luminal structures.

Additional information about triggering or alleviating factors, associated symptoms, prior medical problems and surgeries, and current medical therapies can provide other important clues about the source of abdominal pain. Food intake most commonly influences abdominal pain of gastrointestinal origin, typically functioning as an exacerbating factor. The lag time between the ingestion of food and the onset or exacerbation of pain can help identify the potential source. For example, close to immediate onset of pain with swallowing (i.e., odynophagia) points at the esophagus as a pain generator. Discomfort due to gastric disorders typically manifests within 30 minutes of ingesting a meal, while underlying small bowel abnormalities may have more significant delays of onset. However, gastric filling or lipid nutrient exposure of the duodenum stimulates colonic contractions (gastrocolonic response), which may secondarily trigger discomfort.¹² Ingesting acidic or spicy material often triggers symptoms in patients with gastroesophageal reflux or functional dyspepsia, and bland food or drink may dilute or neutralize these exposures. Thus, food may have a range of effects on pain of gastrointestinal origin.

As gastroduodenal filling may increase pain symptoms, emptying may ease pain. The rate of emptying of an ingested meal is typically relatively slow (hours), which explains a gradual and delayed improvement of postprandial discomfort. However, vomiting, although obviously unpleasant to experience, may more rapidly alleviate pain by quickly decompressing the proximal small bowel and stomach. If the physiologic processes of urination or defecation alter abdominal pain, then this implicates a bladder, distal colon, or rectal source of pain.

Body position and activity may also influence pain intensity. During many acute pain episodes or significant pain exacerbations, increased activity or stretching out in the supine position tends to worsen pain, whereas crouching in the fetal position eases pain. This common phenomenon may be related to decreased tension in the abdominal wall muscles but lacks specificity in discriminating somatic from visceral pain. Abdominal wall sources of abdominal pain by definition are of
somatic rather than visceral origin, yet when not recognized as such, abdominal wall pain frequently triggers recurrent physician visits and extensive testing in search of a visceral source.¹³ Somatic abdominal pain typically has some positional component and is clearly exacerbated by physical activity, such as lifting, or tensing the abdominal muscles (Carnett’s sign). In contrast, levator ani syndrome involves somatic pain from the pelvic floor muscles experienced as perineal pressure and pain that typically worsens when sitting or standing and improves with laying down.¹⁴

Learning about associated symptoms and signs often narrows down the list of possible underlying problems. Dysphagia in patients with chest pain implicates an esophageal source. Nausea and vomiting are common symptoms that may suggest an upper gastrointestinal problem, such as peptic ulcer disease or an obstruction of the gastrointestinal tract. Yet, nausea and vomiting may also result as an autonomic response to acute pain, as described with the intense and colicky pain of passing kidney stones. Similarly, concurrent changes in bowel patterns can provide important diagnostic information pointing to the colon as a source of pain. Tenesmus, an intense cramp-like pain felt in the lower abdominal or pelvic area with associated urgency to defecate and frequent evacuations of only small volumes of often loose and/or bloody feces, suggests a rectal source of pain. This symptom is analogous to the clinical manifestations of bladder infection, which more commonly are felt as pain in the suprapubic region and similarly are accompanied by a high frequency of low volume and often painful urination that may also be bloody (hematuria). Cramps felt within the pelvis that may be associated with vaginal bleeding or discharge, but that are not associated with changed bowel patterns or micturition, may indicate a uterine or ovarian disorder.

Information about prior illnesses or operations and coexisting diseases is essential when approaching patients with abdominal pain. Late complications from abdominal surgeries due to adhesive disease may result in partial or complete bowel obstruction that are among the most common reasons for hospitalization in surgical units.¹⁵ An underlying inflammatory bowel disease may manifest with pain due to a flare or disease-related complications, such as abscess formation or strictures. Patients with medical illnesses such as cardiovascular disease and hypertension have higher risks of aortic aneurysm and mesenteric ischemia. Those with hyperuricemia or hypercalcemia risk the formation of kidney stones. Functional syndromes, such as IBS, functional dyspepsia, or bladder pain syndrome, are often associated with other chronic pain disorders, such as fibromyalgia or migraines.¹⁶ Psychiatric disorders similarly correlate with such functional diseases, partially mediated through hypervigilance, catastrophizing, or somatization.^{17,18,19,20,21}

Medication and drug use, including over-the-counter agents and illicit drugs, may either cause or exacerbate problems that manifest with abdominal pain. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) increase ulcer risk through well-described mechanisms.²² Less common but more serious complications of medical therapy include acute pancreatitis, as seen with azathioprine, eluxadoline, and diuretics, or ischemic colitis with alosetron.^23,24 More commonly, medications (including opioids, antidepressants, anticholinergics, and antibiotics) may influence the motility of the stomach or bowel to generate dyspeptic symptoms and changes in bowel movement patterns. Opioid withdrawal, an increasing problem in the context of the current opioid use epidemic, is characterized by a number of intense physical symptoms. Acute opiate withdrawal may not only lead to psychomotor activation but also to intense abdominal pain that is associated with repeated vomiting and diarrhea. Similarly, the clinical presentation of cyclic vomiting syndrome (CVS) in adults overlaps with such withdrawal symptoms. Although refractory CVS appears to more common in those chronically using opioids, CVS is more commonly associated with long-term cannabinoid use and in such cases is referred to as cannabinoid hyperemesis syndrome.²⁵

The goal of diagnostic evaluations in patients with abdominal pain is to identify the anatomical site of pain generation and, ideally, to determine the mechanism of illness (i.e., gallstone pancreatitis, nephrolithiasis, endometriosis, etc.). The choices of diagnostic modalities range from blood or stool tests to endoscopic evaluations or radiographic studies. Yet, the most common disorders presenting with abdominal pain are “functional disorders” defined by chronic pain and a variety of other symptoms in the absence of distinct structural or other findings on standard diagnostic testing. A better understanding of mechanisms that contribute to such functional disorders has driven the search for biomarkers that may support, perhaps even establish their diagnosis, or at least act as prognostic indicators that can predict treatment outcomes. Isolated tests largely have fallen short of expectations. Composite scores derived from survey data and fecal or serologic biomarkers may hold more promise but have yet to be established as clinically useful tools.

Detailed physiologic investigations of visceral spinal afferents have identified distinct response patterns to low-or high-intensity stimuli.²⁷ These foundational data suggested that painful stimuli can specifically engage specialized nociceptive pathways that are activated only by high-threshold stimulation (specificity coding). However, many visceral afferents that are activated by low-intensity stimuli encode a range of stimulus intensities that extends well into the noxious range. These visceral afferents appear to sensitize after exposure to heat, acid, or inflammatory mediators.²⁸ These findings argue against an exclusive role of specialized, high-threshold nociceptors in mediating painful sensations and instead suggest that the summation of sensory inputs ultimately shapes the perception of discomfort and pain (intensity coding). Furthermore, several neurophysiologic properties that presumably characterize nociceptive neurons are also commonly found in most visceral afferents, including an ability to respond to more than a single stimulus modality, the expression of ion channels and other neurochemical markers classically associated with nociceptors, and axonal conduction velocities in the C-fiber range.^29,30,31

Due to their relatively low innervation density, smaller axonal size, and the difficulty in gaining access to their target organs for precise experimental manipulation, investigators have only recently started to gain insight into the structure-function relationship of afferent nerve endings within the viscera. Detailed anatomic and physiologic studies have identified branching patterns with linear arrays of nerves that run parallel to muscle fibers of the muscular layer of the gut and encode changes in length or stretch.³² Actively generated muscle tension activates fibers with sensory terminals that spread through ganglia of the enteric nervous system.^33,34 Less distinct branching patterns are found along other structures, such as the epithelium or vasculature, and the role of these possible transduction sites in generating visceral sensations and/or pain is only partially understood.^35,36

Most visceral spinal afferents terminate in the superficial layers (lamina I and II) of the dorsal horn. The central terminals branch within the spinal cord and may extend several spinal segments rostral or caudal to their original entry point within these laminae. This anatomical feature contributes to the vague localization of visceral inputs, including pain.³⁷ The second-order neurons within the spinal cord typically also receive convergent input from somatic, often cutaneous sites, explaining the pattern of referred pain described earlier (see Fig. 63.2). Second-order neurons project rostrally primarily through the spinothalamic tract. However, some visceral nociceptive afferents terminate in second-order neurons located within lamina X, surrounding the spinal canal. These second-order neurons send their ascending axons through the dorsal columns, creating a recently recognized pain pathway that may account for descriptions of visceral pain that persists despite bilateral injury or transection of the spinothalamic tract.³⁸

The neural activity of second-order neurons acts as a “gate” that can diminish or enhance pain signals from being relayed to higher brain centers. Importantly, descending projections
from the midbrain and brainstem directly influence the critical synaptic connection between primary afferents and these second-order neurons. Thus, there is a neural substrate for the brain to effectively inhibit or augment visceral and somatic pain signaling at the level of the spinal cord (for more information, see Chapters 5 and 6), and such descending pathways may well provide some of the neuroanatomical basis for the influence of stress, cognitive, and emotional factors on pain perception (see Chapter 7).

The precise cerebral cortical mapping of spinothalamic inputs from the viscera is poorly understood. Classical neurophysiologic experiments in nonhuman primates found that visceral spinal afferents can ultimately project to the trunk representation within primary and secondary somatosensory cortical regions.³⁹ Yet, neuroanatomical tracing experiments in nonhuman primates that mapped spinothalamocortical projections from purely somatic spinal afferents found that only a minority of neurons project directly to the primary somatosensory cortex. Rather, the majority of direct spinothalamic input was received in the dorsal insular cortex, secondary somatosensory cortex, and within the midcingulate motor areas.⁴⁰ Functional brain imaging studies of humans obtained during painful cutaneous and visceral stimulation have led to a wider understanding of central mechanisms that contribute to pain. These studies have largely corroborated the neuroanatomical and neurophysiologic observations from studies in nonhuman primates. Both cutaneous and visceral pain were associated with an overlapping pattern of activation within some subcortical and cortical structures, preferentially including the ventromedial thalamus, anterior cingulate cortex, secondary sensory cortex, and regions of the insula. However, some important differences emerged, such as a greater activation of the primary sensory cortex during visceral pain compared to cutaneous pain. Many of the areas involved in visceral pain processing are also involved in emotional processing, an association that may well account for the disproportionate unpleasantness of visceral pain.⁴¹ Interestingly, the pattern of brain activation triggered by visceral pain is qualitatively similar to patterns observed during less intense or even unperceived visceral stimulation. This observation argues against specific “labeled lines” for visceral nociception and raises the possibility that visceral stimulation in general influences the visceral pain experience (for a more detailed discussion on central pain processing, see Chapter 6).^42,43

Detailed in vitro and in vivo physiologic studies, including investigations in human volunteers, have clearly demonstrated that both peripheral and central visceral sensory mechanisms exhibit significant functional plasticity. Sensitization is defined as an increase in the response magnitude to the same stimulus intensity, and it is the primary form of plasticity that drives the development of visceral hypersensitivity. Visceral hypersensitivity is the key to the clinical manifestations of many functional visceral pain disorders, ranging from functional dyspepsia to chronic pancreatitis and interstitial cystitis.^{44,45,46,47,48} Peripheral and central sensitization can be experimentally dissociated (for detailed discussions on mechanisms of sensitization, see Chapters 3, 4, and 6). Although they are mechanistically distinct, published investigations typically have shown a close interaction between peripheral and central sensitization processes. For example, acid perfusion sensitized the esophagus to subsequent mechanical stimulation and, at the same time, increased its somatic referral area.⁶ Similarly, repeated rectal stimulation led to increased pain ratings and an increase in the somatic territory of referred pain.⁵ Two examples of chronic disorders illustrate the clinical relevance of the complex, reciprocal interaction between peripheral and central mechanisms, which ultimately lead to heightened and long-lasting pain. First, chronic pancreatitis is a disease with ongoing inflammation and significant changes in the structure of peripheral nerves.^49,50,51 The disease typically manifests with pain as the predominant symptom. Despite the often striking abnormalities in pancreatic structure and abnormalities in peripheral nerves, a small but important cohort study demonstrated that a complete neuroaxial block, which abolished all but the vagal sensory input from the pancreas, completely relieved pain in only less than a quarter of the patients.⁵² This observation reflects the ability of increases in peripheral input to drive central sensitization as a secondary process that may ultimately even become more relevant in the clinical manifestation of a disease. Second, several cohort studies have demonstrated that there is a higher incidence of IBS after acute bacterial or viral infections.^53,54,55,56 Although the severity of the initiating infection (i.e., a peripheral factor) functioned as one important independent predictor of lasting symptoms, preexisting anxiety and depression (i.e., central factors) were also independently associated with a higher risk of developing IBS.⁵⁷ The presence of these affective spectrum disorders may play a role in different aspects that characterize this disorder, ranging from influences on descending modulatory pathways to altered vigilance and the cortical processing of pain to increased symptom reporting or health care-seeking behavior.⁵⁸ The impact of psychiatric diseases has been demonstrated in other common pain syndromes, implying that these factors drive more generalized increases in pain sensitivity.^59,60

Detailed neuroimaging studies have revealed changes in cortical thickness within areas activated during pain processing in both chronic pancreatitis and IBS, providing a structural correlate and potential biomarker for the observations described earlier.^61,62 Interestingly, such apparent differences in brain structure may not only be a consequence of ongoing painful input but could also reflect the impact of other factors, such as early adverse life events,⁶³ or correlate with behavioral patterns, such as enhanced stress responses or catastrophizing.⁶⁴ Recognizing these complex interactions between peripheral and central sensitization in individuals with chronic pain conditions may not only improve our mechanistic understanding of visceral pain but could also personalize treatment choices and improve treatment outcomes.^65,66

Genetic studies of patients with pain syndromes do not only have to contend with the interactions between genes and environmental factors but also the fact that different pain disorders may result from a variety of underlying mechanisms (see Chapter 8). Most investigations of genetic influences on abdominal pain have focused on the IBS population primarily because this disorder is highly prevalent throughout the world. However, the theoretical advantage of studying this common disorder is unfortunately confounded its phenotypic variability, as IBS can manifest with diarrhea, constipation, or mixed bowel patterns and varying degrees of pain. Perhaps not surprisingly, studies have identified multiple mechanisms that contribute to IBS, such as differences in nutritional intake, microbial flora, and subtle changes in peripheral inflammation, and to psychological traits that affect health care-seeking behavior. Despite these caveats, a large genetic study in IBS patients showed higher symptom concordance between first-degree rather than second-degree relatives, which is consistent with some contribution of genetic traits to the
development of IBS. However, partners had nearly similar rates of symptom overlap, which points to the role of shared environmental factors.⁶⁷ These results are in line with a large twin study in IBS that failed to show differences between mono-and dizygotic twins.⁶⁸ Thus, there is mixed evidence for a clear genetic underpinning to IBS.

Serotonin (5-HT) plays an important role in gastrointestinal signaling,⁶⁹ and thus, many genetic investigations in IBS have used a candidate gene approach focused on polymorphisms of the gene for the 5-HT transporter. These studies showed variable results. Independent of the inconclusive findings, these same genetic markers are associated with psychiatric comorbidity, making it difficult to attribute the associations to IBS itself rather than to risk factors or cofactors that may influence its clinical manifestations, such as symptom severity.^70,71,72 Genes encoding other components of the 5-HT signaling system have not been as closely examined but may also be associated with altered emotional responses,⁷³ bowel patterns,⁷⁴ or responses to drugs that target 5-HT receptors.⁷⁵ The catechol-O-methyltransferase (COMT) gene has been inconsistently linked to functional pain disorders.⁷⁶ As was true for 5-HT signaling, COMT variants also correlate with psychological traits that influence symptom severity and reporting in IBS.^77,78,79 Similar links between emotional responses and genetic markers have been reported for allelic variants of signaling molecules in the hypothalamic-pituitary-adrenal (HPA) axis, which plays an important role in mediating stress reactions.^80,81

Genes involved in mucosal permeability, innate immunity,⁸² or absorptive pathways^83,84 may sensitize individuals to develop IBS after apparently banal enteric infections. A possible link between innate or adaptive immunity and IBS supports a concept in which interactions between environmental factors, in this context microbial colonization or infection, and host responses contribute to IBS development.^85,86,87,88 Although these studies do not allow us to determine which aspect of the clinical manifestations of IBS are associated with the various genetic traits, the available data point at differences between constipation and diarrhea-predominant IBS, suggesting that these genetic markers may correlate more with bowel patterns rather than the pain of IBS per se.^74,89,90

Nearly three decades ago, studies first linked the exposure to physical and sexual abuse to an increased risk of developing IBS.⁹¹ Subsequent controlled animal experiments have explored the impact of exposure to adverse life events and have shown changes in bowel function and responses to noxious stimuli,^92,93 presumably due to the increased plasticity of the nervous system during this critical phase of development. More detailed assessments argue against specific links between IBS or other abdominal pain syndromes and such traumatic events early on in life^94,95,96,97 and instead suggest that such exposures may alter the activation of the HPA axis and enhance stress responses.⁹⁸ Although the association between abuse or other adverse life events and diseases manifesting with pain may well be more indirect, mediated by heightened vigilance or catastrophizing, it remains clinically relevant as it affects perceived symptom severity and health care-seeking behavior.^99,100,101

Chronic stress also affects the manifestation of IBS and other abdominal pain syndromes. Mechanistic studies described a link between stress experiences, enhanced activation of the HPA axis, and altered attention to and processing of visceral stimuli.¹⁰² As is true for the impact of adverse life events, increased stress exposures negatively influence health outcomes.¹⁰³

Several cohort studies examined the incidence of IBS after large outbreaks of waterborne illnesses and demonstrated that preexisting anxiety and depression independently predict the development of IBS after the infection.^104,105,106 Complex modeling studies indicate that depression may increase somatization,^107,108,109 whereas anxiety may drive vigilance, catastrophizing, and avoidance.¹¹⁰ A simple “common sense model” (Fig. 63.4) highlights the interaction of various psychological factors that contribute to generating increases in perceived symptom intensity.¹¹¹ More comprehensive conceptual models incorporate additional factors such as social and environmental interactions that shape these various psychological factors. In addition, a more comprehensive model needs to consider the impact of autonomic responses, which may alter visceral function and thereby indirectly influence visceral sensory inputs. Consistent with such explanatory models, psychiatric comorbidity plays a central role in illness perception, health care-seeking behavior, and resource utilization.¹¹²

Within the last decade, an increasing number of studies suggest that the microbial colonization of the gastrointestinal tract contributes to symptoms, presumably via effects on epithelial function, permeability, and immune activation.¹¹³ Animal studies and some small human investigations raise questions about an impact on pain experiences, endocrine function, and even emotional responses.^{114,115,116,117} Several studies have demonstrated changes in the microbiome, with secondary changes in fermentation of luminal contents, short-chain fatty acid concentrations, and bile acid metabolism, in IBS.^118,119 Although most of these investigations focused on bacteria, potential differences also involve fungal organisms¹²⁰ and may even include parasites and viruses. Defining dysbiosis as a disrupted pattern of microbial colonization, 70% of IBS patients had abnormal findings, as opposed to 17% of healthy controls; yet, results did not differentiate IBS from inflammatory bowel disease, and patterns
did not seem to reflect whether the inflammatory bowel disease was active or in apparent remission.¹²¹ The impact of microbial colonization of the gut on gastrointestinal function becomes even more complex when we examine the influence of dietary factors. Prospective studies clearly demonstrated that the composition of luminal contents changes the microbial colonization, which, in turn, is associated with changes in gastrointestinal symptoms, raising the question whether the dysbiosis observed in IBS patients is the true cause for symptoms or if it is an epiphenomenon, largely reflecting dietary habits.^122,123

Stress and other environmental or lifestyle factors may influence disease development and manifestations. In functional gastrointestinal disorders, food intake is an important treatment target, as it has complex impacts on the gut, either directly from filling and distension of stomach, or indirectly by altering the gut’s microbiome, resulting in differences in fermentation of luminal contents. More than 80% of IBS patients experience symptom exacerbations in response to foods, with poorly absorbed carbohydrates, dairy, and legumes being the most commonly reported culprits.¹³⁶ As is true for many factors that influence symptom severity, dietary patterns also correlate with resource utilization.¹³⁷ Thus, assessing such habits and considering modifications of meal size, frequency, consistency, or nutrient composition should be a routine part of any treatment plan in gastrointestinal disorders. Consuming foods low in poorly absorbed, poorly fermented foods (i.e., a low-fermentable oligo-di-monosaccharides and polyols [FODMAP] diet) appears to be a viable strategy to treat IBS, particularly in patients that have associated diarrhea, bloating, and increased flatulence.^138,139 A low-FODMAP diet may not only alter food-derived luminal contents but also secondarily changes the microbial colonization of the gut, which could further benefit epithelial and immune function.¹²²