Von Baeyer , C. L. , Spagrud , L. J. , McCormick , J. C. , Choo , E. , Neville , K. , and C onnelly , M. A. ( 2009 b). Th ree new datasets supporting use of the Numerical Rating Scale (NRS-11) for children \200\231s self-reports of pain intensity . Pain , 143 , 223 \200 \223227. Walker , S. and Howard , R. ( 2004 ). Neonatal pain . Pain Reviews , 9 , 69 \200\22379. Wa lker , S. M. , Franck , L. S. , Fitzgerald , M. , Myles , J. , Stocks , J. , and Marlow , N . ( 2009 ). Long-term impact of neonatal intensive care and surgery on somatosensory percep tion in children born extremely preterm . Pain , 141 , 79 \200\22387. Williams , D. G. , Hatch , D. J. , and Howard , R. F. ( 2001 ). Codeine phosphate in pediatric medicine . Br J Anaesthes , 86 , 413 \200\223421. Wolf , A. ( 1999 ). Tears at bedtime: a pitfall of extending pediatric day-case surgery without extending analgesia . Br J Anaesth , 82 , 319 \200\223320. Walker , S. M. , Westin , B. D. , Deumens , R. , Grafe , M. , and Yaksh , T. L. ( 2010 ). E ff ects of intrathecal ketamine in the neonatal rat: evaluation of apoptosis and long-term functional outcome . Anesthesiology , 113 , 147 \200\223159. Wong , D. and Baker , C. ( 1988 ). Pain in children: comparison of assessment scales . Pediatr Nurs , 14 , 9 \200\22317. CHAPTER 28 Pain in palliative care Ross Drake and Ren e McCulloch Summary Pain in palliative care for children is common and is oft en a result of dif- feren t combinations of nociceptive (somatic and/or visceral) and neu- ropathic pain rather than being from a single etiology. Th is pain is best addressed through a collaborative, interdi sciplinary team employing a holistic approach to the child and their family. Medication, pa rticularly opioids, has a central role in management but attempting to relieve pain without addressing the child \200\231s non-physical concerns is likely to lead to frustration. Th e expectation should be for exemplary control of pain bearing in mind some of the syndromes faced can be complex and may require quite sophisticated techniques to be managed appropri - ately including the use of surgical and anesthetic procedures. with non-malignant conditions. Conditions experienced by children are quite diff erent from adults as are the anatomy and physiology of the child and their cognitive responses to pai n and pain therapies. However, even in the absence of evidence, safe and eff ective man- ag ement can be achieved through a sensible, empirical approach centered on good observation a nd evaluation and an understanding of the disease process and therapeutics being used. World Health Organization guidelines Th e WHO has infl uenced the management of pain in chi ldren \200\231s pal- liative care through the publication in 1998 of a simple guideline out lining the rational stepwise approach to the management of can- cer pain in children (WHO, 1998 ). Th e guidelines were eff ective in providing analgesia in this group (Zernikow et a l., 2006 ). Clinically, their use was broadened to include children with non-malignant cond itions although this expansion was never validated; an impor- tant factor as over half of c hildren have a non-malignant condition (Drake et al., 2003 ; Feudtner et al., 2011 ). Introduction Palliative care for children is the active total care of the child \200\231s b ody, mind, and spirit, and also involves giving support to the family. Health providers mus t evaluate and alleviate a child \200\231s physical, psychologi- cal, and social distress ( World Health Organization (WHO), 1998 ) through the prevention and relief of suff ering by early identifi cation and impeccable assessment and treatment of pain (WHO, 1996 ). In 2012 the WHO published a major review of the guidelines (WHO, 2012 ) with the new iterat ion based on the best available evidence and extended to cover persistent pain in children with medical illnesses. Th e analgesic ladder remains at the heart of the guidelines but th e three-step ladder was reduced to two steps by removing the measure for mild to moderate p ain. In eff ect, minor opioids are replaced with a low dose of a major opioid. Th e choice of analgesia is determined through \200\230impeccable assessment \200\231 and the point of entry established by the severity of pain. Two aspects of this statement resonate loudly with health care professionals involved in pa lliative care: the reference to the multi- dimensional nature of assessment and management necessitating a collaborative, interdisciplinary team approach by pediatric trained profess ionals and the elevation of pain to a symptom requiring meticulous attention. Pain is, arguably, the most feared symptom faced by children and their families during thei r palliative journey. Pain has a consist- ently high prevalence (Drake et al., 2003 ; Sirki a et al., 1998 ; Wolfe et al., 2000 ) but the ability to satisfactorily control pain can be quite variable (Sirkia et al., 1998 ; Wolfe et al., 2000 ) and changes over the fi nal wee k of life (Drake et al., 2003 ). Th e ladder is supported by three other \200\230rules \200\231 which remain unchanged to complete a logical framework for prescribing. \227\206 By the clock \200\224encourages the regular scheduling of analgesia to ensure a s teady blood concentration and to reduce the peaks and troughs of intermittent dosing. Th is regular dosing should be supplemented with \200\230as needed \200\231 breakthrough doses for pain that may emerge. A signifi cant key to success involves eff ective communication just as much as choosing th e right intervention. Open, honest dis- cussion of assessment and treatment strategies prov ides the foun- dation of a trusting therapeutic relationship that, in turn, allows for dial og about anxieties and misconceptions that can, if not addressed, hamper appropriate manage ment. \227\206 By the appropriate route \200\224requires the least invasive route of administrat ion to be used; the oral route is preferable in most circumstances. \227\206 By the child \200\224promotes individualized treatment according to the assessed need. Unfortunately, the evidence available to support therapeutic approaches to deal with childr en \200\231s pain during palliative care is sparse. Th is requires clinicians to use eviden ce from studies on acute pain in children and the literature of adult palliative care. Th i s latter source demands cautious extrapolation to children, especially those Th e reliance on opioids for pain management in palliative care is a distinguishing factor. However, there are occasions when chil- dren who could benefi t from opioid therapy are, o r their family are, unwilling to have the child take opioids. Th is is usually based CHAPTER 28 pain in palliative care 281 Challenging pain syndromes in palliative care Episodic pain \200\224breakthrough pain versu s incident pain Episodic pain in palliative care is usually seen in children with advanced cancer and equates to either \200\230breakthrough \200\231 or \200\230incident \200\231 p ain. Th ese are two distinct entities although the terms are oft en used, incorrectly, inte rchangeably. on misconceptions about their use and the perception that opioids mark \200\230the beginni ng of the end \200\231. Th ese fears need to be explored and correct information provided. Unfortunately, reservations can be so powerful that a prescription for an alternative agent may be required even if it has, potentially, inferior effi cacy. Simply, there is little p oint in prescribing the ideal drug if it is clear that the child and/or family will not com ply with its administration. Th is makes the availability of eff ective alternatives (perce ived to be safer) of real practical value. Opioids are introduced once simple analgesia is no longer eff ec- tive or if assessment ind icates the child is having more than mild pain. Th e prescribing of opioids has been covere d in depth by Strassels (Chapter 45, this volume), but in palliative care follows the \200 \230by the clock \200\231 rule reaffi rmed in the 2012 WHO guidelines with both continuous and \200\230as needed \200\231 or rescue analgesia being made available as highlighted in the following clinical case example. Breakthrough pain has been defi ned as \200\230a transitory exacerba- tion of pain superim posed on a background of persistent usually well controlled pain \200\231 (Gomez-Batiste et al., 2002 ). Th e prevalence in children requiring palliative care is unknown although one study (Friedrichsdorf et al., 2006 ) indicated over 50% of children with cancer (n = 27) w ill experience one or more episodes. Th e solution is to adjust the dose of medication, usu ally an opioid, as described in the clinical case example. When the pain occurs at the end of a regular dose this is known as \200\230end-of-dose failure \200\231. Th e remedy for t his situation may simply be to increase the dose but failure (pain breakthrough) further aw ay from the next dose may require short- ening of the interval between doses. For example, consistent break- through pain at hour 9 of a 12 h sustained-release preparation may requir e 8-hourly dosing of the medication. Case example A 10-year-old boy presents with relapsed, metastatic hepatob- lastoma for which there are n o further curative options. He has intermittent albeit frequent aching epigastric pain aver aging 7/10 intensity. Th is equates to severe pain and an opioid in the form of oral morphi ne is commenced. Incident pain refers to an intermittent or episodic, oft en severe, pain associated with sp ecifi c events or activity such as weight bear- ing or coughing and escalation may be relat ed to complications such as a pathological fracture. Management necessitates identify- ing, anticipating, and, if possible, avoiding the provoking factors. Th e requirement of any ph armacological intervention is for the medication to be immediately available, have a very r apid on- and off -set of action (Chu et al., 2008 ) and be highly potent. Th is can complic ate management as analgesics are oft en too slow to be eff ec- tive during the pain episode and cause toxicity as the agent becomes fully active when the pain naturally subsides. Initiation An initial oral dose of 6 mg (0.2 mg/kg/dose) immediate-release mor- phine prepa ration is prescribed as a regular 4 h dose. An additional 6 mg rescue dose is advised to be taken as needed up to every hour (one-sixth of the total daily dose of 36 mg, i.e. 6 mg \227 6 = 36 mg). Titration Day 1: the child requires 5 rescue doses (30 mg) in 24 h. Day 2: the child requires 3 rescue doses (18 mg) in 24 h. At the 48 h review he has average d 4 rescue doses each day indicating the regular dose needs to be increased by 24 mg (i.e. 4 \227 6 mg = 24 mg). Th e administration of parenteral short-acting opioids and nasal or buccal formulations com e closest to the ideal. Interventional approaches should be contemplated especially when in cident pain is unresponsive to medication. Th ese range from simple measures such as a slin g to immobilize the aff ected part to radiation therapy or chemotherapy to more sophisticat ed surgical or anesthetic techniques. Regular dose: new total daily dose is 36 mg + 24 mg = 60 mg over 24 h or 10 mg every 4 h. Breakthrough dose: remains one-sixth of total daily dose or 10 mg (60 mg 6) as needed up to every hour. Day 3: the child requires 1 rescue dose (10mg) in 24 h. Day 4: the child requires no rescue doses in 24 h. At 48 h review the child has averaged less than 1 rescue dose each day indi cating the regular dose does not need to be increased. Th e regular morphine dose can be co nverted to a long-acting preparation. Episodic pain \200\224muscle spasm Episodic pain may also refl ect pain of a sporadic natur e as seen with intestinal colic or muscle spasm. Muscle spasm is a potent source of signifi cant discomfort for many children with severe neurologi- cal impairment, for example, cere bral palsy and neurodegenerative conditions, and oft en predates the involvement of palliat ive care. Management therefore requires collaboration and optimal use of non-pharmacologica l strategies and non-opioid medications before specifi c therapies needing specialist skill (i.e. surgical intervention, botulinum toxin, intrathecal drug delivery) are introduced. Regular dose: total daily dose is 60 mg or 30 mg twice daily of a slow-release morphine formulation. Breakthrough dose: remains 10 mg of immediate-release morphine. Th is example illustrates that the titration phase has ended and the maintenance phase begi ns. Th e maintenance phase starts when a rea- sonably stable dose of regular opioid has bee n reached and the total daily dose no longer needs adjustment. In reality this phase repres ents a period of slower titration where further increases may be required for disease-progr ession and, on occasion, opioid tolerance. Opioids should remain in consideration with anecdotal success reported by pediatric palliat ive care physicians in treating some children with opioids for severe chronic pain secondar y to mus- cle spasm. A recent descriptive practice survey (Slater et al., 2010 ) appears to confi rm the viability for using opioids in children with non-malignant conditions. Howeve r, regard must be given to the potential for children with non-malignant conditions to surv ive for Continual assessment and review is required to ensure adequate analgesia is ongoing. SECTION 4 pain in specific populations and diseases 282 many years and there should be regular review of the eff ectiveness of any opioid prescribe d. Although anecdotal practice supports the use of opioid prescribing in children with non- malignant disorders, trial withdrawal of long-term opioids should be considered on a regula r basis as the cause for the spasm may dissipate with time. Further information on the mana gement of muscle spasm is avail- able in Chapter 17 (Hickman et al., this volume). decreasing recruitment and function of osteoclasts and direct binding to hydroxyapatite cry stals in bone, making it more resistant to resorp- tion. Th ey are available in intravenous and oral forms with second- generation aminobisphosponates like alendronate and pamidronat e and third-generation agents such as ibandronate and zoledronic acid in regular use. Intra venous pamidronate has been the most frequently used agent, but intravenous clonidronate, i bandronate, alendronate, and zolendronate have all been shown to be as eff ective in cancer induced bone pain in adults and are oft en preferred as they are infused over a shorter ti me (15 min; Wardley et al., 2005 ). Bone pain Bone pain is typically a focal, deep-seated, and intense pain that a child may de scribe as \200\230boring \200\231 or \200\230like a drill \200\231. Th e pain can start a s intermittent but escalate to become constant and unremitting and may be complicated by sp ontaneous pain at rest and/or movement- related incident pain. Common side eff ects of bisphosphonate infusions include tran- sient fl u-like symptoms tha t occur 24 to 48 h aft er the fi rst treat- ment but usually not in subsequent infusions an d injection site reactions. Th e symptoms may be improved by prophylactic use of paracetamo l or ibuprofen. Hypocalcaemia is an uncommon prob- lem occurring within 72 h of infusion bu t this can be prevented by a daily intake of 1 to 1.5 g calcium. Renal toxicity is also a r eported concern manifesting in patients with existing renal compromise. It appears to be a common symptom in children requiring palliative care and has been well documented in: \227\206 Non-ambulatory children with chronic neurological conditions (Khoury and Szalay, 2007 ). Long-term adverse eff ects of osteonecrosis of the jaw (ONJ) and ocular infl ammation have been reported. ONJ appears to be iso- lated to adults with cancer with recent studies (Bail largeon, 2011 ; Khan et al., 2008 ) concluding there was insuffi cient evidence to confi rm a causal link between low-dose bisphosphonate use in the osteoporosis patient population a nd ONJ; the majority of children receive bisphosphonates for osteoporosis. \227\206 Inherited metabolic disorders involving: \227\206 primary defects of structural bone proteins \200\224osteogenesis imperfect \227\206 pathological involvement of bone from systemic disease \200\224muco- polysaccharidosis (Rossi et al., 2011 ). \227\206 Secondary distortion of the normal skeletal structures as an eff ect Other approaches for CIBP Treatment of CIBP can require additional approaches such as radi- otherapy to the painful site, procedures that immobilize bone par- ticularly when associat ed with a fracture, and in some selected cases the use of radioisotopes and other minimally invasive techniques. of systemic treatment, e.g. prolonged steroid use. \227\206 Cancer-induced bone pain (CIBP) (Nathrath and Teichert von L ttichau, 2009 ) f rom primary (Eyre et al., 2009 ), infi ltrative bone marrow (Leeson et al., 1985 ), or meta static disease or as a result of treatment (Sala and Barr, 2007 ). Radiotherapy Radiotherapy plays an important role in the palliative treatment of bone metas tases and remains the treatment of choice for localized dis- ease (Falkmer et al., 2003 ; H oegler, 1997 ; Steenland et al., 1999 ). Th is applies even to relatively radio-resistant t umors as a small reduction in the size of the lesion can have a signifi cant modulating eff ect on pain. Th ere are limited studies on the eff ectiveness of palliative radi- otherapy in children but those that have been done are convincing (Caussa et al., 2011 ; Deutsch an d Tersak, 2004 ; Gibbs et al., 2006 ). Bone pain from chronic neurological conditions oft en results from low bone density for a v ariety of reasons and children are at an increased risk of non-traumatic fracture or fractu re from minimal trauma when moved or handled (Henderson et al., 2004 ; Khoury and Szalay, 2 007 ). Th e precise mechanism for CIBP continues to be debated with work implicating local infl ammatory and neuropathic mechanisms as well as central mechanisms. Management Th e eff ective management of bone pain relies upon an individu- alized response tailored to the identifi ed cause(s) and the child \200\231s clinical condition, life expe ctancy, and quality of life. As previously discussed, non-pharmacological methods and the W HO approach remain relevant. Th e delivery of single fractions or short courses of radiotherapy are generally well toler ated by children. Th e acute toxicities are few and may include local erythema, pain, and i tching at the site and the occurrence of nausea, vomiting, and tiredness. Revision of the c hild \200\231s opioid dose may be required as pain abates. Long-term tox- icity is not a co nsideration given the child \200\231s prognosis. Specifi c treatment involves using bisphosphonates while CIBP may require additional approaches. Radiopharmaceuticals and interventional radioablative techniques Radioactive bone-seeking a gents are preferentially absorbed at areas of high bone turnover such as metastatic sites a nd are generally con- sidered in the earlier stages of multisite disease, rather than being a last resort treatment. Several diff erent radiopharmaceuticals are available with stront ium-89 and samarium-153 approved and in common use. Evaluation in adult patients has indica ted that radiop- harmaceuticals are eff ective in reducing pain and analgesic require- ment s and improving quality of life. Th e onset of analgesia is within days to weeks and the du ration of action varies according to the extent of metastatic bone disease. As such, it is not recommended in those with a life expectancy of less than approximately 4 weeks. Bisphosphonate therapy Th ere is extensive experience in bisphosphonate therapy in chil- dr en with congenital and acquired forms of osteoporosis (Batch et al., 2003 ; Kotecha et al., 2010 ) with them appearing to be not only eff ective but safe, even with prolonged use (Ba chrach et al., 2010 ; Henderson et al., 2002 ; Howe et al., 2010 ). In contrast use in adul ts has focused on treatment of painful metastatic malignant disease (Fulfaro et al., 1998 ) and malignant hypercalcaemia. Bisphosphonates are analogs of inorganic pyrophosphate, a nat- ural inhibitor for the forma tion of calcium phosphate crystals, and directly reduce bone resorption (Fleisch, 1998 ). T h is is achieved by CHAPTER 28 pain in palliative care 283 Diff erent image-guided percutaneous techniques such as abla- tion, radiofrequency ionizati on, and cementoplasty can be used separately or in combination for palliation of symptoms i n patients with primary or metastatic bone tumors. Th e therapeutic goal is managing pain t hrough reduction in tumor volume, prevention and/or treatment of pathological fractures and decompression/ debulking of bone tumors, specifi cally those protruding into the spinal ca nal. Th ese treatments are gaining popularity in adult pal- liative medicine and several st udies have shown success in lytic lesions refractory to conventional therapy (Belfi ore et al., 2008 ; Th anos et al., 2008 ). Even newer treatment modalities such as mag- netic reso nance-guided focused ultrasound (Liberman et al., 2009 ) have been reported to off er safe, non-invasive, and clinically eff ec- tive palliation of bone metastases. metastasis, vertebral fracture) and does not preclude patients from being cared for in thei r preferred setting (Anghelescu et al., 2010 ). Polypharmacy and continual addition or incr ement of medica- tion, without consideration for withdrawal or effi cacy of drugs, should b e avoided. Of particular concern can be the phenomena of opioid-induced hypersensitivity (O IH). Th is may well go unrecog- nized and is signifi cantly under reported in children in t he litera- ture (Hallett and Chalkiadis, 2012 ; Heger et al., 1999 ). OIH is most broadly defi ned as a state of nociceptive sensitization caused by exposure to opioids. Th e state is characterized by a para- doxical response whereby a person receiving opioids for the treatment of pain may become more sensitive to pain and is thought to be d ue to neuroplastic changes in the central and peripheral nervous system (Chu et al., 2008 ) . It is important to note that OIH and analgesic tol- erance are two distinct pharmacologic al phenomena that can result in similar net eff ects on opioid requirements. However, incre asing the dose of opioid in OIH will paradoxically aggravate the problem and worsen the pat ient \200\231s pain. Considerable diagnostic confi dence is required to reduce the opioid c onsumption in a child with end-stage cancer. It is therefore recommended to rotate the opio id, potentially in combination with a N-methyl-D-aspartate (NMDA) receptor antagonist (Laul in et al., 2002 ; Mercadante and Arcuri, 2005 ; Sj gren et al., 1994 ) and methadone has been reported to have effi cacy in reducing high-dose OIH (Axelrod and Reville, 2007 ). Cancer pain Cancer pain is detailed by Hickman et al. (Chapter 17, this vol- ume) and furth er discussion relates specifi cally to palliative care. Progressive cancer usually results in increasing illness burden and a myriad of complex and challenging symptoms with the evid ence showing pain to be a distressing and prevalent symptom towards the end of life in chil dren with this disease (Heath et al., 2010 ; Pritchard et al., 2008 ). In a recent study of 141 parents of children who died of cancer, more than 10% considered hastening their child \200\231s death; this was more likely if their child was in pain (Dussel et al., 2010 ). A nticipation and continuous planning of analgesic need is crucial to eff ective management p articularly with the drive in many countries to provide as much care as possible outside of the hospital environment. Cerebral irritation Cerebral irritability is a term used to describe the clinical pres- ent ation of persistent, unremitting agitation and distress. In the pediatric palliative care s etting it is most oft en associated with the non-verbal child with severe neurological impa irment or the child with progressive, oft en neurodegenerative disorders such as adrenoleuc odystrophy or AIDS encephalopathy and, occasionally, towards the end of life in children wi th malignancy. At the end of life most causes can be anticipated and planned for, such as h ypoxia in respiratory failure or cerebral hemorrhage in bleeding disorders or brain tumors. Cerebral irritability may also be confused with an agitated delirium at the end of life al though clinical management, at this stage, is very similar. As disease progresses the goals of care alter to maximize qual- ity of life and minimize in vasive treatments and procedures. Diagnoses regarding pain etiology are based upon knowledg e of disease pathology and clinical signs with minimal imaging and, fre- quently, the antic ipation of pain or the assumption that pain must be present, particularly in the non-verbal child. Not infrequently palliative chemotherapy may be off ered in the hope of slowing disease pro gression and improving symptoms (Farah et al., 2011 ; Pui et al., 2011 ) but there is littl e solid evidence to show that it improves analgesia. Th ere is clear data; however, that pa lliative radiotherapy with locally advanced disease can improve analgesic requirements, par ticularly when it is off ered in combina- tion with other treatment modalities (Bhasker et al., 2008 ; Hechler et al., 2008 ). It is a commonly held belief that cerebral irritability in the neu- rologically impaired ch ild, in the absence of new pathology, is due to an abnormal brain, and abnormal neurologica l processing (Klick and Hauer, 2010 ) and it can be diffi cult to know whether the child is experiencing pain. Morally and ethically, the assumption has to be that pain is a feature of this condition until proven otherwise. Decision-making regarding palliative chemotherapy is complex. It is important to understand and acknowledge the multidimen- sional complexities surrounding these issues when consider ing additional treatments. One study has shown cancer-directed ther- apy at the time of dea th to be rated negatively by parents (Hechler et al., 2008 ). In contrast, a prospective st udy showed that parents strongly favored aggressive treatment in the palliative phase com- pared with health professionals and ranked hope as a more impor- tant factor for making dec isions about treatment (Tomlinson et al., 2011 ). Clinically, for most of these children behavior deviates from their known non-distressed ba seline and cerebral irritability can mimic previous pain behaviors for which a cause has be en found (Breau et al., 2001 ; Stallard et al., 2002 ). Several papers have acknowledged th at pain of unknown cause is oft en severe in chil- dren with impaired cognition (Breau et a l., 2003 ; Hauer, 2010 ; Hauer et al., 2007 ). Th e classical symptom in an infant or non-verbal child with severe neurological impairment is an unrelenting, high-pitched scream. However, a diverse range of pathologies can portra y similar neurological pain-related behaviors ( Figure 28.1 ) resulting in the child \200 \231s distress. If symptoms present as an acute change in behav- iour, a full medical revie w may be required with appropriate inves- tigations to identify the etiology and exclude a reversible cause. However, in the neurologically impaired child, the cause oft en Th ere is increasing experience with anesthetic or neurosurgi- cal analgesic options, for e xample, epidural/intrathecal infusions or neurolytic blocks, when systemic analgesia has fa iled (Whyte and Lauder, 2012 ). Epidural and peripheral nerve catheters can be used successfully despite typical contraindi cations (thrombocytopenia, fever, spinal SECTION 4 pain in specific populations and diseases 284 GER, UTI, Pancreatitis, Fractures, Hip Subluxation Recurrent Respiratory Exacerbations Dyspnea Nociceptive Pain Surgical Procedures, Peripheral Neuropathy Medication Toxicities Pain Behaviors: Crying, Moaning, Grimacing, Inconsolability, Withdrawal, Sleeping, Restless ness, Agitation, Arching, Sti \200ening, Diaphoresis, Pallor, Tachycardia Neuropathic Pain Spasticity Central Pain Dysautonomia Figure 28.1 Potential sources of pain behavior in children with severe neurological injury. Reprinted from Pediatric Palliative Care , Volume 40, Issue 5, Je \200 rey C. Klick and J ulie Hauer, Current Problems in Pediatric and Adolescent Health Care, pp. 120 \200\223151, Copyright 2010, with permission from Elsevier, http://www.sciencedirect.com/ science/jou rnal/15385442. Decreased Central Inhibition to A \200erent Input GI Dysmotility Retching/ Vomiting Visceral Hyperalgesia GI injury and in \202ammation, Constipation and Visceral Distention, Surgical Procedures remains undefi ned and the behavior frequently evolves with the condition and becomes a chr onic pattern bringing about a signifi - cant burden for parents and carers with ensuing exh austion and a sense of demoralization. Several hypotheses exist for this situation with two , central neuropathic pain and visceral hypersensitivity, well supported. by direct trauma or secondary damage by neurological disease or infection within the centra l nervous system (CNS) with disordered nociceptive processing at the molecular, cellular, a nd circuit level leading to system-wide changes in neuroexcitability that ultimately lead t o central sensitization and an amplifi ed pain experience (Hains and Vera-Portocarrero, 201 1 ). Many metabolic, genetic, neurodegenerative, and neurological conditions in children co uld fulfi l this defi nition by causing \200\230disease \200\231 or \200\230injury \200 \231 of the CNS through diverse pathologies. Central neuropathic pain Central pain is a growing area of interest as improved understand- ing of pain pathways and processes makes it probable that it exists in infants and childre n with both non-malignant and malignant conditions. Th e concept of central pain was fi rst introduced in 1891 (Edinger, 1891 ) and 15 years la ter, Dejerine and Roussy ( 1906 ) in their semi- nal paper \200\230Le Syndrome Th alamique \200\231, described a small case series of adult patients with a lesion in the thalamus an d internal cap- sule causing \200\230severe, persistent, paroxysmal, oft en intolerable pa in on the hemiplegic side not yielding to any analgesic treatment \200\231. Central pain wa s hence termed \200\230thalamic pain \200\231 with the thalamus thought to play a key role , either as a generator of pain or by abnor- mal processing of ascending input (Craig et al ., 1994 ; Wilkins and Brody, 1969 ). However, not all patients with a thalamic lesion suf- fered from pain and the spinothalamocortical pathway, important for temperature and pain se nsibility, was also implicated (Boivie et al., 1989 ). Case example A 13-year-old girl with early onset Huntingdon \200\231s chorea is per- sistently distresse d whilst having her hair brushed or her head touched. Her parents are convinced that this r esponse and her disordered sleeping are pain related. Examination, on multiple occasions, r eveals a consistent behavioral distress to both brush and cold sensation testing over the s calp. Magnetic resonance imaging indicates bilateral lesions in the basal ganglia consist- ent with juvenile Huntingdon \200\231s chorea and a diagnosis of central pain is presumed. Th e girl was treated with and responded well to amitriptyline. In adults the intensity of pain is reported to fl uctuate and can be increased by internal or external stimuli such as stress or cold, and be alleviated by rest or distraction (Bowsh er, 1996 ). Parallels can be found with infants and children with cerebral irritability as they have similar specifi c pain patterns, precipitating factors and they oft en respond we ll to sleep and sedation and, in some cases, distraction methods. 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 ).