Over the past two decades, there has been significant progress in the understanding of neuroanatomy, physiology, and the pharmacology of analgesics in children, which has led to considerable advancements in pediatric pain management. This chapter discusses developmental anatomy and neurochemistry, pain assessment, pharmacologic treatment of pain, and techniques for providing pain relief.
DEVELOPMENTAL ANATOMY AND NEUROCHEMISTRY
The Infants and fetuses in the last trimester are neurologically sophisticated in their ability to transmit pain signals and respond to stress.1 Cutaneous sensory nerve terminals are present in the perioral region at 7 weeks’ gestation and spread to all body areas by 20 weeks’ gestation. Nerve growth factors regulate the extension of peripheral nociceptive fibers into the dorsal spinal cord, with the larger A fibers entering prior to the C fibers at 8 to 12 weeks’ gestation. At birth, A and C fiber territories overlap in the developing substantia gelatinosa.2 Therefore, the neonatal response to a nonspecific sensory stimulus is low-threshold, nonspecific, and poorly organized, as are the well-defined neonatal motor reflexes.3,4 Noxious and non-noxious stimuli produce similar physiologic and behavioral infant responses, which complicate an accurate assessment of pain.5
In the central nervous system (CNS), the full complement of cortical neurons, approximately 1000 million, is present at 20 weeks’ gestation. Pain transmission pathways complete myelination in the spine and brain stem between 22 and 30 weeks’ gestation. Myelination extends to the thalamus by 30 weeks, and to the cortex by 37 weeks or term. Research using near-infrared spectroscopy (NIRS) shows activation of somatosensory cortex in preterm infants after noxious stimulation.5,6 Cortical descending inhibition develops post-term. Excitatory and inhibitory neurotransmitters and neuromodulators are present in the fetus, with the balance favoring excitation. Calcitonin gene-related peptide (CGRP), substance P, and the glutamate-NMDA systems are present at 8 to 10 weeks’ gestation. Enkephalins and vasoactive intestinal peptide (VIP) appear at 10 to 14 weeks’ gestation. Catecholamines are present in late gestation, and serotonin at 6 weeks’ postnatal. Of note, the receptors for excitatory neurotransmitters are numerous and widely distributed in the neonate, regressing toward an adult system in the postnatal months. As well, in the developing nervous system, inhibitory chemicals, such as γ-aminobutyric acid (GABA) and glycine, may act as excitatory transmitters. In an experimental murine model, the spinal cord concentration of N-methyl-D-aspartate (NMDA) receptors, and their ligand-affinity, is greater in neonates than in older animals. Neurokinin 1 (NK1) receptor density is also maximal in late fetal and early postnatal life; however, substance P levels are lower at birth than adult levels.7
In relation to stress responses, the functional neuroendocrine pathways between hypothalamus and pituitary are present at 21 weeks’ gestation. Corticotropin-releasing factor (CRF) may stimulate fetal adrenocorticotropic hormone (ACTH) and β-endorphin from that time period, and cortisol and β-endorphin increases have been assayed following intrauterine sampling for exchange transfusion. Norepinephrine is present in paravertebral ganglia and adrenal chromaffin cells at 10 weeks’ gestation and is released with intrauterine stress (asphyxia). A smaller amount of epinephrine is present after 23 weeks’ gestation.7
The long-term consequences of untreated pain in the developing organism are currently being defined, and a number of studies suggest that early pain responses influence later pain behaviors.8 In one murine model, skin wounds on rat pups caused increased innervation and lowered pain thresholds in the area of injury for 3 months postinjury. In the rats that had recurrent painful stimuli from birth, the changes in the receptive fields of the dorsal horn neurons were persistent.9 Another study exposed rat pups to repeated hindpaw injections over several days. When compared with control pups and at adult age, the rats that experienced repeated noxious stimuli showed increased responses to painful and nonpainful stimuli relative to their controls. Pathologically, the experimental group showed a loss of nociceptive primary afferents.10 A third study found that the pain-conditioned behaviors of rats differed according to the timing of the stimulus. Rat pups exposed to early, repetitive noxious stimulation had a decrease in pain threshold compared with control rats. Adult rats that were given repetitive painful stimuli showed greater stress responses, such as freezing and digging, than controls.11
In humans, pain in infancy influences plasticity in a number of pain transmission pathways, including peripheral nerve sprouting, dorsal horn sensitization, decreased descending inhibitory control, and priming of the stress/hypothalamo-pituitary-adrenal (HPA) axis.12 Many but predominantly empiric studies show late behavioral effects of painful stimuli, and the balance of potential pharmacologic toxicity versus adequate pain control is an important consideration.13 One report describes that neonatal males who received a eutectic mixture of topical local anesthetic prior to circumcision had 12% to 25% less facial grimacing and tachycardia than randomized control infants without treatment.14
An earlier study reported that males circumcised by 2 days of age had longer periods of crying and higher pain ratings than uncircumcised males.15
Another report compared 18 preterm infants, subject to repeated painful procedures in the neonatal intensive care unit (NICU), with matched full-term infants regarding their somatic complaints at 18 months of age. Twenty-five percent of mothers of preterm infants with prolonged NICU stays noted a significantly increased number of somatic complaints in their toddlers compared with zero percent of mothers of full-term infants briefly managed in the normal nursery.16 Alternatively, a recent study of 24 preterm infants compared with matched full-term infants had similar behavioral pain scores when exposed to a finger prick at 4 months of age.17
In summary, the neonatal pain transmission system is adequately developed, centrally hyperexcitable, with the necessary components of central sensitization, but generally nonspecific in its response to stimuli. Neonates and infants feel pain, but assessment of the phenomenon remains challenging.18,19,20 Long-term effects of neonatal pain are being investigated; however data support prevention and management of pain in the newborn.21
PAIN ASSESSMENT IN INFANTS AND CHILDREN
Pain assessment is a fundamental and essential part of pain treatment. The ability to assess pain reliably facilitates the diagnosis of painful conditions and to evaluate efficacy of pain relief methods. The assessment of pain in infants and children, however, is one of the most difficult challenges faced by health care providers (HCPs) in part because of differences in verbal and cognitive developmental abilities, differences in pain expression and perception, and the subjective nature of pain. For these reasons pain assessment in infants and children requires a comprehensive approach that utilizes self-report when available, observations, and physiologic measures. As discussed, there is evidence to suggest that inadequately treated pain can have both short-term and long-term consequences. For example, it is well established that full-term and preterm infants develop physiologic stress responses to pain and inadequate anesthesia that can result in greater postoperative complications.1,13-17 Self-report methods are considered to be the most reliable guides to pain assessment for most patients. However, infants and preverbal children are unable to communicate their experience of pain and must rely on caregivers to interpret signs of pain and distress. Pain assessment methods that combine self-report with other measures, such as behavioral and physiologic responses, may provide more accurate measures of pain. There can be limitations in the use of behavioral and physiologic indices for pain assessment. The distinction between pain and distress may be difficult in young children. For example, a young child may cry and exhibit characteristic facial grimacing during an ear examination because of fear and anxiety rather than pain. Physiologic signs may also mislead measures of pain in certain situations. For example, patients who are septic, hypoxic, or receiving vasopressors may exhibit increase in heart rate or blood pressure that reflect other processes not related to pain. Most pain scales are designed for assessment of acute pain and tend to underestimate persistent or chronic pain in children.22
Most pain assessment scales used for infants and preverbal children rely on behavioral observation and physiologic parameters to guide assessment. Observational measures alone may not represent pain intensity accurately because HCPs tend to underestimate pain when compared with a patient or parent report.23,24 Parent report also tends to underestimate children's pain but to a lesser extent than report by HCPs.25 Behavioral parameters typically used are facial grimacing, cry, body movement, and sleep pattern. The typical pain facial expression of eyes tightly closed, furrowed brows, and square mouth is considered to be one of the most consistent signals of pain in infants.26 Physiologic parameters such as heart rate, oxygen saturation, blood pressure, and palmar sweating provide objective evidence of pain.
The Premature Infant Pain Profile (PIPP) (Fig. 64-1) and CRIES (Fig. 64-2) are pain scales used for preterm and full-term infants, respectively, that combine behavioral observations and physiologic criteria to assess pain.27,28
Premature infant pain profile.
Absent is defined as 0 to 9% of the observation time; minimal, 10% to 39% of the time; moderate, 40% to 69% of the time; and maximal as 70% or more of the observation time. In this scale, scores vary from 0 to 21 points. Scores equal or lower than 6 indicate absence of pain or minimal pain; scores above 12 indicate the presence of moderate to severe pain. GA – Gestational Age. NB – Newborn.
The PIPP was specifically designed to assess acute pain in preterm infants with consideration to gestational age. The CRIES scale, an acronym for Crying, Requires O2, Increased vital signs, Expression, and Sleepless, consists of five behavioral and physiologic parameters designed to rate postoperative pain in neonates.
The FLACC scale combines five types of pain behaviors, including facial expression, leg movement, activity, cry, and consolability which have been shown to have good interrater reliability and validity in children (Fig. 64-3). It is widely used because it is quick, versatile, and can be applied to infants and older children, including those with developmental disabilities.29
Each of the five categories (F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolability is scored from 0-2, which
results in a total score between 0 and 10.
Children aged 3 to 7 years become increasingly able to communicate their experience of pain to parents and caregivers. Children in this age group may not understand the abstract concept of pain, but most are able to indicate pain intensity using either pictographic or faces scales30,31,32 (Figs. 64-4, 64-5). Although self-report measures are most reliable, a number of factors may alter a child's report of pain.33 For example, children with inadequately treated persistent pain from cancer or surgery may appear very quiet, still, and withdrawn, giving a false impression of adequate analgesia. Some children may underreport or deny pain for fear of receiving a painful analgesic “shot.” Numeric scales are not useful in this age group because although many are proficient at counting, children younger than 7 years do not understand the quantitative significance of numbers. Several self-report methods have been developed that are validated and reliable in children as young as 4 years of age.34,35,36 The Bieri faces scale is a series of facial expressions depicting degrees of pain and was found to be preferred by most children.37,38
Bieri faces scale. (From Bieri D, et al. The Faces Pain Scale for the self-assessment of the severity of pain experienced by children: development, initial validation, and preliminary investigation for ratio scale properties. Pain. 1990;41:139)
Wong-Baker pain rating scale. (Reprinted, with permission, from Hockenberry M, Wilson D, Winkelstein ML. Wong's Essentials of Pediatric Nursing, 8th ed. Copyright 2009, Mosby, St. Louis)
Children aged 8 years and older generally can use standard “0 to 10” visual analog scales accurately, but many of the scales used in younger children such as the Bieri faces can also be used. Children in this age group may have concerns over loss of control, or may fear painful injections of analgesics that can distort their self-report. Older children and adolescents have the cognitive ability to understand the meaning of pain and tend to use behavioral coping strategies for pain.
Pain assessment in children with developmental disabilities is particularly challenging for parents and caregivers. Pain assessment in this population of children must be based on the child's individual abilities. Some children with developmental disabilities can self-report and should be given this opportunity. Others require behavioral or physiologic measures of pain. In the last decade, several pain assessment tools have been developed addressing the specific needs for this patient population.39,40,41
In general, pain assessment is best accomplished by correlation of self-report, behavioral, and physiologic measures with the child's overall clinical picture. The choice of pain assessment scale should be individualized and based on a child's age, clinical condition, environment, cognitive abilities, and coping style. Often, explanation and practice of the chosen pain assessment scale during the preoperative visit can facilitate the child's use after surgery.
PHARMACOLOGIC GUIDELINES IN THE NEWBORN AND INFANT
Infants and young children have age-related differences in the pharmacokinetics and pharmacodynamics of analgesics which are relevant to the safe and effective dosing of analgesics in this age group. Analgesics with high-water solubility have a larger volume of distribution, sometimes resulting in the need for larger initial dosing. However, neonates and young infants have immature hepatic enzyme systems involved in conjugation, glucuronidation, and sulfation of analgesics such as opioids and amide local anesthetics, which cause prolongation of elimination half-life and increase the risk of drug accumulation. Most infants and young children will have maturation of hepatic enzyme systems by 6 months of age; however, there is considerable variation in maturation rates. Neonates have decreased plasma-protein binding due to decreased levels of albumin and α1 acid glycoprotein, resulting in increased free pharmacologically active drug and greater first-pass toxicity. Renal function, including glomerular filtration and renal tubular secretion, is decreased in the first few weeks of life compared with adults. Renal immaturity also results in the slower elimination of glucuronides of morphine, hydromorphone, and of monoethylglycinexylidide (MEGX), a principal metabolite of lidocaine. In addition, infants, particularly premature infants have immature ventilatory reflexes in response to hypoxia and hypercarbia and have increased risk of hypoventilation in response to opioids. Because of the developmental pharmacokinetic and pharmacodynamics differences in neonates and young children, dosing of opioids and local anesthetics require careful titration and increased vigilance for side effects.
PHARMACOLOGIC TREATMENT OPTIONS
Non-opioid analgesics include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and selective cyclooxygenase (COX-2) inhibitors. Analgesic effect occurs from peripheral and central actions involving inflammatory processes in the spinal cord and brain.42,43 Because of their opioid-sparing effect, non-opioid analgesics are often first-line treatment for mild to moderate pain in children.
Acetaminophen is the most commonly and widely used analgesic in children and has a good safety record in children of all ages.44 The analgesic and antipyretic effects of acetaminophen are largely via sites within the CNS through action at cyclooxygenase (COX-3 and COX-2) isoenzymes, cannabinoid receptors, and on tyrosine-related protein (TRPV1) receptors.45,46 Although a weak analgesic, acetaminophen is a useful adjuvant for acute pain treatment and is often combined, synergistically, with opioids. The elimination of acetaminophen is primarily through glucuronidation and sulfation; elimination rates are similar among infants, children, and adults.47 The recommended single dose is 15 to 20 mg/kg and 10 to 15 mg/kg with repeated dosing. Maximum daily dosing is 100 mg/kg/day in children, 75 mg/kg/day in term infants, and 40 mg/kg/day in preterm infants. Inadvertent overdosing can lead to fulminant hepatic failure.48,49 Acetaminophen is available in several routes of administration—intravenous (IV), tablets, capsules, suspensions, and suppositories. Concentrated infant drops have been discontinued to reduce inadvertent overdosing.50,51 The IV dosing in children 2 to 12 years is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours with a maximum daily dose of 75 mg/kg/day. The rectal dose is 35 to 40 mg/kg initially followed by 20 mg/kg every 6 to 8 hours; absorption is low and variable. Rectal absorption peaks at 70 minutes.52,53
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for mild-to-moderate pain and are often combined with opioids to improve analgesia and to help reduce opioid side effects. The use of NSAIDs has been shown to reduce postoperative opioid use by approximately 30% to 40%.54 The anti-inflammatory effect of NSAIDs is through reversible inhibition of COX-1 and COX-2 isoenzymes and inhibition of the conversion of arachidonic acid to prostanoids.55 The clearance of ibuprofen, ketorolac, and several other NSAIDs is more rapid in toddlers and preschool children compared with adults.56 NSAIDs in general have a good safety margin in children 6 months of age and older, particularly with short-term use. A large-scale study in children administered short-term use of ibuprofen showed a very low overall risk of severe side effects.57 There are limited safety data on the use of NSAIDs in neonates and young infants.58,59 Much of the pharmacokinetic and safety data of NSAIDs in use in neonates come from the use of ibuprofen and indomethacin to facilitate closure of patent ductus arteriosus. Ibuprofen is associated with less risk of renal toxicity and hyponatremia compared with indomethacin in this age group. Significant bleeding caused by NSAIDs is relatively uncommon in healthy children. There are mixed data regarding the risk of NSAIDs use in children after tonsillectomy procedures.60-62 Although analgesic trials show good analgesia, due to the potential risk of life-threatening bleeding after tonsillectomy procedures, the practice at this institution is to avoid NSAIDs in the perioperative period for children undergoing tonsillectomies. There is evidence in adult patients to suggest that NSAID use can impair bone healing after orthopedic surgeries that involve osteoclast activation and new bone formation. Children are less likely to have impairment of new bone formation; however, it is reasonable to avoid use of NSAIDs in children after orthopedic surgeries requiring significant active bone formation. Table 64-1 lists dosing of commonly used non-opioid analgesics.
Dosing Guidelines for Non-Opioid Analgesicsa
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Dosing Guidelines for Non-Opioid Analgesicsa
| || |
Dose < 60 kg
Dose > 60 kg
10–12.5 mg/kg q4h PO or IV
650 mg q4h PO or IV
6–10 mg/kg q6–8h PO
400–600 mg q6h PO
5 mg/kg q12h PO
250–500 mg q12h PO
2–4 mg/kg q12h PO
100–200 mg q12h PO
0.5 mg/kg q6–8h IV, not for > 5 d
30 mg q6–8h IV, not for > 5 d
Opioids are widely used for the treatment of infants and children with moderate-to-severe pain. Safe and effective administrations of opioids require careful patient selection, an understanding of age-related differences in metabolism, dose titration, and aggressive treatment of opioid side effects.
As discussed, opioids are associated with an increased risk of respiratory depression and apnea and a prolonged duration of action in neonates and infants, particularly in premature infants, because of delayed hepatic enzyme maturation and immature renal excretion. Neonates and young infants also have reduced protein binding as a result of developmental changes in the expression of P-glycoproteins in the gastrointestinal tract and in the blood-brain barrier. Data from infant rat models show immature opioid receptor sites in the peri-aqueductal gray matter and descending pathways. Studies of use of opioids for procedural pain in neonates have shown mixed results; randomized trials assigning ventilated neonates to receive morphine infusions versus placebo infusions have not shown clear advantages in the morphine infusion groups.63,64 In addition to neonates and young infants, others at risk for opioid-induced respiratory depression include children with obstructive sleep apnea, children with craniofacial abnormalities, and children with neurologic conditions. Dose reduction with careful dose titration, cardiorespiratory electronic monitoring, and close observation are necessary for safe and effective opioid treatment in neonates, infants, and children at risk for respiratory side effects.
Evidence indicates that codeine is ineffective as an analgesic and is associated with significant side effects.65-68 Codeine is a pro-drug and is converted to morphine through the CYP2D6 enzyme pathway. There is significant polymorphism of CYP2D6 enzymes, leading to patients who are poor metabolizers, rapid metabolizers, and ultra-rapid metabolizers.69,70 Pharmacogenic data show that 30% of children are poor metabolizers and unable to convert codeine to morphine, making codeine inactive in these patients.71 Gene duplication in ultra-rapid metabolizers increases the amount of morphine metabolized from codeine. There have been fatalities and life-threatening events due to opioid overdose among children who were ultra-rapid metabolizers.70,72 Breast-fed infants are at risk of overdose when their lactating mothers, having been prescribed codeine-containing products for postpartum analgesia, are ultrarapid metabolizers.73 As a result of the safety and efficacy concerns for codeine, our institution has removed codeine from its formulary and from all medical record prescription software.74,75
Oxycodone is widely used in children with moderate pain, particularly in the postoperative setting when transitioning from IV opioids to oral opioids. It is metabolized via CYP3A4 to inactive metabolites, although a secondary pathway involving CYP2D6 generates potent oxymorphone, which is renally eliminated and has been associated with increased risks among ultrarapid metabolizers.76,77 Pharmacokinetic data of oxycodone in children show significant variability in clearance and elimination half-life, particularly in neonates.78 Our prevailing impression is that oxycodone is associated with fewer side effects in children compared with codeine. Typical starting doses are 0.05 to 0.1 mg/kg every 4 hours as needed for mild pain and 0.1 to 0.2 mg/kg every 4 hours as needed for moderate to severe pain. Oxycodone is available in an elixir form for children unable to swallow pills. Sustained-release preparation of oxycodone (OxyContin) is used for older children with chronic pain requiring opioids.
Morphine is often the first-line opioid considered for parenteral use in children. There is extensive pharmacokinetic data for morphine in children of all ages.79-82 Metabolism occurs primarily in the liver via glucuronidation to morphine-3-glucuronide which has neuroexcitatory properties such as delirium, myoclonus, and agitation; and to morphine-6-glucuronide which has analgesic, sedative, and respiratory depressant actions. Glucuronides are renally eliminated and can accumulate in children with renal failure. Data suggest that morphine is metabolized preferentially to morphine-3-glucuronide in neonates, increasing the potential risk of seizures in this age group. Elimination half-life of morphine is prolonged in infants and neonates, particularly in premature infants whereas clearance of morphine is reduced, increasing the risk of opioid side effects.82,83
Due to similar duration of action to morphine, hydromorphone is often used for patient-controlled analgesia (PCA) in children. It is metabolized primarily in the liver via glucuronidation and is five times more potent than morphine when given IV in steady-state dosing.84 Hydromorphone is metabolized to glucuronides that can accumulate in patients with renal failure. There is little data about the metabolism of hydromorphone in neonates. Randomized blinded comparisons between morphine and hydromorphone have found few differences in the frequency of side effects.85
Methadone has a long elimination half-life with a prolonged duration of action; however, there is significant variability in elimination half-life, ranging from 6 to 30 hours. The bioavailability is approximately 70% to 90%.86,87 Methadone can produce analgesia similar to that achieved by continuous infusion of other opioids when administered at prolonged dosing intervals. It can also be given orally in liquid form to young children in place of sustained-release preparations that are in pill form. The action of the d-isomer of methadone resulting in NMDA receptor antagonism is the basis for its use in the treatment of neuropathic pain.88 Because of incomplete cross-tolerance, dose conversion between methadone and other mu opioids is often complex and different for opioid-naïve versus opioid-tolerant patients such that opioid-tolerant patients are likely to require much less methadone for equianalgesic dosing when switching from other mu (µ) opioids.89,90 This is particularly relevant when converting morphine to methadone in children with advanced cancer and when weaning nonventilated children from prolonged opioid therapy.91 For acute postoperative pain management in opioid-naïve children, our practice is to use an every 4 hour “sliding scale” of 0.025 mg/kg for mild pain, 0.05 mg/kg for moderate pain, and 0.075 mg/kg for severe pain. Patients are then converted to regular scheduled dosing after the first 24 hours. Because of its unique pharmacokinetic properties of prolonged but variable elimination half-life and incomplete cross-tolerance, methadone requires careful titration and vigilance to avoid overdosage.
Fentanyl is highly lipophilic and is 70 to 100 times more potent than morphine when given as a single dose. It is primarily metabolized in the liver to inactive metabolites, making it useful for patients with renal failure. The brief effect of a single dose of fentanyl is due largely to redistribution; however, with a continuous infusion or with repeated doses, the effect is much more prolonged and is more determined by elimination rather than redistribution.92 The context-sensitive half-life of fentanyl is particularly prolonged in neonates receiving continuous infusions.93
Because single dosing of fentanyl has a rapid onset and brief duration, it is often used for procedural sedation in children undergoing lumbar punctures, bone marrow biopsies, dressing changes, and other brief painful procedures either alone or in combination with benzodiazepines or general anesthesia.94,95 Doses of 0.5 to 1 µg/kg titrated every 3 to 5 minutes typically provide effective procedural sedation. Rapid administration may cause glottis and chest wall rigidity which can be particularly prominent in neonates; treatment may require assisted ventilation, and in some cases neuromuscular blockade and naloxone. Oral transmucosal fentanyl is also used for brief painful procedures in children and for children with cancer pain.96 The bioavailability is approximately 50% since the oral transmucosal dose is partially absorbed through the buccal mucosa and partially swallowed.97 Most children tolerate oral transmucosal dosing; however, almost 90% of children experience facial pruritus. Transdermal fentanyl is used in select opioid-tolerant children with cancer pain, chronic pain requiring opioids, and in select opioid-tolerant children with limited IV access.98,99 After initial patch application or with dose changes, approximately 12 to 24 hours are needed to reach steady-state thus making transdermal fentanyl not effective for treating rapidly fluctuating pain. Adverse events including death have been reported with transdermal fentanyl use for opioid-naïve patients, particularly when used for acute postoperative pain.100
Intravenous Opioid Administration
Intermittent IV bolus dosing is a common method of opioid administration; however, it is associated with wide swings in plasma opioid concentrations and fluctuations in analgesia and opioid side effects. Plasma opioid concentration is typically low prior to a bolus dose, resulting in suboptimal analgesia but with relatively few opioid side effects. After the bolus dose is administered, patients experience effective analgesia but often with significant side effects because plasma opioid concentrations are sometimes supratherapeutic. Continuous opioid infusions tend to provide stable levels of analgesia with steady-steady plasma opioid concentration; however, this method does not account for changes in pain intensity such as with chest physiotherapy or with coughing. Patient-controlled analgesia (PCA) takes into account individual variations in opioid pharmacokinetics and fluctuations in pain intensity. It is widely used for postoperative pain control in children as well as in the treatment of cancer pain and pain due to vaso-occlusive crises. Most children older than 6 years of age can use PCA effectively; there is a higher incidence of failure among younger children because of the inability to understand the causal relationship between pushing the PCA button and receiving medication for pain. Nurse-controlled analgesia (NCA) has been shown to be safe and effective and is commonly used for infants, young children not able to understand how to use PCA, children with cognitive limitations and those with physical limitations.101 Morphine, hydromorphone, and fentanyl are most commonly used in PCA. There is evidence that basal infusions tend to improve sleep and pain scores although other data show an increased risk of hypoventilation, respiratory pauses, and nighttime oxygen desaturation.102,103
Our practice is to use demand dose only for children who received peripheral nerve catheters for postoperative pain and for those who are expected to have mild-to-moderate postoperative pain. Children expected to have severe postoperative pain such as those having spinal fusions and major hip surgery typically receive a basal infusion for the first 1 to 2 days postoperatively. Children with cancer pain and with painful vaso-occlusive crises generally receive approximately 40% of their total opioid dose through a basal infusion. Parent-controlled analgesia is primarily reserved for select cases of children in palliative care setting.
Safe opioid administration requires protocols to detect oversedation, signs of respiratory depression and impending respiratory failure. Protocols should include regular nursing assessments to document level of pain and sedation, vital signs, and the use of cardiorespiratory monitoring when indicated. In general, we recommend cardiorespiratory monitoring for children younger than 6 months, infants with history of apnea and bradycardia, opioid-naïve children receiving a continuous opioid infusion, and other children with neurologic or structural anomalies that increase the risk of respiratory depression. Typical starting doses for PCA are listed in Table 64-2.
Typical Starting Doses for Patient-Controlled (Nurse-Controlled) Analgesia
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Typical Starting Doses for Patient-Controlled (Nurse-Controlled) Analgesia
Treatment of Opioid Side effects
All opioids produce side effects that in some cases can be as distressing to children as pain. Infants and preverbal children experiencing intolerable pruritus or nausea from opioids can present with crying, irritability, and other behaviors that may be interpreted by caregivers as pain. Side effects occur by actions at both peripheral and central sites. For example, opioid-induced nausea and vomiting involve activation of receptors in the brainstem and the gastrointestinal tract.104 Some opioids produce pruritus by peripheral release of histamine; however, small doses of intrathecal morphine are associated with profound pruritus, supporting a neurogenic central cause involving signaling and neurotransmission in the spinal dorsal horn and nucleus caudalis. Standardized protocols and ordersets for treatment of opioid side effects allow for prompt initiation of therapy. Data show that low-dose infusions of naloxone are effective in children for the treatment of opioid-induced nausea, vomiting, and pruritus without reversing analgesia.105 A study measuring plasma levels of naloxone and morphine found comparable levels in children who had good relief of side effects compared with those who failed therapy suggesting that the effectiveness of naloxone in treating opioid side effects was unrelated to plasma levels.106
Methylnaltrexone is a peripherally constrained opioid antagonist that blocks opioid actions in the gastrointestinal tract and can be effective in treating opioid-induced constipation in children.107,104 Table 64-3 outlines the treatment of common opioid side effects in children.
Management of Common Opioid Side Effects
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Management of Common Opioid Side Effects
Consider switching to different opioid
10–30 kg: 1–2 mg IV q 8 h>30 kg: 2–4 mg IV q 8 h
Naloxone infusion 0.25–1 µg/kg/h
Metoclopramide 0.1–0.2 mg/kg
PO/IV q 6 h
Exclude other causes (e.g., drug allergy)
Consider switching to different opioid
Nalbuphine 10–20 mg/kg/dose IV q 6 h
Naloxone infusion 0.25–1 µg/kg/h
Add nonsedating analgesic (e.g., ketorolac) and reduce opioid dose
Consider switching to different opioid
Methylphenidate 0.05–0.2 mg/kg PO bid (morning and midday dosing)
Dextroamphetamine 5–10 mg every day
Regular use of stimulant and stool softener laxatives
Child: 10–40 mg PO daily
Adults: 50–200 mg PO daily
Child: 5 mg PO/PR daily
Adult: 10 mg PO/PR daily
REGIONAL ANESTHESIA AND LOCAL ANESTHETICS IN INFANTS AND CHILDREN
Over the past 30 years, pediatric applications of postoperative regional anesthesia and analgesia have expanded rapidly.108 Regional anesthesia techniques are also used for the diagnosis and treatment of a variety of chronic pain conditions. In contrast to adults who are able to report paresthesias, severe pain with needle insertion and symptoms of local anesthetic toxicity, most regional anesthesia in children is performed under deep sedation or general anesthesia. A number of motivated, older children may require sedation only for certain blocks. There are prospective and retrospective safety studies that support the safe and widespread practice of performing regional anesthesia under general anesthesia in children.109-111 A multi-center consortium of pediatric centers in the United States (Pediatric Regional Anesthesia Network) prospectively collected data on all regional blocks and showed overall very good safety of neuraxial and peripheral blocks in infants and children performed by clinicians in the participating hospitals.111 Totals of nearly 15,000 blocks were performed in a 3-year period. Ninety percent of blocks were placed under general anesthesia. There were no deaths or complications with sequelae lasting greater than 3 months. Respiratory depression in several patients receiving neuraxial opioids was detected by respiratory monitoring, which stresses the importance of electronic respiratory monitoring and vigilance required in patients receiving neuraxial opioids. There were no cases of local anesthetic toxicity; however, there were several cases of positive test doses. Our provisional recommendations for epidural analgesia in anesthetized children:
Limit epinephrine dosing to the test dose (0.5 µg/kg in 0.1 mL/kg)
Prevent or promptly treat severe hypotension
Consider severe hypertension following a test dose to possibly indicate severe pain response to intraneural placement
Perform loss of resistance to saline, not air
Use dilute local anesthetic solutions for intraoperative epidural solutions; inject bolus doses slowly
In the postanesthetic care unit, document degree of sensory and motor blockade. If blockade appears dense, stop the infusion and assess for clear regression.
Epidural analgesia is widely used for infants and children undergoing a number of surgical procedures, such as lower extremity and pelvic orthopedic surgery, major abdominal surgery, thoracic procedures and for certain chronic pain conditions such as Complex Regional Pain Syndrome.
Bupivacaine, ropivacaine and, in select cases, chloroprocaine are most frequently used local anesthetics for continuous epidural infusions in infants and children (Table 64-4). Pharmacokinetic studies of bupivacaine in children older than 6 months have reported good safety for infusion rates of bupivacaine of below 0.4 mg/kg/h with plasma bupivacaine levels in a safe range of less than 2 to 3 μg/mL.112 Neonates have reduced clearance of bupivacaine and pharmacokinetic studies in neonates receiving continuous bupivacaine infusions have shown a continuous rise in plasma bupivacaine levels after the first 48 hours.
Recommended Epidural Infusion Rates (mL/kg/h)a
Our practice is to use a maximum dose of 0.4 mg/kg/h of bupivacaine for continuous epidural infusions in children over the age of 6 months. For children younger than 4 to 6 months of age, we restrict the dose of bupivacaine to 0.2 mg/kg/h. Pharmacokinetic studies in infants and children receiving single boluses of epidural ropivacaine show that as with bupivacaine, clearances for ropivacaine are reduced in infants. Overall, infusion rates of 0.4 mg/kg/h in older infants and children and 0.2–0.3 mg/kg/h in neonates and younger infants appear to be safe.113-115
Because of the limitations in dosing of amide local anesthetics in young infants, we typically use adjuvants such as opioids and clonidine to epidural infusions for synergistic effect. Studies of combinations of epidural clonidine with local anesthetics in children have shown a low side-effect profile.116 Epidural infusions containing hydromorphone are rarely used in infants younger than 6 months due to increased risk of respiratory depression. Chloroprocaine is used as an alternative to amide local anesthetics for continuous epidural infusions in neonates and very young infants to avoid the toxicity of amide local anesthetics and to safely permit sufficient epidural infusion rates. Even in neonates, chloroprocaine is rapidly metabolized with an elimination half-life of less than 6 minutes, making it an attractive choice for continuous epidural infusions in neonates. Studies of continuous epidural chloroprocaine infusions in term and preterm infants have shown good sensory blockade with no signs of neurotoxicity.117
All patients with continuous epidural infusions require electronic monitoring, careful nursing observation and regular assessment of level of sedation, pain score and measurement of vital signs. Table 64-4 lists recommended doses for epidural infusions.
Prospective and retrospective data have demonstrated the safety of peripheral nerve blocks in children with very good postoperative pain management. Advances in the use of ultrasound and an increased understanding of age-related pharmacology of local anesthetic have greatly increased the use of peripheral nerve blocks in children. A general trend of clinical trials of regional blocks is an observation of effective analgesia with low adverse events that compares favorably to systemic opioids or epidural infusions. In a randomized trial comparing popliteal block with epidural analgesia for foot and ankle surgery, popliteal block results in superior analgesia with reduced incidences of nausea, vomiting, and urinary retention.118 Peripheral nerve catheters are used increasingly in infants and children for a number of upper and lower extremity and truncal surgical procedures, as well as in select patients with chronic neuropathic pain to facilitate physical therapy. Multicenter prospective registry will provide ongoing monitoring of adverse events, data on techniques and outcome data.
PAINFUL CONDITIONS IN PEDIATRIC HOSPITAL CARE
Infants and children with cancer experience a number of types of pain related to cancer treatment and to their disease process. Pain from cancer treatment can result from painful mucositis, postamputation pain, repeated painful needle procedures, and peripheral neuropathies. Tumor-related is often present as disease progresses to bone, spinal cord, and neural plexuses. Children with hematologic malignancies often experience bone pain from bone marrow infiltration and abdominal pain from capsular stretch of liver and spleen. Evidence suggests that as successful chemotherapeutic protocols, radiation therapy and surgical techniques have evolved for pediatric cancers, pain related to cancer treatment accounts for the more predominant source of pain and suffering in infants and children.119
Infants and children undergoing treatment for cancer frequently require diagnostic and sometimes painful procedures such as lumbar punctures, radiation therapy, bone marrow biopsies and central line insertions and removals. Topical analgesia should be used routinely for minor needle procedures such as IV line insertions and assessing implanted vascular access ports. Cognitive-behavioral interventions such as hypnosis and relaxation techniques have shown to be effective for procedural pain.120 Conscious sedation or general anesthesia is used for more invasive needle procedures such as bone marrow biopsies and lumbar punctures and for radiation therapy requiring immobility.
Mucositis is painful inflammation of the mucosa and is a common side effect in children receiving chemotherapy or radiation. Mucositis is especially severe and prolonged with bone marrow transplantation. Topical agents are often used but with limited data regarding efficacy. Parenteral opioids through PCA or NCA are generally used for moderate to severe pain from mucositis. Data support the safety and efficacy of opioid infusions and PCA for the treatment of mucositis.121,122
Our practice is to administer approximately 60% of the total daily opioid dose through a basal infusion to provide sustained analgesia and without requiring the patient to use the PCA button repeatedly during the day and night. There are data showing efficacy of low-dose ketamine infusion for children with severe mucositis pain not relieved by standard PCA or NCA.123-125
Many children will have resolution of cancer pain after initial chemotherapy induction; however, some children will continue to experience pain due to tumor invasion of solid organs, bone, nerves and plexuses. Morphine, hydromorphone and other opioids are titrated to effect as pain escalates.126 Oral opioids are generally used when possible. For children with persistent pain, it is useful to use a long-acting opioid such as methadone or sustained-release preparations of opioids. Short-acting morphine, hydromorphone, oxycodone, or other opioids are added for breakthrough pain. Oral methadone is a long-acting opioid available as an elixir formulation and is useful for children unable to swallow pills. Parenteral opioids are used for patients whose pain is rapidly escalating, are unable to tolerate oral opioids due to nausea, vomiting, painful mucositis, or are unable to swallow. Continuous infusions and PCA or NCA allow rapid titration for escalating pain. Opioid side effects should be aggressively treated. We frequently prescribe anticonvulsants and antidepressants for children who experience neuropathic pain although this practice is extrapolated from adult data.127,128 Children with advanced cancer have a number of overlapping symptoms including fatigue, somnolence, sleep disturbance, and depressed mood.129 Fatigue and sedation can be a result from the use of opioids and other sedating medications or from the underlying disease process.
Dose escalation of opioids effectively treats cancer pain for most children. However, some children will continue to experience unremitting pain despite massive doses of opioids. Refractory pain not well controlled by massive dose escalation of opioids is typically seen in children with exquisite neuropathic pain from tumor invasion to spinal cord and major nerves. Low-dose ketamine infusion can be used in this setting; rates below 0.2 mg/kg/h are generally well-tolerated with low rates of dysphoria and dissociation.125 Our approach to persistent refractory neuropathic pain in this setting is to use regional anesthetic techniques such as implanted intrathecal ports with the catheter advanced to the dorsal horn level nearest the patient's location of pain. We prefer intrathecal route rather than epidural placement because epidural dosing of local anesthetics is limited by systemic toxicity.
CHILDREN WITH CYSTIC FIBROSIS
Patients with cystic fibrosis (CF) experience a range of pain including chronic back pain, abdominal pain, and limb pain. The incidence of chronic pain, particularly headache and chest pain increases sharply during the last 6 months of life.130
Chest pain is the most commonly reported pain among children with CF, regardless of the severity of lung disease and is usually multifactorial. Recurrent coughing and increased work of breathing result in chronic musculoskeletal chest pain. Severe coughing can produce rib fractures and severe pleuritic chest pain.
Greater than 50% of patients with CF report chronic headaches. Causes of headaches in this patient population include chronic hypoxia and hypercarbia, migraines, chronic musculoskeletal strain from coughing, and chronic sinusitis. Sinus disease is found in most patients with CF; surgery can help to treat underlying sinus disease and reduce pain for some patients. As disease progresses, headaches due to hypercarbia, hypoxia, and constant coughing are common.
The treatment of chronic pain in patients with CF depends on the nature of pain, the severity of lung disease and disease progression, as well as individual patient responses to NSAIDs and opioids. NSAIDs are often used in combination with opioids for opioid-sparing effect. There may be a role for COX-2 inhibitors in patients with pain and frequent hemoptysis. Because patients with CF experience a high incidence of constipation with opioids, aggressive use of stimulant laxatives and methylnaltrexone should be considered. We commonly use thoracic epidural analgesia or bilateral paravertebral catheter infusions for patients with CF undergoing lung transplantation. Many patients with CF who require lung transplantation have severe chronic chest pain and we typically use slightly more concentrated infusions of local anesthetics to achieve optimal analgesia. Patients with CF and severe pain from rib fractures may benefit from thoracic epidural catheter or from thoracic paravertebral catheter infusions.
PAIN ASSOCIATED WITH SICKLE CELL VASO-OCCLUSIVE EPISODES
Children with sickle hemoglobinopathies experience pain from acute vaso-occlusive episodes as well as pain from compression fractures, avascular necrosis, acute cholecystitis, splenic sequestration, priapism, and stroke. Painful vaso-occlusive episodes are the most common causes of pain in children with sickle cell disease and can occur in children as young as 6 months of age as the protective effect of fetal hemoglobin decreases. Painful vaso-occlusive crises are typically unpredictable in severity and location and can range from mild episodes managed at home with oral analgesics to frequent and severe exacerbations requiring numerous hospitalizations and IV opioid administration. Children with severe pain or escalating pain generally require hospitalization and treatment with PCA and NSAIDs.131,132
Surveys suggest that even with generous opioid dosing, pain scores remain high for a considerable percentage of patients.133 Patients with severe chest pain high despite doses of opioids may experience excessive somnolence, inability to cough effectively leading to worsening hypoxia, and further pulmonary decline. For selected patients, continuous epidural analgesia or paravertebral catheter infusions can result in improved analgesia while decreasing systemic opioids and somnolence.
Over the past 20 years, there have been significant clinical advances in the treatment of acute pain in children. Improved analgesics, better understanding of pediatric pharmacology and neurodevelopment, and increased experience in regional techniques in children have led to these clinical advances. Optimal management of acute pain requires reliable assessment of pain and aggressive management of pain and side effects with consideration to emotional and social factors contributing to pain. Multicenter clinical trials will be helpful for conducting adequately powered research for many forms of acute and chronic pain in pediatrics.
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