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Cancer pain and palliative care in children
Techniques in Regional Anesthesia and Pain Management (2005) 9, 145-151
Cancer pain and palliative care in children Alyssa Lebel, MD From the Children’s Hospital Boston. Pain Management Service, Boston, Massachusetts. KEYWORDS: Pain; Cancer; Children; Palliative care; Pain assessment; Pharmacotherapy
Pediatric cancer-related mortality has fallen in the past 25 years, but terminal symptoms and pain persist. This brief report on cancer pain in children reviews the barriers to adequate care, the presentation of pediatric pain problems, developmental features of pain assessment, and current pain management strategies for this vulnerable population. © 2005 Elsevier Inc. All rights reserved.
Cancer is the second leading cause of death in children, following accidents. Recent evidence1 shows that, although the cancer-related mortality rate has fallen from 5.4/100,000 to 2.8/100,000 between 1975 and 1998, approximately 25% of children with cancer die of their disease. Few studies address the experience of symptoms in children with cancer, but some current reports indicate that terminal symptoms and pain are not adequately relieved. In one study,2 structural interviews conducted with 66 children and their families following cancer therapy showed that treatment-related pain was a constant and dominating problem (49%), greater than procedural pain (39%) and pain related to the primary disease (12%). In another review using patient charts of children who died of cancer between 1990 and 1997, parents were interviewed about their child’s end-of-life experience.3 Parents reported that 89% of the children suffered “a lot” or “a great deal ” from at least one symptom in their last month of life. Pain, followed by fatigue and dyspnea, were most common. Treatment of pain was successful in 27% of patients. Suffering from pain was more likely in patients whose parents reported that the physician was not actively involved in end of life care (odds ratio 2.6). Achieving effective pain in the pediatric cancer population, despite the analgesic advances of the past 30 years, remains an emergent need. Inadequate care is perpetuated by: ●
Persistent misconceptions regarding pain control in children;
Address reprint requests and correspondence: Dr. Alyssa Lebel, Children’s Hospital Boston, Pain Management Service, 333 Longwood Avenue, 5th Floor, Boston, MA 02115. E-mail address: [email protected]. 1084-208X/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2005.06.005
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Challenges of pain assessment without self report and sensitive to the cognitive and developmental stage of the patient; Paucity of pharmaceutical testing of analgesics in the pediatric population; Minimal access to pediatric specialists in palliative care and symptom management; and Limited training of pediatric oncologists in palliative care.4
Two resistant misconceptions, slowly discredited by increasing data, are the immaturity of the neonatal pain transmission system and the fear of aggressive opioid administration due to potential addiction. Current research disputes the concept of neonatal hypoalgesia. Pain transmission pathways develop during fetal life. Nerve tracts in the spinal cord and brainstem begin to myelinate around the gestational age of 22 weeks and are completely myelinated by 28 to 30 months after birth. More specifically, myelination is complete up to the thalamus by 30 weeks’ gestation, and the thalamocortical pain connections to the cortex are myelinated by 37 weeks’ gestation. Thus, pathways that conduct noxious information from nociceptor to cortex are present in the newborn infant. Cortical descending inhibition develops postterm. The majority of neurotransmitters and neuromodulators are present in the fetus. Calcitonin gene-related peptide (CGRP) and substance P are present at 8 to 10 weeks’ gestation, while others such as enkephalin and vasoactive intestinal peptide (VIP) appear 2 to 4 weeks later. Catecholamines are present in late gestation, and, in the human fetus, serotonin has been found at 6 weeks postnatally. Neurotransmitters that enhance the perception of pain are produced earlier in the fetus than are endogenous opioids.
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It appears, therefore, that pain processing in the mature fetus and newborn is adequately developed so that the infant may exhibit behavioral and physiologic responses to noxious stimuli and may even have enhanced nociception. (However, a concious experience of “suffering” in the neonate, considered to require mature forebrain development, remains controversial). The misconception that neonates and infants do not feel pain, combined with a fear of using opioids in very young children, resulted in gross undertreatment of pain in this population. Recent research has emphasized the importance of providing adequate pain control in newborns and young infants. It is now clear that the undertreatment of pain can have short-term significant physiologic effects. The long-term consequences of untreated pain in the developing organism are not yet defined, but some studies suggest that early pain responses influence later pain behaviors.5,6
Opioid use in children Addiction is extremely rare when opioid medications are prescribed for pain management. However, regulations and social stigma may still discourage opioid use. Studies of children treated for pain associated with sickle cell disease, bone marrow transplant, or surgical procedures report essentially no risk of addiction with the prescribed use of opioids.7,8 Morphine remains the primary pediatric analgesic for the management of moderate to severe cancer pain and for palliative care, as well as an essential agent for treating sickle cell vaso-occlusive crises, acute postoperative pain, and burn pain.
Assessment of pain9-16 The assessment of pain in children should be systematic, and requires re-evaluation throughout the course of the illness. Because infants cannot communicate verbally, behavioral and physiologic responses can be used to assess pain in the very young, including facial expression, tachycardia, and stress-related hormones. However, these signs may not be specific to pain. The child’s cognitive development and ability to understand pain influence the choice of suitable measurement tools. In children, pain measurement must include the following10: ● ●
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The child’s report of pain is the best indicator of pain. Pain that appears unexplained by known causes may indicate disease progression or other factors, and should be investigated. The denial of pain when there is evidence of tissue damage should be investigated. Neonates and infants feel pain. Developmental factors should be considered before selecting the appropriate measures of pain intensity (this is more difficult under 2.5 years of age).
Self report Children as young as 18 months can indicate their pain and give a location, but it is not possible to obtain a selfreport of intensity of pain before about 3 years of age. Children who are 3 years of age can give a gross indication, such as “no pain,” “a little pain,” and “a lot of pain.” Similarly, many children at this age can use concrete measures such as “poker chips” of “pieces of hurt” to convey the intensity of their pain. The use of more abstract self-report instruments, such as the “smiling faces scale” are generally not valid for use in children under 5 years of age. Simple self-report measures are recommended for children older than 6 years of age. Among the most useful scales for measuring intensity of pain are visual analog scales, either vertical or horizontal, and simple numeric scales. For example, “If 0 means no hurt or pain and 10 means the biggest pain you ever have, what is your pain now?” The use of adjectival categorical scales such as “mild,” “moderate,” severe,“ and excruciating” are not recommended for children younger than 13 years of age. Behavioral observations should not be used in lieu of self-report. However, behavioral observations are invaluable when self-report is not available, for example, in children younger than 2 years of age or in children without verbal ability due to disability or disease. In the presence of noxious stimuli, behavioral pain indicators may arouse suspicion and prompt investigations even in the absence of a verbal report of pain. Neonates and infants feel pain, and neonates are no less sensitive to noxious stimulation than are older children and adults. Therefore, assessment of pain, although more complex than in older children, should be considered essential in the care of neonates and infants. In infants, reliance on facial expression, crying, posture, and physiologic variables such as heart rate, respiratory rate, blood pressure, and palmar sweating are important as potential indicators of pain, and scoring systems, such as the CRIES scale described by Krechel and Bildner (1995) are useful. Specific scales are summarized in Table 1.16 There are currently no physiologic measures that reliably indicate pain, and pain treatment should never be withheld because of a lack of physiologic evidence alone.
Pharmacotherapy17-19 Advances in treatment protocols for childhood cancer generally create treatment-related rather than tumor-related pain problems. With treatment failure and relapse, tumorrelated pain predominates. Young adult survivors of cancer may also experience nonmalignant chronic pain syndromes, such as neuropathy, phantom limb pain, avascular necrosis, mechanical spine and limb pain, and, infrequently, postherpetic neuralgia, especially in previously irradiated areas. Chronic disease-related pain is most frequently neuropathic—visceral, peripheral, or both. Somatic pain is often responsive to initial tumor therapy and routine analgesics. Neuropathic pain may be due to tumor compression or infiltration of peripheral nerves or the central nervous system. Characteristically, this pain is frequently sharp, shoot-
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TABLE 1
Pediatric pain assessment scales
Behavioral observational scales: The primary method of pain assessment for infants, children less than 3 yrs old, and developmentally disabled patients. Validated tools include: CRIES: Assesses Crying, Oxygen requirement, Increased vital signs, facial Expression, Sleep. An observer provides a score of 0–2 for each parameter based on changes from baseline. For example, a grimace, the facial expression most often associated with pain, gains a score of 1 but if associated with a grunt will be scored a 2. The scale is useful for neonatal postoperative pain. Facial expression, cry, breathing pattern, arms, legs, and state of arousal are observed for 1 minute. NIPS: Neonatal/Infants Pain Scale has been used mostly in infants less than 1 yr of age. Minute intervals before, during, and after a procedure and a numeric score are assigned to each. A score ⬎3 indicates pain. www.anes.ucla.edu/pain FLACC: Face, legs, activity, crying, consolability scale validated from 2 mo to 7 years. 0–10 scoring. CHEOPS: Children’s Hospital of Eastern Ontario. Intended for children 1–7 yrs old. Assesses cry, facial expression, verbalization, torso movement, if child touches affected site, and position of legs. A score ⱖ 4 signifies pain. www.anes.ucla.edu/pain Self report: Children 3 years of age and older can rank their pain using one of several validated scales including: Wong-Baker Faces scale: 6 cartoon faces showing increasing degrees of distress. Face 0 signifies “no hurt” and face 5 the “worst hurt you can imagine”; the child chooses the face that best describes own pain at the time of assessment. www.childcancerpain.org; www.harcourthealthsciences.com/WOW/faces.html Bieri-Modified: 6 cartoon faces starting from a neutral state and progressing to tears/crying. Scored 0–10 by the child. Used for children ⬎3 years. Visual analogue scale: uses a 10 cm line with one end marked as no pain and the opposite end marked as the worst pain. The child is asked to make a mark on that line that is then measured in cm from the no pain end. www.helpforpain.com
ing, electrical, stabbing, or burning (dysesthesia), with pain induced by usually nonpainful stimuli (allodynia) and often paradoxically felt in a region of sensory deficit. Chronic treatment-related pain is also often neuropathic in quality and may be secondary to chemotherapy-induced neuropathy, ischemic neuropathy and necrosis postirradiation, and postoperative phantom limb symptoms. For treatment of pediatric neuropathic pain, pharmacologic choices are generally based on adult studies and on the use of the same agents for nonpainful problems, with the caveats of slow titration and anticipation of side effects superimposed. The classes of medications include: antidepressants; anticonvulsants; local anesthetics and their analogs; and adequate doses of opioids. Current understanding of the pathophysiology of neuropathic pain guides therapy and supports synergy when combining medication for intractable cases. For example, a patient with postvincristine neuropathy likely has spontaneous neuronal discharge in peripheral sensitized small nerve fibers as well as central
147 spinal cord disinhibition of pain transmission due to loss of dorsal horn inhibitory neurons. An anticonvulsant, gabapentin, may block nerve discharge by binding to inappropriately active sodium and neuronal calcium channels, and an antidepressant, amitriptyline, may block the reuptake of inhibitory pain neurotransmitters in the dorsal horn, enhancing spinal pain inhibition. More specifically, tricyclic antidepressants potentiate the analgesic actions of serotonin and norepinephrine at nerve terminals in the central nervous system. Their side effects are due to additional cholinergic, histaminergic, and adrenergic actions, resulting in possible dry mouth, constipation, urinary retention, sedation, weight gain, orthostatic hypotension, tachycardia, and heart block. Although the cardiac risks for children are low, it is recommended to obtain an EKG before and during dose escalation and to possibly exclude patients with known rhythm disorders and cardiomyopathy (ie, adriamycin). Amitriptyline is the best known agent but also has the most significant sedative, anticholinergic, and orthostatic profile. Therefore, nortriptyline, with minimal sedation and orthostasis, is often the first choice.
Tricyclic dosing Amitriptyline and Nortriptyline: 0.2-.4mg/kg po qhs; titrate upward by .25mg/kg q 5 to 7 days; may divide bid; maintenance 0.2-.3mg/kg. Other antidepressants, such as fluoxetine, sertraline, citalopram, escitalopram, trazadone, venlafaxine, and trazadone, are best used for associated symptoms such as anxiety, sleep disturbance, and mood disorder. The data regarding their analgesic efficacy remain anecdotal. Anticonvulsants are now first-line agents for treatment of neuropathic pain and may depress abnormal neuronal discharges in damaged nerves as well as raise the inappropriately lowered threshold in chronic pain states for neuronal activation. They are variably active at voltage-gated ion channels, and at glutamate, N-methyl-D-aspartate, gammaaminobutyric acid, and glycine receptors. Much pediatric experience is reported for these medications regarding use in seizure management. Their use as analgesics is extrapolated, but, as for adults, analgesic trials involving anticonvulsants are more frequent and promising. The first generation agents, such as phenytoin, carbamazepine, valproate, and clonazepam, are best studied but are also associated with complicating hematologic, hepatic, dermatologic, immunologic, and maxillofacial effects. The second generation medications, such as gabapentin, lamotrigine, topiramate, zonisamide, levetiracetam, and pregabalin, may not require laboratory monitoring, have less sedation or cognitive effects, and, overall, present less confounding adverse effects. However, as our pediatric experience increases, these agents are not free of side effects.
Anticonvulsant dosing (oral) Carbamazepine: 5 to 10mg/kg/24hrs divided bid; incremental increase of 10mg/kg/24hrs per week; maximum dose ⬎ 12yrs ⫽ 1.6 to 2.4 g/24hrs. Oxcarbazepine: ⬎ 12yrs ⫽ 300 to 600mg/24hrs; maximum dose 900 to 2400mg/24hrs.
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Phenytoin: 2 to 3mg/kg divided bid-three times per day incremental increase of .5mg/kg q 3 to 4 wks; maximum dose: 5mg/kg/d (1000 mg/d). Valproic Acid: 5 to 15mg/kg divided qd-three times per day incremental increase of 5 to 10mg/kg every 5 to 7 days; maximum dose 60mg/kg/d. Gabapentin: 5 to 10mg/kg qhs, day 2 bid, day 3 three times per day maximum dose 2400 to 3600mg/24hrs. Lamotrigine: 0.15-.6mg/kg/24hrs qd- bid; slow incremental increase q2 weeks. Topiramate: 1 to 3mg/kg/24hrs; maximum dose ⫽ 600mg/24hrs. Zonisamide: 2 to 4mg/kg/24hrs; maximum dosage ⫽ 400mg/24hrs. NMDA–receptor antagonists show promise as regulators of the central nervous changes present during chronic neuropathic pain states but are yet to be used regularly in the clinic. Pediatric use may be particularly limited due to the developmental regulation of these receptor subtypes. The pathophysiologic mechanism of analgesia is considered to be a decrease in the central sensitization or “ wind-up ” of spinal dorsal horn and other CNS neurons. The dorsal horn of the spinal cord is a crutial and dynamic area of statedependent neuronal plasticity which may both upgrade and downgrade pain signal transmission. With repetitive stimulation of afferent C-fibers, there may be a progressive discharge in second-order dorsal horn neurons involving synapses that use the neurotransmitter glutamate and NMDA (N-methyl-D-aspartate) receptors. NMDA receptor activation results in neuronal calcium ion influx, with subsequent activation of cellular protein kinase C, nitric oxide synthase, cyclooxygenase, and cyclic adenosine monophosphate response element binding protein (CREB). Molecular changes in neuronal subtype may also be demonstrated. This chemical barrage ultimately causes nociceptive neurons to increase their firing rate, amplifies peripheral input, and activates more rostral pain transmission centers producing increased pain perception.
Dosing of NMDA antagonists Dextromethorphan: ⬎12yrs 30mg q6 to 8hrs; maximum dose 120mg/24hrs. Memantine: adult recommendations ⫽ 5mg/24hrs; maximum dose 20mg/24hrs. Ketamine: parenteral use for pain in pediatrics not yet known; data in adults promising.20
Dosing of opioids For chronic somatic pain, opioids are a mainstay of cancer pain treatment and are preferably administered at regular intervals with generous rescue dosing (5-10% of total daily dose q 2-4hrs or 50-200% of hourly basal IV rate; see Table 2). Pharmacokinetic studies of opioids in children are available for morphine, fentanyl, sufentanil, methadone, and hydromorphone, and in process for such newer oral agents as oxycodone and oxycontin. The choice of a specific opioid is based on potency, desired route of administration, and adverse effects. Mor-
TABLE 2
Initial opioid dosing (⬍ 50 kg)
Drug
Oral
Morphine
0.3mg/kg q 3–4 hrs
Hydromorphone
0.02–0.08mg/kg q 3–4 hrs
Fentanyl
NA
Methadone
0.2mg/kg q 4–8 hrs
Codeine
0.5–1mg/kg q 3–4 hrs 0.1–0.2mg/kg q 3–4 hrs
Oxycodone
Parenteral 0.05–0.1 mg/kg q 4 hrs, 0.02mg/kg/hr infusion 0.02mg/kg q 2–3 hrs, 0.006mg/kg/hr infusion 0.5–1 g/kg q 1–2 hrs 0.1mg/kg q 4– 8 hrs NA NA
phine is the first choice for parenteral boluses and infusions. Children with reactive airway disease may, rarely, be more sensitive to the histaminergic effects of morphine, but, generally, tolerate this agent well. Rash and pruritis are occasionally present in atopic individuals as well as idiosyncratically. All opioids affect visceral sphincters equally. Meperidine is minimally used secondary to its excitatory effects on the cardiac and central nervous system with repetitive dosing. Hydromorphone is anecdotally preferred in patients with incipient renal failure; putatively due to less accumulation of toxic metabolites (3,6-diglucuronide) compared with morphine.21 Fentanyl is an alternative parenteral opioid, with a short half-life that is useful for painful procedures. It is often a choice in neonates with congenital heart disease due to little cardiac effect except bradycardia. High doses, and, rarely, low doses, may produce glottic and chest wall rigidity, treated with naloxone and/or neuromuscular blockade. For older patients with chronic pain, fentanyl may be administered rapidly and transmucosally, in a candy matrix, or over 72 hours transdermally, via patch placement and subdermal release following deposition. Methadone provides a form of sustained release administration, with attention to the accumulation of effect, from 3 to 4 hours to 24 hours, with repetitive dosing. It is often used to wean opioids after sustained parenteral infusion. Of note, the D-isomer of methadone acts as an NMDA antagonist, which may aid in the treatment of neuropathic pain as well as reduce opioid tolerance. Therefore, the conversion ratio for methadone to other opioids depends on the preexisting opioid-tolerance of the patient. For a single intravenous dose, methadone is equipotent to morphine. With short-term repetitive dosing in an opioid naïve patient, methadone is more slowly eliminated than morphine, and the total daily dose of methadone may be 1/3 to 2/4 the total daily dose of morphine. For a very tolerant patient, such as one using 100 mg/hr of morphine, the daily methadone dose may be 1/10 the daily morphine dose. Sufentanil is used primarily as a general anesthetic. Intermittent intramuscular dosing of analgesics is contraindicated in pediatrics, due to the common needle aversion and often-incomprehensible pain with injection in this
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population. As a rough dosing guide, premature infants and neonates require 1/10 the usual adult dosage: 1-month olds, 1/8; 1-year olds, 1/4; and 7-year olds, 1/2. Oral administration for mild to moderate pain, often following recovery from acute surgery or trauma, includes oral opioid preparations (codeine, oxycodone, morphine elixir, and rapid-release tablets) and opioid / NSAID combination (acetaminophen with codeine, oxycodone with acetaminophen). Codeine is a pro-drug, requiring hepatic conversion to morphine for analgesic effect. Five to 15% of patients lack this hepatic enzymatic pathway and are codeine-resistant. Oxycodone is also a relatively weak opioid, unless prescribed in an oral dose ⬎0.1 mg/kg. At 0.2 mg/kg, oral oxycodone is approximately equivalent to 0.1 mg of IV morphine. Tramadol is an unusual opioid, recently studied regarding pediatric pharmacokinetics, with morphine-like mu1-receptor agonism, incompletely antagonized by naloxone, and some additional reuptake-blockade of norepinephrine and serotonin. Rectal suppositories of morphine and hydromorphone are available for patients NPO who are not neutropenic or immunosuppressed. Neuroaxial opioids well-tolerated and commonly used in pediatrics are fentanyl and hydromophone. Premature and term infants show reductions in clearance of most opioids. Pharmacologic guidelines for opioid use in the newborn and infant are as follows: ●
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Neonates have immature cytochrome P450 hepatic enzyme system and conjugate opioids and local anesthetics slowly. Watch for delayed toxicity with prolonged infusions. Renal function— glomerular filtration and renal tubular secretion—is decreased in the neonatal period (especially in premature infants) when compared with adults. The half-lives of opioids and their metabolites may be increased. Delay respiratory depression and sedation by increasing dosing intervals and decreasing doses. Neonatal body water is increased compared with adults, and fat is minimal. Remember that analgesics with high water solubility have a large volume of distribution. Neonates have decreased plasma protein binding, albumin, and ␣-1 acid glycoprotein. Analgesics have increased circulating free-drug and greater first-pass toxicity. Ventilatory reflexes are immature in the neonate. Opioids may induce hypoventilation.
Patient-controlled analgesia (PCA) is effective for children and adolescents aged 5 years and older. However, some children and adolescents may not have the cognitive, emotional, or physical resources to use PCA and require nurse-controlled anlgesia (NCA). In palliative care, the standard home infusion pumps all include a PCA option. Often these cancer pateints receive approximately 60% of prior opioid dosing as a basal infusion rate and 40% through PCA boluses, unless the patient has infrequent, episodic pain (dressing changes). Very high doses of opioids, rarely accompanied by respiratory depression, may be required for end-of-life care.22
149 TABLE 3
Dosing of NSAIDs
Drug Acetaminophen (po, pr) Aspirin Ibuprofen Ketorolac (iv)
Dose 10–15 mg/kg q 4 hrs 10–15 mg/kg q 4 hrs 4–10 mg/kg q 6–8 hrs 0.5 mg/kg q6–8 hrs, not ⬎ 5 d
Dosing of NSAIDS Acetaminophen and non-steroidal antiinflammatory drugs (NSAIDs) (Table 3) are additional agents in chronic somatic pain management but of limited benefit due to risks of chronic toxicity and effects on platelet aggregation in often coagulopathic and immunocompromised cancer patients. Acetaminophen (paracetamol) is the most commonly and widely used analgesic and antipyretic in children. Its has no peripheral antiinflammatory effects, and it putatively acts on cyclo-oxygenase (COX-1 more than COX-2) through central nervous system mechanisms. Although a weak analgesic, it is a generally safe agent, if proper pediatric doses are administered. The recommended single doses are 15 to 20 mg/kg, 10 to 15 mg/kg with repeated dosing. Toxicity occurs at 90 mg/kg in children and adolescents, 60 mg/kg in infants, and 45 mg/kg in preterm infants. Excess acetaminophen is metabolized in the liver to reactive nucleophilic benzoquinones which bind DNA, leading to parenchymal necrosis. Treatment of overdose must occur within 12 hours of intake in adult patients, with the use of N-acetylcysteine or glutathion. Acetaminophen is available in multiple routes of administration, tablets, capsules, suspensions, and suppositories. The rectal route is usually contraindicated in cancer patients. NSAIDs act peripherally, without significantly crossing the blood– brain barrier, and have a prominent antiinflammatory effect as well as analgesia and antipyresis. Their use is guided as well by their adverse effects, including gastritis, potential GI bleeding, and platelet and renal dysfunction. Respiratory depression and dysphoria, often seen with opioid use, are not concerns with these agents. The major mechanism of action of NSAIDs through inhibition of prostaglandin synthesis by blockade of constitutive and expressed cyclo-oxygenase (COX). The pharmacology of most NSAIDs has been studied in children 2 years and older, in which population the elimination half-life is similar to adults. In children 3 months to 2.5 years, the volume of distribution and clearance of ibuprofen and ketorolac are increased, suggesting a possible need for higher loading and maintenance dosing in children. Aspirin (acetylsalicylic acid), although used for acute pain and fever for greater than 100 years, is contraindicated for fever in pediatrics due to an association with Reyes Syndrome, described 20 years ago. Therefore, acetaminophen and ibuprofen are the primary agents for fever and mild–moderate pain. For severe pain, parenteral ketorolac is effective. The oral formulation is similar in strength and efficacy to older NSAIDs. Ketololac has been studied as a single dose postoperatively and is well-tolerated and opioid-
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sparing. It is generally prescribed every 6 hours, over 24 to 48 hours, with frequent reevaluation and a maximum period of 5 days. The newer COX 2 inhibitors, celecoxib and valdecoxib, are currently being studied in pediatric multicenter pharmacokinetic and postoperative efficacy trials. The vasoocclusive effects reported in adult trials have not been investigated for the pediatric population.
Other techniques Children are excellent subjects for hypnosis, relaxation, and biofeedback training, all of which are especially useful for recurrent pain such as headache and for brief painful medical procedures. Children over the age of 7 years generally benefit from such programs, but some behavioral treatment strategies have applied to children as young as 3 to 4 years. In the context of childhood cancer, cognitivebehavioral techniques are commonly used to decrease distress and enhance coping with procedures. They are generalizable to new and stressful situations, such as end-of-life care.23 Regional blockade techniques have been developed for children of all ages, including newborns, and are generally performed with sedation or light general anesthesia because of patients’ fear of needles. Regional, caudal epidural and lumbar epidural blockade provide excellent analgesia with wide margins of safety. Hemodynamic and respiratory effects of epidural or subarachnoid blockade in infants are mild. The distribution and clearance of bupivacaine and lidocaine following regional blockade in children over 6 months of age resemble those in adults. Bupivacaine clearance is mildly delayed in newborns. Epidural and subarachnoid infusions of opioid and local anesthetics have been effectively used in infants and children who have refractory cancer pain, deafferentation pain, and complex regional pain syndrome, type I (CRPS I). Combinations of epidural bupivacaine, fentanyl, and clonidine may limit adverse effects.24 It is important to administer local anesthetic slowly in children, with constant assessment for clinical signs of intravascular effect. Infants and children may also receive viscous lidocaine for mucosal analgesia. A single mucous dose of lidocaine should not exceed 4 mg/kg; a repeated oral administration of up to 2 mg/kg is generally safe. Infants and young children should receive dilute lidocaine sprays, such as 1% in neonates and 2% in children versus the 4% to 10% used in adults. The use of transdermal 5% lidocaine patch (lidoderm), applied to dermal areas of localized peripheral neuropathic pain, 1 to 3 patches/12 hrs, is currently being studied in children. EMLA use is now considered safe in neonates and preterm infants. Sucrose solutions are effective until approximately 4 to 6 months of age, possibly activating the descending analgesic system.
Adverse effects The treatment of adverse effects due to all pharmacologic interventions is an integral part of analgesia in cancer pain management. Common symptoms include nausea, sedation, pruritis, muscle spasms, breathlessness, and sleep
disruption. With opioids, constipation is the most common and persistent adverse effect, and sedation and mental confusion are the most limiting adverse effects. Some beneficial adjuvant agents are: ondansetron, 0.1-.15 mg/kg IV q 6 hrs with max dose ⫽ 4 mg; diphenhydramine, 1 mg/dose, q4 to 6 hrs with max dose ⫽ 50 mg; metaclopramide, 0.1-.2 mg/kg/dose q 6 hrs with max dose ⫽ 10 mg; methylphenidate 10 mg po q am an q early pm; senokot 10 mg/kg po prn; baclofen 1 mg/kg/24hrs divided three times per day and diazepam 0.1 to 0.2 mg/kg q 4 to 6 hrs. In general, the pharmacologic approach to the management of side effects is similar to that in adults. However, children may have difficulty communicating subjective symptoms, which reflect difficulties with pruritus, nausea, and dysphoria. Therefore, if an infant or child become restless or irritable with increased opioid dose, treatment of side effects is suggested empirically, as is a change to an alternative opioid. Opioid rotation may limit both adverse effects of and tolerance to opioid medication during cancer pain treatment in children.25 For acute respiratory depression, as dictated by professional judgment, children may receive naloxone titrated to the desired effect. The initial dose of naloxone in a child is 0.5 to 1.0 g/kg. When disease progresses despite standard and often during experimental therapies, ideally, the interdisciplinary health care team, together with the patient and family, focuses on realistic goals. A concurrent care approach often predominates in pediatric end-of-life care. This practice combines the use of cancer-directed therapy, symptomatic antibiotics and blood products, as well as pain and comfort measures. Ongoing communication is imperative as is recognition of the child’s complex pain experience, which includes physical, emotional, and spiritual factors. Symptom management predominates, with attention to fatigue, pain, dyspnea, and nutrition. Hope is maintained for realistic outcomes.26 In conclusion, pain in children with cancer is a compelling problem with significant impact on the child as well as family and caregivers. The previously described challenges of pain assessment and evolving pharmacotherapy are the targets of current clinical research, actively pursued in both the developed and the developing world. There is great value in “adding life to the child’s years, not simply years to the child’s life.”27
References 1. World Health Organization: Cancer Pain Relief and Palliative Care in Children. Geneva, WHO, 1998 2. Ljungman G, Gordh T, Sorenson S, et al: Pain variations during cancer treatment in children: a descriptive survey. Ped Hem Oncol 17:211221, 2000 3. Wolfe J, Grier HE, Klar N, et al: Symptoms and suffering at the end of life in children with cancer. N Engl J Med 284:2469-2475, 2000 4. Fields MJ, Behrman RE (eds): [for Committee on Palliative care and End-of Life care for Children and their Families, Institute of Medicine]: When children die: improving palliative care and end-of-life care for children and their families. Washington DC, The National Academies Press, 2003 5. Anand KJ: International Evidence-Based Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn. Arch Pediat Adolescent Med 155:173-180, 2001
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6. Taddio A, Katz J, Ilersich AL, et al: Effect of neonatal circumcision on pain response during subsequent vaccination. Lancet 349:599-603, 1997 7. Chapman CR, Hill HF: Prolonged morphine self-administration and addiction liability: evaluation of two theories in the bone marrow transplant unit. Cancer 63:1636-1644, 1989 8. Pegelow CH: Survey of pain management therapy provided for children with sickle cell disease. Clin Pediatr 31:211-214, 1992 9. Solomon MZ, Dokken DL, Fleischman AR, et al: The initiative for pediatric palliative care (IPPC): background and goals. Newton, MA, Education Development Center, Inc. Available at http:// www.ippcweb.org. 10. McGrath PA: Pain in Children: Nature, Assessment, and Treatment. New York, NY, Guilford Press, 1990 11. Hockenberry M, Wilson D, Winkelstein M, et al: Wong’s Nursing Care of Infants and Children (ed 7). St. Louis, MO, CV Mosby, 2003, pp 1052-1053 12. Zempsky WT, Schechter NL: What’s new in the management of pain in children. Pediatr Rev 24:337-347, 2003 13. Wong On Web. http://www.harcourthealthsciences.com/WOW/ fyi03.html. 14. Merkel SI, Voepel-Lewis T, Shayevitz JR, et al: The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs 23:293-297, 1997 15. Hicks CL, von Baeyer CL, Spafford PA, et al: The Faces Pain ScaleRevised: toward a common metric in pediatric pain measurement. Pain 93:173-183, 2001 16. Walker G, Arnold R: Fast Facts and Concepts #117: Pediatric Pain Assessment Scales. June 2004. End-of-Life Physician Education Resource Center. Available at http://www.eperc.mcw.edu.
151 17. Berde CB, Sethna NF: Analgesics for the treatment of pain in children. N Engl J Med 347:1094-1103, 2002 18. Ross EL: The evolving role of antiepileptic drugs in treating neuropathic pain. Neurology 55:41-46, 2000 (suppl 1) 19. Schecter NL, Berde CB, Yaster M (eds): Pain in infants, children, and adolescents. Philadelphia, PA, Lipincott William and Wilkins, 2003 20. Block BM, Christo PJ: Ketamine analgesia for the opioid-tolerant cancer patient. Int J Pain Med Palliative Care 2:71-74, 2003 21. Hunt A, Joel S, Dick G, et al: Population pharmacokinetics of oral morphine and its glucuronides in children receiving morphine as immediate-release liquid or sustained-release tablets for cancer pain. J Pediatr 135:47-55, 1999 22. Collins JJ, Grier HE, Kinney HC, et al: Control of severe pain in children with terminal malignancy. J Pediatr 126:653-657, 1995 23. McGrath PA: Intervention and management, in Bush JP, Harkins SW (eds): Children in Pain: Clinical and Research Issues from a Developmental Perspective. New York, NY, Springer-Verlag, 1991, p 476 24. Sveticic G, Gentillini A, Eichenberger U, et al: Combinations of bupivacaine, fentanyl, and clonidine for lumbar epidural postoperative analgesia. Anesthesiology 101:1381-1393, 2004 25. Hurwitz CA, Duncan J, Wolfe J: Caring for the child with cancer at the close of life. J Am Med Assoc 293:2141-2149, 2004 26. American Academy of Pediatrics: Committee on Bioethics and Committee on Hospital Care: palliative care for children. Pediatrics 106: 351-357, 2000 27. Drake R, Longworth J, Collins JJ: Opioid rotation in children with cancer. J Palliative Med 7:419-422, 2004
Cancer pain and palliative care in children Alyssa Lebel, MD From the Children’s Hospital Boston. Pain Management Service, Boston, Massachusetts. KEYWORDS: Pain; Cancer; Children; Palliative care; Pain assessment; Pharmacotherapy
Pediatric cancer-related mortality has fallen in the past 25 years, but terminal symptoms and pain persist. This brief report on cancer pain in children reviews the barriers to adequate care, the presentation of pediatric pain problems, developmental features of pain assessment, and current pain management strategies for this vulnerable population. © 2005 Elsevier Inc. All rights reserved.
Cancer is the second leading cause of death in children, following accidents. Recent evidence1 shows that, although the cancer-related mortality rate has fallen from 5.4/100,000 to 2.8/100,000 between 1975 and 1998, approximately 25% of children with cancer die of their disease. Few studies address the experience of symptoms in children with cancer, but some current reports indicate that terminal symptoms and pain are not adequately relieved. In one study,2 structural interviews conducted with 66 children and their families following cancer therapy showed that treatment-related pain was a constant and dominating problem (49%), greater than procedural pain (39%) and pain related to the primary disease (12%). In another review using patient charts of children who died of cancer between 1990 and 1997, parents were interviewed about their child’s end-of-life experience.3 Parents reported that 89% of the children suffered “a lot” or “a great deal ” from at least one symptom in their last month of life. Pain, followed by fatigue and dyspnea, were most common. Treatment of pain was successful in 27% of patients. Suffering from pain was more likely in patients whose parents reported that the physician was not actively involved in end of life care (odds ratio 2.6). Achieving effective pain in the pediatric cancer population, despite the analgesic advances of the past 30 years, remains an emergent need. Inadequate care is perpetuated by: ●
Persistent misconceptions regarding pain control in children;
Address reprint requests and correspondence: Dr. Alyssa Lebel, Children’s Hospital Boston, Pain Management Service, 333 Longwood Avenue, 5th Floor, Boston, MA 02115. E-mail address: [email protected]. 1084-208X/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2005.06.005
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Challenges of pain assessment without self report and sensitive to the cognitive and developmental stage of the patient; Paucity of pharmaceutical testing of analgesics in the pediatric population; Minimal access to pediatric specialists in palliative care and symptom management; and Limited training of pediatric oncologists in palliative care.4
Two resistant misconceptions, slowly discredited by increasing data, are the immaturity of the neonatal pain transmission system and the fear of aggressive opioid administration due to potential addiction. Current research disputes the concept of neonatal hypoalgesia. Pain transmission pathways develop during fetal life. Nerve tracts in the spinal cord and brainstem begin to myelinate around the gestational age of 22 weeks and are completely myelinated by 28 to 30 months after birth. More specifically, myelination is complete up to the thalamus by 30 weeks’ gestation, and the thalamocortical pain connections to the cortex are myelinated by 37 weeks’ gestation. Thus, pathways that conduct noxious information from nociceptor to cortex are present in the newborn infant. Cortical descending inhibition develops postterm. The majority of neurotransmitters and neuromodulators are present in the fetus. Calcitonin gene-related peptide (CGRP) and substance P are present at 8 to 10 weeks’ gestation, while others such as enkephalin and vasoactive intestinal peptide (VIP) appear 2 to 4 weeks later. Catecholamines are present in late gestation, and, in the human fetus, serotonin has been found at 6 weeks postnatally. Neurotransmitters that enhance the perception of pain are produced earlier in the fetus than are endogenous opioids.
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It appears, therefore, that pain processing in the mature fetus and newborn is adequately developed so that the infant may exhibit behavioral and physiologic responses to noxious stimuli and may even have enhanced nociception. (However, a concious experience of “suffering” in the neonate, considered to require mature forebrain development, remains controversial). The misconception that neonates and infants do not feel pain, combined with a fear of using opioids in very young children, resulted in gross undertreatment of pain in this population. Recent research has emphasized the importance of providing adequate pain control in newborns and young infants. It is now clear that the undertreatment of pain can have short-term significant physiologic effects. The long-term consequences of untreated pain in the developing organism are not yet defined, but some studies suggest that early pain responses influence later pain behaviors.5,6
Opioid use in children Addiction is extremely rare when opioid medications are prescribed for pain management. However, regulations and social stigma may still discourage opioid use. Studies of children treated for pain associated with sickle cell disease, bone marrow transplant, or surgical procedures report essentially no risk of addiction with the prescribed use of opioids.7,8 Morphine remains the primary pediatric analgesic for the management of moderate to severe cancer pain and for palliative care, as well as an essential agent for treating sickle cell vaso-occlusive crises, acute postoperative pain, and burn pain.
Assessment of pain9-16 The assessment of pain in children should be systematic, and requires re-evaluation throughout the course of the illness. Because infants cannot communicate verbally, behavioral and physiologic responses can be used to assess pain in the very young, including facial expression, tachycardia, and stress-related hormones. However, these signs may not be specific to pain. The child’s cognitive development and ability to understand pain influence the choice of suitable measurement tools. In children, pain measurement must include the following10: ● ●
● ● ●
The child’s report of pain is the best indicator of pain. Pain that appears unexplained by known causes may indicate disease progression or other factors, and should be investigated. The denial of pain when there is evidence of tissue damage should be investigated. Neonates and infants feel pain. Developmental factors should be considered before selecting the appropriate measures of pain intensity (this is more difficult under 2.5 years of age).
Self report Children as young as 18 months can indicate their pain and give a location, but it is not possible to obtain a selfreport of intensity of pain before about 3 years of age. Children who are 3 years of age can give a gross indication, such as “no pain,” “a little pain,” and “a lot of pain.” Similarly, many children at this age can use concrete measures such as “poker chips” of “pieces of hurt” to convey the intensity of their pain. The use of more abstract self-report instruments, such as the “smiling faces scale” are generally not valid for use in children under 5 years of age. Simple self-report measures are recommended for children older than 6 years of age. Among the most useful scales for measuring intensity of pain are visual analog scales, either vertical or horizontal, and simple numeric scales. For example, “If 0 means no hurt or pain and 10 means the biggest pain you ever have, what is your pain now?” The use of adjectival categorical scales such as “mild,” “moderate,” severe,“ and excruciating” are not recommended for children younger than 13 years of age. Behavioral observations should not be used in lieu of self-report. However, behavioral observations are invaluable when self-report is not available, for example, in children younger than 2 years of age or in children without verbal ability due to disability or disease. In the presence of noxious stimuli, behavioral pain indicators may arouse suspicion and prompt investigations even in the absence of a verbal report of pain. Neonates and infants feel pain, and neonates are no less sensitive to noxious stimulation than are older children and adults. Therefore, assessment of pain, although more complex than in older children, should be considered essential in the care of neonates and infants. In infants, reliance on facial expression, crying, posture, and physiologic variables such as heart rate, respiratory rate, blood pressure, and palmar sweating are important as potential indicators of pain, and scoring systems, such as the CRIES scale described by Krechel and Bildner (1995) are useful. Specific scales are summarized in Table 1.16 There are currently no physiologic measures that reliably indicate pain, and pain treatment should never be withheld because of a lack of physiologic evidence alone.
Pharmacotherapy17-19 Advances in treatment protocols for childhood cancer generally create treatment-related rather than tumor-related pain problems. With treatment failure and relapse, tumorrelated pain predominates. Young adult survivors of cancer may also experience nonmalignant chronic pain syndromes, such as neuropathy, phantom limb pain, avascular necrosis, mechanical spine and limb pain, and, infrequently, postherpetic neuralgia, especially in previously irradiated areas. Chronic disease-related pain is most frequently neuropathic—visceral, peripheral, or both. Somatic pain is often responsive to initial tumor therapy and routine analgesics. Neuropathic pain may be due to tumor compression or infiltration of peripheral nerves or the central nervous system. Characteristically, this pain is frequently sharp, shoot-
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TABLE 1
Pediatric pain assessment scales
Behavioral observational scales: The primary method of pain assessment for infants, children less than 3 yrs old, and developmentally disabled patients. Validated tools include: CRIES: Assesses Crying, Oxygen requirement, Increased vital signs, facial Expression, Sleep. An observer provides a score of 0–2 for each parameter based on changes from baseline. For example, a grimace, the facial expression most often associated with pain, gains a score of 1 but if associated with a grunt will be scored a 2. The scale is useful for neonatal postoperative pain. Facial expression, cry, breathing pattern, arms, legs, and state of arousal are observed for 1 minute. NIPS: Neonatal/Infants Pain Scale has been used mostly in infants less than 1 yr of age. Minute intervals before, during, and after a procedure and a numeric score are assigned to each. A score ⬎3 indicates pain. www.anes.ucla.edu/pain FLACC: Face, legs, activity, crying, consolability scale validated from 2 mo to 7 years. 0–10 scoring. CHEOPS: Children’s Hospital of Eastern Ontario. Intended for children 1–7 yrs old. Assesses cry, facial expression, verbalization, torso movement, if child touches affected site, and position of legs. A score ⱖ 4 signifies pain. www.anes.ucla.edu/pain Self report: Children 3 years of age and older can rank their pain using one of several validated scales including: Wong-Baker Faces scale: 6 cartoon faces showing increasing degrees of distress. Face 0 signifies “no hurt” and face 5 the “worst hurt you can imagine”; the child chooses the face that best describes own pain at the time of assessment. www.childcancerpain.org; www.harcourthealthsciences.com/WOW/faces.html Bieri-Modified: 6 cartoon faces starting from a neutral state and progressing to tears/crying. Scored 0–10 by the child. Used for children ⬎3 years. Visual analogue scale: uses a 10 cm line with one end marked as no pain and the opposite end marked as the worst pain. The child is asked to make a mark on that line that is then measured in cm from the no pain end. www.helpforpain.com
ing, electrical, stabbing, or burning (dysesthesia), with pain induced by usually nonpainful stimuli (allodynia) and often paradoxically felt in a region of sensory deficit. Chronic treatment-related pain is also often neuropathic in quality and may be secondary to chemotherapy-induced neuropathy, ischemic neuropathy and necrosis postirradiation, and postoperative phantom limb symptoms. For treatment of pediatric neuropathic pain, pharmacologic choices are generally based on adult studies and on the use of the same agents for nonpainful problems, with the caveats of slow titration and anticipation of side effects superimposed. The classes of medications include: antidepressants; anticonvulsants; local anesthetics and their analogs; and adequate doses of opioids. Current understanding of the pathophysiology of neuropathic pain guides therapy and supports synergy when combining medication for intractable cases. For example, a patient with postvincristine neuropathy likely has spontaneous neuronal discharge in peripheral sensitized small nerve fibers as well as central
147 spinal cord disinhibition of pain transmission due to loss of dorsal horn inhibitory neurons. An anticonvulsant, gabapentin, may block nerve discharge by binding to inappropriately active sodium and neuronal calcium channels, and an antidepressant, amitriptyline, may block the reuptake of inhibitory pain neurotransmitters in the dorsal horn, enhancing spinal pain inhibition. More specifically, tricyclic antidepressants potentiate the analgesic actions of serotonin and norepinephrine at nerve terminals in the central nervous system. Their side effects are due to additional cholinergic, histaminergic, and adrenergic actions, resulting in possible dry mouth, constipation, urinary retention, sedation, weight gain, orthostatic hypotension, tachycardia, and heart block. Although the cardiac risks for children are low, it is recommended to obtain an EKG before and during dose escalation and to possibly exclude patients with known rhythm disorders and cardiomyopathy (ie, adriamycin). Amitriptyline is the best known agent but also has the most significant sedative, anticholinergic, and orthostatic profile. Therefore, nortriptyline, with minimal sedation and orthostasis, is often the first choice.
Tricyclic dosing Amitriptyline and Nortriptyline: 0.2-.4mg/kg po qhs; titrate upward by .25mg/kg q 5 to 7 days; may divide bid; maintenance 0.2-.3mg/kg. Other antidepressants, such as fluoxetine, sertraline, citalopram, escitalopram, trazadone, venlafaxine, and trazadone, are best used for associated symptoms such as anxiety, sleep disturbance, and mood disorder. The data regarding their analgesic efficacy remain anecdotal. Anticonvulsants are now first-line agents for treatment of neuropathic pain and may depress abnormal neuronal discharges in damaged nerves as well as raise the inappropriately lowered threshold in chronic pain states for neuronal activation. They are variably active at voltage-gated ion channels, and at glutamate, N-methyl-D-aspartate, gammaaminobutyric acid, and glycine receptors. Much pediatric experience is reported for these medications regarding use in seizure management. Their use as analgesics is extrapolated, but, as for adults, analgesic trials involving anticonvulsants are more frequent and promising. The first generation agents, such as phenytoin, carbamazepine, valproate, and clonazepam, are best studied but are also associated with complicating hematologic, hepatic, dermatologic, immunologic, and maxillofacial effects. The second generation medications, such as gabapentin, lamotrigine, topiramate, zonisamide, levetiracetam, and pregabalin, may not require laboratory monitoring, have less sedation or cognitive effects, and, overall, present less confounding adverse effects. However, as our pediatric experience increases, these agents are not free of side effects.
Anticonvulsant dosing (oral) Carbamazepine: 5 to 10mg/kg/24hrs divided bid; incremental increase of 10mg/kg/24hrs per week; maximum dose ⬎ 12yrs ⫽ 1.6 to 2.4 g/24hrs. Oxcarbazepine: ⬎ 12yrs ⫽ 300 to 600mg/24hrs; maximum dose 900 to 2400mg/24hrs.
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Phenytoin: 2 to 3mg/kg divided bid-three times per day incremental increase of .5mg/kg q 3 to 4 wks; maximum dose: 5mg/kg/d (1000 mg/d). Valproic Acid: 5 to 15mg/kg divided qd-three times per day incremental increase of 5 to 10mg/kg every 5 to 7 days; maximum dose 60mg/kg/d. Gabapentin: 5 to 10mg/kg qhs, day 2 bid, day 3 three times per day maximum dose 2400 to 3600mg/24hrs. Lamotrigine: 0.15-.6mg/kg/24hrs qd- bid; slow incremental increase q2 weeks. Topiramate: 1 to 3mg/kg/24hrs; maximum dose ⫽ 600mg/24hrs. Zonisamide: 2 to 4mg/kg/24hrs; maximum dosage ⫽ 400mg/24hrs. NMDA–receptor antagonists show promise as regulators of the central nervous changes present during chronic neuropathic pain states but are yet to be used regularly in the clinic. Pediatric use may be particularly limited due to the developmental regulation of these receptor subtypes. The pathophysiologic mechanism of analgesia is considered to be a decrease in the central sensitization or “ wind-up ” of spinal dorsal horn and other CNS neurons. The dorsal horn of the spinal cord is a crutial and dynamic area of statedependent neuronal plasticity which may both upgrade and downgrade pain signal transmission. With repetitive stimulation of afferent C-fibers, there may be a progressive discharge in second-order dorsal horn neurons involving synapses that use the neurotransmitter glutamate and NMDA (N-methyl-D-aspartate) receptors. NMDA receptor activation results in neuronal calcium ion influx, with subsequent activation of cellular protein kinase C, nitric oxide synthase, cyclooxygenase, and cyclic adenosine monophosphate response element binding protein (CREB). Molecular changes in neuronal subtype may also be demonstrated. This chemical barrage ultimately causes nociceptive neurons to increase their firing rate, amplifies peripheral input, and activates more rostral pain transmission centers producing increased pain perception.
Dosing of NMDA antagonists Dextromethorphan: ⬎12yrs 30mg q6 to 8hrs; maximum dose 120mg/24hrs. Memantine: adult recommendations ⫽ 5mg/24hrs; maximum dose 20mg/24hrs. Ketamine: parenteral use for pain in pediatrics not yet known; data in adults promising.20
Dosing of opioids For chronic somatic pain, opioids are a mainstay of cancer pain treatment and are preferably administered at regular intervals with generous rescue dosing (5-10% of total daily dose q 2-4hrs or 50-200% of hourly basal IV rate; see Table 2). Pharmacokinetic studies of opioids in children are available for morphine, fentanyl, sufentanil, methadone, and hydromorphone, and in process for such newer oral agents as oxycodone and oxycontin. The choice of a specific opioid is based on potency, desired route of administration, and adverse effects. Mor-
TABLE 2
Initial opioid dosing (⬍ 50 kg)
Drug
Oral
Morphine
0.3mg/kg q 3–4 hrs
Hydromorphone
0.02–0.08mg/kg q 3–4 hrs
Fentanyl
NA
Methadone
0.2mg/kg q 4–8 hrs
Codeine
0.5–1mg/kg q 3–4 hrs 0.1–0.2mg/kg q 3–4 hrs
Oxycodone
Parenteral 0.05–0.1 mg/kg q 4 hrs, 0.02mg/kg/hr infusion 0.02mg/kg q 2–3 hrs, 0.006mg/kg/hr infusion 0.5–1 g/kg q 1–2 hrs 0.1mg/kg q 4– 8 hrs NA NA
phine is the first choice for parenteral boluses and infusions. Children with reactive airway disease may, rarely, be more sensitive to the histaminergic effects of morphine, but, generally, tolerate this agent well. Rash and pruritis are occasionally present in atopic individuals as well as idiosyncratically. All opioids affect visceral sphincters equally. Meperidine is minimally used secondary to its excitatory effects on the cardiac and central nervous system with repetitive dosing. Hydromorphone is anecdotally preferred in patients with incipient renal failure; putatively due to less accumulation of toxic metabolites (3,6-diglucuronide) compared with morphine.21 Fentanyl is an alternative parenteral opioid, with a short half-life that is useful for painful procedures. It is often a choice in neonates with congenital heart disease due to little cardiac effect except bradycardia. High doses, and, rarely, low doses, may produce glottic and chest wall rigidity, treated with naloxone and/or neuromuscular blockade. For older patients with chronic pain, fentanyl may be administered rapidly and transmucosally, in a candy matrix, or over 72 hours transdermally, via patch placement and subdermal release following deposition. Methadone provides a form of sustained release administration, with attention to the accumulation of effect, from 3 to 4 hours to 24 hours, with repetitive dosing. It is often used to wean opioids after sustained parenteral infusion. Of note, the D-isomer of methadone acts as an NMDA antagonist, which may aid in the treatment of neuropathic pain as well as reduce opioid tolerance. Therefore, the conversion ratio for methadone to other opioids depends on the preexisting opioid-tolerance of the patient. For a single intravenous dose, methadone is equipotent to morphine. With short-term repetitive dosing in an opioid naïve patient, methadone is more slowly eliminated than morphine, and the total daily dose of methadone may be 1/3 to 2/4 the total daily dose of morphine. For a very tolerant patient, such as one using 100 mg/hr of morphine, the daily methadone dose may be 1/10 the daily morphine dose. Sufentanil is used primarily as a general anesthetic. Intermittent intramuscular dosing of analgesics is contraindicated in pediatrics, due to the common needle aversion and often-incomprehensible pain with injection in this
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population. As a rough dosing guide, premature infants and neonates require 1/10 the usual adult dosage: 1-month olds, 1/8; 1-year olds, 1/4; and 7-year olds, 1/2. Oral administration for mild to moderate pain, often following recovery from acute surgery or trauma, includes oral opioid preparations (codeine, oxycodone, morphine elixir, and rapid-release tablets) and opioid / NSAID combination (acetaminophen with codeine, oxycodone with acetaminophen). Codeine is a pro-drug, requiring hepatic conversion to morphine for analgesic effect. Five to 15% of patients lack this hepatic enzymatic pathway and are codeine-resistant. Oxycodone is also a relatively weak opioid, unless prescribed in an oral dose ⬎0.1 mg/kg. At 0.2 mg/kg, oral oxycodone is approximately equivalent to 0.1 mg of IV morphine. Tramadol is an unusual opioid, recently studied regarding pediatric pharmacokinetics, with morphine-like mu1-receptor agonism, incompletely antagonized by naloxone, and some additional reuptake-blockade of norepinephrine and serotonin. Rectal suppositories of morphine and hydromorphone are available for patients NPO who are not neutropenic or immunosuppressed. Neuroaxial opioids well-tolerated and commonly used in pediatrics are fentanyl and hydromophone. Premature and term infants show reductions in clearance of most opioids. Pharmacologic guidelines for opioid use in the newborn and infant are as follows: ●
●
●
●
●
Neonates have immature cytochrome P450 hepatic enzyme system and conjugate opioids and local anesthetics slowly. Watch for delayed toxicity with prolonged infusions. Renal function— glomerular filtration and renal tubular secretion—is decreased in the neonatal period (especially in premature infants) when compared with adults. The half-lives of opioids and their metabolites may be increased. Delay respiratory depression and sedation by increasing dosing intervals and decreasing doses. Neonatal body water is increased compared with adults, and fat is minimal. Remember that analgesics with high water solubility have a large volume of distribution. Neonates have decreased plasma protein binding, albumin, and ␣-1 acid glycoprotein. Analgesics have increased circulating free-drug and greater first-pass toxicity. Ventilatory reflexes are immature in the neonate. Opioids may induce hypoventilation.
Patient-controlled analgesia (PCA) is effective for children and adolescents aged 5 years and older. However, some children and adolescents may not have the cognitive, emotional, or physical resources to use PCA and require nurse-controlled anlgesia (NCA). In palliative care, the standard home infusion pumps all include a PCA option. Often these cancer pateints receive approximately 60% of prior opioid dosing as a basal infusion rate and 40% through PCA boluses, unless the patient has infrequent, episodic pain (dressing changes). Very high doses of opioids, rarely accompanied by respiratory depression, may be required for end-of-life care.22
149 TABLE 3
Dosing of NSAIDs
Drug Acetaminophen (po, pr) Aspirin Ibuprofen Ketorolac (iv)
Dose 10–15 mg/kg q 4 hrs 10–15 mg/kg q 4 hrs 4–10 mg/kg q 6–8 hrs 0.5 mg/kg q6–8 hrs, not ⬎ 5 d
Dosing of NSAIDS Acetaminophen and non-steroidal antiinflammatory drugs (NSAIDs) (Table 3) are additional agents in chronic somatic pain management but of limited benefit due to risks of chronic toxicity and effects on platelet aggregation in often coagulopathic and immunocompromised cancer patients. Acetaminophen (paracetamol) is the most commonly and widely used analgesic and antipyretic in children. Its has no peripheral antiinflammatory effects, and it putatively acts on cyclo-oxygenase (COX-1 more than COX-2) through central nervous system mechanisms. Although a weak analgesic, it is a generally safe agent, if proper pediatric doses are administered. The recommended single doses are 15 to 20 mg/kg, 10 to 15 mg/kg with repeated dosing. Toxicity occurs at 90 mg/kg in children and adolescents, 60 mg/kg in infants, and 45 mg/kg in preterm infants. Excess acetaminophen is metabolized in the liver to reactive nucleophilic benzoquinones which bind DNA, leading to parenchymal necrosis. Treatment of overdose must occur within 12 hours of intake in adult patients, with the use of N-acetylcysteine or glutathion. Acetaminophen is available in multiple routes of administration, tablets, capsules, suspensions, and suppositories. The rectal route is usually contraindicated in cancer patients. NSAIDs act peripherally, without significantly crossing the blood– brain barrier, and have a prominent antiinflammatory effect as well as analgesia and antipyresis. Their use is guided as well by their adverse effects, including gastritis, potential GI bleeding, and platelet and renal dysfunction. Respiratory depression and dysphoria, often seen with opioid use, are not concerns with these agents. The major mechanism of action of NSAIDs through inhibition of prostaglandin synthesis by blockade of constitutive and expressed cyclo-oxygenase (COX). The pharmacology of most NSAIDs has been studied in children 2 years and older, in which population the elimination half-life is similar to adults. In children 3 months to 2.5 years, the volume of distribution and clearance of ibuprofen and ketorolac are increased, suggesting a possible need for higher loading and maintenance dosing in children. Aspirin (acetylsalicylic acid), although used for acute pain and fever for greater than 100 years, is contraindicated for fever in pediatrics due to an association with Reyes Syndrome, described 20 years ago. Therefore, acetaminophen and ibuprofen are the primary agents for fever and mild–moderate pain. For severe pain, parenteral ketorolac is effective. The oral formulation is similar in strength and efficacy to older NSAIDs. Ketololac has been studied as a single dose postoperatively and is well-tolerated and opioid-
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sparing. It is generally prescribed every 6 hours, over 24 to 48 hours, with frequent reevaluation and a maximum period of 5 days. The newer COX 2 inhibitors, celecoxib and valdecoxib, are currently being studied in pediatric multicenter pharmacokinetic and postoperative efficacy trials. The vasoocclusive effects reported in adult trials have not been investigated for the pediatric population.
Other techniques Children are excellent subjects for hypnosis, relaxation, and biofeedback training, all of which are especially useful for recurrent pain such as headache and for brief painful medical procedures. Children over the age of 7 years generally benefit from such programs, but some behavioral treatment strategies have applied to children as young as 3 to 4 years. In the context of childhood cancer, cognitivebehavioral techniques are commonly used to decrease distress and enhance coping with procedures. They are generalizable to new and stressful situations, such as end-of-life care.23 Regional blockade techniques have been developed for children of all ages, including newborns, and are generally performed with sedation or light general anesthesia because of patients’ fear of needles. Regional, caudal epidural and lumbar epidural blockade provide excellent analgesia with wide margins of safety. Hemodynamic and respiratory effects of epidural or subarachnoid blockade in infants are mild. The distribution and clearance of bupivacaine and lidocaine following regional blockade in children over 6 months of age resemble those in adults. Bupivacaine clearance is mildly delayed in newborns. Epidural and subarachnoid infusions of opioid and local anesthetics have been effectively used in infants and children who have refractory cancer pain, deafferentation pain, and complex regional pain syndrome, type I (CRPS I). Combinations of epidural bupivacaine, fentanyl, and clonidine may limit adverse effects.24 It is important to administer local anesthetic slowly in children, with constant assessment for clinical signs of intravascular effect. Infants and children may also receive viscous lidocaine for mucosal analgesia. A single mucous dose of lidocaine should not exceed 4 mg/kg; a repeated oral administration of up to 2 mg/kg is generally safe. Infants and young children should receive dilute lidocaine sprays, such as 1% in neonates and 2% in children versus the 4% to 10% used in adults. The use of transdermal 5% lidocaine patch (lidoderm), applied to dermal areas of localized peripheral neuropathic pain, 1 to 3 patches/12 hrs, is currently being studied in children. EMLA use is now considered safe in neonates and preterm infants. Sucrose solutions are effective until approximately 4 to 6 months of age, possibly activating the descending analgesic system.
Adverse effects The treatment of adverse effects due to all pharmacologic interventions is an integral part of analgesia in cancer pain management. Common symptoms include nausea, sedation, pruritis, muscle spasms, breathlessness, and sleep
disruption. With opioids, constipation is the most common and persistent adverse effect, and sedation and mental confusion are the most limiting adverse effects. Some beneficial adjuvant agents are: ondansetron, 0.1-.15 mg/kg IV q 6 hrs with max dose ⫽ 4 mg; diphenhydramine, 1 mg/dose, q4 to 6 hrs with max dose ⫽ 50 mg; metaclopramide, 0.1-.2 mg/kg/dose q 6 hrs with max dose ⫽ 10 mg; methylphenidate 10 mg po q am an q early pm; senokot 10 mg/kg po prn; baclofen 1 mg/kg/24hrs divided three times per day and diazepam 0.1 to 0.2 mg/kg q 4 to 6 hrs. In general, the pharmacologic approach to the management of side effects is similar to that in adults. However, children may have difficulty communicating subjective symptoms, which reflect difficulties with pruritus, nausea, and dysphoria. Therefore, if an infant or child become restless or irritable with increased opioid dose, treatment of side effects is suggested empirically, as is a change to an alternative opioid. Opioid rotation may limit both adverse effects of and tolerance to opioid medication during cancer pain treatment in children.25 For acute respiratory depression, as dictated by professional judgment, children may receive naloxone titrated to the desired effect. The initial dose of naloxone in a child is 0.5 to 1.0 g/kg. When disease progresses despite standard and often during experimental therapies, ideally, the interdisciplinary health care team, together with the patient and family, focuses on realistic goals. A concurrent care approach often predominates in pediatric end-of-life care. This practice combines the use of cancer-directed therapy, symptomatic antibiotics and blood products, as well as pain and comfort measures. Ongoing communication is imperative as is recognition of the child’s complex pain experience, which includes physical, emotional, and spiritual factors. Symptom management predominates, with attention to fatigue, pain, dyspnea, and nutrition. Hope is maintained for realistic outcomes.26 In conclusion, pain in children with cancer is a compelling problem with significant impact on the child as well as family and caregivers. The previously described challenges of pain assessment and evolving pharmacotherapy are the targets of current clinical research, actively pursued in both the developed and the developing world. There is great value in “adding life to the child’s years, not simply years to the child’s life.”27
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