Visceral pain is caused by disorders of internal organs such as the stomach, kidney, gallbladder, urinary bladder, and intestines as well as changes in the central nervous system. Pain can result from distension, impaction, ischemia, inflammation, or traction on the mesentery and can be associated with symptoms such as nausea, fever, malaise, and pain.¹² Growth of visceral tumors disrupts normal physiologic processes secondary to compression and invasion of adjacent structures. Progression of disease may be asymptomatic until a critical event manifests (e.g., obstruction of a hollow viscus). Under these conditions, the first symptom a patient may experience is pain.^13,14,15

Visceral pain is unique in quality of presentation when compared to pain that arises from musculoskeletal structures of the body. Visceral pain is usually vague in its presentation and may be confused by referral to a variety of somatic locations secondary to viscerosomatic convergence.¹⁶ The phenomenon of viscerosomatic convergence refers to the diffuse nature of visceral pain and its referral to superficial structures due to the convergence of visceral and somatic afferents on the same dorsal horn neurons and secondary hyperalgesia. Symptoms may seem out of proportion to physical examination and imaging.¹⁷ Additionally, visceral pain may be attributable both to the malignancy itself and to chemotherapeutic and radiation therapies. Increased pain following symptomatic relief may suggest the local recurrence of disease or a new locus of disease requiring repeat evaluation of the patient.¹⁸

Some features of visceral nociception may offer a better understanding of the experience of patients with visceral pain. Visceral pain is more frequently accompanied by an autonomic response than is somatic pain or pain from skin injury, unless the pain is referred visceral pain mimicking somatic pain.¹⁶ There is a poor correlation between the extent of visceral tissue damage and the severity of pain experienced. Visceral pain is poorly localized because of poor representation within the primary somatosensory cortex. The majority of visceral afferents are specific to motor or reflex responses with few neural afferents that are specialized for pain transmission. Those afferents that are specialized for pain are sparsely distributed throughout the viscera; both high-threshold nociceptors and low-threshold “silent” nociceptors are invoked in the pain experience.¹⁵

Studies have demonstrated multiple visceral pain mechanisms as well as the mechanisms by which one class of visceral pain may relate to other sources of malignant pain. There are four primary classes of visceral pain:

Surgery, chemotherapy, or radiation therapy of cancer can also be responsible for iatrogenic damage of the viscera, associated visceral structures, or nerves. Applying a stimulus that causes tissue damage (e.g., cutting, burning, or pinching) to skin or muscle reliably produces the perception of pain, but these stimuli do not reliably evoke reports of pain when applied to visceral structures. Pain secondary to distension of a hollow viscous, such as in the case of bowel obstruction, does not necessarily produce a similar perception when applied to surface structures. In controlled studies, visceral pain can be consistently demonstrated by mechanical distension of hollow organs using distending fluids or balloon devices.¹⁹ These modalities of inducing pain most closely reproduce the natural or pathophysiologic processes causing pain. Mechanical distension can be specifically applied to a given organ structure in isolation of other structures, mimicking processes involving the gastrointestinal, biliary, and urinary tracts which may occur from tumor obstruction (or adhesions) in these sites. Distension of organ capsules, such as the splenic, renal, or hepatic capsule, has also been demonstrated to produce profound pain. On the other hand, gentle or slow but progressive distension or obstruction may not produce pain until a critical point in which ischemia or rupture results. Torsion or stretch on mesenteric structures or omentum may produce states of ischemia, infarct, and inflammatory response producing reports of severe pain.²⁰

Inflammatory processes in visceral structures may produce pain as a result of ischemic response, but some tumors may produce inflammatory mediators with no inciting ischemic event. Both prostaglandin E₂ and serotonin have been demonstrated as independent chemical stimuli in the production of pain as malignancy invades adjacent structures.^21,22,23 Experimental studies have demonstrated that the application of inflammatory chemical stimuli can evoke pain behaviors, yet specific mechanical means of eliciting pain have been limited in their translation to studies of other visceral structures.²⁴

Ischemic pain has also been described as occurring secondary to occlusion of visceral vasculature or by compression of visceral structures by tumor growth. When tumor growth exceeds vascular supply, necrosis may result, inducing a variety of inflammatory processes.²³ Inflammatory mediators, such as hydrogen ions, kinins, prostanoids, leukotrienes, or other cytokines, are initiators of visceral pain. These chemical agents also sensitize neurologic afferents of organ structures amplifying nociception associated with mechanical stimuli. In general, healthy viscera are typically insensate to pain, whereas superficial structures are continually sensate.²⁴ When diseased, however, visceral organs produce pain severe enough to be incapacitating to other physical activity. Pain from surface structures of the body evokes reflexive motion in the classic “fight or flight” response, whereas the sensation of visceral pain discourages motion or physical activity. Anecdotal evidence supports an association between pain of visceral origin and emotional response and is commonly held to be more anxiety-provoking than pain from somatic structures. Some argue that this anxiety comes from a patient’s inability to visualize the cause of the pain.²⁵ Anxiety scales are reported higher in patients with visceral pain ratings of 2 on a scale of 10 when compared to a higher rated pain experience with visible cause on a superficial structure.²⁶ Furthermore, some symptomatology is more common in patients with visceral pain. Perception of both nausea and dyspnea are more commonly associated with pain of a visceral organ. An autonomic response to visceral pain is far more common than to pain of superficial structures.^27,28

Psychological processing of visceral pain is distinct from that related to somatic pain. There are a low number of visceral nociceptors compared with somatic nociceptors. There is a lack of specialization of visceral afferents. Many visceral afferents are polymodal nociceptors. Viscera have unique ascending tracts through the dorsal column and poor representation within the primary somatosensory cortex.^29,30 Viscera have significant input through the medial thalamus to the limbic cortex, amygdala, anterior cingulate, and insular cortex, which influence the affective aspect of pain perception.³¹ Viscera also have a close association with autonomic nerves. The perception of visceral pain may be disproportionate to pathology exhibited by physical examination or imaging. As an example, a small nephrolith may offer some of the most severe pain states, whereas extensive cancer metastasis may evoke little or no discomfort. Disorders such as chronic pancreatitis demonstrate very little correlation between laboratory studies and flares in pain perception. Disorders such as irritable bowel syndrome and noncardiac chest pain syndrome appear to lack a definitive histopathologic basis for the discomfort and pain.^32,33

Many models exist for visceral pain including intraperitoneal injection of a chemical, distension of hollow organs (cecum, colon, rectum), distension of the gallbladder and associated biliary system, and distention or chemical stimulation of the bladder and other urinary tract structures, as well as distension, compression, or traction on reproductive organs. However, lesions studied in one organ are limited in that they are specific to a given stimulus and do not necessarily translate to application in other visceral structures.³⁴

Sensitization occurring secondary to the repeated presentation of visceral stimuli has been noted in human psychophysical studies as well as in animal studies. Repeated presentation of the same visceral stimuli produces increasing strength of response in neuronal, cardiovascular, and visceromotor reflex responses. Inflammation of visceral structures increases the magnitude of response to a given mechanical stimulus and decreases the stimulation thresholds for the evocation of nociceptive responses.³⁵ Inflammation of visceral structures significantly modifies behavioral, neuronal, autonomic, and motor responses to visceral stimulation in experimental models. This model mirrors clinical circumstances because inflammation in visceral structures frequently leads to reports of pain.³⁶

Painful conditions such as mucositis, esophagitis, gastritis, pancreatitis, and colitis all exhibit mucosal inflammatory changes. The inflammatory sensitization may take place at primary afferents. These afferents are normally nonreactive to most stimuli and have been described as “silent” in nonpathologic states. However, in the context of an inflammatory tissue response, they become spontaneously active and highly reactive to mechanical stimuli. Silent afferents may comprise 50% of the neuronal sample in a visceral organ but are infrequently noted in superficial or cutaneous structures. Lack of baseline sensitivity in normal viscera may be secondary to sparsity of visceral afferentation. There are fewer afferents per unit area than similar measures of cutaneous afferents. Because of this sparse innervation, increased activity may be necessary to cross a threshold for perception. Spinal neurons responsive to visceral stimuli also change their responsiveness to visceral stimuli in the presence of inflammation. The cause of this behavior is unknown, although voltage-gated sensitization by the transient receptor potential vanilloid 1 (TRPV-1) and tetrodotoxin-resistant (TTX-R) receptors may play a role.^37,38 Increased afferent activity, altered intrinsic properties of dorsal horn neurons, and altered modulatory influences or some combination may all serve a role in the process. Dorsal column pathways have been demonstrated to play a role in visceral nociception but not in cutaneous nociception. The results of multiple studies suggest that visceral pain requires a sensitization process both in the periphery and the spinal cord.³⁹

Visceral pain is classically thought of as deep and diffuse in presentation. Localization of the pain generator can be difficult to identify by physical examination. Superficial pain, in contrast, can be elicited by examination with precise localization and with consideration to the site of the body examined; pain locus can be identified within millimeters. Moreover, surface pain loci reliably localize to the same site, never migrating to other body areas, in the absence of neural injury.

Visceral pain is characterized as migratory in its presentation, often perceived in several loci simultaneously or migrating regionally in spite of localization of pathology. This is evident in the presentation of appendicitis. Furthermore, the perception of pain associated with visceral pathology is not normally localized to the organ itself but to somatic structures that receive afferent inputs at the same spinal segments as the visceral afferent entry. For this reason, visceral pain is classically described as either unlocalized pain or as referred pain that may have two separate features. Sensation of the diseased viscera is transferred to a surface site (e.g., an ischemic myocardium can be felt in neck and arms) or additional sites may become hypersensitive to inputs applied directly to those other sites (e.g., flank muscle becomes sensitive to palpation with urolithiasis). This latter phenomenon is referred to as secondary somatic hyperalgesia.

Psychophysical studies of internal organ sensation have focused on a given organ using simple stimuli, correlating the given stimuli to a given organ with perception at the respective site of stimulus. Other psychophysical studies using visceral stimuli have examined the referred sensations described by subjects. These studies have often failed to contrast referred pain to a body surface with cutaneous sensations at the same surface. Patient illustrations of referred sensations tend to extend over large surface areas, whereas studies using cutaneous stimuli generate pinpoint localization to highly precise sites.

The phenomenon of secondary somatic hyperalgesia produced by visceral pathology has been compared to sites of sensitivity with lesions produced by herpes zoster. These initial studies were fundamental to the development of dermatomal mapping. In visceral disease processes, multiple dermatomes have been identified suggesting that secondary somatic hyperalgesia is widely distributed (i.e., poorly localized).

Recent psychophysical studies have attempted to compare visceral with nonvisceral pain. In one study, the sensation produced with balloon distension of the esophagus was compared to thermal stimulation of the mid-chest skin. Subjects perceived larger areas of sensation for esophageal distension than for intensity-matched, heat-evoked sensation on body maps. Temporally, there was also a difference. A rapid response was noted with heat stimulus, whereas there was poor correlation with the esophageal stimulus and the perception of the sensation. Intense visceral discomfort remained after discontinuation of the distending apparatus but not after discontinuation of the cutaneous stimulation. Visceral sensation was concluded to be diffuse both spatially and temporally. Corollary observation of cerebral blood flow identified that similar cerebral areas were activated by both stimuli.

When evaluating the patient in visceral pain with malignancy, the early presentation may be misleading with vague midline discomfort. It may be poorly localized and accompanied by both an emotional response and autonomic event. Later in the evolution of disease process, patients may complain of somatic or referred pain hypersensitivity at the spinal level of the visceral nociceptor terminus. Referred pain is sharp and localized. It is often associated with allodynia and muscle spasm. Furthermore, visceral hypersensitivity may induce the perception of pain in another organ receiving innervation from the same spinal segment.

Visceral primary afferents differ significantly from cutaneous primary afferents in both number and pattern of distribution. Visceral sensory pathways are organized into nerve fascicles and cell body groupings extending from prevertebral regions to contact viscera predominately via perivascular pathways. Cell bodies of visceral primary afferent nerve fibers are located in the visceral dorsal root ganglia of the thoracic and upper lumbar spine, but the peripheral axons of these neurons follow a circuitous path to visceral organs passing via the paravertebral sympathetic chain and ganglia as well as nerve fascicles that are termed the cardiac and splanchnic nerves. The splanchnic nerves are divided into the greater, lesser, least, thoracic, and lumbar divisions. The pelvic nerves arise from dorsal root ganglia at sacral levels, accepting sympathetic chain input before innervating urogenital structures.

Visceral sensory processing also differs from cutaneous sensory processing because visceral neuronal synapses exist at cell bodies of prevertebral ganglia such as the celiac ganglion, superior mesenteric ganglion, and pelvic ganglion, producing changes in local visceral function outside central control. The gastrointestinal tract is also supplied by an independent enteric nervous system relating to functions of digestion and absorption. In the pelvis, structures receive dual innervation with afferents from lower thoracic to upper lumbar segments and from sacral segments. Testicle and ovary embryologically originate in the superior aspect of the abdomen and, therefore, receive thoracic innervation. The urinary bladder has a similar thoracolumbar innervation with sensory inputs extending up to the T10 level but also receives sacral inputs (the pelvic nerve) with other tissues originating from sacral dermatomes (rectum, genital structures).

Pelvic organs also receive efferent and afferent connections from the vagus nerve and local ganglionic circuitry, resulting in a complex and diffuse neuroanatomy. Afferents with endings in a focal visceral site may have cell bodies in the dorsal root ganglia of 10 or more spinal levels in a bilaterally distributed fashion. In contrast, cutaneous afferents from a particular body surface arise from only 3 to 5 unilaterally located dorsal root ganglia.

Visceral receptors are located in mucosa, serosa, and muscle of hollow organs as well as visceral mesentery. They are not reported in parenchyma of solid organs. The specialized receptors that discriminate a variety of stimuli in somatic structures are absent in viscera. The mesentery, however, does contain Pacinian corpuscles. Hollow organs contain specialized low-threshold and high-threshold mechanoreceptors. Low-threshold receptors serve a basic regulatory function, whereas high-threshold receptors are activated only with noxious mechanical stimuli. Visceral nociception results from summation of nociceptive input to regulatory low-threshold receptors and noxious high-threshold and silent nociceptors rather than activation of stimulus-specific nociceptors.⁴⁰

Visceral afferent fiber activation causes an increase in nitric oxide synthase in the dorsal horn of the spinal cord, causing expression of the oncogene c-Fos in laminae I, V, VII, X of the dorsal horn within the thoracolumbar spine. Similar upregulation is seen in the amygdala and paraventricular hypothalamic nuclei and consequent elevation in norepinephrine production within the locus ceruleus.

Features of visceral pain processing differing from somatic processing include dorsal column ascending secondary sensory afferents, the spinal trigeminal to parabrachioamygdaloid tract, and the spinohypothalamic pathway. In the visceral system, both ventrolateral and dorsal column postsynaptic neurons have a role in nociception. Ascending tracts synapse at the lateral thalamus first, then limbic centers, and then somatosensory cortex.

Whereas somatic nociception is represented somatotopically within the primary somatosensory cortex, visceral pain is represented in the secondary somatosensory cortex and poorly represented within the primary somatosensory cortex. Visceral pain is well represented in the limbic system, including anterior cingulate gyrus, insular cortex, and amygdala, suggesting a basis for the strong emotional component of visceral pain. Whereas visceral pain elicits decreased patient activity, nausea, and hypotension, somatic pain elicits agitation, reactive activity, and hypertension. Nociceptive activity within the gastrointestinal tract induces inhibition of dorsal motor neurons of the vagus within the medulla leading to gastroparesis and nausea.