A recent defi nition suggests central neuropathic pain is \200\230pain arising as a direct consequence of a lesion or disease aff ecting the central somatosensory system \200\231 (T reede et al., 2008 ). It is triggered CHAPTER 28 pain in palliative care 285 Strictly speaking, the newly proposed grading system to diagnose this condition requires a history suggestive of a relevant lesion, the presence of pain with a distinct sensory distr ibution in a corre- sponding body part, indication of negative or positive sensory signs wi thin the area and confi rmation of the lesion by a diagnostic test (Treede et al., 2008 ). Unfortunately, many children and infants with a possible diagnosis are not able to communic ate making it very diffi cult to elicit sensory changes. However, if sensory disturbances l ike allodynia or dysaesthesia are consistently present then a strong indicator for central neuropathic pain is present. anticonvulsants, and NMDA receptor antagonists (Davis et al., 2009 ; Hauer et al., 2007 ; Z angen et al., 2003 ). Th e paucity of pediatric data on this topic is striking consider- ing the regular prescrib ing of anticonvulsants in pediatric prac- tice. A single case report of a 3-month-old infan t with neurological impairment and cerebral irritability detailed improvement in tone and d isposition aft er the infant was treated with 5 mg/kg gabap- entin at night following the f ailure of regular lorazepam and inter- mittent morphine to provide relief. Gabapentin was w ell tolerated and dose increases lead to further improvement (Behm and Kearns, 2001 ). Th e other challenge for pediatric clinicians caring for a non-ver- bal child with severe n eurological impairment is that these children oft en have assorted types of pain. For insta nce, the complicated issue of whether spasticity is the primary cause of pain, or the resul t of pain from another source. Attention must be given to exploring and managing each pain type in a systematic way. Visceral hypersensitivity Visceral hypersensitivity or hyperalges ia is an altered response to visceral stimulation resulting in activation of pain sensation and has been regarded as a cause of functional gastrointestinal disease (Delgado-Aros and Camilleri, 2005 ). A recent review by Woolf reports that visceral pain hypersensitivity syn dromes in the diges- tive system looks to have a component of central sensitization which i s dynamically maintained by input from the gastrointestinal system (Woolf, 2011 ). Opioids are not a fi rst-line medication in this situation although they have been shown to improve pain in some central neuropathic pain conditions (Attal et al., 2010 ; Dworkin et al., 2007 ). Th ey may be appropriate as a short-term control measure for acute neuro- path ic pain until other agents have been introduced and titrated to eff ect (Barrera-Chacon et al., 2011 ; O \200\231Connor and Dworkin, 2009 ; Rowbotham et al., 2003 ). However, as the use of any analgesic medication for children with cerebral irritability may be necessary fo r a prolonged period of time the potential for long-term eff ects of using the medication m ust be given due consideration. In the case of a long-term opioid the development of tolera nce or opioid-in- duced hyperalgesia is a concern. Despite these measures some chil- dren w ill have intractable symptoms and may require additional medications such as benzodiazepine s, phenobarbitone, or agents such as levomepromazine and haloperidol. Gastrointestinal pain is commonly reported in children with severe cognitive impairment (Ha uer, 2010 ; Hauer et al., 2007 ; Houlihan et al., 2004 ; Klick and Hauer, 2010 ) and chroni c cerebral irritability in this group is oft en temporally related to gastrointesti- nal sy mptoms and signs including feed intolerance, fl atus, retching, vomiting and pain. Developm ent is thought to result from repeated painful gastrointestinal experiences in infancy; it is an outcome of sensitization not the underlying neurological injury. Th e con- sequence o f these painful experiences is recruitment of previously silent nociceptors and sensitizati on of peripheral visceral aff erent fi bres causing pain (Hauer et al., 2007 ; Zangen et al ., 2003 ). Such experiences might include a history of prolonged neonatal care, gastro-oeso phageal refl ux, constipation, gastrostomy feeding and fundoplication. Visceral pain has al so been associated with motor abnormalities of the gut, exaggerated intraluminal pressures and pain sensation and an important factor in pain generation appears to be the presence of nociceptors in the gut wall that can be acti- vated by a variety of modulators at lower, n ormally ineff ective, intraluminal pressures (Bu no et al., 2000 ). Neural stimulation therapy including motor cortex stimulation (Fontaine et al., 2009 ), dee p brain stimulation (Owen et al., 2006 ), and transcranial magnetic stimulation (Leung et a l., 2009 ) have been reported to be successful in adults with treatment resistant central p ain. Th ere are no reports of any of these methods being used in children; however, the use of cortical brain stimulation is well established in children with refractory epilepsy and has a good therapeutic and safety profi le. Neuropathic pain Th e cause of neuropathic pain is very dependent on the disease process an d is oft en related to compression, direct invasion, or infection of the peripheral nerves or spinal cord and is detailed fur- ther in this volume by Walker (Chapter 21) and pharmaco logical treatment is described by Rastogi and Campbell (Chapter 48). In palliative care for children the mainstays of therapy involve the use of opioids and adjuvant analgesics. Alth ough neuropathic pain is more likely than other types of pain to be partially or wholly opi oid resistant (Collins et al., 1995 ), opioid responsiveness cannot be reli- ably predicted in individual patients solely on the basis of the type of pain (Cherny et al., 1994 ). Th erefore, a trial of opioid therapy should not be withheld or limited solely on the basis of inferred pathophysiology. Management Children with cerebral irritability present with their own individ- ual narrativ e, symptoms, and signs. Th e most important step in the management is to obtain a detailed history and evaluation. In the case of chronic cerebral irritability, it may be necessary t o request a symptom diary to establish temporal factors and understand the impact upon the child and family. Th is should be followed by the relevant investigations to exclude all ot her possible causes of pain and irritability. Treatment is then directed at the identifi ed cause. Intractable pain Palliative sedation in end of life care is an accepted but contro- versial means of providing relief from otherwise refractory and intolerable symptoms and distress (Chater et al., 1998 ; Manzini, 2011 ). Th e European Association for Palliative Care defi nes pal- liative sedation as the monitored use of medications intended to induce a state of decreased or absent awareness in order to relieve the burden of otherwise intractable suff ering in an ethically accept- able manner (Cherny et al., 2009 ). Th e use of sedation in the setting Pharmacological management directed at central neuropathic pain and visceral hypersensitivi ty has been poorly studied and, in adults, central neuropathic pain has been classically di ffi cult to treat (Klit et al., 2009 ). Approaches with medication would usually involve a trial of adjuvant agents including tricyclic antidepressants, SECTION 4 pain in specific populations and diseases 286 of refractory pain assumes that all possible analgesic therapies have been employed and tha t there is no acceptable means of providing analgesia without compromising consciousness (C ollins, 2010 ). Bachrach , S. J. , Kecskemethy , H. H. , Harcke , H. T. , and Hossain , J. ( 2010 ). Decrea sed fracture incidence aft er 1 year of pamidronate treatment in children with spastic quad riplegic cerebral palsy . Dev Med Child Neurol , 52 (9), 837 \200\223842. Th ere is a considerable lack of information regarding pallia- tive sedation in pediatrics; there are no international guidelines for children and little is known about the clinical eff ectiveness of sedation practice. A recent review of the pediatric literature off ers so me insight into practice by stating that sedation in children remains controversial and is infl uenced by educational, cultural, legal, moral, and health policy issues. Importantly, it highlighted that physical symptoms are described as an indication for practice but exist ential suff ering must also be considered in the evaluation of refractoriness of symptoms ( Kiman et al., 2011 ). Existential suff er- ing of parents must also be acknowledged, as the ir distress behav- iour may impact upon patient management and this was explored in the stu dy by Dussell et al. (2010). Baillargeon , J. ( 2011 ). Osteonecrosis of the jaw in older osteoporosis patients treated with intravenous bisphosphonates . Ann Pharmacother , 45 (10), 1199 \200\2231206. Barrera-Chacon , J. M. , Mendez-Suarez , J. L. , J uregui-Abrisqueta , M. L. , Palazon , R. , Barbara-Bataller , E. , and Garc a-Obrero , I. ( 2011 ). Oxycodone improves pain c ontrol and quality of life in anticonvulsant- pretreated spinal cord-injured patients with neuropathic pain . Spinal Cord , 49 (1), 36 \200\22342. Batch , J. A. , Couper , J. J. , Rodda , C. , Cowell , C. T. , and Zachaarin , M. ( 2003 ). Use of bisphosphonate therapy for osteoporosis in children and adolescence . J Paediatr Ch ild Health , 39 , 88 \200\22392. Behm , M. O. , and Kearns , G. L. ( 2001 ). Treatment of pain with gabapentin in a neonate . Pediatrics , 108 (2 II), 482 \200\223485. Belfi ore , G. , Tedeschi , E. , Ronza , F. , Belfi ore , M. , Della Volpe , T. , Zeppetell a , G. , et al . ( 2008 ). Radiofrequency ablation of bone metastases induces long-lasting palliation in patients with untreatable cancer . Singapore Med J , 49 (7), 565 \200\223570 . Reports of pain and suff ering at the end of life are mainly described for children with en d-stage cancer, but also recognized in HIV/AIDS (Bennett and Givens, 2011 ; Collins, 1995). Recent studies have shown that incidence may be higher than perhaps expected. A retrospect ive case series of children with end-stage cancer showed that 25 of 37 patients (68%) recei ved \200\230palliative sedation \200\231 for unrelieved suff ering, with pain being the mo st com- mon symptom cited (Postovsky et al., 2007 ). Also, a survey (Pousset et al., 2011 ) of Belgian physicians signing death certifi cates of all children between the ages of 1 an d 17 years found that continuous, deep, and persistent sedation was used in 21.8% of all de aths; 46.8% of all non-sudden deaths. Physicians had the explicit or concurrent intention o f hastening death in one-fourth of cases. Th e incidence of continuous sedation in this stu dy was higher than the 14.5% found in a comparable study of adults (Chambaere et al., 2010 ). Bennett , R. and Givens , D. ( 2011 ). Easing suff ering for a child with intractable pain at the end of life . J Pediatr Health Care , 25 (3), 180 \200\223185. Bhasker , S. , Bajpai , V. , and Turaka , A. ( 2008 ). Palliative radiotherapy in pediatric malignancies . Singapore Med J , 49 (12), 998 \200\2231001. Boivie , J. , Leijon , G. , and Johansson , I. ( 1989 ). Central post-stroke pain. A study of the mechanisms through analyzes of the sensory abnormalities . Pain , 37 (2), 173 \200 \223185. Bowsher , D. ( 1996 ). Central pain: clinical and physiological characteristics . J Neurol Neurosurg Psychiatry , 61 (1), 62 \200\22369. Breau , L. M. , Camfi eld , C. , McGrath , P. J. , Rosmus , C. , and Finley , G. A. ( 2001 ). Measuring pain accurately in children with cognitive impairments: refi nement of a careg iver scale . J Pediatr , 138 (5), 721 \200\223727. Breau , L. M. , Camfi eld , C. S. , McGrath , P. J. , and Finley , G. A. ( 2003 ). Th e inc idence of pain in children with severe cognitive impairments . Arch Pediatr Adolesc Med , 1 57 (12), 1219 \200\2231226. For the specifi c cohort who requires sedation for intracta- ble pain, recommended therapeu tic modalities include opioids, benzodiazepines, neuroleptic and anesthetic agents such as propofol. Bu no , L. , Fioramonti , J. , and Garcia-Villar , R. ( 2000 ). Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. III Visceral aff erent path-ways: a source of new therapeutic targets for abdominal pain . Am J Physiol Gastrointest Liver P hysiol , 278 (5), G670 \200\223676. Conclusion Managing pain is only one of the aspects of providing palliative care for childr en but in reality it is a core task as pain is one of the com- monest symptoms experienced by dying children. It is encountered in every existential dimension and a child in severe p ain cannot engage with carers in a way that allows meaningful exploration of wider fears or concerns. Even where the primary painful stimulus is physical, its perception and experien ce by a child will be dictated by the spiritual and psychosocial context in which it occurs . Good pain management therefore not only requires the use of appropriate analgesics but sp ecifi c attention to psychosocial, cultural, spiritual, and other physical issues. Caussa , L. , Hijal , T. , Michon , J. , and Helfre , S. ( 2011 ). Role of palliative radio therapy in the management of metastatic pediatric neuroblastoma: a retrospective single-ins titution study . Int J Radiat Oncol , 79 (1), 214 \200\223219. Chambaere , K. , Bilsen , J. , Cohen , J. , Rietjens , J. A. , Onwuteaka-Philipsen , B. D. , Mortier , F. , et al . ( 2010 ). Continuous deep sedation until death in Belgium: a natio nwide survey . Arch Intern Med , 170 (5), 490 \200\223493. Chater , S. , Viola , R. , Paterson , J. , and Jarvis , V. ( 1998 ). Sedation for intractab le distress in the dying \200\224a survey of experts . Palliat Med , 12 (4), 255 \200\2232 69. Cherny , N. I. , Radbruch , L. , Chasen , M. , Coyle , N. , Charles , D. , Dean , M. , et a l . ( 2009 ). European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care . Palliat Med , 23 (7), 581 \200\223593. Cherny , N. I. , Th aler , H. T. , Friedlander-Klar , H. , Lapin , J. , Foley , K. M. , Hou de , R. , et al . ( 1994 ). Opioid responsiveness of cancer pain syndromes caused by neurop athic or nociceptive mechanisms: a combined analysis of controlled, single-dose studies . N eurology , 44 (5), 857 \200\223861. References Anghelescu , D. L. , Faughnan , L. G. , Baker , J. N. , Yang , J. , and Kane , J . R. ( 2010 ). 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Zernikow , B. , Smale , H. , Michel , E. , Hasan , C. , Jorch , N. , and Andler , W. ( 2006 ). Pediatric cancer pain management using the WHO analgesic ladder: results of a prospecti ve analysis from 2265 treatment days during a quality improvement study . Eur J Pain , 10 ( 7), 587 \200\223595. CHAPTER 29 Recurrent abdominal pain Jennifer Verrill Schurman , Amanda Drews Deacy , and Cr aig A. Friesen Summary Recurrent abdominal pain is a common complaint in children and adolescents; however , it has been historically understudied and not well understood. Recently, an improved diag nostic classifi cation sys- tem has resulted in new research information being generated at an increasing rate. Although signifi cant gaps in our knowledge remain, we are gradually c oming to understand the complex etiology of recurrent abdominal pain in children and are ma king strides in clini- cal treatment. However, specifi c clinical practice guidelines do no t yet exist and evidence remains limited for most, if not all, of the com- mon treatments e mployed. Th is chapter highlights current theory and evidence available to guide offi ce-ba sed assessment and inter- vention eff orts, as well as promising directions for future rese arch. rendered useless to guide diagnosis or treatment. In recent years, there has been increasin g eff ort to redefi ne RAP into more distinct groups to guide research and clinical decisio n-making. Continuing work began in 1990, the Rome II working group established dis- crete d iagnostic criteria for several functional gastrointestinal dis- orders (FGIDs) in children (Rasquin-Weber et al., 1999 ). Th ese were revised to the current Rome III diagnostic crite ria in 2006 (Rasquin et al., 2006 ). As defi ned by the Rome criteria, the FGIDs are a set of diagnoses with specifi c symptom profi les in the absence of structural or biochemical a bnormalities to explain the symptoms. FGIDs related to chronic or recurrent abdominal pain include irri- table bowel syndrome (IBS), functional dyspepsia (FD), functional abdominal p ain (FAP), and abdominal migraine (see Box 29.1 for symptom-based criteria). Both the Ameri can Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, He patology, and Nutrition have supported this shift in diagnostic classifi cation, calling fo r the term \200\230RAP \200\231 to be retired in 2005 (Di Lorenzo et al., 2005 a). Althoug h the Rome criteria have not been fully validated, there is evidence that the great majorit y of children who would have formerly been diagnosed with RAP meet criteria for at least on e FGID, with IBS and FD being the two most common (Schurman et al., 2005 ; Walker et al., 2 004 ). Although clinical expe- rience would support the utility of Rome criteria, this util ity has yet to be established in well-designed research studies. In addition, there is vari ability in how the Rome criteria are applied and the defi nition of \200\230organic diseas e \200\231 is not universal (Chogle et al., 2010 ). Th e diagnosis also can vary depending on who provides the his- tory. For example, children and parents can vary greatly with rega rd to stool history (Schurman et al., 2005 ). While there is still work to be done to refi ne and validate the criteria, Rome III diagnoses represent the best available classifi cati on for children with recur- rent abdominal pain and are the current basis for entry into mo st therapeutic trials. Introduction Epidemiology Recurrent abdominal pain has long been acknowledged to be one of the most common chronic pain entities in children. However, only recently has it been recog nized as a global health problem. Th e prevalence has been estimated at 0.3% to 19% (median 8.4) in Western populations (Chitkara et al., 2005 ), with similar rates recently document ed worldwide and including developing countries (Devanarayana et al., 2011 ; Zhou et al., 2 011 ). Prevalence appears to peak in early school-age (4 \200\2236 years) and preadolescent children, with females somewhat overrepresented at older ages (Chitkara et al., 2005 ). Ab dominal pain can persist for years with many chil- dren continuing to have problems with bo th abdominal pain and associated symptoms into adulthood (Gieteling et al., 2008 ). History In the late 1950s, Apley and Naish fi rst described the entity which became known a s recurrent abdominal pain of childhood or \200\230RAP \200\231 (Apley and Naish, 1958 ). RAP was described as three or more bouts of pain severe enough to aff ect activities that o ccurred over a period of at least 3 months. Less than 10% of the patients evaluated by Aple y and Naish were determined to have an organic etiology for their pain. Given the lack of d iagnostics available during that time, it is likely that some children with organic disease were included under this heading. Even more important, children with a wide variety of cli nical presentations and aetiologies were lumped under the single clinical \200\230diagnosi s \200\231 of RAP. RAP was so inclusive as to be Etiology FGIDs are probably best understood utilizing a biopsychosocial model which states that abdominal pain occurs as a result of vary- ing contributions from, and interactions be tween, biological factors, psychological factors, and social factors. Each of these factors may initiate or contribute to the frequency, duration, or intensity of pain. Further, this model is dynamic; children are believed to achieve the same end result (i.e. abdominal pai n) through diff erent pathways. SECTION 4 pain in specific populations and diseases 290 Biological factors Th e biological factors most implicated in the generation of abdom- inal pain include motility disturbances, visceral hypersensitivity, and infl ammation. A variet y of motility disturbances have been well documented in adults with both IBS and FD. Althou gh there are many fewer pediatric studies, the fi ndings in children tend to parallel those in adults. IBS is associated with either rapid colonic transit typical of diarrhea-predomi nant IBS (D-IBS) or delayed colonic transit typical of constipation-predominant IBS (C-IBS) . However, transit is increased in only 48% of adults with D-IBS and decreased in only 20% of those with C-IBS (Camilleri and Di Lorenzo, 2012 ). FD has been associated with a wide a rray of electromechanical disturbances in adults including delayed gastric emptying, gastri c electrical disturbances, impaired fundic accom- modation (relaxation) with meals, and dis coordinated gastroduo- denal motility (Timmons et al., 2004 ). Delayed gastric emptying and gastric electrical disturbances have each been demonstrated in approximately 50% of childr en with FD (Friesen et al., 2006 ). Symptom severity also has been correlated with delayed empty- ing, gastric electrical abnormalities, impaired antral motility, and impaired accomm odation in children with FD (Friesen et al., 2006 ; Devanarayana et al., 2008 , 2012 ; Olaf sdottir et al., 2000 ). Box 29.1 Rome III symptom criteria for functional gastrointestinal disorders related to abd ominal pain in children Functional dyspepsia All of the following present at least once weekly for at least 2 months: \227\206 Persistent or recurrent abdominal pain or discomfort centered in the upper abdomen. \227\206 Pain not relieved by defecation or associated with a change in stool frequency or form. \227\206 No evidence of an infl ammatory, anatomic, metabolic, or neo- plastic process to explain the symptoms. Irritable bowel syndrome All of the following present at least once weekly for at least 2 months: \227\206 Abdominal discomfort or pain associated with two or more of the following: \227\206 improvement with defecation \227\206 onset associated with a change in stool frequency Visceral hypersensitivity is believed to be of central importance in the generation of pain in FGIDs in adults with similar, but some- what confl icting, studies in children. In adul ts with IBS, increased rectal sensitivity to stretch has been reported in 21% to 95% of pat ients (Camilleri and Di Lorenzo, 2012 ). Rectal hypersensitivity has been demonstrated to h ave a sensitivity of 89% and a specifi city of 83% in identifying children with IBS (Camill eri and Di Lorenzo, 2012 ). However, other studies have demonstrated much lower rates of hy persensitivity with no diff erences between pediatric patients with IBS and FAP. In adults with FD, visceral hypersensitivity to dis- tension has been demonstrated in 34% to 65% of p atients (Timmons et al., 2004 ). Hypersensitivity to acid has also been reported in adults with FD (Oshima et al., 2012 ). Water load volume, an indicator of visceral sensitivity, ha s been shown to diff er between children with abdominal pain (including those specifi cally with FD) and controls (Anderson et al., 2008 ; Schurman et al., 2007 ). \227\206 onset associated with a change in stool form. \227\206 No evidence of an infl ammatory, anatomic, metabolic, or neo- plastic process to explain the symptoms. Functional abdominal pain All of the following present at least once weekly for at least 2 months: \227\206 Episodic or continuous abdominal pain. \227\206 Does not meet criteria for another FGID. \227\206 No evidence of an infl ammatory, anatomic, metabolic, or neo- plastic process to explain the symptoms.