9/10/2015 Visceral Pain Nevenka Krcevski Skvarc University Clinical Center Maribor, Maribor, Slovenia Visceral pain • Definition Pain arising from the internal organs of the body: • Heart, great vessels, and perivascular structures (e.g. lymph nodes) • Airway structures (pharynx, trachea, bronchi, lungs, pleura) • Gastrointestinal tract (esophagus, stomach, small intestine, colon, rectum) • Upper abdominal structures (liver, gallbladder, billiary tree, pancreas, spleen) • Urological structures (kidneys, ureters, urinary bladder, urethra) • Reproductive organs (uterus, ovaries, vagina, testes, vas deferens, prostate) • Omentum, visceral peritoneum 1 9/10/2015 Key points • General characteristics of visceral pain • Burden of visceral pain • Visceral nociception • General clinical features • Chronic visceral pain • Functional syndromes Visceral pain: organic or functional nociceptive inflammatory neuropathic mixed Various etiology 4 the most frequent: Functional Inflammation syndromes Infection Gallstones Functional abdominal pain: Disorders of mechanical Pancreatitis 0,5%- 2% function Appendicitis IBS: 10% - 20% Tumors Diverticulitis Functional dyspepsia 20% - 30% Disorders of neural Functional gallbladder function disorders: 7,6% - 20,7% Ischemic disorders Painful bladder syndrome: 3% Idiopathic Cardiac pain syndrome : 3% 2 9/10/2015 Visceral (abdominal) pain: from transitory to chronic Catastrophic onset Colicky Severity Short to long duration Subside spontaneously Time General characteristics of pain due to visceral pathology True visceral pain • Is poorly discriminated in the same general area • Has marked neurovegetative and emotional features • Has no hypersensitivity on palpation of the painful area • Visceral pain has a temporal evolution • Is poorly localized with referral to somatic structures • Is not in correlation with organ damage • Produces nonspecific regional or whole body motor responses • Produces strong autonomic responses • Leads to sensitization of somatic tissues • Produces strong affective responses 3 9/10/2015 From life-threatening underlying case to chronic visceral pain • Myocardial infarction • Referred visceral pain • Intestinal obstruction • Visceral hyperalgesia • Acute pancreatitis • Viscerovisceral • Peritonitis hyperalgesia • Functional syndromes Organic or dysfunctional •Purely defined Burden of Pain •Purely treated •Health problems Quality of Life •Social and economic problems •Cost Societal Impact •Well being Burden of visceral pain Intermittent abdominal pain 22% - 28% Thoracic pain 20% - 28% Pelvic pain 24% Irritable bowel syndrome = the second reason for sick leave, immediate after cold Patients with chronic visceral pain use 50% more money for healthcare The cost for functional abdominal pain care: USA: 16,6 billion/year Europe: 28,4 billion/year GB: 100 million Pound/year 4 9/10/2015 Is visceral pain specific entity? What differs it from somatic pain? Is visceral pain specific entity? What differs it from somatic pain? Limited sensation Density of sensory innervation Join pathways with autonomic fibers Intrinsic and extrinsic sensory system Divergence of the visceral input within CNS Complex neural network among cognitive, emotional, autonomic, endocrine centers and immune system and local visceral sensory system 5 9/10/2015 Somatic Visceral pain pain Polymodal sensation Limited sensation (more specific receptors: (less specific receptors: 90% projection to spinal ˂ 10% projecon to spinal cord) cord) Pain Pain Touch Unpleasantness Temperature Tension Itching Sticking Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations: fullness, bloating, nausea, discomfort, urgency and pain 3 distinct anatomical pathways to the central nervous system Visceral nociception Alteration in this complex ANS have been linked to a numerous visceral pain syndromes 6 9/10/2015 Pathways for visceral sensation: Primary afferents Projection of the primary afferent fibers innervating viscera into CNS via three pathways: 1. In the vagus nerve and its branches 2. Within and alongside sympathetic afferent fiber pathways (sympathetic chain and ssplanchnic branches, including greater, lesser, least, thoracic, and lumbar branches) 3. In the pelvic nerve (within parasympathetic efferents) and its branches Visceral nociception Cortex Brain steam Limbic system Spinal events Pain inhibition is modulated by descending projections Peripheral from the anterior cingulate stimulus that activate PAG to further activate serotoninergic (caudal raphe) and opioidergic (RVM) antinociceptive systems. Second – order processing of visceral stimuli occurs at spinal segments and brainstem sites receiving primary afferent input. Pain facilitatory systems Visceral nociceptive information travels by both traditional can be engaged by spinothalamic pathways as well as by ipsilateral and dorsal amygdala modulation Visceral primary afferents spinal pathways. of the paraventricular enter spinal cord and nucleus of the arborize extensively at Relay sites for ascending information have been identified at multiple spinal segments medullary, pontine, mesencephalic, and thalamic levels. hypothalamus for HPA and different depth of Tertiary neurons in the thalamus distribute the pain signal to axis activity and of the dorsal horn neurons. cortical areas for localization while other regions provide LC for the The result is intensity and emotional components of the pain stimuli. sympathomedullary extensive, diffuse Amygdala is also activated to integrate the axis. CNS activation. responses of the ANS and HPA axis. Cortical processing of visceral information has been noted in the insular cortex, anterior cingulate cortex, and somatosensory cortex. 7 9/10/2015 Pathways for visceral sensation • Characteristic: diffusely organized both peripherally and centrally • Unreliable nature of visceral sensation: Healthy visceral tissues evoke minimal sensations. Actually inflamed tissues are more likely to produce painful sensations, but chronic inflammation has unreliable effects. Electrophysiological studies have identified primary afferent nerve fibers that encode mechanical and/or chemical stimuli. The most primary afferents are „silent“ and unresponsive or minimally responsive to mechanical stimuli at baseline and become mechanically sensitive and highly responsive to other stimuli in the presence of inflammation. 1. Visceral fibers • Sensory and afferent functions (conscious sensations and autonomic regulation) • Exclusively tiny myelated Aδ-fibers and unmyelated C-fibers • „silent“ nociceptors – mechanically insensitive afferents (MIAs) 2 . Viscerosomatic and viscerovisceral convergence • Relative contribution of visceral afferent fibers to the total spinal cord afferent input is less than 10% 3. Brain-gut axis • Bidirectional neural pathways linking cognitive, emotional and autonomic center in the brain to neuroendocrine centers, the enteric nervous system and the immune system . • Altered interactions can contribute to autonomic dysregulation of the gut and associated pain and perceptual changes in visceral disorders 8 9/10/2015 Pathways for visceral sensation: Intrinsic afferent nerve fibers Intensity encoding mechanoreceptors High threshold mechanoreceptors Mechanically insensitive (silent) receptors Chemical mediators: Bradykinin, serotonin, histamin, PGE2, NGF Figure 2 Neuroplasticity in enteric neurons during and after gut inflammation Inflammation produces a rapid loss of enteric and viscerofugal neurons: Decreased secretion and motility Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103 9 9/10/2015 Pathways for visceral sensation • Characteristic: diffusely organized both peripherally and centrally Extrinsic: Change in the intestinal lumen Distension of the gut wall Mechanical distension of the mucosa Changes in osmolality Hormones Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103 Extrinsic system of brain –gut axis Ganglion nodosum (inferior vagal) Vagus nerve Pain pathway Triggers: Luminal distension Inflammatory mediators Hormonal changes DRG Gut Spinal cord 10 9/10/2015 Figure 5 Neuroplasticity in extrinsic sensory afferent pathways during and after resolution of gut inflammation Afferents are activated at reduced stimulus intensities and display enhanced mechanical responsiveness Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103 Figure 3 Neuroplasticity in sympathetic neurons during and after gut inflammation Enhanced sympathetic outflow results in decreased secretion and reduced motility Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103 11 9/10/2015 Figure 4 Inflammation-induced neuroplasticity: contribution of neuroactive signaling molecules and the channels/receptors they act on Brierley, S. M. & Linden, D. R. (2014) Neuroplasticity and dysfunction after gastrointestinal inflammation Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2014.103 2. Viscerosomatic and viscerovisceral convergence • Noxious stimulation of viscera triggers pain referred to somatic sites • May occur as a result of the