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. \227\206 Medical procedures \227\206 Acute postoperative \227\206 Chronic postoperative: phantom limb, radiculopathies \227\206 Chemotherapy: \227\206 Mucositis \227\206 Neuropathic \227\206 Extravasation burns \227\206 Radiation therapy: Th e pathognomonic feature of neuropathic pain is dysaesthe- sia, with or without a \200 \230burning \200\231 quality to the pain. Patients may also complain of \200\230electrical \200\231 pain, paroxysmal, brief \200\230shooting \200\231 or \200\230stabbing \200\231 pain, or allodynia and hyperpathia. Neuropathic pain can be challenging to treat. Medicatio ns used include the adjuvant drugs such as tricyclic antidepressants, neuromodulators such as gabapentin, and local anesthetics. Natural antidepressants such as St John \200\231s wor t have also been used but with limited data on \227\206 Mucositis \227\206 Skin burns \227\206 Local tissue injury \227\206 Graft -versus-host disease \227\206 Infection. CHAPTER 17 pediatric cancer pain 159 surgical resection needs early implementation of opioids. Regional techniques are also help ful if not contraindicated by the presence of coagulopathy due to thrombocytopenia, dissemi nated intravas- cular coagulation, or the presence of acquired factor inhibitors. Epidurals are eff ective in management of postoperative pain and they can be tunneled for longer-ter m use. Coeliac plexus blocks can be useful for unresponsive tumors such as bladder rhabdomy osa- rcoma, neuroblastoma or pancreatic tumors, but have not gained widespread acceptance i n the pediatric realm despite reports of their effi cacy in terminal cancer pain in adults (Berde et al., 1990; Tanelian and Cousins, 1989). Newer radiographic techniques such as thr ee-dimensional rotational angiography may facilitate correct placement of coeliac plexus bl ocks in children (Goldschneider et al., 2007). Rate per 100,000 20 Delay-Adjusted Incidence 15 10 Mortality Regardless of the etiology of visceral pain, it is necessary to implement treatment early t o prevent the later development of central pain syndromes and visceral hyperalgesia, which can be extremely challenging to treat. CBT must be included as part of the treatment protoc ol. 5 0 1975 Pain with central nervous system tumors CNS tumors are the most common solid tumors in chil d- hood. Th e child oft en presents with symptoms suggestive of raised intracranial pressur e from the mass eff ect of the tumor, such as headache or emesis. Surgical resection is und ertaken for locally invasive tumors without metastatic potential such as astrocyto- mas (Su tton et al., 1995). Pain may persist from residual disease if complete surgical resection w as not possible. In tumors that metas- tasize such as medulloblastoma, chemotherapy and/or radiation may be part of the treatment regimen either prior to or aft er surgical resection . Opioids are the mainstay of treatment in this population. Corticosteroids may be used to reduce cerebral oedema postopera- tively. NSAIDs may be used if there is no contraindicatio n due to the eff ects of chemotherapy or radiation therapy. Th e side eff ects of opioid tr eatment, such as nausea, emesis, and constipation, are best addressed pre-emptively, especi ally since the former symptoms can be confused with symptoms from the primary tumor. Adjuva nt agents such as benzodiazepines may have a role in decreasing anxi- ety, facilitating sle ep, and reducing muscle spasm postoperatively. 1980 1985 1990 1995 2000 2005 2009 Year of Diagnosis/Death Figure 17.1 Cancer incidence and mortality in the United States 197 5 to 2009. Reproduced from Howlader N et al. (eds), SEER Cancer Statistics Review 1975 \200 \2232009 (Vintage 2009 Populations), Section 28 Childhood Cancer by Site Incidence, Surviva l and Mortality , Figure 28.1, National Cancer Institute, Bethesda, MD, USA, available from <http://seer.cancer.gov/csr/1975_2009_pops09/results_merged/sect_28_ childhood_cancer.pdf> , based on November 2011 SEER data submission, posted to the SEER web site, April 2012. eff ectiveness (Galeotti et al., 2010; Otto et al., 2007; Sindrup et al., 2001). Of the opi oids, methadone is the one with the best data for being eff ective in neuropathic pain (Fis her et al., 2004; Lynch, 2005). Non-pharmacological approaches such as physical therapy, ac upuncture, and cognitive-behavioral therapy (CBT) should always be considered. Visceral pain Visceral pain results from infi ltration and distension of thoracic and abdom inal viscera with capsular wall stretching, organ compression by primary or metastatic tumo r, hollow organ obstruction from tumor, tumor regrowth within an organ, or peritoneal cavit y bleed- ing. It is poorly localized pain and described as \200\230deep \200\231, squeezin g \200\231, and \200\230pressure-like \200\231. When acute, it could be associated with na usea, vomit- ing, and diaphoresis. Primary tumors of the liver, such as hepatob- lastoma or hepatocellular carcinoma, and tumors that metastasize to the liver, such as neuroblastoma, result in visceral pain. Acute pain due to cancer treatment As cancer treatment protocols evolve, treatment-related pain has become more prevalent. Common treatment-related type pain includes, but is not lim ited to, mucositis, infection, antineoplastic therapy-related pain, and postoperative pain. Mucositis is the painful infl ammation of the mucous mem- branes lining the digestive tract in response to cancer treatments with chemotherapeutic agents and radiation. It can aff ec t the entire digestive tract from mouth to anus and can be quite pain- ful. Symptoms includ e swollen gums, ulcerations in the mouth, diarrhea, abdominal cramping, or rectal ulceratio ns. Pain due to these symptoms oft en precludes talking, eating, and, on occa- sion, swallo wing. Treatment for oral lesions involves using various mouthwash mixtures which can have a gents such as saline, sodium bicarbonate, hydrogen peroxide, sucralfate, nystatin, or visco us lidocaine. In more severe cases, PCA may be necessary (Dunbar et al., 1995; Mackie et al ., 1991). In the case of visceral pain due to organ invasion or tumor regrowth, reduction in tumor si ze is the primary modality for treat- ment of pain. In the setting of intestinal obstructio n from tumor growth, treatment is determined by the nature of the tumor. For example when o bstruction is from Burkitt \200\231s lymphoma, treatment consists of chemotherapy and/or ra diation, as surgery is not eff ec- tive (Delarue et al., 2008; England et al., 2012; Gupta et al., 2007; Meyer et al., 2012). A multimodal approach that includes surgery, chemotherap y, and/or radiotherapy is common in solid organ abdominal cancers, such as Wilms \200\231 t umor. Postoperative pain from SECTION 4 pain in specific populations and diseases 160 Table 17.1 Adjuvant analgesics: major classes Drug class Examples Multipurpose analgesics Antidepressants Tricyclic antidepressants Amitriptyline (Elavil ) (tertiary amine) nortriptyline (Pamelor ), desipramine (Norpramin ); (secondary amines) Selective serotonin reuptake inhibitors Fluoxetine (Prozac ), paroxetine (Paxil ), sertraline (Zoloft )citalopram (Celexa ), es citalopram (Lexapro ), \202 uvoxamine (Luvox ) Noradrenaline/serotonin reuptake inhibitors Venlafaxine (E \200 exor ), duloxetine (Cymba lta ), milnacipran (Savella ) Others Bupropion (Wellbutrin ) Corticosteroids 2-adrenergic agonists Dexamethasone (Decadron ), prednisone(Deltasone ; Orasone ) Clonidine (Catapres ), tizanidine(Zana \202 ex ) Neuroleptics Olanzapine (Zyprexa ) For neuropathic pain Anticonvulsants Gabapentin (Neurontin ), topiramate(Topamax ), lamotrigine(Lamictal ), carbamazepine(Car batrol ; Tegretol ),levetiracetam (Keppra ),oxcarbazepine (Trileptal ),pregabalin (Lyri ca ), tiagabine(Gabitril ), zonisamide(Zonegran ), phenytoin(Dilantin ), valproic acid( Depakene ) Local anesthetics Lidocaine (Xylocaine ; Lidoderm ),mexiletine (Mexitil ) N-methyl-D-aspartate receptor antagonists Ketamine, dextromethorphan, memantine (Namenda ), amantadine (Symmetrel ) Other baclofen (Lioresal ) cannabinoids psychostimulant drugs: methylphenidate (Concerta ; Metadate CD ; Methylin ; Ritalin ), moda \201 nil (Provigil ) Topical drugs Lidocaine/prilocaine (EMLA ), Lidocaine 4% (LMX4 ), capsaicin For bone pain Corticosteroids Dexamethasone, prednisone Calcitonin (Miacalcin ) Bisphosphonates Pamidronate (Aredia ), zoledronic acid (Zometa ), risedronate (Actonel ), Alendronate (F osamax ) Radiopharmaceuticals Strontium89, samarium153 For musculoskeletal pain Muscle relaxants Cyclobenzaprine (Flexeril ), orphenadrine (Nor \202 ex ), carisoprodol (Soma ), metaxal one (Skelaxin ), methocarbamol (Robaxin ), Tizanidine (Zana \202 ex ) Baclofen (Lioresa l ) Benzodiazepines Diazepam (Valium ), lorazepam (Ativan ), clonazepam (Klonopin ) Adjuvants for pain from bowel obstruction Octreotide (Sandostatin ) Anticholinergics Hyoscine (scopolamine), glycopyrrolate (Robinul ), hyoscyamine (Levsin ) Corticosteroids Adapted with permission from David Lussier, Angela G. Huskey and Russell K. Portenoy, Adjuv ant analgesics in cancer pain management, Th e Oncologist , Volume 9, Number 5, 571 \200 \223591, Copyright 2004 by AlphaMed Press. Infection is common in children with cancer and can oft en be associated with pain. Common sites of pain include perio- ral, perirectal, abdominal, and skin infections. Severe abdomi - nal pain can be due to typhlitis, infection of the cecum, in the immunocompromised, neutr openic patient (Hiruki et al., 1992). Treatment of the pain involves treatment of the infec tion. While being treated for the infection, analgesics such as opioids may need to be impl emented on a short-term basis until the infection clears. occasionally develops aft er injection of chemotherapy into a periph- eral vein (Booth and Weiss, 1981). Intrathecal chemotherapy has been associated with arachnoiditis and meningeal irritation syn- drome, which manifest as headache, nuchal rigidity, fever, nausea, and vom iting (D \200\231Angio, 1983; Geiser et al., 1975). Children with cancer undergo many surgical procedures such as port/line placements, tumor r esections, peripheral and central biopsies, etc. Th ese children have postoperative pain ju st as their non-cancerous counterparts do. Management of postoperative pain in the child wi th cancer is similar to the management of patients without malignancy. Th ey will generally receive postoperative Injection of some chemotherapeutic agents may be associ- ated with local pain at the time o f injection. Th rombophlebitis CHAPTER 17 pediatric cancer pain 161 treatment was attributed by the patients and families to procedures (Ljungman et al., 1999, 2000). In a follow-up study of pediatric oncology patients undergoing procedures including bone mar- row aspiration and lumbar puncture, persistently high pain scores were reported, in spite of ostensibly therapeutic doses of analgesia (Weisman et al., 1998). Aggressive a nd widely available interven- tions for procedure pain management are an essential componen t of pediatric cancer treatment. Interventions range from simple cognitive-behavioral distr action techniques to formal training in biofeedback or hypnosis to active use of topical an esthetics to mild or moderate pharmacologic sedation and, fi nally, to using general anesth esia, when needed. Box 17.3 Using adjuvant analgesics in the management of cancer pain 1. Consider optimizing the opioid regimen before introducing an adjuvant analgesic. 2. Consider the burdens and potential bene \201 ts in comparison with other techniques use d for pain that is poorly responsive to an opioid, including: (a) opioid rotation, (b) more aggressive side effect management, (c) a trial of spinal drug administra- tion, and (d) tr ials of varied non-pharmacological approaches for pain control (e.g. nerve blocks, rehabili tative therapies, and psychological treatments). Oncology patients experience venepuncture, intravenous line placement, port access procedur es, intramuscular and subcutane- ous therapies, plus more invasive lumbar punctures and bon e mar- row aspirations or biopsies. Preparation by the staff or even staff specialized in c ognitive-behavioral techniques can help prepare these patients for the complicated road the y will traverse (Zeltzer et al., 1989, 1990). Topical analgesics can greatly reduce the dis com- fort of the painful cutaneous procedures mentioned (see Stevens and Zempsky, Chapter 2 ; Taddio, Chapter 19, this volume). 3. Select the most appropriate adjuvant analgesic based on a comprehensive assessment of th e patient, including inference about the predominating type of pain and associated factors (comorbidities) or symptoms. 4. Prescribe an adjuvant analgesic based on knowledge of its pharmacological characteristic s, actions, approved indica- tions, unapproved indications accepted in medical practice, li kely side effects, potential serious adverse effects, and interac- tions with other drugs. Many children will receive chemotherapy via a lumbar puncture. Th e drugs themselves may re sult in headache, but as many as 20% of teens are at risk for developing postdural tap head aches when standard 20- or 22-gauge needles are used for sampling and drug delivery (Burt e t al., 1998; Scher et al., 1992; Wee et al., 2008). Pain is fi rst managed with conservativ e bed rest, fl uids, and analgesics. If symptoms persist for several days, an epidural bloo d patch, per- formed by an anaesthesiologist or pain specialist will usually result in reso lution of the headache (Safa-Tisseront et al., 2001). 5. The adjuvant analgesics with the best risk:bene \201 t ratios should be administered as \201 rst-line treatment. 6. Avoid initiating several adjuvant analgesics concurrently. 7. In most cases, initiate treatment with low doses and titrate gradually according to anal gesic response and adverse effects. 8. Reassess the ef \201 cacy and tolerability of the therapeutic regi- men on a regular ba sis, and taper or discontinue medications that do not provide additional pain relief. Bone marrow aspiration and biopsy are common procedures for children with leukemia, certain sarcomas, and neuroblas- toma. Cutaneous management, as discussed earlier, is essential. I n addition, deeper tissue infi ltration that includes the periosteum is critical to eff ect ive pain relief. Distress during these procedures is well described, over 30 years ago (Jay et al., 1983; Katz et al., 1980). Th ese are oft en done in conjunction with lumbar punctu re and hence it is widely accepted that these children will not only have some form of cuta neous anesthesia, but they will also have procedural sedation, moderate, deep, or even gene ral anesthesia (see Cravero, Chapter 20, this volume). 9. Consider combination therapy with multiple adjuvant analge- sics in selected patients. Reprinted with permission from David Lussier, Angela G. Huskey and Russell K. Portenoy, Adj uvant analgesics in cancer pain management, Th e Oncologist , Volume 9, Number 5, 571 \200 \223591, Copyright 2004 by AlphaMed Press. opioids, regional blocks, or neuraxial therapy to manage their pain. Patients who have been receiving preoperative opioids have usually developed some degree of opioid tolerance and should have their daily dose of opioids calculated into the postoperative treatment formula . Th is preoperative amount of opioid becomes their base- line to which additional opioids are added for the purpose of con- trolling new postoperative pain. If this principle is ign ored, there will be dramatic under-dosing in the opioid-dependent oncology patient. Pain syndromes Pain syndromes can occur as a consequence from the treatment of cancer. Th e se syndromes can be a result of the surgical, chemother- apeutic, or radiation treatments u ndertaken while trying to cure the disease process. A variety of problems have been encount ered in long-term survivors of childhood cancer that include, but are not limited to, chron ic abdominal pain of uncertain etiology, phantom limb pain, avascular necrosis of multiple joints, and neuropathic pain syndromes. Procedure-related pain Pain and suff ering from painful procedures that take place for diag nosis, treatment, and surveillance of children with cancer are overall the greatest sources of distress. Angela Miser was the fi rst to report the burden of procedure pain in pediatr ic oncol- ogy patients in 1987 (Miser et al., 1987). Further delineation of problem took pl ace in a series of reports from Sweden in 1999 and 2000. Ljungman reported that over 40% of pain during cancer Amputation and limb-salvage procedures may be used as surgi- cal approaches to achieve loca l control of a tumor that can lead to phantom limb pain. Th is pain is experienced when the patient continues to have pain appearing to come from where the aff ected amputated limb u sed to be. Krane and Heller (1995) found the prev- alence of phantom pain in pediatric ampu tees to be 92%. Th e pain generally occurred within the fi rst week aft er the loss of the limb. SECTION 4 pain in specific populations and diseases 162 Th e practitioner can use both pharmacological and non-pharma- cological treatment modaliti es. Th e most important pharmacologi- cal treatment is eff ectively treating the pain preop eratively via the use of anesthetic techniques such as an epidural. Th e use of epi- durals prior to amputation can help prevent dorsal horn sensitiza- tion. Aft er amputation, the f ocus becomes treating any neuropathic type symptoms. Chronic opioids are not usually eff ec tive in treating this type of neuropathic pain. A more successful approach usually involves the use of either gabapentin, pregabalin, or amitriptyline (or related tricyclic antidepre ssants). Non-pharmacological treat- ments or CAM treatments (complementary and alternative) can consist of hypnotherapy, massage, and acupuncture. An interest- ing approach to phanto m limb treatment has emerged which uses mirror boxes (Chan et al., 2007; Ramachandran et al ., 1996). Th is technique allows the amputee to place the remaining extremity into the mirr or box. Th e projected image of the normal extrem- ity appears to the patient to be the con tralateral aff ected extremity. Repetitive therapeutic activity of the normal limb, viewed as the missing limb appears to \200\230retrain \200\231 and normalize neuronal pathways. T h ough phantom pain can be diffi cult to treat, in the pediatric population phantom pain te nds to decrease over time regardless of the treatments. CIN. Supportive and symptomatic treatment is the mainstay of cur- rent CIN treatment. Manag ement for CIN is similar to that of other neuropathic pain which entails analgesics, antide pressants, and antiepileptic drugs. Management of pain in cancer Recommendations for pain management in this population should encompass not only what we consider to be traditional pharma- cological interventions, but must be founded in a truly interdisci- plinary model that should include behavioral and psy chological interventions and appropriate physical modalities. Psychological distress is inv ariably secondary to the pain of the disease or treat- ment. Obviously, children with under lying psychological diagnoses will require ongoing management of this during the course of their diagnosis and treatment for cancer. It is important for the pain specialist to unders tand the extent of the child \200\231s disease and onco- logical treatment plan, the role o f anticancer therapy, duration of treatment, expected duration of side eff ects from antica ncer treat- ments, the child \200\231s prior pain experiences and the expectations for pain management amongst the patient, guardians and oncology/ surgery care team members. Treatment regimens for cancer such as high-dose steroids and radiation treatments can have negative eff ects. Th ese treatments can cause compromised blood supply to the bones which then leads to cell death in these areas resulting in avascular necrosis (AVN). Th e hip bon e is the most common site, but knee, shoulder, and other bones can be aff ected. Th e incid ence is 5% in childhood ALL and it usually develops during therapy although it has a latenc y period as long as 13 years aft er treatment is completed (Hanif et al., 2006; Mattano et al., 2000; Wei et al., 2000). Medical therapy for AVN is typically NSAIDs and physical ther apy. However, if surgical inter- vention is needed it can include core decompression, bone graft ing, osteotomies, or even joint replacement. Pharmacotherapy for management of cancer pain in children Th e few analgesic studies that h ave been performed in children with cancer are limited by the paucity of subjects, and few are ran- domized controlled trials (Collins, 1998). Pharmacokinetic and pharmacodynamic pro perties of most opioids have been stud- ied in children, but little information is availabl e about oral bio- availability and potency ratios amongst the opioids (Collins and Weisman, 2003). Th ere have been no controlled clinical trials of adjuvants drugs in pediatric canc er patients. Th e prescription of analgesics for children with cancer pain is based on vari ous guide- lines developed by content experts including the WHO guideline on cancer pain re lief and palliative care in children (McGrath, 1996), the American Pain Society guideline f or the management of cancer pain in adults and children (Miaskowski et al., 2004), the Nati onal Comprehensive Cancer Network practice guide- lines for cancer pain (Benedetti et al., 2000), and Supportive Care of Children with Cancer: Current Th erapy and Guidelines from th e Children \200\231s Oncology Group (Altman and Children \200\231s Oncology Group, 2004). T h e original WHO ladder proposed that treatment of pain should begin with a non-opioid medi cation, progress- ing, as necessary, to a weak opioid and then to a more power- ful opioid. It also included the possibility of adding adjuvants for neuropathic pain. Since its appli cation into clinical practice in 1990 of the original guideline, the WHO stepladder has bee n quite useful for guiding the relief of pain from cancer (WHO, 1990). Its rationale and si mplicity turned it into a very useful tool to unequivocally provide eff ective analgesia in malignant pain (American Pain Society, 2003). In recent years, several sources have propos ed modifi cations to the original three-step ladder, recommending elimination of weaker opi oids, use of stronger opioids as the fi rst line in cancer pain treatment, using adjuvants early in the course of treatment, and incorporating neurolytic regional techniques in manag ement when indicated (Jadad and Browman, 1995). Chemotherapy-induced peripheral neuropathy (CIN) causes numerous debilitating symptoms and impairs functional capacity. Vincristine, vinblastine, cisplatin, oxaliplatin, and ifosfami de are most commonly implicated (Frisk et al., 2001; Guti rrez-Guti rrez et al., 2010 ; Le Deley et al., 2010; Lindeman et al., 1990; Reddy and Witek, 2003; Reinders-Messelink e t al., 2000; Sandier et al., 1969). It can manifest with sensory symptoms, pain, motor symp toms, refl ex loss, autonomic involvement, or a combination of these symptoms. Sensory symp toms tend to be most signifi cantly manifested in the lower extremities. Th ese manifest as itching, decreased or hyperac- tive responses to touch or vibration, and proprioception lo ss which can aff ect gait. Pain is an important side eff ect for many patients. It can occu r early in treatment as painful paraesthesias or it can be a late and chronic consequence o f treatment. Motor symptoms can be minor or more severe with athetoid movements and can pro gress to paralysis. Th ere can be strength loss or symptomatic foot drop. Muscle cramping i s also an underestimated motor mani- festation. Refl exes can also be lost with the most co mmon being the ankle refl ex. Infrequently, patients develop symptoms of auto- nomic dysfun ction. Th ese can include orthostatic hypotension, constipation, or dysfunction of the urin ary bladder (Windebank and Grisold, 2008). Prevention of CIN is the goal during treatment. Th ere are agents that provide neuroprotection during therapy such as acetyl-L-carnitine, g lutathione, vitamin E, or erythropoietin. Th ese can be given to either prevent or even hel p treat developing CHAPTER 17 pediatric cancer pain 163 Non-opioid analgesics Non-opioid analgesics include acetaminophen, traditional NSAIDs, sele ctive cyclo-oxygenase (COX)-2 inhibitors, and tramadol (a unique analgesic described later in this section). the severe pain associated with their disease and its sequelae. An oral to parenteral ratio of 3:1 is usually used for administration (Cherny and Foley, 1996; Cherny et al., 1995). Some patients benefi t from the convenience of a patient-con- trolled analgesic (PCA) pump. Typical initial morphine doses for intravenous PCA administration range from 0.01 to 0.02 mg/kg for both a basal infusion and demand dose. Sustained-release oral preparations of mor phine are available and are usually adminis- tered once or twice daily. Dosing at 8 h inter vals can also be used in cancer patients (Hunt et al., 1999). Sustained-release preparation s are appropriate only in children who can swallow pills, as crushing produces immediate re lease of a large dose of morphine. Sustained- release capsules with time-released pellets ( e.g. Kadian ) may be an option in the child unable to swallow pills, as they can be mixed with semisolids (Broomhead et al., 1997). Acetaminophen is one of the most commonly used non-opioid analgesics used in children. It h as analgesic and antipyretic eff ects. It inhibits prostaglandin synthesis primarily in the CNS. It does not have the side eff ects of gastritis and inhibition of platelet function t hat are concerns with aspirin and most of the NSAIDs (Lesko and Mitchell, 1999). Although i t has the potential for hepatic and renal injury, this is usually not a concern in commonly used therapeutic doses (Sandler et al., 1989). It does not have an association with Reyes syndrome (Halpin et al., 1982; Hurwitz et al., 1985). Th e anti- pyretic action of acetamin ophen may be contraindicated in neutro- penic patients in whom monitoring of fever is criti cal. Th e NSAIDS include the traditional non-selective COX inhibi- tors as well as the selective COX-2 inhibitors such as celecoxib and partially selective meloxicam. Th ey are useful ana lgesics in chil- dren with adequate platelet number and function, both alone, and in combin ation with opioids or acetaminophen. Th ey have anti- infl ammatory, analgesic, and antipyr etic potential. Chronic use increases the concern for analgesic nephropathy, gastritis, and hae- mostatic eff ects. Th e selective COX-2 inhibitors have a lower risk of gastrointesti nal and minimal haemostatic adverse eff ects, but the risk of renal compromise appears no d iff erent (Brater, 1999). Th ere are no data on the safety, effi cacy, and tolerability of COX-2 inhibi- tors in children with cancer. Th e non-selective NSAID choline magnesium tris alicylate reportedly does not interfere with platelet aggregation, but its use should be av oided in children with platelet counts less than 20 000 or with active bleeding (Collins an d Berde, 1997; Stuart and Pisko, 1981). Hydromorphone Hydromorphone is an alternative, when treatment is limited by the side eff ec ts of morphine. It is a safe drug to use in patients with impaired renal function, as its m ajor metabolites are not active (Collins et al., 1996; Goodarzi, 1999). It is available for oral, intrave- nous, subcutaneous, epidural, and intrathecal administration and can also b e used in a PCA pump, although dosing can be somewhat cumbersome in smaller patients. It ha s been reported to be an eff ec- tive analgesic in several studies of patients with cancer (Babul et al., 1995; Broomhead et al., 1997; Dunbar et al., 1995, 1996; Weisman and Wishnie , 1996). It has been shown to be fi ve to six times more potent than morphine in studies of children with cancer (Collins et al., 1996; Weisman and Wishnie, 1996). Little is known ab out its pharmacokinetics in infants and children (Babul et al., 1995; Murray and Hagen, 200 5). Tramadol is a synthetic, centrally acting analgesic that exerts its eff ects through the receptors, similar to opioids but not chemi- cally related. It also stimulates the release of serotonin and inhibits reuptake of both serotonin and noradrenaline, thus simulating th e properties of an antidepressant (Garrido et al., 2006). It is available in oral form alon e in the US, but a parenteral form is being used in Europe and other countries. Long-acting forms are also available, allowing once-daily or twice-daily dosing. A concern with tramad ol is that it lowers the seizure threshold, thus making its use challeng- ing in cancer pat ients who could be on a multitude of other drugs with epileptogenic potential. It is curren tly a non-scheduled drug but concerns about its abuse potential have been raised (Grond et al., 1999). Oxycodone Oxycodone is a semisynthetic opioid used for moderate to severe pain. It is avail able as a slow-release preparation and as an immedi- ate-release preparation with or withou t acetaminophen. Oxycodone has a higher clearance value and a shorter elimination half-life in children than adults and appears to have a potency of about 1.5:1 with morphine (El-Tah tawy et al., 2006; Kokki et al., 2004, 2006; Poyhia et al., 1993). Th ere are no controlled trials studying the use of oxycodone in children with cancer, but it is widely used with p resumed effi cacy (Collins, 2001). Fentanyl Fentanyl is a synthetic opioid approximately 50 to 100 times more potent than morp hine with intravenous administration. It can be administered by intrathecal, epidural, tran smucosal, and transdermal routes. It is an alternative for patients with dose-limiting side eff ects to morphine and hydromorphone (Cherny and Foley, 1996). It is com- monly used in a transdermal form for patients requiring continuous opioids (Collins et al., 1999; Finkel et al., 2005). It has a proven track record for use in adult breakthrough cancer pain when administered by the transmucosal route (oral or nasal; Benitez-Rosario et al., 2005; Coluzz i et al., 2001; Payne et al., 2001; Zeppetella, 2000). Opioid analgesics Opioids are now considered the fi rst line of treatment in cancer (see St rassels, Chapter 45, this volume). Morphine Morphine is possibly the most widely used opioid for moderate to severe cancer pai n in children. It can be administered by multiple routes including oral, sublingual, intrav enous, subcutaneous, epi- dural, and intrathecal routes. An oral dose of 1 to 2 mg/kg/day i s a reasonable starting point (Hunt et al., 1999). Oral morphine has a signifi cant fi rst- pass metabolism in the liver. A number of patients with cancer, however, require intravenou s administration to address Methadone Methadone is a synthetic opioid with a long and variable half-life (12 \200\22324 h). Th e oral to parenteral potency ratio is 2:1. Methadone SECTION 4 pain in specific populations and diseases 164 provides equivalent but more prolonged analgesia than morphine (Berde et al., 1991; Davis a nd Walsh, 2001; Ripamonti et al., 1998). Its variable half-life predisposes to a risk of de layed sedation occur- ring several days aft er initiating treatment. Methadone does carry w ith it a cardiac risk with prolongation of QT intervals so serial electrocardiographic stud ies are advised in patients on long-term therapy (Kornick et al., 2003; Krantz et al., 2002 , 2007). Methadone PCA has been reported as an eff ective delivery method in adults (Fitzgi bbon and Ready, 1997; Shaiova et al., 2008). by depression. Th e sedating tricyclic antidepressants are oft en added when the patient co mplains of insomnia, while the anxi- olytic selective serotonin reuptake inhibitors can be useful in anxious patients, and bupropion can be considered in sedated or fatigued patients .