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 ). \231 Multidimensional Measure for Recurrent Abdominal Pain (MM-RAP) also quantifi es non- pain symptoms associated with bowel disease (nausea or vomiting, heartburn, diarrhea, const ipation, fl atulence, loss of appetite, bloating, sour taste, bad breath, sleep problems, a nd problems with ingestion of milk) and disability. It is best used in an outpatient settin g Pain assessment Pain assessment is discussed elsewhere in this text, but examples of use in children with abdominal pain include: SECTION 4 pain in specific populations and diseases 260 for children with long standing recurrent abdominal pain (Malaty et al., 2005 ; see also Sc hurman et al., Chapter 29, this volume). Infl ammation can be controlled by the following (Sandhu et al., 2010 ): \231 Exclusive enteral nutrition is an eff ective treatment for children with Crohn \200 \231s disease and induces remission in 60% to 80% of the cases (Fell et al., 2000 ). Polyme ric or elemental diets are equally eff ective. Duration of exclusive enteral nutrition is u su- ally 6 weeks, and depending on patient symptoms, food may be cautiously reintroduced wh ilst weaning the enteral feed over 1 to 3 weeks. In \202 ammatory bowel disease Infl ammatory bowel disease (IBD) is a chronic relapsing il lness aff ecting the gastrointestinal system that includes: \231 Crohn \200\231s disease (CD) is a chronic, idiopathic transmural infl am- mation whi ch can aff ect one or several segments anywhere in the digestive tract. CD is also characte rized by the type of disease into infl ammatory, fi stulating, and structuring disease. \231 Corticosteroids are potent anti-infl ammatory agents for mod- erate to severe relaps es of both UC and CD. Th ey act through inhibition of several infl ammatory pathways \200 \224suppressing interleukin transcription, induction of I B that stabilizes the NF B complex, suppression of arachidonic acid metabolism, and stimulation of apoptosis of lympho cytes within the lamina propria of the gut (Steinhart et al., 2001 ). Commonly used ster- o ids are prednisolone in the dose of 2 mg/kg/day (max 40mg/ day). Side eff ects include acne , moon face, sleep and mood dis- turbance, dyspepsia, or glucose intolerance. Eff ects asso ciated with prolonged use include osteoporosis, osteonecrosis of the femoral head, myopathy , impaired growth, and susceptibility to infection. \231 Ulcerative colitis (UC) is a chronic idiopathic mucosal infl am- mation limited to t he colon. It extends from the rectum continu- ously over a variable length of the colon fro m the distal to the proximal end. \231 Indeterminate colitis (IC) is reserved for cases of colitis in which fi ndings are n ot suffi cient to allow diff erentiation between CD and UC. Th e disease is characterized b ased on its severity ranging from mild to severe and its distribution in the gastrointestin al tract. Th e aetiologies of both UC and CD remain unknown, but a response to environmental triggers like infection, drugs, or chemi- cal agents in genetically susceptible individuals is the current con- sensus. Approximately 20% to 30% of patients with IBD present before the age o f 18 years (Heyman et al., 2005 ; Sawczenko et al., 2001 ; Vind et al., 2006 ). \231 Monoclonal antibody therapy such as infl iximab, a chimeric anti- tumor necrosis fac tor monoclonal antibody with potent anti- infl ammatory eff ects. It was initially develope d for use in patients with moderate to severe luminal or fi stulizing CD who are refrac- to ry to standard medical therapy, but is now being used more widely. Although used predominan tly to treat CD, recent data suggest that infl iximab also may have a role in the managemen t of UC (Lawson et al., 2006 ). Clinical presentation Th e common presenting features are abdominal pain, diarrhea, and wei ght loss. Other features can include rectal bleeding, leth- argy, anemia, anal fi ssures or abscesses, mouth ulcers, or arthritis. Abdominal pain is a presenting feature in up to 72% of children with IBD (Sawczenko and Sandhu, 2003 ), and is the most debilitat- ing symptom . Evaluation of pain is an important part of assessing disease severity and is a component of several disease activity indi- ces. Pain may be due to ongoing intestinal infl ammation or second- ary to complications such as strictures, subacute bowel obstruction and abscesse s seen in CD, or toxic megacolon in UC. Other con- ditions causing pain in IBD include gall stones, renal calculi, and chronic pancreatitis, and management principally involves treat ing the underlying pathology. Perianal disease can result in localized severe and diffi cul t to control pain. Surgery, such as abscess drainage or fi stulotomy, may be required for complications (Sandh u, 2010 ). Pain management in in \202 ammatory bowel disease Non-steroidal anti-infl ammatory drugs ( NSAIDs) act by inhibit- ing the production of prostaglandins by cyclo-oxygenase (COX) enzym es (see Anderson, Chapter 43, this volume). Th e eff ect is mediated through inhibition of both the inducible form of the enzyme, COX-2, and the constitutively produced COX-1 enzyme, resulting in reduced prostaglandin production, which may also result in gastrointestinal s ide eff ects. NSAIDs have been linked in some reports to a higher likelihood of disease exa cerbation. A 20% to 30% increase in risk of fl are-ups was seen with use of NSAIDs in IBD, and all NSAID-treated patients experienc- ing a fl are were able to re-attain remission sim ply by stopping the NSAID (Takeuchi et al., 2006 ). Even though controlled tri- als using N SAIDs in IBD are lacking, a large study including 500 adults failed to fi nd any associatio n between disease relapse and use of NSAIDs (Bernstein et al., 2010 ). NSAIDs can probably be safely used in children with IBD, particularly in the short term, but should be withdraw n if gastrointestinal side eff ects are seen or the disease fl ares and the NSAIDs are felt to be a factor. NSAID- induced enterocolitis is seen rarely (Geramizadeh et al., 2009 ). About 20% to 30% of adults with IBD continue to have pain without evidence of active infl a mmation, obstruction, or other bio- logically defi ned abnormalities (Bielefeldt et al., 20 09 ; Colombel et al., 2010 ). Similarly, ongoing pain in children with IBD could be due to persistent sensitization in the gastrointestinal tract fol- lowing infl ammation and high r ates of irritable bowel syndrome. Psychological and cognitive factors may also infl uence p ain experi- ence (Docherty et al., 2011 ). Management In patients with active infl ammation, analgesics alone are generally less eff e ctive until the underlying cause is resolved. Infl ammation or stricture formation requirin g more intense medical or even surgical therapy likely explain why signifi cant pain requir ing analgesic ther- apy is a negative prognostic indicator (Lichtenstein et al., 2006 ). Hyoscine butylbromide blocks the eff ects of acetylcholine at muscarinic receptors in the p eriphery, and has no central eff ects (unlike hyoscine hydrobromide) as it does not cross t he CHAPTER 26 pain and gastroenterological diseases 261 blood \200\223brain barrier. Hyoscine butylbromide has an inhibitory eff ect on smooth musc le and reduces gastrointestinal motility. As only 2% to 8% of an oral dose is absorbed, eff ects are mainly related to topical actions in the proximal gut, with no eff ect on the jej unum. Intravenous administration inhibits motility through- out the bowel (Dollery, 1998 ). Box 26.1 Symptoms and signs of gastro-oesophageal re \202 ux disease (GORD) Symptoms \227\206 Recurrent regurgitation with/without vomiting Opioids are mainly used for the management of acute pain in IBD, and have a well-defi ned r ole in the management of postoperative pain in children with IBD requiring surgery. Th e us e in acute cases of disease fl are-up is controversial, as opioids can induce signifi cant adverse eff ects on gastrointestinal function and gut motility. Even at low doses, morphine decreases gastric motility, and may prolong gastric emptying time by up to 12 h as the ton e of the antral por- tion of the stomach and the fi rst part of the duodenum is increased. Propulsive contractions are reduced in the duodenum and colon, and colonic muscle tone is i ncreased (the ileum is less aff ected), leading to constipation which can be severe (Brunto n et al., 2011 ). Opioids also exert complex eff ects on the immune system via centrally me di- ated and direct cellular eff ects; and immunomodulatory eff ects are an area of active research in infl ammatory bowel disease (Mani and Moore, 2009 ; Philippe et al., 2006 ; Zag on and McLaughlin, 2011 ). \227\206 Weight loss or poor weight gain \227\206 Irritability \227\206 Ruminative behavior \227\206 Heartburn or chest pain \227\206 Dysphagia, odynophagia \227\206 Wheezing \227\206 Stridor \227\206 Cough \227\206 Feeding refusal. Signs \227\206 Esophagitis In children presenting with an acute fl are of IBD, opioids should be used with extreme cau tion and close monitoring for signs of toxic megacolon (e.g. tachycardia, fall in blood pre ssure, and increasing abdominal distension). Th e N-methyl-D-aspartate antagonist keta- min e has been shown to reduce acute visceral hyperalgesia in adult volunteers (Willert et al., 2004 ), but effi cacy and potential long- term side-eff ects have not been evaluated in ch ildren with gastro- enterological disease. \227\206 Oesophageal stricture \227\206 Barrett esophagus \227\206 Laryngeal/pharyngeal infl ammation \227\206 Recurrent pneumonia \227\206 Anemia \227\206 Dental erosion Long-term opioid use in children with IBD is discouraged, and has been associated with poor er outcomes in adults (Cross et al., 2005 ). Th e TREAT registry prospectively followed ove r 6000 patients with Crohn \200\231s disease, half of whom received infl iximab. Chronic na rcotic analgesics use was associated with an increased risk of infection (odds ratio, 2.38; 95% confi dence interval 1.56 \200\2233.63; Lichtenstein et al., 2006 ). However, the incr eased complications associated with opioid use may be an indicator of more severe IBD, as a dults treated with opiates were more likely to have increased disease activity, and were al most twice as likely to require surgical intervention (Cross et al., 2005 ). \227\206 Dystonic neck posturing (Sandifer syndrome) \227\206 Apnoea spells. persist beyond 18 months of age, there is higher likelihood of a pathological cause (Gold, 2004 ). Alterations in several protective mechanisms allow physiological refl ux to become GORD: delay in gastric emptying, poor clearance of refl uxed gastric juices from the esopha gus, or abnormal position of the lower oesophageal sphincter in the thoracic cavity (Cosgro ve and Dodge, 1998 ). Diagnosis Th e diagnosis of GORD is predominantly based on history and examination or on re sponse to treatment. It is important to dif- ferentiate this condition from foregut dysmoti lity, in which infants present with symptoms of vomiting and discomfort aft er feeds, but t he typical features of arching, excess salivation, and feed refusal are absent. Infants wit h dysmotility have associated intermittent abdominal distension and altered bowel habits. A pH study can quantify oesophageal acid exposure by the number and duration of refl ux epis odes (pH <4.0) and the percentage of the entire record that oesophageal pH is less than 4.0 . Although this test has estab- lished normal ranges, it is likely that a continuum between physi- ological GORD and pathological GORD exists, and the severity of pathologic acid ref l ux does not consistently correlate with symptom severity or demonstrable complications. O esophageal pH monitor- ing can also help determine if a temporal association exists between episodes of refl ux and atypical symptoms (chronic cough, stridor, wheezing, apnoea, irrit ability, or opisthotonic posturing) and eval- uate the effi cacy of antisecretory therapy ( Colletti et al., 1995 ). Gastro-oesophageal re \202 ux disease Gastro-oesophageal refl ux results in passage of the gastric juices and acid into the esophagus. It is a normal physiological process occur- ri ng several times a day, particularly in the post-prandial period. Frequent episodes of tran sient relaxation of the lower oesophageal sphincter in response to gastric distention and v agal stimulation normally last for 10 to 30 sec, allowing retrograde fl ow of the stom- ach contents. Infants develop symptoms, such as vomiting, irrita- bility and coughing aft er f eeds if there are prolonged or excessively frequent relaxations of the sphincter ( Box 26.1 ). Symptoms resolve by 6 months of age in 60% of children with refl ux, and by 1 year in a pproximately 90% of infants (Martin et al., 2002 ). A higher frequency of transient lower oesophageal sphincter relaxation and prolonged durati on of oesophageal acid expo- sure may result in pathological gastro-oesophageal refl ux dis ease (GORD), with associated complications such as erosive oesophag- itis, respiratory comp lications, or weight loss. When symptoms SECTION 4 pain in specific populations and diseases 262 Management Management of GORD in children is based on its severity, the degree of functiona l impairment, and presence or absence of com- plications. Th e goals for treatment are to r elieve symptoms, heal oesophagitis if present, maintain remission of symptoms, and man- age or prevent complications. Treatment options include: Box 26.2 Etiology of acute and chronic pancreatitis in children Acute pancreatitis \227\206 Infectious: \227\206 Coxsackie B virus \227\206 Epstein \200\223Barr Virus \231 Dietary management by modifying infant feeding techniques and changing formula compo sition with addition of thicken- ing agents. In one study, this improved vomiting and irrit ability in approximately one-fourth of infants with GORD symptoms (Shalaby et al., 2003 ). As symptoms of milk protein allergy can overlap those of GORD, a 2-week trial of hypoallerg enic formula can be considered (Rudolph et al., 2001 ). \227\206 Hepatitis \227\206 Measles \227\206 Rubella \227\206 Malaria \227\206 Mumps \227\206 Mycoplasma \231 Pharmacological therapy suppresses gastric acid production by histamine H 2 receptor blockers such as ranitidine, or proton pump inhibitors (PPIs) such as omeprazole, which ha ve been shown to be more eff ective in reducing gastric acidity (van der Pol et al., 2011 ) . Omeprazole given for 12 weeks resolved moderate-to-severe GORD symptoms in all but 7% of paedi- atric patients aged 1 to 16 years (Hassal et al., 2000). Th ere is some confl icting data on whether histological fi ndings as well as symptoms are improved (van der Pol et al ., 2011 ). PPIs are safe and well tolerated in children of all ages (Faure et al., 2001 ; H assal et al., 2000), with adverse events (headache, con- stipation, diarrhea, and abdominal pain) in less than 5% of patients. \227\206 Infl uenza A & B. \227\206 Hereditary pancreatitis. \227\206 Drugs and toxins: \227\206 Alcohol \227\206 Azathioprine/6-mercaptopurine \227\206 Corticosteroids \227\206 Valproic acid \227\206 Sulfonamides \227\206 Erythromycin \231 Surgery may be indicated for failed medical therapy or symptom recurrence. Fundoplic ation is performed with consideration of a pyloroplasty if there is delayed gastric emptyin g, and/or a gas- trostomy if there are feeding problems (Granderath et al., 2002 ). Postope rative analgesic requirements did not diff er in a rand- omized trial of laparoscopic versu s open fundoplication (McHoney et al., 2011 ), and a meta-analysis reported reduced postope rative complications, faster recovery, but an increased risk of reoperation following lapar oscopic versus open surgery (Peters et al., 2009 ). \227\206 Enalapril \227\206 L-aspariginase \227\206 Vincristine. \227\206 Trauma. \227\206 Obstructive: \227\206 Pancreatic duct abnormality \227\206 Biliary tract malformations Pancreatitis Pancreatitis is an infl ammatory process associated with autodigestion of the gland by its enzymes, and can be acute or chronic. Although relatively rare in children, it is associated with high morbidity, but mortality rates are lower than in adult populations (Mekitarian et al., 2012 ). In a series of 279 pediatric cases, causes of pancreatitis in children included trauma (36%), systemic disease (22%), metabolic (6%), biliary (5%), drugs (3%), and viral illness (2%); but 25% were deemed idiopathic (Nydegger et al., 2007 ) ( Bo x 26.2 ). \227\206 Sphincter of oddi dysfunction \227\206 Pancreas divisum \227\206 Choledocal cyst \227\206 Duplication cyst \227\206 Complication of endoscopic retrograde cholangio-pancrea- tography (ERCP) \227\206 Tumors. Pathophysiology Mechanisms of pain associated with chronic pancreatitis may include (Tsioto u 2000 ): \227\206 Systemic disease: \227\206 Alpha 1 antitrypsin defi ciency \227\206 Cystic fi brosis \231 Increased pressure and tension within the gland due to block- age of the ducts. Th i s hypothesis prompted development of tech- niques to endoscopically decompress the gland. \227\206 Haemochromatosis \227\206 Haemolytic uraemic syndrome \227\206 Malnutrition \231 Mechanical blockage of surrounding structures such as the duo- denum secondary to en largement of the gland, resulting in par- tial obstruction and pain. \227\206 Hyperparathyroidism \227\206 Vasculitis syndromes \231 Local nerve injury and neuropathic pain. CHAPTER 26 pain and gastroenterological diseases 263 Management Management of children with pancreatitis requires analgesia, fl uid replacement, nutritional support, and treatment of any initi- ating cause ( Table 26.2 ) or associated complications (Mekitarian et al., 2012 ): Box 26.2 (Continued) \227\206 Hypercalcaemia \227\206 Hyperlipidaemia \227\206 Sepsis/shock. Chronic pancreatitis \231 Analgesia : providing adequate analgesia is an important part of management of acute pancreatitis, and opioids are commonly used. Th ere is no defi nitive human study to suppo rt the wide- spread belief that morphine exacerbates pancreatitis by stimulat- ing the sphi ncter of Oddi to contract (Toouli et al., 2002 ), and no studies suggest that use of morphi ne is contraindicated in acute pancreatitis (Th ompson 2001 ). Other drugs which may be ben efi cial include acetaminophen and non-steroidal anti-infl am- matory agents. Drugs for neu ropathic pain may be considered in chronic cases (see Rastogi and Campbell, Chapter 48, thi s volume). Pregabalin reduces acute acid-induced hyperalgesia in adult volunteers (Chua et al., 2012 ), but there is currently no data to confi rm effi cacy or inform appropriate pat ient selection in children who may have visceral hyperalgesia. \227\206 Hereditary pancreatitis \227\206 Idiopathic fi brosing pancreatitis \227\206 Cystic fi brosis \227\206 Hyperlipidaemia/hypercalcaemia \227\206 Trauma \227\206 Congenital anomalies \227\206 Wilson \200\231s disease. Th e innervation of the pancreas is complex, involving both somatic \200\223visceral and au tonomic nerves. Painful stimuli, such as pressure, acid or chemicals released by cellular n ecrosis activate receptors on somatic \200\223visceral nociceptive neurons in the pancreati c bed. Th e signal passes cephalad along both unmyelinated C-fi bres and small myelinated A fi bres, through the celiac plexus via the left and right greater splanchnic nerves, an d through the sympa- thetic trunk ganglia to the cell body in the dorsal root ganglia, to s ynapse in the spinal cord at levels T5 to T9. Sensory neurons from the back and epigastric rectus abdominus muscles are also found at this level, resulting in pain of pancreatitis be ing referred to the back and/or epigastric region. \231 Pancreatic rest : in acute cases, preventing oral intake \200\230rests \200\231 the pancreas and provides symptomatic relief (Lordan et al., 2009 ). Without any food being pr esented to the gut, secretions from the gastric glands are reduced, and reduced enzyme rele ase by the pancreas decreases both autodigestion and pancreatic distension. Nutrition is cr itically important in patients with pancreatitis and an early positive nitrogen balance imp roves survival rates in adults (Meier et al., 2006 ). In adult studies, placement of a naso je- junal tube for feeding has been shown to as eff ective as parenteral nutrition, with re duced infectious complications (Kalfarentzos et al., 1997 ), and both assist in controlling pain (Raimondo et al., 2005 ). In patients with chronic pancreatitis there is limited rese arch on the benefi t of restricted diets, and it would be pru- dent to provide a well-balan ced nutritionally complete diet (Shea et al., 2000 ; Toouli et al., 2002 ). Clinical presentation Acute pancreatitis presents with vomiting and abdominal pain, which i s characteristically a sharp, steady pain of sudden onset, aggravated by eating and improve d by drawing the knees up to the chest. Th e pain is generally epigastric, but may be exper ienced in the middle or even lower abdomen, or referred to the back. Physical signs include fever and tachycardia. White cell count and infl amma- tory markers may be increased. Seru m amylase is usually elevated and starts to subside by 3 to 5 days, but the degree of eleva tion does not correlate directly with severity of disease severity, and normal levels do no t rule out the diagnosis (Lautz et al., 2011 ). Serum lipase may also remain elevated for 1 to 2 weeks. Ultrasound imaging can demonstrate an enlarged, oedematous pancreas, a dilated main pancreatic duct indicates obstruction, and calcifi cations are oft en seen in older c hildren with recurrent pancreatitis. \231 Somatostatin analogs : octreotide has been used in adults for management of acute pa in in pancreatitis as it suppresses chole- cystokinin and pancreatic secretions (Uhl et al. , 1999), and some but not all data suggests improved outcome (Beechey Newman 1993 ; Heikene n et al., 2002 ). Pediatric data is limited to case reports, and octreotide is not routinel y used in children with acute pancreatitis, although some benefi t has been shown for the Table 26.2 Groups of medication used in management of constipation Class of drug Example Mechanism of action Osmotic laxatives Lactulose, macrogols, magnesium sulfate, phosphate enema Draws and retain water in large bowel by osmosis Most episodes of acute pancreatitis in children are isolated and self-limited, but patients with recurrent episodes may progress to chronicity. Recurrent acute pancreatitis is common ly associated with congenital malformations of pancreatico-biliary tract, gall- stones, cys tic fi brosis, and familial pancreatitis (Nydegger et al., 2006 ). Familial pancreatitis ha s been associated with mutations in: cationic trypsinogen gene (e.g. PRSS1 ) which enhances trypsin activation; SPINK1 (serine protease inhibitor Kazal type 1) gene resulting in an a bnormal pancreatic secretory trypsin inhibitor; and the CFTR (cystic fi brosis transmembran e conductance regu- lator) gene, which reduces the pancreatic fl uid secretion capacity (Ny degger et al., 2006 ). Stimulant laxatives Anthraquinones, e.g. senna Bisacodyl, picosulphate Increase intestinal motility Lubricants/softeners Arachis oil, liquid para \203 n, docusate Softens impacted stool Bulking agents Fiber, bran, isphagula, methylcellulose Increase fecal mass and improves peristalsis Prokinetics Erythromycin Improves transit by increasing peristalsis SECTION 4 pain in specific populations and diseases 264 management of complications, such as ascites and pseudocysts. (Bosman-Vermeeren et al., 199 6 ; Rushforth et al., 1993 ). Box 26.3 Symptoms and signs suggestive of underlying pathology in children with constipatio n \231 Administration of oral pancreatic enzymes may reduce pain via negative feedback inhi bition to the pancreas, with some benefi t shown in adults (Layer et al., 1990 ), but data in children is lacking. \227\206 Constipation reported from birth or fi rst few weeks of life. \227\206 Failure to pass meconium/delay (more than 48 h) in a term baby. \231 Antioxidant therapy has been suggested for chronic pancreatitis in adults (Bhardwaj et al., 2004 ), but there is confl icting data about effi cacy, and further research is nee ded (Gachago et al., 2008 ). \227\206 Infrequent/very large (ribbon) stools. \227\206 Faltering growth. \231 Antibiotics may prevent secondary bacterial infections, limit complications, and imp rove outcome; however, they are best reserved for severe cases, especially where pancreatic necrosis is present (Sainio et al., 1995 ). \227\206 Previously known or undiagnosed weakness in legs/locomotor delay. \227\206 Abdominal distension with vomiting. \231 Surgical intervention is rarely required in management of pan- creatitis except in c ases of congenital malformations or manage- ment of complications such as drainage of pseud ocysts. \227\206 Perianal inspection \200\224 abnormal appearance/patency/position of anus, anter iorly placed anus or absent anal wink, fi ssures, fi stulae, bruising, tight or patulous an us. \227\206 Gross abdominal distension, palpable fecal mass (in at least Constipation Constipation is a very common (5 \200\22330%) cause of abdominal pain in child ren (van den berg et al., 2006 ). Most children do not have an underlying cause and the ROM E III criteria for diagnosis of func- tional constipation include presence of two or more o f the follow- ing for more than 1 month (Rasquin et al., 2006 ): half of these patients). \227\206 Spine and gluteal examination \200\224 asymmetry of gluteal muscles, scoliosis, evidence of sacral agenesis, overlying skin over sacral region with discoloration, naevi, s inus, hairy patch, lipoma or central pit. \227\206 Deformity in lower limbs such as talipes. \231 Two or fewer defecations per week. \227\206 Abnormal neuromuscular signs unexplained by any existing \231 At least one episode/week of incontinence aft er the acquisition of condition, such as cerebral palsy. toileting skills. \227\206 Abnormal tendon refl exes. \231 History of excessive stool retention. \231 History of painful or hard bowel movements. for compliance (sitting on the toilet) at fi rst and then for success (opening bowel in the toilet). \231 Presence of a large fecal mass in the rectum. \231 History of large-diameter stools which may obstruct the toilet. \231 Drug treatment: laxatives are used in the management of acute as well as chronic con stipation. As abdominal pain in these children is principally due to fecal impaction it is poorly responsive to analgesics. History and clinical examination aim to assess the severity of symp- toms and resulting fun ctional impairment. Symptoms and signs that are suggestive of underlying pathology ( Box 26 .3 ) should be sought to ensure diagnosis or exclusion of organic conditions. \231 Disimpaction of stools can reduce pain (Poenaru et al., 1997 ). Senna or polyethylen e glycol can be used as sole agents in high doses. In severe cases, sodium picosulphate (li quid or sachets) may be required. Rectal medications (suppositories, enemas) are used if al l oral medications have failed. Manual evacuation of the bowel under anesthesia is rarely c onsidered, and only if oral and rectal treatments fail. Management Th e UK National Institute for Health and Clinical Excellence (NICE) produced a clinical guideline \200\230 CG99 Constipation in children and young people: Diagnosis and management of idiopathic childhood constipation in primary and secondary care \200\231 in M ay 2010 (< http:// www.nice.org.uk/cg99 >). Th e management of chronic functional constipat ion oft en requires a multidisciplinary approach, based on the following principles: \231 Laxatives are oft en needed for prolonged maintenance therapy, but need to be closel y monitored, weaned only aft er a sustained period of normal bowel actions with no soiling, and used in conjunction with other supportive strategies. Polyethylene gly- col (Movicol ) is widely used. Senokot given in the evening, at reasonable doses, is eff ective. Th e choice of agent depends on local preference as well as individual patient circumstances ( Table 26.2 ). Young children should remain on laxatives until toi- let training is well e stablished. \231 Explanation of normal bowel function aids the family \200\231s understand- ing and i mproves compliance. Parents and children should be reas- sured that constipation is common and responds well to treatment. \231 High-fi bre diet is recommended along with adequate fl uid intake because it adds bulk to the stool. \231 Regular exercise promotes peristalsis and helps bowel transit. Neuromuscular motility disorders Motility disorders present with features of gastrointestin al obstruc- tion in the absence of a mechanical cause. Th e spectrum of motil- ity disorder s ranges from relatively benign conditions such as \231 Regular toileting is a crucial part of the management to encour- age regular emptying of the rectum. \231 Behavioral advice and reward schemes (star charts) are helpful to gain child \200 \231s trust in the management. Rewards can be given CHAPTER 26 pain and gastroenterological diseases 265 gastro-oesophageal refl ux and functional constipation, to life-threat- ening illnesses suc h as chronic intestinal pseudo-obstruction. It can result from any process that interferes with coordinated patterns of propulsive movement of intestinal musculature. Chronic disorde rs of motility account for 15% of patients with intestinal failure necessitat- ing the use of parenteral nutrition (Connor et al., 2006 ) and irrevers- ible cases may require intesti nal transplant (Gupte et al., 2007 ) cases, symptoms are present from birth or early infancy. Pain is usually a prominent featur e and is a result of uncoordinated con- traction of bowel musculature (Takahashi, 2005 ). Management Management requires a multidisciplinary team that includes a gastroenterologist, surgeon, dietician, and psychologist. Chronic abdominal pain or the fear of pain is a comm on problem in children with chronic intestinal pseudo-obstruction. Luminal dilatation, repe ated invasive procedures, and mucosal infl ammation may all contribute to the development o f visceral hyperalgesia with sensiti- zation of peripheral and central pain pathways (Anand et al., 2004 ; Christianson et al., 2009 ; Feng et al., 2012 ). Th e stress of chronic dis ease can also infl uence pain report and altered family dynamics (see also Birnie et al., C hapter 12; Fogeron and King, Chapter 13, this volume). Intestinal pseudo-obstruction can be divided into acute or chronic. Chronic pseudo obstruct ion can be primary or second- ary to systemic illness. Primary pseudo-obstruction is a resu lt of disorders of intestinal smooth muscle (myopathic) or myentric plexus (neuropathic), a nd can involve either the whole of or a localized segment of the bowel ( Box 26.4 ). Neurop athic disorders are more common and may be primary or secondary (e.g. in utero insults such as fetal alcohol syndrome or postnatal injuries such as ischaemic events or viral infectio ns; Rudolph et al., 1997 ). Antro- duodenal manometry measures the intraluminal pressure of the antrum and duodenum and is useful to distinguish myopathy (con- traction amplitude is reduced but spatial and temporal organization is preserved), from neuropathy (contractions have normal ampli- tude but are uncoordinated and lack normal physiologic patterns) (Hyman et al., 1993 ).