Conclusion SCD is a complex pain disorder that remains poorly understood with limited evide nce base for analgesic therapies. Pain from vaso-occlusion of sickle erythrocytes can occur in multiple mus- culoskeletal locations, several internal viscera such as the spleen, as w ell as the penis. Such pain is typically intermittent in child- hood, and oft en responds t o NSAIDs and opioid analgesics sim- ilarly to acute pain in many other pain disorders. Adol escents with SCD oft en experience more frequent pain, and those with bone disease in spine , hips, or shoulders may experience chronic pain, which may show limited responses to opioi ds as in other chronic pain disorder. Many cognitive-behavioral strategies are helpful as p art of multidisciplinary pain management, par- ticularly in adolescents, who may also benef i t from psychological support for coexistent mood disorders, to increase coping skills, an d to support appropriate school and family functioning. Future advances are needed to furth er the evidence base for effi cacious pharmacological and psychological therapies to amelio rate the substantial burden of pain in children and adolescents with SCD. Ultimately preven tive therapies for vaso-occlusion, infl amma- tory and ischaemic tissue damage, and develop ment of hyperal- gesia will fi nally change the face of this common genetic disorder ( Figu re 25.1 ). Sickle pain pathophysiology Several studies in mouse models of SCD have described sen- sory changes consistent with altered nociceptor function. Paw withdrawal threshold and withdraw al latency (to mechanical and thermal stimuli, respectively) and grip force were lower in h omozygous and hemizygous Berkley mice, which express only human sickle hemoglobin, compared with control mice express- ing human hemoglobin A consistent with deep/musculoskeletal and cutaneous hyperalgesia (Kohli et al., 2010 ). Th is mechani- cal hypersensitivity is furth er exacerbated when hypoxia is used to induce acute sickling (Hillery et al., 2011 ). Sever al research groups are working with these and similar mouse models to defi ne unique molecu lar mechanisms of pain and identify poten- tial therapeutic targets. Preliminary human studies suggest similar sensory changes consistent with hyperalgesia in c hildren and adults with SCD. Early studies suggested reduced pressure pain thresholds in sc hool-age and adolescent SCD children compared to age- matched children with juvenile idiopa thic arthritis, or com- pared to control children with asthma (Walco et al., 1990 ). In a r ecent cross-sectional study using quantitative sensory testing to thermal and mechanical st imuli in SCD pediatric patients in 3 7 11 15 19 23 27 31 35 39 43 47 51 55 61 72 Figure 25.1 Age distribution of opioid usage in the year prior to registry enrolment. Bars represent the number of individuals in each year of age, with bars on the left representing SC or SB + thal subjects, while bars on the right represent the number of subjects with SS or SB0thal. Dark bars within each group represent the number of subjects reporting chronic daily opioid usage. 20 0 20 40 60 All SC-SB subjects All SS-SB0 subjects SC-SB and prior year opioids SS-SB0 and prior year opioids SECTION 4 pain in specific populations and diseases 254 Case example clinical response. With the assistance of her volunteer tutors, she was able to graduate fr om high school with her class, and will be starting a reduced schedule of community college classes in preparation for a healthcare-related degree program. JK is a 18-year-female with homozygous sickle cell disease (SS) diagnosed at birth through the local state newborn hae- moglobinopathy screening program. Her mother noticed prominent swelling of the dorsum of left hand and fi ngers of her daughter associated with reduced v oluntary movement and discomfort with palpation at age 18 months preceded by a mild upper r espiratory infection that responded to oral ibuprofen. Several subsequent episodes involvin g one or both hands and feet or sometimes her lower legs occurred over the next several yea rs and were managed at home with oral ibuprofen and oral acetaminophen/codeine. Her family would oft en apply warm compresses and massage her limbs to help relieve swelling and pain. At age 5 she was admitted for several days with more severe pain managed with intravenous fl uids, NSAIDs, and intravenous opioids (morphine). By age 12, similar admissions began to occur once to twice per year, which were interspersed with less severe episodes once or tw ice a month lasting several days. She began to miss considerable amounts of school and beca me somewhat withdrawn and spent less time with her friends. Oral hydroxyu- rea was started but had little impact on her pain complaints, in part because of poor adherence. More poten t intermittent oral opioids were started, and provided some initial improvement in pain rel ief, but subsequently poorly controlled pain necessitated a switch to daily oral methadone. A variety of adjuvant medica- tions were tried but were found to be too sedating or had ot her signifi cant side eff ects. A TENS unit was provided, which she found to be useful for mild to moderate pain. At age 13, her phys- ical activity was further compromised by persis tent right-sided hip pain; hip X-rays and MRI demonstrated signifi cant avascular necrosis of her right femoral head with partial collapse. References Abdulmalik , O. , Safo , M. K. , Chen , Q. , Yang , J. , Brugnara , C. , Ohene- Frempong , K. , et al . 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When she was 15 years of age, her family, who were increas- ingly concerned with her isolat ion, depression, and poor school performance, requested a multidisciplinary case conference with members of the sickle cell team, physical therapy, the hospital- based school teacher , child psychology, and a representative from the local hospital-based pain team. A compreh ensive man- agement plan was developed with the concurrence of JK and her family that inclu ded a 12- to 18-month period of chronic transfusions in an attempt to ameliorate her underl ying SCD, intensive physical therapy to improve conditioning and to assist with physical mo bility of her hips, and individual and family psy- chology sessions to teach more eff ectiv e communication styles and more successful active coping skills. A variety of relaxation te chniques were to be taught to assist with stress management and to improve sleep hygiene. U nder careful medical and psychologi- cal supervision, off -label use of duloxetine was star ted to improve pain control based on data from other pain disorders, and provide some antid epressant action. She was encouraged to become more active in her local church youth group, and was referred to a local African American college sorority program that provided high s chool academic tutoring and role-modeling. Her frequency of hospitalization gradually decre ased on this intensive supportive care program, and she was able to be weaned to a small do se of daily opioids with further improvements in her pain charac- teristics, suggestive of some previous degree of opioid-induced hyperalgesia. She restarted oral hydroxyurea with an improved Brandow , A. M. , Kattappuram , R. , Stucky , C. L. , Hillery , C. A. , and Panepinto , J. A. ( 2011 ). Patients with sickle cell disease have increased sensitivity to cold and heat stimuli, 2 . ASH Annual Meeting Abstracts , 118 , 2116 . 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Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm . Proc Natl Acad Sci U S A , 99 , 3047 \200\2233051. CHAPTER 26 Pain and gastroenterological diseases Akshay Batra , Amanda Bevan and R. Mark Be attie Summary Pain is a common complaint in children with gastrointestinal tract pathology and it has signifi cant consequences for patients \200\231 qual- ity of life. A thorough evaluati on should be performed to deter- mine the cause and severity. Understanding the pathophysio logy of pain in various conditions is key to eff ective management. Th is chapter outlines the etiology and general principles of the man- agement of pain in gastrointestinal disease . Th e specifi c manage- ment of common gastrointestinal conditions associated with pain, e .g. infl ammatory bowel disease, gastro-oesophageal refl ux disease, pancreatitis, and gut dysmotility disorders are discussed. Th ree broad classes of primary aff erent neurons associated with the gut are: \231 Intrinsic primary aff erent neurons (IPANs), with cell bodies and connections in the gut wall, either in the myenteric plexus or in the submucus plexus, and processes extendin g to muscu- laris mucosa. Th ey are the primary sensors and regulators of the enteric nervo us system (Gershon et al., 2005 ). \231 Extrinsic primary aff erent neurons, with cell bodies in vagal and dorsal root (spin al) ganglia, carry information about the state of the gastrointestinal tract to the CNS. Th ey appear to monitor all aspects of gut function, and also carry nociceptive information v ia thinly myelinated A and unmyelinated C fi bres (Sengupta, 1994 ; Sikander and Dickens on, 2012 ). Both the submucosal and muscular nerve plexus respond to multiple stimuli and t ransmit pain to the CNS. Introduction Pain is an important and common symptom of gastrointestinal disease. It can be the fi rst indication of a new pathology, or it can signify a change in a known condition. Th e recognition of the pain pattern and its signifi cance is crucial to the early diagnos is and treatment. Th e relief of pain is frequently of diagnostic importance and is oft en the best indicator of successful treatment. Th is chap- ter will focus on the various gastr ointestinal disorders causing pain and their management with special emphasis on conditions causing acute debilitating pain. Recurrent abdominal pain is reviewed by Schurman et al. ( Chapter 29, this volume). \231 Intestinofugal neurons, with cell bodies in the gut and projec- tions to neurons outside the gut wall. Visceral sensory nerves follow three main anatomical pathways from the gastrointestinal tra ct to the CNS: the vagal, splanchnic, and pelvic nerves (Kirkup et al., 2001 ; Sikandar and Dickenson, 2012 ) ( Figure 26.1 ). Th e splanchnic aff erent neurons transmit pain sensa- tion, whereas the parasympathetic aff erent fi bres transmit physio- logical information an d non-noxious sensation (Goyal et al., 1996 ). Th e cell bodies of primary visceral aff ere nt neurons are contained in the nodose ganglia (vagal aff erents) and dorsal root ganglia ( spi- nal aff erents). Th e central terminals of vagal sensory neurons are in the brainstem, whereas the central terminals of spinal visceral aff er- ent neurons are organized diff us ely over several spinal segments. Th e vagal aff erents do not directly participate in pain signaling but can indirectly modify spinal pain processing. Innervation of the gastrointestinal tract Th e lining of the gastrointestinal tract is the largest vulnerable sur- face that faces the external environment. Pain perception in the ga strointestinal tract is mediated via a complex pathway of enteric, autonomic, and central n ervous system (CNS) structures (Knowles and Aziz, 2009 ). Th e autonomic nervous system, by way of the sympathetic and parasympathetic systems, also controls the secretory and muscular functions of the gut. Parasympathetic eff erent fi bres run in the vagus and sacral nerves, and exert an excitatory eff ect on the enteric neu- ro ns. Th e sympathetic eff erent fi bres inhibit gastrointestinal activ- ity. Th e enteric ne rvous system though functioning independently interacts with the CNS allowing bidirectional communication. As a result the brain can integrate information from the gastrointestinal t ract and respond appropriately. Th is is especially true for stimuli Enteric nervous system Th e enteric nervous system provides the intrinsic innervation to th e gut. It is composed of Auerbach \200\231s and Meissner \200\231s plexuses. Auerbach \200 \231s plexus is a myenteric plexus which lies between the longitudinal and circular muscle layers. Its role is mainly to control the contractions of the smooth muscle in the bowel. T h e submucosal Meissner \200\231s plexus lies below the mucosal layer and performs a predom inantly sensory function in obtaining information about the luminal contents. SECTION 4 pain in specific populations and diseases 258 Dorsal column DC Medulla NG NTS 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 1 2 3 4 5 Vagus nerve Cervical GI Tract Thoracic Esophagus (distal), stomach, gall bladder, small bowel, liver, spleen pancreas, kidney prox imal colon S1 S2 CG SMG S3 IMN IMG S4 Distal colon, rectum, uterus, prostate, urinary bladder, anus, genitalia HGN Lumbar PG PN Sacral Figure 26.1 Schematic of gastrointestinal tract innervation. Visceral a \200 erents innerv ating organs in thoracic and abdominal cavities travel either along the vagus nerve with ce ll bodies in the nodose ganglion (NG) and central terminals in the nucleus tractus solitari i (NTS), or along the dorsal column pathway (dotted line) with cell bodies in dorsal column nuclei (DC) in the brainstem. Other a \200 erents innervating the same organs have termin als in the spinal cord, before passing through pre- and/ or paravertebral ganglia en route with cell bodies in dorsal root ganglia (not illustrated). Straight lined pathways indicate sympathetic innervation and hyphenated pathways indicate parasympathetic innervation. Prev ertebral ganglia, CG: coeliac ganglion; SMG: superior mesenteric ganglion; IMG: inferior me senteric ganglion; PG: pelvic ganglion. Nerves, S1, S2, S3, S4: greater, less, least, and l umbar splanchnic nerves, respectively; IMN: intermesenteric nerve; HGN: hypogastric nerve; PN: pelvic nerve. Republished from Sikandar, Shafaq and Dickenson, Anthony H, Visceral pain : the ins and outs, the ups and downs, Current Opinion in Supportive and Palliative Care , Volume 6, Issue 1, pp. 17 \200\22326, Copyright 2012 Lippincott Williams & Wilkins, Inc. , http://journals.lww.com/co-supportiveandpalliativecare/pages/default.aspx. like hunger, satiety, and defecation (Blackshaw and Gebhart, 2002 ) thus providing a degree of conscious control over these functions; however, we are normally unaware of the complex signaling events which continuously occur within our internal organs. \231 Direct activation or mucosal damage due to excess hydrogen ions in conditions such as oesophagitis. \231 Activation by pro-infl ammatory neurotransmitters (e.g. hista- mine and substance P) that increase excitability of the receptors (i.e. peripheral sensitization) in infl ammato ry bowel disease. Various neurotransmitters within the enteric nervous system take part in relaying this info rmation. Th e excitatory neurotransmitters include acetylcholine, and substance P and inhib itory transmitters include adenosine triphosphate, vasoactive intestinal peptide, and nitri c oxide. Serotonin, a monoamine neurotransmitter, plays a key role in the initiation of per istaltic and secretory refl exes, and in modulation of visceral sensations. \231 Direct involvement of the nerve in the infl ammatory process (i.e. neuritis) as is s een in transmural infl ammation with Crohn \200\231s disease. Muscular aff erents respond to mechanical stimuli, especially disten- tion, and consist of specialized terminals which surround myenteric ganglia termed intraganglionic laminar endin gs (ILEs; Lynn et al., 2003 ). Pain can result from pathological conditions in which disten - tion is beyond the tolerance threshold of the organ (e.g. acute intesti- nal obstruction) ; or be associated with a lower tolerance to distention, which is a proposed mechanism in f unctional abdominal pain. In conditions like chronic pseudo-obstruction there is a combinat ion of the two factors: perception of distention is altered secondary to neuropathy, and th ere is also excessive distention secondary to myo- pathic changes (Gebhart, 2000 ). In addi tion, a subgroup of visceral aff erent fi bres are mechanically insensitive, so-called mech anically insensitive aff erents (MIAs) or \200\230silent \200\231 nociceptors, but which a cquire Neural pathways for pain Peripheral visceral mechanisms Sensory nerve endings (i.e. viscera l nociceptors), in the mucosal or muscular layer are activated by a range of stimuli, such as mucosal and serosal infl ammation, traction on the mesentery, rapid luminal dis- tention , ischaemia, and forceful smooth muscle contraction. Mucosal aff erents appear as bare endi ngs in the lamina propria of intestinal villi and respond to luminal and local chemical sti mulation of the mucosal surface. Th is may involve (Berthoud et al. 1995 ; Gebhart, 2000 ): CHAPTER 26 pain and gastroenterological diseases 259 Table 26.1 Classi \201 cation of conditions presenting with abdominal pain spontaneous activity and mechanosensitivity aft er tissue insults such as infl ammation or mechanical trauma (Feng et al., 2012 ). Gastrointestinal conditions presenting with abdominal pain As the density of visceral sensory innervation is relatively sparse and there is marked div ergence of visceral input into the spinal cord, visceral pain tends to be diff use and poor ly localized (Sikandar and Dickenson, 2012 ). Diseases a \200 ecting the mucosal lining Esophagitis: \227\206 Re \202 ux esophagitis \227\206 Eosinophillic esophagitis \227 \206 Infections of esophagus Peritoneal pain Pain may also be produced by chemical stimulation, ischaemia, infl am- mati on, or stretching of the parietal peritoneum, which is innervated by branches from somatic eff erent and aff erent nerves that also supply the muscles and skin of the overlying body wall. Th e parietal perito- neum lining the anterior abdominal wall is supplied by lower si x tho- racic and fi rst lumbar nerves; and in the pelvis is mainly supplied by the obturato r nerve, which is a branch of the lumbar plexus. Parietal pain is sharp, severe, and very w ell localized, and experienced in con- ditions such as peritonitis, appendicitis, and pancr eatitis. Gastritis Peptic ulcer disease Duodenal ulcers In \202 ammatory bowel disease Crohn \200\231s disease Ulcerative colitis Indeterminate colitis Eosinophillic gastroenteritis Central processing of visceral pain In the spinal cord, visceral aff erent input converges with somatic aff erent input, resulting in referred visceral pain. In addition, ongo- ing a ctivity due to sensitization of peripheral aff erents, recruitment of MIAs, and interaction s with intestinal immune cells (mast cells, macrophages, and lymphocytes) can result in sen sitization of cen- tral nociceptive processing. Visceral pain sensitivity can also be modul ated by descending pathways, particularly from the rostro- ventral medulla, and this may co ntribute to associations between of anxiety, stress, and functional abdominal pain (Feng et al., 2012 ; Sikander and Dickenson, 2012 ). Infective enterocolitis Diseases a \200 ecting the smooth muscles Acute intestinal obstruction Chronic intestinal pseudo-obstruction Functional recurrent abdominal pain v Distal intestinal obstruction syndrome (DIOS) Constipation Diseases involving the parietal peritoneum Pancreatitis Appendicitis Postnatal development of visceral pain mechanisms Age-related changes in the distribution o r function of gastroin- testinal aff erents have not been directly evaluated throughout pos tnatal development (Christianson et al. 2009 ). However, it is clear that visceral mechanis ms are functional in neonates and infants, as referred visceral hyperalgesia can be measure d by changes in abdominal skin refl exes (Andrews et al., 2002 ), and repeated noxious stim uli in early life may contribute to persistent hyperalgesia (Anand et al., 2004 ). Peritonitis Non-gastrointestinal causes of abdominal pain Lower respiratory tract infection Urinary tract infection Cholecystitis Henoch \200\223Sch nlein purpura Sickle cell crisis Testicular torsion Assessment Assessment of a child with abdominal pain requires a careful and detailed histor y and examination. Th e main aim is to locate the cause of the pain, where possible ( Table 26.1 ), and determine its severity and resulting disability. Th e history should focus on the site and radi- ation, type and duration of pain, aggravating and relieving factors, and its intensity. Pain needs to be interpreted in the context of any known pathology, potenti al new pathology, and the impact of pain on functioning. Examination includes overall impre ssion (e.g. ill/well, malnourished, pale) and assessment of the systemic impact of pain wit h regard to changes in heart rate and blood pressure. Abdominal examination may help identi fy the site of pain by associated features including tenderness, guarding, and rebound, and identify any other associated factors such as organomegaly or palpable masses. Pelvic in \202 ammatory disease Pyelonephritis Diabetic ketoacidosis Haemolytic uremic syndrome \231 Self-report tools have been used to quantify pain intensity with good agreement betw een the Wong \200\223Baker Faces Scale and visual analog scale in children (8 \200\22317 ye ars) presenting to the emer- gency department with acute pain, of whom 19% had abdominal pa in (Garra et al. 2010 ).