Pain in Inflammatory Bowel Disease


Mechanisms of visceral pain in IBD can be divided into two categories: peripheral and central mechanisms of pain. Peripheral visceral pain can be caused by the ongoing activation of intrinsic and extrinsic afferent neurons that project to the enteric and central nervous system. As most of the sensory neurons respond to low- intensity stimuli such as distension, flow or chemical signals within the gut lumen, the shift in balance between stimulus intensity and perception in IBD results in perception of these stimuli as painful and noxious. Inflammation also indirectly affects primary sensory neurons. The release of serotonin or adenosine triphosphate (ATP) by enteroendocrine cells and other epithelial cells during inflammation activates sensory neurons through serotonin and purinergic receptors.10


Also, during the inflammatory process, serotonin, prostaglandin, bradykinin, ATP and other signalling molecules are increasingly released and contribute to the sensitisation of sensory neurons that can convert non-noxious stimuli into pain-producing stimuli. This combination of increased neuronal excitability and enhanced release of mucosal signals provides the basis for the peripheral sensitisation seen during visceral inflammation. Furthermore, colonic inflammation triggers a shift in the normal stimulus–response relationship, leading to enhanced behavioural responses during low-intensity stimulation and increasing the magnitude of responses over the entire range of stimulus intensities.


However, as subjective symptoms correlate poorly with biological markers of disease activity and about 20% of patients without evidence of ongoing inflammation or obstruction continue to have pain, factors other than inflammation and sensitisation of afferent pathways contribute to the clinical manifestation of the disorder. In IBD, experimental and clinical evidence suggests that as peripheral sensitisation increases the excitability of primary afferents, secondary type I arthropathy changes in higher-order sensory neurons in the spinal cord or brain occur. As an example, even quiescent IBD patients showed higher discomfort thresholds in response to rectal distension compared with patients with irritable bowel syndrome (IBS), a finding that correlated with stronger activation of medullary structures.11,12


Consistent with the theory of a lowered threshold of visceral perception and processing, in a recently conducted survey, 80% of the participating IBD patients identified one or more specific triggers as worsening pain such as food intake (51%), mental distress (30%), physical activity (23%) and menstruation (22%).13


Obviously, next to pain perception, organic obstructions due to stenosis or adhesions are often present as local intermittent colicky pain in the absence of systemic inflammation. Fistulas, abscesses and scissures can worsen during bowel movements. In addition, extraintestinal manifestations of IBD can contribute to pain. Extraintestinal manifestations include, for example, the involvement of the musculoskeletal system – one of the major causes of extraintestinal pain.14


Enteropathic peripheral arthritis


Arthralgia (pain without evidence of inflammation) is not recognised as an extraintestinal manifestation but is reported by 16% of patients and has a significant impact on quality of life16 more detail below).


(discussed in EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW


without axial involvement can be subdivided into a pauciarticular, large-joint arthropathy mostly associated with flare-ups (arthropathy type I) and bilateral symmetrical polyarthropathy often unrelated to acute intestinal inflammation (arthropathy type II). Axial arthropathy includes inflammatory back pain presenting in up to 20–30% of patients with radiological evidence of sacroiliitis in 20–25% of these patients.15


Significant pain also occurs in patients without evidence of concurrent inflammation. As in IBD, pain perception is similarly altered in IBS. Thus, the prevalence of IBS in IBD patients (in remission) reporting Rome criteria symptoms is estimated to be as high as 45%.17,18


Similar to the role of anxiety in the development of IBS, psychological disorders are associated with persistent symptoms of IBD patients in clinical remission. Two large Canadian epidemiological studies determined a prevalence of depression in 16.3 and 14.7% of IBD patients, which is three times that of the general population.19


Recent work has focused on exploring


mechanisms of modified pain processing and perception due to emotions, cognitive factors and inflammation.


Pain in IBD has several distinct causes. Thus, a change in symptoms or newly developing discomfort should always lead to an appropriate diagnostic work-up considering exacerbation or complication of underlying disease. Besides disease-related causes, consideration should also be given to pain resulting from medical therapy, such as acute pancreatitis (azathioprine), osteoporosis (corticoids) or upper gastrointestinal ulcers (corticoids, non-steroidal anti-rheumatics [NSARs]). In order to find the most appropriate therapy, the underlying cause should be individually traced by careful history-taking and evaluation of the pain characteristics. Thus, the differentiation between somatic, visceral and neuropathic pain, as well as the exploration of pain-triggering circumstances, is necessary.


A Special Situation – Therapy of Inflammatory Bowel Disease-related Arthropathy


With an incidence of 20–30%, joint manifestations are the most frequent extraintestinal manifestation in IBD.14


Not only are the


pathophysiology and causes of IBD-related arthropathy unknown, there is also an absence of randomised, controlled trials aimed at investigating therapeutic options in IBD-related arthropathy. As a result, the treatment of IBD-related arthropathy is based almost entirely on extrapolation from treatment of rheumatoid arthritis or other forms of spondyloarthropathies.


Peripheral arthritis in IBD is quite distinct from specific forms of arthritis since there is little or no joint destruction, and tests for rheumatoid factor and antinuclear antibodies are negative. There are two types of peripheral arthritis in IBD that should be distinguished from unspecific arthralgia or myalgia. Type I (pauciarticular) arthropathy affects fewer than five large joints (predominantly of the lower limbs) and the swelling is acute and often self-limiting. Type I arthropathy is related to activity of the underlying bowel disease. The mean duration is five weeks, but some 25–40% of patients will have recurring arthritis. As type I arthropathy and disease activity are linked, pain therapy for peripheral arthropathy type I is most effective when the intestinal inflammation is controlled. The efficacy of infliximab and adalimumab has been confirmed in several placebo-controlled trials and these drugs are recommended in patients intolerant or refractory to NSAIDs.20


By contrast, the use of etanercept is not recommended because of an increased risk of intestinal disease relapse.21 Salazopyrine can be recommended for treatment of peripheral arthritis. Besides medical therapy, local corticosteroid injections and physiotherapy may help to reduce pain. Type II (polyarticular) arthropathy is a symmetrical polyarthritis, frequently involving five or more of the small joints (e.g. knuckle joints). Its course is independent of disease activity and may last for several months. Type II IBD arthritis generally requires long-term treatment. In persisting disease,


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