On the positive side, the development of the pain assessment tools for children with I/DD ( reviewed earlier) and the establish- ment of pharmacological research in children will make it feasi- ble to start with pharmacokinetic and pharmacodynamic studies specifi c to child ren with I/DD that, in turn, will provide evidence for decision aids to manage their pain ( Valkenburg et al., 2012a). Walker advocates that pain management is more than the meas- ure ment of pain intensity; it should include a global assessment of inter-related current cond itions and general health, nature of the surgery (if relevant), prior pain experience, curr ent response to analgesia in terms of effi cacy, and side eff ects (Walker, 2012). Pain treatment in cerebral palsy A key component of pain management in individuals with CP is the reduction of muscle spasticity that contributes to musculoskeletal pain. A variety o f therapeutic modalities are used to relieve pain associated with muscle spasticity (Aisen et al., 2011; Roscigno, 2002). Oral antispasticity medications include baclofen, dantro- le ne, diazepam, and tizanidine. Baclofen can also be delivered intrathecally by an implanted pump. Botulinum toxin A is used through multiple injections made to targeted muscle groups, aft er local anesthesia with EMLA and procedural sedation or under general anesthesia (d epending on location of injection, number of muscle groups to be treated, age, comorbiditie s and previous experiences). Th e toxin \200\231s inhibition of the release of acetylcho- l ine at the neuromuscular synapse results in relief of spasticity that lasts 3 to 4 months \200\224and for some individuals there is cor- responding pain reduction. Th rough neurosur gery selective dorsal rhizotomy involves the cutting of sensory nerves to reduce mus- cle s pasms (Grunt et al., 2011). A randomized controlled trial in 27 children with CP showed tha t epidural analgesia can give bet- ter analgesia and less muscle spasms aft er selective do rsal rhizo- tomy than intravenous morphine infusions (Malviya et al., 1999). Non-pharmacolo gical interventions including massage and other interventions are widely reported as eff ec tive in relieving pain and promoting comfort (Glew et al., 2010), though there has been lit tle research-based evidence demonstrating these benefi ts. Pharmacokinetics In general, children with I/DD are at greater risk to develop side eff ect s (Reiss, 1997), but epidemiological data are missing. Case \200\223 control studies have s hown that children and adults with Down syndrome are at increased risk to develop side eff ects and toxicity when treated with paracetamol (Griener et al., 1990) or methotrex- ate (B uitenkamp et al., 2010). Aft er inhalational induction with sevofl urane, bradycardia and h ypotension occurred in 57% of the children with Down syndrome versus in 12% of the children with- out Down syndrome (Kraemer et al., 2010). From observational clinical studies it is clear that there is variability in the dosing of analgesics and there is a high prevalence of comorbidities and treat- ment with psychotropic and anticonvulsant drugs in children wit h I/DD (Valkenburg et al., 2010). For adequate pain management, it would be ideal to predict the pharmacokinetics (what the b ody does to a drug) and pharmaco- dynamics (what the drug does to the body) of the analgesi cs for the individual patient. It would mean that we have knowledge of the pharmacokinetic covariate eff ects (size, age, and organ function) as well as pharmacodynamic covariate eff ects (target organ per- fusion, receptor sensitivity, effi cacy, pharmacogenomic changes). As a group, children with I/DD are at risk for variability in both the pharmacokinetics an d pharmacodynamics, due to, for exam- ple, the use of antiepileptic drugs, cerebral patholo gy, and genetic abnormalities such as trisomy 21. It will be a challenge to focus pharmacok inetic and pharmacodynamic studies on the drugs with the highest priority and the groups of children that are the most at risk for polypharmacy and side eff ects, but understanding o f the factors that contribute to variability will help to individualize pain management. Physical therapy In addition to ID, many children with I/DD have a physical dis- ability. C P causes motor disorders such as an altered muscle tone, impaired postural control, and mus cle synergetic action (Martin et al., 2010). Motor development is oft en delayed in childre n with Down syndrome and they are at high risk for musculoskeletal disor- ders due to joint hypermobility and ligamentous laxity (Weijerman and de Winter, 2010). Physical therapy tre atment goals are aimed at improving muscle strength, range of motion, gross motor func- tio n, endurance, and overall quality of life including pain reduc- tion (Martin et al., 2010; Opheim et al., 2011). A survey among American physical therapists revealed that 80% of the respondents used pain assessment tools in children with I/DD. Distraction, pro- cedural tal k, and praise were the most used pain management tech- niques (Swiggum et al., 2010). Physi cal therapy will be used to treat and prevent pain from musculoskeletal disorders, but the therapy can be painful itself. Pain reduction should be evaluated over the course of physic al therapy sessions and moderate to severe proce- dural pain should be treated. Antiepileptic drugs Epilepsy is common among children with I/DD; incidence rates from 14% t o 79% have been reported (Beavis et al., 2007). Th e more severe and extensive the cerebral pathology, the greater is the risk for epilepsy. Diff erent antiepileptic drugs have varyi ng degrees of protein binding and (liver) enzyme induction (Kofk e, 2010). Chronic treatmen t with antiepileptic drugs can aff ect also the pharmacokinetics of other drugs that are me tabolized by the same (P450) enzymatic pathway. Th is could be an explanation for Conclusion Moving forward, the clinical and scientifi c agenda is clear \200\224to con- tin ue to leverage discoveries from basic and clinical pain research and apply them to solve th e problem of pain for children with I/DD. CHAPTER 16 pain in children with intellectual or developmental disabilities 153 Th e remarkable achievements in pain scale development in the last decade for communicative ly and cognitively compromised indi- viduals needs to be converted to demonstrations that p ain is being more eff ectively and effi ciently identifi ed and managed in health- care, re habilitative, educational, and home environments. subjects with I/DD. When possible, evaluations of levels of cogni- tive and communicative f unctioning would be preferable to blanket characterizations (e.g. verbal versus non-verbal) . Better specifi cation of I/DD related features would permit more accurate determination o f how these variables interact with the main phenomena \200\224some aspect of pain \200\224 under investigation. Trials should be developed and designed in accordance with recent cons ensus statements from the IMMPACT group further bringing in line results from studies with children with I/DD with other pediatric pain trials (McGrath et al., 2008). Th e Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT \200\224a recurri ng internationally-recognized consensus group of pain experts from academia, government age ncies, the pharmaceutics industry, and self-help organizations) recommended a number of cor e pain out- come domains including: (1) pain intensity, (2) physical function- ing, and (3) ratings of overall improvement. Th ere is no reason that pediatric pain outcomes research focusing on children with I/DD cannot incorporate the same core outcome domains. Children with I/DD have been found to have a prevalence of chronic pain as high as 73%; thi s compares with recent estimates that approximately 33% of children in the general populati on expe- rience chronic pain (Peterson et al., 2006; Roth-Isigkeit et al., 2004). Pain asse ssment is particularly challenging when encountering the array of individual cognitive and communication patterns found among children with I/DD. Early recognition and accurate asses s- ment of pain is essential to prevent the development of pain syn- dromes resulting from untreated nociceptive pain. A broad array of instruments are available to support better pa in management, and it is time for these instruments to be incorporated into randomized cont rolled trials and pharmacokinetic/pharmacodynamic studies in children with I/DD. Th e notion of \200\230altered neural substrates \200\231 has only recently begun to be ad dressed (de Knegt and Scherder, 2011). At issue here is whether some point along the pain n euroaxis is compromised depending on the nature of the neural impairment leading to the int ellectual or developmental disability. Although the specifi c brain pathophysiology underly ing the myriad subgroups of I/DD is not oft en known, it may be reasonable to speculate on how known processing problems associated with some I/DDs and their neu- ral correlates coul d aff ect pain (transduction, transmission, etc.). One reasonable framework could be to con sider the three classic pain dimensions (sensory \200\223discriminative, aff ective \200 \223motivational, cognitive \200\223evaluative) as a way to organize imaging and neuropsy- chological assessment fi ndings from diff erent I/DD syndromes to consider whether specifi c features of pain processing are disrupted and whether the disruption co-varies with speci fi c neurocognitive features of the I/DD. One pragmatic outcome of such an approach would b e to broaden current approaches to pain assessment and management in the I/DD population be yond \200\230nociceptive \200\231 only pain (sensory-discriminative features) and push HCP s to consider relevant motivational, aff ective, and cognitive factors as well. Case example: pediatric chronic pain I/DD case presentation KL is a young girl (3 years, 6 months) with a past medical history signifi cant for prenata l CMV (cytomegalovirus) exposure with resultant CP, spastic quadriparesis GMFCS (gross moto r func- tion classifi cation system) class V, static encephalopathy, global developmental d elay, intractable epilepsy, restrictive lung disease, disordered sleep, and cortical visual impairment who presents to clinic with a chief complaint of persistent distressing symptom s. Th e family has concerns that every 7 to 10 days, KL will have 2 to 3 days of increased crying, irritability, and discomfort. Th ey state they have tried many medications includin g hydroxyzine, methadone, diazepam, oxycodone, ibuprofen, and acetami- nophen. Of all the m odalities the father states that ibuprofen and acetaminophen seem to be what gives the best relief; however, this is very transient. Th e day before some of these spells KL will usua lly be less engaged and they sense that she is \200\230winding up \200\231. She will then have increasing amounts of \200\230whining \200\231 at which time they will administer ibu profen or an extra dose of methadone. She will then enter an inconsolable crying spell wher e she will wake up and generally be crying all day and take a nap at 14.00. Th ey can tell when KL is in pain as they have been using the TOPS scale and have been very adept at knowi ng when she is in distress. Additionally, the family states that when she is in one of thes e spells her heart rate is typically in the 170s and will stay there even when appearing ca lm. Th ey state that there has been no major change in bowel or bladder function. Th ey als o do have concerns that she is hypertensive during these episodes. Th ey feel as if some of these events can be precipitated by major tempera- ture changes, which can cause her to \200\230lose it \200\231. Additionally, they note an association with bowel or bladder disc omfort that seems to \200\230set her off \200\231. Clearly, there remains much work to be done. Th e weight of the (limited) evidence (provide d, in part, by the scales developed during the last decade) suggests that children with I/D D have been sub- ject to practices and procedures with little regard for their ability to e xperience or express pain. We need to continue to refi ne behav- ioural methods for the ass essment of pain intensity, along with a measurement framework that can account for and pred ict the individual pain trajectory/course over time. More objective meth- ods such as quant itative sensory testing (QST) might hold promise for the assessment of pain in children wit h I/DD, although modi- fi cations of these methods are needed to adapt to individuals not c apable of cooperating with a standard QST protocol. In addition to cognitive and communicat ion limitations, many other biopsychoso- cial factors are likely to contribute to inadequat e pain management in this population, for example: atypical responses to treatment, polypha rmacy, chronic pain conditions, repeated surgical interven- tion, genetic abnormalities, al tered stress/arousal responses. Better specifi cation of such variability will aid clinicia ns in developing pain management plans tailored to the needs of the individual child. Clinical decision-making Aft er reviewing the past medical history with the family, we work ed with the notion that a signifi cant amount of KL \200\231s distress was likely secondary to her underlying neurological insult with resultant Research studies involving such a heterogeneous population must specify with as much detail as possible the specifi c features of study SECTION 4 pain in specific populations and diseases 154 References Aisen, M. L., Kerkovich, D., Mast, J., Mulroy, S., Wren, T. A. L., Kay, R. M., e t al . (2011). Cerebral palsy: clinical care and neurological rehabilitation. Lancet Neurol , 10 (9), 844 \200\223852 . autonomic dysfunction, exacerbated by pain, discomfort, tem- perature swings, and bowel and bladder dysfunction. Th e initial intervention included treatment of the underlying autono mic dys- function with optimized doses of gabapentin and cyproheptadine. Additionally, KL w as weaned off of her scheduled methadone. Finally, we off ered the following \200\230rescu e plan \200\231 protocol when KL was experiencing an exacerbation of her distressing sympto ms: American Association on Intellectual and Developmental Disabilities. (2012). American Assoc iation on Intellectual and Developmental Disabilities website. Available at: <http://www.aa idd.org> (accessed 15 February 2012). American Society of Anesthesiologists. (2012). Practice guidelines for acute pain managemen t in the perioperative setting: an updated report by the American Society of Anesthesiologi sts Task Force on Acute Pain Management . Anesthesiology , 116 (2), 248 \200\223273 . a. Administer acetaminophen and ibuprofen in combination (180 mg and 120 mg respectively) v ia gastrostomy tube every 6 h as needed for pain or fever. b. If no effect in 30 min may administer diphenhydramine 12.5 mg via gastrostomy tube every 6 h as needed for agitation. Beavis, J., Kerr, M., and Marson, A. G. (2007). Pharmacological interventions for epilepsy in people with intellectual disabilities. Cochrane Database Syst Rev , 3, C D005399 . c. If no effect in 30 min may administer diazepam 4 mg via gas- Benini, F., Trapanotto, M., Gobber, D., Agosto, C., Carli, G., Drigo, P., et al . (2004). E valuating pain induced by venipuncture in pediatric patients with developmental delay. Clin J Pain , 20 (3), 156 \200\223163 . trostomy tube every 6 h as needed for severe agitation. d. If no effect within 30 min, may administer propranolol 3 mg via gastrostomy tube every 6 h as needed for autonomic storming. Bettelheim, B. (1967). Th e empty fortress: infantile autism and the birth of the self. New York: Free Press . Bodfi sh, J., Harper, V., Deacon, J., and Symons, F. (2001). Identifying and measuring pain in persons with developmental disabilities: a manual for the Pain and Discomfort Scale (PA DS). Morganton, NC: Western Carolina Center Research Report. Clinical outcomes On 1-month follow-up, family had been able to enjoy positive changes in K L, including sleeping through the night. Th ey stated that her irritability does continue, but it is intermittent, as opposed to constant, within the day. Most episodes during the da y occur early in the evening, usually beginning at 18.00, and ending by 21.00. Th is was an improvement from the all-day 07.00 to 21.00 inconsolable crying. Th e family also notes th at the \200\230rescue plan \200\231 has been working well at night-time; however, when tri ed during the day, it does not appear as eff ective. Th ey state that overall they feel tha t KL appears more comfortable, she is more aware of her surroundings, and engaged at times when not irritable. Breau, L. M. and Burkitt, C. (2009). Assessing pain in children with intellectual disabilities. Pain Res Manag , 14(2), 116 \200\223120. Breau, L. M. and Camfi eld, C. S. (2011). Pain disrupts sleep in children and youth with in tellectual and developmental disabilities. Res Dev Disabil , 32(6), 2829 \200\2232840. Breau, L. M., Camfi eld, C. S., McGrath, P. J. and Finley, G.A. (2007). Pain \200\231s impa ct on adaptive functioning. J Intell Disabil Res , 51(2), 125 \200\223134, Breau, L. M., Ca mfi eld, C. S., McGrath, P. J., and Finley, G. A. (2003b). Th e incidence of pain in childr en with severe cognitive impairments. Arch Pediatr Adolesc Med , 157(12), 1219 \200\2231226 . Breau, L. M., Finley, G. A., McGrath, P. J., and Camfi eld, C. S. (2002). Validation of the Non-communicating Children \200\231s Pain Checklist- Postoperative Version. Anesthesiology , 96 (3), 528 \200\223535 . Based on this feedback, we further optimized her cyprohepta- dine and adjusted her protocol as follows: Breau, L. M., MacLaren, J., McGrath, P. J., Camfi eld, C. S., and Finley, G. A. (2003a). Ca regivers \200\231 beliefs regarding pain in children with cognitive impairment: relation be tween pain sensation and reaction increases with severity of impairment. Clin J Pain , 19 ( 6), 335 \200\223344 . a. Administer acetaminophen and ibuprofen in combination (180 mg and 120 mg, respectively) via gastrostomy tube every 6 h as needed for pain or fever. Buitenkamp, T. D., Math t, R. A., de Haas, V., Pieters, R., and Zwaan, C. M. (2010). Met hotrexate-induced side eff ects are not due to diff erences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica , 95 (7), 1106 \200\223 1113 . b. If no effect in 30 min, may administer to give diazepam 4 mg via gastrostomy tube every 6 h as needed for severe agitation. c. If no effect in 20 to 30 min, may administer diphenhydramine 12.5 mg via gastrostomy tub e every 6 h as needed for agitation. Castle, K., Imms, C., and Howie, L. (2007). Being in pain: a phenomenological study of youn g people with cerebral palsy. Dev Med Child Neurol , 49 (6), 445 \200\223449 . d. If no effect, may administer propranolol 3 mg via gastrostomy tube every 6 h as needed for autonomic storming. Clancy, C. A., McGrath, P. J., and Oddson, B. E. (2005). Pain in children and adolescents w ith spina bifi da. Dev Med Child Neurol , 47 (1), 27 \200\22334 . Couston, T. (1954). Indif f erence to pain in low-grade mental defectives. Br e. 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Valkenburg, A., van Dijk, M., de Leeuw, T., Meeussen, C., Knibbe, C., and Tibboel, D. (2012 a). Anesthesia and postoperative analgesia in surgical neonates with or without Down \200 \231s syndrome: is it really diff erent? Br J Anaesth , 108 (2), 295 \200\223301 . McGrath, P. J., Walco, G. A., Turk, D. C., Dworkin, R. H., Brown, M. T., Davidson, K., et a l . (2008). Core outcome domains and measures for pediatric acute and chronic/recurrent pai n clinical trials: PedIMMPACT recommendations. J Pain , 9 (9), 771 \200\223783 . Valkenburg, A. J., van der Kreeft , S. M., de Leeuw, T. G., Stolker, R. J., Tibboel, D., an d van Dijk, M. (2012b ). Pain management in intellectually disabled children: a survey of p erceptions and current practices among Dutch anesthesiologists . Pediatr Anesth , 22(7), 68 2 \200\223689. Merskey, H. and Bogduk, N. (1994). Classifi cation of chronic pain, IASP Task Force on Taxonomy . Seattle , WA: IASP Press. Valkenburg, A. J., van Dijk, M., de Klein, A., van den Anker, J. N., and Tibboel, D. (2010) . Pain management in intellectually disabled children: Nagasako, E. M., Oaklander, A. L., and Dworkin, R. H. (2003). Congenital insensitivity to pain: an update. Pain , 101 (3), 213 \200\223220 . SECTION 4 pain in specific populations and diseases 156 World Health Organization. (1996) Cancer pain relief: with a guide to opioid assessment, treatment, and translational research. Dev Disabil Res Rev , 16 (3), 248 \200 \223257 . availability (2nd edn). Geneva: World Health Organization . World Health Organization. (2001). International classifi cation of functioning, Walker, S. M. (2012). Perioperative care of neonates with Down \200\231s syndrome: disability, and health. Geneva. World Health Organization. should it be diff erent? Br J Anaesth , 108 (2), 177 \200\223179 . Weijerman, M. E., and de Winter, J. P. (2010 ). Clinical practice: the care of children wit h Down syndrome. Eur J Pediatr , 169(12), 1445 \200\2231452 . CHAPTER 17 Pediatric cancer pain Jennifer Hickman , Jaya Varadarajan , and Steven J. Weisma n Introduction Th e publication of the World Health Organization (WHO) \200\231s monograph Ca ncer Pain Relief in 1990 may be one of the groundbreaking events in the advancement of trea tment for cancer pain (WHO, 1990). A result of this work was the fi rst published guideline for the treatment of cancer pain in children (Berde et al., 1990; McGrath et al., 1990; Ze ltzer et al., 1990). Since that time, several other guidelines and monographs have been pub lished which provide very useful frameworks for the treatment of cancer pain (Anonymous, 19 96; Benedetti et al., 2000; Miaskowski et al., 2004). Case example A 9-year-old boy with high-functioning autism was hospitalized for a several-week history o f low grade fevers, progressive fatigue, pharyngitis, night sweats, and diff use lymphadeno pathy. Workup revealed an elevated white cell count and led to a diagnosis of high-risk acu te myelocytic leukemia. He received three courses of induction chemotherapy and was in remission aft er the fi rst course. Given his poor prognosis he was slated for an unrelated bone marrow transplant (BMT ). His post-transplant course was complicated by pseudomonas bacteraemia, G-tube site infec tion, steroid-induced hyperten- sion, sinusitis, mucositis, neutropenia, and high fevers su ggestive of graft -versus-host disease (GVHD), eventually resulting in non-engraft ment and rejection. He required multiple visits to the operating room for maxillary sinus taps and irrigations. He was treated with methylprednisolone, and then received a second haploidenti cal bone marrow transplant from his mother. He developed serum sickness with anti-thymocyte globulin and GVHD of the skin, needing immune suppression. His prolonged hospital course w as further complicated by streptococcal viridans bacteraemia, viraemia, haemorrhagic cystit is, respiratory syncy- tial virus upper respiratory infection requiring ribavirin therapy, Clostridium diffi cile enterocolitis, feeding issues requiring enteral and total parenteral nutrition, episodic premature atrial contrac- tions, intermittent prolonged QT syndrome, c onstipation, pan- creatitis, hyperglycaemia, seizures, and chronic pain. Many of these issu es were complications of therapy for his primary illness, but some were related to medicati ons used for pain, insomnia, and mood. He was discharged aft er 7 months in the hospital. Although the incidence of childhood cancer has remained rela- tively stable over the last 3 5 years, the survival rate has increased dramatically. In 1975, approximately 14.7/100 000 children from 0 to 19 years were diagnosed with cancer (Howlader et al., 2012). Although th e overall incidence did rise slightly to 17.0/100 000, mortality rate has decreased from 5. 4/100 000 to 2.5/100 000 per year. In addition, the 5-year survival rates for pediatric can cer have improved from 61.7% to 83.1% between 1975 to 1977 and 2002 to 2008. Certain types of pediatric malignancy now have survival rates near or above 90% at 5 years (Hodgkin \200 \231s lymphoma, 96.9%; Wilms \200\231 tumor 89.8%; and acute lymphoblastic leukemia (ALL) 8 8.7%). Th ese remarkable survival statistics have not come without a heavy burden and price . As described later in this chapter, these children have multiple challenges to overcome w hen exposed to aggressive treatments that include complex and repetitive surger- ies, chemo therapeutic and radiation treatment regimens, and bone marrow transplantation. As exemplifi ed in the following case example, each patient seems to follow a unique trajec tory and, for the pain clinician, will present unique challenges that require agility and f l exibility to design sat- isfactory pain treatment protocols. Using a systematic approach that encompasses the notion that pain in pediatric cancer is usu- ally the result of multip le intersecting causes will usually provide satisfactory results for the patients and their watchdog families supervising their care. For the continually decreasing numbers of childr en who cannot survive their disease, our palliative care colleagues can continue multimodal pain management in conjunc- tion with their pain management resources to ensure a dignifi ed and comfortable end of life. Almost 2 years after his initial diagnosis, the patient \200\231s condition seemed to stabi lize and his physical symptoms began to improve. He remained in remission, continued to be transfusion-dependent, but with no further evidence of GVHD. He was taken off systemic immu nosuppression 3 years aft er BMT. He was able to wean a number of his medications and retur ned to school in a special education program. As part of his recov- ery, he enrolled in a t herapeutic riding program and won the Child Equestrian Award 2 years ago. He is still consi dered high risk for secondary malignancies and is screened yearly. SECTION 4 pain in specific populations and diseases 158 Aetiologies and characteristics of pain in cancer Pain is one of the most prevalent symptom s in cancer (Collins et al., 2000; Ljungman et al., 1999; Miser et al., 1987a, 1987b). Pain in cancer can be a direct result of the disease, but it is largely due to cancer treatment s or the combined long-term eff ects of both. Th e aetiologies of disease-related pain incl ude bone pain from metas- tases or infi ltration of tissues, somatic pain from solid tumors , visceral pain, and neuropathic pain (Box 17.1 ). or \200\230gnawing \200\231 in nature in children who are able to communicate. Th e clinic al presentation varies depending on the age of the child and the bones aff ected. Very youn g children, who are unable to communicate their pain, may present with a limp or an inabili ty to walk. Children who have recently started walking may actually demonstrate regression in motor function. An older child, who is able to communicate, might report diff use pain a ll over the body that is diffi cult to localize. Adolescents may localize the pain to a spe cifi c long bone and might mistakenly attribute it to a sports- related injury, thus delayi ng diagnosis and treatment. Cortical thinning could result in a pathological fracture with localized pain at the site. Treatment then would involve treatment of both the primary illn ess and its sequelae. Treatment-related pain can be the result of chemotherapy, radia- tion therapy, acute and ch ronic postoperative pain, graft -versus-host disease, or procedure-related pain (Box 17.2 ) . Malignant bone tumors such as osteosarcoma and Ewing \200\231s sarcoma can cause signifi ca nt pain in the pediatric cancer patient. Direct tumor invasion causes bone pain from destru ction of the normal trabecular bone pattern while periosteal new bone forma- tion causes so ft tissue infl ammation and, in turn, pain. Th e bone pain from these processes is oft en s evere and requires multimodal therapy. Solid tumors such as neuroblastoma can metastasize t o both bone marrow and long bones. Its bone pain can be similar to that in the leukaemias. Pain from bone marrow in \201 ltration, primary malignant bone tumors, and metastases Abou t a third of childhood cancers are leukaemias, the most common being ALL. Along with cancer s of the central nervous system (CNS) they make up more than half of childhood can- cers (H owlader et al., 2012). Th e rapid growth of leukemic blast cells from leukemic infi ltratio n in the bone marrow results in diff use bone pain. Pain from primary or metastatic bone di s- ease is somatic in nature. It is oft en described as being \200\230aching \200\231 Treatment of the primary cancer is the most eff ective method for managing cancer pain. In younger patients with leukemia, decrease in the leukaemic burden following chemotherapy res ults in dramatic improvement of bone pain. Adolescents may be more challenging to treat due to more resistant disease, and require con- sistent analgesia. Local radiation therapy can also cause a reduc- tion in bony pain. Th is will oft en be employed for palliation in sit uations where primary treatment has failed. Pharmacological treatment involves administrati on of opioids, oft en as continu- ous infusions or using patient- (PCA) or parent/nurse-con trolled analgesia (PNCA). Adjuvant analgesics are also oft en employed. It is important to consider that in patients with bone marrow infi l- tration, there is oft en concomitant bon e marrow suppression with thrombocytopenia. Use of non-steroidal anti-infl ammatory drugs ( NSAIDs) can therefore place these patients at risk for bleeding from both quantitative and qualitative platelet defects. Box 17.1 Disease-related cancer pain \227\206 Bone marrow infi ltration (leukemia, metastatic tumors) \227\206 Visceral pain (invasion, obstruction, compression, bleeding) \227\206 Somatic pain (rhabdomyosarcoma, osteosarcoma, Ewing \200\231s sarcoma, leukemia) \227\206 Neuropathic pain (neural compression/invasion, brain/spinal cord tumors). Box 17.2 Treatment-related cancer pain Neuropathic pain Neuropathic pain is the result of tumor compression or infi ltration of pe ripheral nerves or the spinal cord. Direct injury to a nerve can also occur with soft tissu e tumors in compartmental areas, such as with Ewing \200\231s sarcoma or rhabdomyosarcoma a rising in the pelvis. Neuropathic pain can also occur as a result of infl ammation of a ner ve root from malignancy or infection. Reactivation of a herpes zoster infection can occur i n the immune-compromised cancer patient causing neuropathic pain. Cancer treatment is a com mon cause of neuropathic pain. Vincristine is one of the chemothera- peutic agents known to cause neurotoxicity.