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 . Corticosteroids Th ese agents may have a role in managing bone pain due to meta- static bon e disease, neuropathic pain from infi ltration or compres- sion of neural structures, heada che due to increased intracranial pressure, metastatic spinal cord compression, arthralgia, pain due to obstruction of a hollow viscous, or organ capsule distension. In cancer patients, opioids should be administered at sched- uled intervals to provide cons istent pain relief. Th e dosing interval should be determined by the needs of the patient. Dose escala- tion may be required aft er treatment is initiated and periodically thereaft e r as tolerance to therapeutic eff ects is seen aft er a period of treatment (Portenoy, 1994 b). Additional \200\230as needed \200\231 doses may be incorporated into the regimen for a dditional episodic break- through pain (Cleary, 1997). Oral and intravenous morphine and hy dromorphone, and intranasal and oral transmucosal fentanyl are some of the options for brea kthrough pain (Coluzzi et al., 2001; Zeppetella 2000). Dexamethasone is the most frequently used steroid on account of its high potency, duration of action, and minimal mineralocor- ticoid eff ect. Prednisone and methylprednisolone can a lso be used. Corticosteroids produce analgesia by a variety of mechanisms, including anti-i nfl ammatory eff ects, reduction of tumor oedema, and potentially by a reduction of spontan eous discharges in injured nerves. Th ey can improve appetite, nausea, malaise, and overall quality of life (Watanabe and Bruera, 1994). Adjuvant analgesics Th ese are a heterogeneous group of medications that have a pri- mary i ndication other than pain management, but are analgesic in some conditions (see also Rastog i and Campbell, Chapter 48, this volume). Th ey are commonly prescribed in conjunction with primary analgesics (Portenoy, 1993). Th eir use is indicated when there is evidence of neu ropathic pain, metastatic bone pain, anxiety, sleep disturbances, nausea and emesis, anorex ia, poor appetite, cachexia, poor analgesic response to traditional anal- gesics, increased intracranial pressure, spinal cord compression, perineural oedema, and nerve compression ( Lussier et al., 2004). Th ey include drugs that come under the category of antidepres- sant s, anticonvulsants, neuroleptics, psychostimulants, antihis- tamines, corticosteroids, and centrally acting skeletal muscle relaxants (George and Ahmedzai, 2000). Few adjuvants have been studied in the pediatric cancer population. To a large extent, drug selection, dosing, and monitoring approaches refl ect extrap- olation from the literature on non-malignant pa in. Selection of an adjuvant is dictated by comorbid conditions and a comprehensive assessm ent of the patient. In some cases, the type of pain suggests the value of one category of a djuvant over another; in others, the existence of another symptom concurrent with pain favo rs the use of a specifi c drug. Alpha 2 agonists Clonidine, dexmedetomidine, and tizanidine may be used as adjuvants but si de eff ects such as somnolence and hypotension can be limiting. Clonidine administered oral ly, transdermally, or intraspinally has been studied in non-malignant neuropathic pain. Int raspinal and epidural clonidine has been reported to be helpful in intractable cancer pain (Coombs et al., 1986; Eisenach et al., 1995). Limited experience with the use of dexmedetom idine as an adjuvant for refractory cancer pain has begun to appear in the literature (Robe rts et al., 2011; Ugur et al., 2006). Hypotension occurs less commonly with tizanidine, whi ch is an antispastic- ity/muscle relaxant agent. Th ere is evidence for its use in myofas- cial pain syndrome and headaches, but not cancer (Chou et al., 2004). Neuroleptic drugs Th e neuroleptic drugs have been used for years in adults with can- cer p ain (Breitbart, 1998; Patt et al., 1994). Th ere is little direct proof of their analgesic eff ect. Th ese drugs do have profound sedat- ing properties, which could explain the perce ption of co-analgesia (Richter and Burk, 1992). Methotrimeprazine appears to have anal- ges ic properties in the setting of adult cancer pain (Beaver et al., 1966). However, this old neuroleptic drug is not being manufac- tured. Olanzapine (Zyprexa ) was reported to decrea se pain inten- sity and opioid consumption, and improve cognitive function and anxiety, in cancer patients (Khojainova et al., 2002). Apart from these limited observations, evidence that commercially available neuroleptic drugs have analgesic properties is very meager. Th e mechanism of analgesia and role as an adjuvant in pediatric can- cer pain remains unclear . Given their potential for causing tardive dyskinesia and neuroleptic malignant syndrome, they are not rou- tinely used as adjuvant analgesics unless delirium or agitation is presen t. Th e potential analgesic properties might allow a decrease in opioid consumption, which might in turn be helpful in resolving opioid-induced delirium. Neuroleptics tend to increas e appetite, which may be desirable in some cancer patients. Tricyclic antidepressants Th ese are oft en considered fi rst-line treatment in the managem ent of neuropathic pain of various aetiologies. Th ey have been used for a variety of pain conditions including cancer pain (Magni, 1991; Magni et al., 1987a, 1987b). Although common ly used in practice, there is limited evidence from controlled trials evaluating their effi - cacy in cancer patients. Since the antidepressants have established benefi t in diverse types of neuropathic pain, t he strongest indication for their use as an adjuvant in the cancer population occurs in the patient with neuropathic pain who has not derived much benefi t from opioids. Early use of antidepressants is justifi ed when pain is accompanied CHAPTER 17 pediatric cancer pain 165 Adjuvants for neuropathic pain Anticonvulsants Most view the anticonvulsants as the mainsta ys for managing neuropathic pain (Backonja 2000; Tremont-Lukats et al., 2000). Carbamazepin e, phenytoin, and valproic acid have been the main- stay for years in treating neuropathic pain (Hardy et al., 2001; Harke et al., 2001; McCleane, 1999; Tanelian and Brose, 1991). Th eir use is limited by the potential hematological side eff ects, including neutropenia and thrombocytopenia. In recent years, gabapentin has been established in several types of non -malignant neuropathic pain, and it is now widely used to treat cancer-related neuropathic pain (Caraceni et al., 2004). Due to its proven analgesic eff ect in several types of neuro pathic pain, its good tolerability, and low inci- dence of drug \200\223drug interactions, gabapentin is now recommended as a fi rst-line agent for the treatment of neuropathic pain of diverse aetiologies (Dworkin et al., 2007). Th e most common adverse eff ects are somnol ence, dizziness, and unsteadiness. If titrated care- fully, it is usually well tolerated. pain is still unclear (Prommer, 2004). Th e d-isomer of the opioid methadone also blocks th e NMDA receptor and might have a role in neuropathic cancer pain (Davis and Inturrisi 1999) . Miscellaneous Oral dronabinol and Marinol have been shown to be eff ective in cancer pain but more studies are needed (Campbell, 2001; Huskey, 2006). Th ere is limited and confl ic ting evidence for analgesic eff ects from benzodiazepines, but a trial of clonazepam can be justifi ed in refractory neuropathic pain, especially in the presence of anxiety. Psychostimulants Th ere is evidence that psychostimulant drugs such as dextroam- phetamine, methylphenidate, and caff eine have analgesic eff ects (Rozans et al., 2002). It appears, however, that their major use is in alleviating somnolence and sedation from opioids and ot her anal- gesics. Th e psychostimulants dextroamphetamine and methylphe- nidate have been u sed in children with cancer pain (Yee and Berde, 1994). Dextroamphetamine potentiates opioi d analgesia and meth- ylphenidate can reduce opioid-induced somnolence, improve cog- nition , treat depression, and alleviate fatigue. Potential side eff ects include anorexia, insomn ia, and dysphoria. Modafi nil, a newer psy- chostimulant, has been used to reduce opioid-in duced somnolence in cancer patients (Webster et al., 2003). Although there are cur- rently no scientifi c data supporting its use to reduce opioid-induced sedation, atomoxetine, a se lective noradrenaline reuptake inhibitor, approved for the treatment of attention-defi cit/ hyperactivity disor- der, has been used successfully in clinical practice. Other newer anticonvulsants can be tried in patients who either have not responded satisfac torily to, have contraindications to, or have experienced adverse eff ects to gabapentin an d other fi rst-line adjuvants. Local anesthetics Intravenous infusion of lidocaine has been shown to be eff ective in non- malignant neuropathic pain (Attal et al., 2000). Randomized clinical trials of lidocaine in neuropathic cancer pain have not been promising, but anecdotal reports of benefi t may jus tify its use (Bruera et al., 1992; Buchanan and MacIvor, 2010; Ellemann et al., 1989). Reli ef is usually transient. If lidocaine is found to be eff ec- tive, but pain recurs, long-te rm systemic local anesthetic therapy can be initiated with an oral drug, mexiletine. For th e rare patient that responds only to intravenous infusions, long-term subcuta- neous infusi on may be an option (Brose and Cousins, 1991). Th e predictive value of a lidocaine infusio n for subsequent eff ectiveness of oral mexiletene has not been established. It is therefor e reason- able to start therapy with the oral drug in patients that have not responded to a ntidepressants or anticonvulsants. Th ere is a high rate of adverse eff ects and discontinu ation due to toxicity, especially gastrointestinal distress. Topicals Options include EMLA (eutectic mixture of prilocaine and lido- caine), topical l idocaine, liposomal lidocaine, and lidocaine 5% patches (Devers and Galer, 2000; Rowbotham et al., 1996). Topical capsaicin causes depletion of substance P and selective blockade of the TRPV1 receptor from the nerve terminals and decreased pain perception (Ellison et al., 1997). It has been helpful in postsurgi- cal neuropathic pain in cancer patients and in HIV -neuropathy (Simpson et al., 2008). Adjuvants for bone pain An NSAID or steroid may be useful in multifocal bone pain. Calciton in is useful in pain from bony metastases and neuropathic pain. It can be administered by t he subcutaneous and intranasal routes for home care. Th ere are also reports of epidural an d intrath- ecal use in metastatic cancer (Blanchard et al., 1990). Monitoring of calcium an d phosphorous is recommended. Bisphosphonates inhibit bone resorption. Th e analgesic effi cacy of pamidronate and zoledronic acid has been well established in patients with metas- t ases (Fulfaro et al., 1998; Rosen et al., 2001). Th ese agents are also reported to decreas e skeletal morbidity such as pathological frac- tures, need for radiation or surgery, spina l cord compression, and hypercalcaemia. Clodronate is an agent with good oral bio-availa- b ility (Ernst et al., 1992). N-methyl-D-aspartate (NMDA) receptor antagonists Th ese include the antitussive dextrometho rphan, the dissociative anesthetic ketamine, the antiviral amantadine, memantine, which is approved for Alzheimer \200\231s disease, and methadone. Ketamine has been shown to be eff ective in relieving cancer pain and reducing opioid requirements in children (Anghelescu an d Oakes, 2005; Bell et al., 2003; Finkel et al., 2007). It is typically administered by the intravenous or subcutaneous routes, but oral therapy has also been used (Kannan et al., 20 02, Lauretti et al., 1999). Dextromethorphan has been shown to improve analgesia and decrea se analgesic requirements in patients undergoing surgery for cancer, but long- term results are mixed (Mercadante et al., 1998; Weinbroum et al., 2003). Amantadine is a non-competiti ve NMDA antagonist with confl icting data on its effi cacy in cancer pain (Pud et al., 1998 ). Memantine also supposedly possesses analgesic properties (Grande et al., 2008). Th e rol e of these agents in cancer-related neuropathic Radionuclide therapy For painful osseous metastases the use of radionuclide therapy has bee n reported in the adult literature. Th ey may be eff ective as monotherapy or as an adjunct to conventional radiation therapy SECTION 4 pain in specific populations and diseases 166 (Anderson, 2002; Silberstein 1993, 1994; Silberstein and Williams, 1985; Silberstein et al. , 1992, 1998). Radionuclides are absorbed at areas of high bone turnover. Th ey include str ontium-89, phospho- rus-32, iodine-131, tin-117m, and samarium-153. Th ere are reports of t heir use in older children and adolescents. I 131 has been studied in children with painful metastatic bone disease from neuroblas- toma (Cheung et al., 2001; Voute et al., 1988; Wes tlin et al., 1995). Given the potential for myelosuppression associated with their use, the se drugs are considered when pain is refractory to other modalities. and 8 and Chapters 59 (Weydert) and 60 (Zeltzer) in this volume. Specifi c issues related t o malignancy are discussed in the rest of this section. Physical Radiotherapy, chemotherapy, and surgery can result in acute and long-term injury t o the heart, lungs, and skeletal muscles. Th ese impairments can aff ect the child \200\231 s physical fi tness, necessitating rehabilitation during and aft er treatment. Physical the rapy should be an integral part of the treatment process in order to minimize sys- temic ef f ects and improve pain control. Th ere is growing evidence for the positive eff ects of ph ysical training on organ system function, fatigue and physical well-being in children durin g and aft er treat- ment for cancer (Huang and Ness, 2011; Marchese et al., 2003). Adjuvants for musculoskeletal pain Cancer patients oft en have pain that originates in musc le or con- nective tissue. Muscle relaxants include drugs in a variety of classes including antihistamines (orphenadrine), tricyclics (cyclobenz- aprine), and others such as carisopr odol, metazolone, and meth- ocarbamol. Although the effi cacy of these drugs in muscle spas m is fairly well established, their effi cacy for musculoskeletal pain in the cancer popula tion is unclear. Th eir risk:benefi t ratio rela- tive to the NSAIDs or opioids in also unk nown. Sedation, which is a side eff ect with these drugs, can become an issue if it com- po unds the sedation caused by opioids and other centrally acting drugs in these patients. Cau tion is also advised when using these drugs in patients with a history of substance abuse. If muscle spasm is believed to be the primary cause for pain, drugs with established eff ec ts on skeletal muscle such as diazepam, other benzodiazepines, the 2 -agonist tizanidine , or baclofen should be used (Lussier et al., 2004). Botulinum toxin injections can be tria led for refractory musculoskeletal pain from spasms (Van Daele et al., 2002). Massage is one of the most commonly reported CAM therapies among children with cancer. It h as positive eff ects on pain, stress, anxiety, and the immune system (Hughes et al., 2008; Post-White et al., 2009). However, specifi c massage guidelines, including type and duratio n for the incorporation of massage for children with cancer have yet to be developed. Also, in a study of children with ALL, a daily massage over a one month period was found to have an impact on the immune system (Field et al., 2001). Acupuncture helps with pain, but it can also help with common symptoms experienced by child cancer patients such as headache, nausea, and vomiting. Acupuncture has not been widely di ssemi- nated into pain treatment regimens for the pediatric population due to the belief pr actitioners have that children will be afraid of the needles. On the contrary, it has been shown that for those children who have been referred to acupuncture for various chronic pai n syndromes, over two-thirds report that it was a positive experience and an eff ective mod ality for treatment of their pain (Friedman et al., 1997; Pitetti et al., 2001). Adjuvants for pain caused by bowel obstruction Management of malignant bowel obstruction is challenging, espe- cially when surgery is not an option. Th ere is the need to control pai n and other symptoms such as nausea, vomiting, and distension. Opioid escalation may not be an option due to dose-limiting gas- trointestinal side eff ects or sedation. Anecdotal rep orts suggest that anticholinergic drugs, the somatostatin analog octreotide, and corticoste roids may be useful in this setting. Anticholinergic drugs reduce gut motility and secretio ns. Octreotide has similar eff ects but possibly causes them more rapidly (Mercadante et al ., 2000; Yuan et al., 2000). Methylnaltrexone has recently been approved for the treatment of opioid-induced constipation and appears quite effi cacious in adults (Th omas et al., 20 08; Yuan and Foss, 2000). Steroids may also have a role in malignant bowel obstruction but the mode of action is unclear. Behavioral Th ere are many behavioral therapies that can be employed to assist with pain ma nagement. Cognitive-behavioral therapy techniques are most commonly used to decrease distress and enh ance a child \200\231s ability to cope with medical procedures (Chen et al., 1999; Liossi a nd Hatira, 2003; Zeltzer et al., 1991). Th ese techniques have also been popularized as adj uvant therapy of the treatment of nausea and vomiting ding chemotherapy treatments (Rheinga ns, 2007). During non-painful procedures such as radiotherapy, children can be assisted by using hypnotic techniques. References Altman, A. J. and Children \200\231s Oncology Group. (2004). Supportive care of children with cancer: current therapy and guidelines from the Children \200\231s Oncology G roup (3rd edn). Baltimore, MD: Johns Hopkins University Press . Complementary and alternative treatment options Th ere are multiple non-pharmacological the rapies that can be employed for pain management in the pediatric cancer patient. Th ese inc lude the biobehavioural plus complementary and alter- native medicine (CAM) therapies. CAM techniques are not oft en taught in medical schools, but can be powerful in the treatment o f pain. Th ese therapies are extensively discussed in Sections 7 American Pain Society. (2003). Principles of analgesic use in the treatment of acute pain a nd cancer pain (5th edn). Glenview, IL: American Pain Society . Anderson, P. M. (2002). High-dose samarium-153 ethylene diamine tetramethylene phosphonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol , 20 (1), 189 \200\223196 . Anghelescu, D. L. and Oakes, L. L. (2005). Ketamine use for reduction of opioid tolerance i n a 5-year-old girl with end-stage abdominal neuroblastoma. J Pain Symptom Manage , 30 (1), 1 \200\2233 . CHAPTER 17 pediatric cancer pain 167 Chan, B. L., Witt, R., Charrow, A. P., Magee, A., Howard, R., Pasquina, P. F., et al . (200 7). Mirror therapy for phantom limb pain. N Engl J Med , 357 (21), 2206 \200\2232207 . Anonymous. (1996). Practice guidelines for cancer pain management. A report by the American Society of Anesthesiologists Task Force on Pain Management, Cancer Pain Section. Anesthesi ology , 84(5), 1243 \200\2231257. Attal, N., Gaude, V., Brasseur, L., Dupuy, M., Guirimand, F., Parker, F., et al . (2000). Intravenous lidocaine in central pain: a double-blind, pla cebo- controlled, psychophysical study. Neurology , 54 (3), 564 \200\223574 . Chen, E., Zeltzer, L. K., Craske, M. G., and Katz, E. R. (1999). Alteration of memory in th e reduction of children \200\231s distress during repeated aversive medical procedures. J C onsult Clin Psychol , 67 (4), 481 \200\223490 . Cherny, N. I. and Foley, K. M. (1996). Nonopioid and opioid analgesic pharmacotherapy of ca ncer pain. Hematol Oncol Clin North Am , 10 (1), 79 \200\223102 . Babul, N., Darke, A. C., and Hain, R. (1995). Hydromorphone and metabolite pharmacokinetics in children. J Pain Symptom Manage , 10 (5), 335 \200\223337 . Backonja, M. M. (2000). Ant iconvulsants (antineuropathics) for neuropathic Cherny, N. J., Chang, V., Frager, G., Ingham, J. M., Tiseo, P. J., Popp, B., et al . (1995) . Opioid pharmacotherapy in the management of cancer pain: a survey of strategies used by p ain physicians for the selection of analgesic drugs and routes of administration. Cancer , 76 (7), 1283 \200\2231293 . pain syndromes. Clin J Pain , 16 (2 Suppl), S67 \200\22372 . Beaver, W. T., Wallenstein, S. L., Houde, R. W., and Rogers, A. (1966). A comparison of the analgesic eff ects of methotrimeprazine and morphine in patients with cancer. Clinical Pha rmacology & Th erapeutic , 7 (4), 436 \200\223446 . Cheung, N. K., Kushner, B. H., LaQuaglia, M., Kramer, K., Gollamudi, S., Heller, G., et al . (2001). N7: a novel multi-modality therapy of high risk neuroblastoma (NB) in children di agnosed over 1 year of age. Med Pediatr Oncol , 36 (1), 227 \200\223230 . Bell, R., Eccleston, C., and Kalso, E. (2003). Ketamine as an adjuvant to opioids for cance r pain. Cochrane Database Syst Rev , 1, CD003351 . Benedetti, C., Brock, C., Cleeland, C., Coyle, N., Dube, J. E., Ferrell, B., et al . (2000). NCCN practice guidelines for cancer pa in. Oncology , 14 (11A), 135 \200\223150 . Chou, R., Peterson, K., and Helfand, M. (2004). Comparative effi cacy and safety of skeleta l muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pa in Symptom Manage , 28 (2), 140 \200\223175 . Benitez-Rosario, M. A., Martin, A. S., and Feria, M. (2005). Oral transmucosal fentanyl cit rate in the management of dyspnea crises in cancer patients. J Pain Symptom Manage , 30 (5) , 395 \200\223397 . Cleary, J. F. (1997). Pharmacokinetic and pharmacodynamic issues in the treatment of breakt hrough pain. Semin Oncol , 24 (5 Suppl 16), S16 \200\22313 \200\2239 . Berde, C., Ablin, A., Glazer, J., Miser, A., Shapiro, B., Weisman, S., et al . (1990). Repo rt of the Subcommittee on Disease-Related Pain in Childhood Cancer. Pediatrics , 86 (5), 81 8 \200\223825 . Collins, J. J. (1998). Pharmacologic management of pediatric cancer pain. In R. K. Portenoy and E. Bruera (eds) Topics in palliative care , pp. 7 \200\22328. New York: Oxford Univers ity Press. Berde, C. B., Beyer, J. E., Bournaki, M. C., Levin, C. R., and Sethna, N. F. (1991). Compar ison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old chi ldren. J Pediatr , 119 (1 (Pt 1)), 136 \200\223141 . Collins, J. J. (2001). Cancer pain management in children. Eur J Pain , 5 (SA), 37 \200\22341 . Collins, J. J., and Berde, C. B. (1997). Mangement of pain in children . In P. A. Pizzo and D. G. Poplack (eds) Principles and practice of pediatric oncology (3rd edn), pp. 1183 \200 \2231199. Philadelphia , PA: Lippincott-Raven. Berde, C. B., Sethna, N. F., Fisher, D. E., Kahn, C. H., Chandler, P., and Grier, H. E. (19 90). Celiac plexus blockade for a 3-year-old boy with hepatoblastoma and refractory pain. P ediatrics , 86 (5), 779 \200\223781 . Collins, J. J., Byrnes, M. E., Dunkel, I. J., Lapin, J., Nadel, T., Th aler, H. T., et al . (2000). Th e measurement of symptoms in children with cancer. J Pain Symptom Manage , 19 ( 5), 363 \200\223377 . Blanchard, J., Menk, E., Ramamurthy, S., and Hoff man, J. (1990). Subarachnoid and epidural calcitonin in patients with pain due to metastatic cancer. J Pain Symptom Manage , 5 (1), 42 \200\22345 . Collins, J. J. and Weisman, S. J. (2003). Management of pain in childhood cancer. In N. L. Schechter, C. B. Berde, and M. Yaster (eds) Pain in infants, children and adolescents (2nd edn), pp. 517 \200\223538. Philadelphia, PA: Lippincott Williams & Wilkins . Booth, B. W., and Weiss, R. B. (1981). Venous thrombosis during adjuvant chemotherapy. N Engl J Med , 305 (3), 170 . Brater, D. C. (1999). Eff ects of nonsteroidal anti-infl ammatory drugs on renal function: focus on cyclooxygenase-2 \200\223selective inhibition. Am J Med , 107 (6), 65 \200\22370 . Coombs, D. W., Saunders, R. L., Fratkin, J. D., Jensen, L. E., and Murphy, C. A. (1986). Co ntinuous intrathecal hydromorphone and clonidine for intractable cancer pain. J Neurosurg , 64 (6), 890 \200\223894 . Breitbart, W. (1998). Psychotropic adjuvant analgesics for pain in cancer and AIDS. Psychooncology , 7 (4), 333 \200\223345 . D \200\231Angio, G. J. (1983). Early and delayed complications of therapy. Cancer , Broomhead, A., Kerr, R., Tester, W., O \200\231Meara, P., Maccarrone, C., Bowles, R., et al . (1997). Comparison of a once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain. J Pain Symptom Manage , 14 (2), 63 \200\22373 . 51 (12 Suppl), 2515 \200\2232518 . Davis, A. M. and Inturrisi, C. E. (1999). D-methadone blocks morphine tolerance and N-methy l-D-aspartate-induced hyperalgesia. J Pharmacol Exp Th er , 289 (2), 1048 \200\2231053 . Brose, W. G. and Cousins, M. J. (1991). Subcutaneous lidocaine for treatment Davis, M. P. and Walsh, D. (2001). Methadone for relief of cancer pain: a review of pharmac okinetics, pharmacodynamics, drug interactions and protocols of administration. Support Car e Cancer , 9 (2), 73 \200\22383 . of neuropathic cancer pain. Pain , 45 (2), 145 \200\223148 . Bruera, E., Ripamonti, C., Brenneis, C., Macmillan, K., and Hanson, J. (1992). A randomized double-blind crossover trial of intravenous lidocaine in the treatment of neuropathic canc er pain. J Pain Symptom Manage , 7 (3), 138 \200\223140 . Delarue, A., Bergeron, C., Mechinaud-Lacroix, F., Coze, C., Raphael, M., Patte, C., et al. (2008). Pediatric non-Hodgkin \200\231s lymphoma: primary surgical management of patients p resenting with abdominal symptoms. Recommendations of the Lymphoma Committee of the French Society to Combat Pediatric Cancers (SFCE). J Chir , 145 (5), 454 \200\223458 . Buchanan, D. D., and J MacIvor, F. (2010). A role for intravenous lidocaine in severe cance r-related neuropathic pain at the end-of-life. Support Care Cancer, 18 (7), 899 \200\223901 . Devers, A. and Galer, B. S. (2000). Topical lidocaine patch relieves a variety of neuropath ic pain conditions: an open-label study. Clin J Pain , 16 (3), 205 \200\223208 . Burt, N., Dorman, B. H., Reeves, S. T., Rust, P. F., Pinosky, M. L., Abboud, M. R., et al . (1998). Postdural puncture headache in pediatric oncology patients. Can J Anaesth , 45 (8) , 741 \200\223745 . Dunbar, P. J., Buckley, P., Gavrin, J. R., Sanders, J. E., and Chapman, C. R. (1995). Use o f patient-controlled analgesia for pain control for children receiving bone marrow transpla nt. J Pain Symptom Manage , 10, 604 \200\223611. Campbell, F. A. (2001). Are cannabinoids an eff ective and safe treatment option in the man agement of pain? A qualitative systematic review. Br Med J , 323 (7303), 1 \200\2236 . Caraceni, A., Zecca, E., Bonezzi, C., Arcuri, E., Yaya Tur, R., Maltoni, M., et al . (2004) . Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol , 22 (14), 2909 \200\2232917 . Dunbar, P. J., Chapman, C. R., Buckley, F. P., and Gavrin, J. R. (1996). Clinical analgesic equivalence for morphine and hydromorphone with prolonged PCA. Pain , 68 (2 \200\2233), 26 5 \200\223270 . SECTION 4 pain in specific populations and diseases 168 Grond, S., Radbruch, L., Meuser, T., Loick, G., Sabatowski, R., and Lehmann, K.A. (1999). H igh-dose tramadol in comparison to low-dose morphine for cancer pain relief. J Pain Symptom Manage , 18 (3), 174 \200\223179 . Dworkin, R. H., O \200\231Connor, A. B., Backonja, M., Farrar, J. T., Finnerup, N. B., Jens en, T. S., et al . (2007). Pharmacologic management of neuropathic pain: evidence-based rec ommendations. Pain , 132 (3), 237 \200\223251 . Gupta, H., Davidoff , A. M., Pui, C. H., Shochat, S. J., and Sandlund, J. T. (2007). Clinic al implications and surgical management of intussusception in pediatric patients with Burki tt lymphoma. J Pediatric Surg , 42 (6), 998 \200\223 1001 ; discussion 1001. Eisenach, J. C., DuPen, S., Dubois, M., Miguel, R., and Allin, D. (1995). Epidural clonidin e analgesia for intractable cancer pain. Th e Epidural Clonidine Study Group. Pain , 61 (3) , 391 \200\223399 . Ellemann, K., Sjogren, P., Banning, A. M., Jensen, T. S., Smith, T., and Geertsen, P. (1989 ). Trial of intravenous lidocaine on painful neuropathy in cancer patients. Clin J Pain , 5 (4), 291 \200\223294 . Guti rrez-Guti rrez, G., Sereno, M., Miralles, A., Casado-S enz, E., and Guti r rez-Rivas, E. (2010). Chemotherapy-induced peripheral neuropathy: clinical features, diagno sis, prevention and treatment strategies. Clin Transl Oncol , 12 (2), 81 \200\22391 . Ellison, N., Loprinzi, C. L., Kugler, J., Hatfi eld, A. K., Miser, A., Sloan, J. A., et al . (1997). Phase III placebo-controlled trial of capsaicin cream in the management of surgic al neuropathic pain in cancer patients. J Clin Oncol , 15 (8), 2974 \200\2232980 . Halpin, T. J., Holtzhauer, F. J., Campbell, R. J., Hall, L. J., Correa-Villasenor, A., Lane se, R., et al . (1982). Reye \200\231s syndrome and medication use. JAMA , 248 (6), 687 \200\223691 . El-Tahtawy, A., Kokki, H., and Reidenberg, B. E. (2006). Population pharmacokinetics of oxy codone in children 6 months to 7 years old. J Clin Pharmacol , 46 (4), 433 \200\223442 . Hanif, I., Mahmoud, H., and Pui, C. H. (2006). Avascular femoral head necrosis in pediatric cancer patients. Med Pediatr Oncol , 21 (9), 655 \200\223660 . Hardy, J. R., Rees, E. A., Gwilliam, B., Ling, J., Broadley, K., and A \200\231Hern, R. (20 01). A phase II study to establish the effi cacy and toxicity of sodium valproate in patien ts with cancer-related neuropathic pain. J Pain Symptom Manage , 21 (3), 204 \200\223209 . England, R. J., Pillay, K., Davidson, A., Numanoglu, A., and Millar, A. J. (2012). Intussus ception as a presenting feature of Burkitt lymphoma: implications for management and outcom e. Pediatr Surg Int , 28 (3), 267 \200\223270 . Ernst, D. S., MacDonald, R. N., Paterson, A. H. G., Jensen, J., Brasher, P., and Bruera, E. (1992). A double-blind, crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage , 7 (1), 4 \200\22311 . Field, T., Cullen, C., Diego, M., Hernandez- Reif, M., Sprinz, P., Beebe, K., et al . (2001). Leukemia immune changes following massage therapy. J Bodywork Movement Th er , 5 (4), 271 \200\223274 . Harke, H., Gretenkort, P., Ladleif, H. U., Rahman, S., and Harke, O. (2001). Th e response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and susta ined-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Analg , 92 (2), 488 \200\223495 . Hiruki, T., Fernandes, B., Ramsay, J., and Rother, I. (1992). Acute typhlitis in an immunoc ompromised host. Report of an unusual case and review of the literature. Dig Dis Sci , 37 ( 8), 1292 \200\2231296 . Finkel, J. C., Finley, A., Greco, C., Weisman, S. J., and Zeltzer, L. (2005). Transdermal f entanyl in the management of children with chronic severe pain: results from an internation al study. Cancer , 104 (12), 2847 \200\2232857 . Finkel, J. C., Pestieau, S. R., and Quezad o, Z. M. (2007). Ketamine as an adjuvant for treatment of cancer pain in children and adole scents. J Pain , 8 (6), 515 \200\223521 . Howlader, N., Noone, A. M., Krapcho, M., Neyman, N., Aminou, R., Altekruse, S. F., et al . (2012). SEER cancer statistics review, 1975 \200\2232009 (vintage 2009 populations), based on November 2011 SEER data submission . Bethesda, MD: National Cancer Institute .