SECTION E: Pediatric and Geriatric Pain

INTRODUCTION

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

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

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 scales^30,31,32 (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

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

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.

OPIOIDS

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.

Codeine

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

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

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

Hydromorphone

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

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

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.

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.

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:

1. Limit epinephrine dosing to the test dose (0.5 µg/kg in 0.1 mL/kg)

2. Prevent or promptly treat severe hypotension

3. Consider severe hypertension following a test dose to possibly indicate severe pain response to intraneural placement

4. Perform loss of resistance to saline, not air

5. Use dilute local anesthetic solutions for intraoperative epidural solutions; inject bolus doses slowly

6. 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

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.

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.

PERIPHERAL NERVE BLOCKS

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

Cancer Pain

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.

SUMMARY

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.

REFERENCES

INTRODUCTION

Children may experience a variety of recurrent chronic pain, such as headache or abdominal pain. Chronic pain is more common in children than persistent pain and is less likely to be associated with underlying organic disease. Some common conditions that may turn chronic pain into persistent pain include rheumatoid arthritis, malignancies, sickle-cell disease (SCD), and neuropathic pain syndromes.

The management of chronic pain is an important part of pediatric practice. It requires an understanding of pediatric illnesses as well as the psychosocial aspects of chronic pain conditions experienced by children. Most of the pediatric pain and related problems are undertreated. Because of the complex nature of chronic pain, treatment is often approached from a broad-based, comprehensive medical model that utilizes the expertise of psychologists, neurologists, anesthesiologists, nurses, and other health care providers (HCPs). This chapter evaluates some common types of recurrent and persistent pain in infants and children and summarizes treatment strategies, including pharmacologic and nonpharmacologic therapies.

HEADACHES

Recurrent headaches are an exceedingly common form of recurrent pain in pediatric patients. The most common types of headaches children experience include migraine, tension headache, and combined migraine-tension headache. Up to 10% of all children experience recurrent headaches.¹ The prevalence of nonmigrainous headache in childhood and adolescence is 10% to 25%.² Migraine headaches are more commonly experienced by boys than girls in early childhood but become more common in girls upon reaching puberty. There is usually a strong family history of migraine headaches. Children typically report an abrupt onset of unilateral or bilateral severe, throbbing headache pain, which is often associated with nausea and vomiting. Although some children experience classic visual or auditory auras of migraine, many experience more subtle premonitory signs such as pallor, irritability, and fatigue.³ Patients typically experience relief after sleep. Tension headaches are most common among adolescents. Typically, there is no associated aura, nausea, or vomiting. These headaches are usually described as a squeezing pain located circumferentially around the head. It is not uncommon for patients with tension headaches to experience them daily. Children with combined headaches experience both chronic tension headache and episodic acute migraine headache and their associated abdominal pain, nausea, and vomiting. The diagnosis of chronic daily headache is made when headache has been present for more than 15 days per month, with a duration of 3 months or longer.

Chronic progressive headache is most likely the result of a secondary etiology, such as changes in intracranial pressure, infection, or neoplasm.⁴

Most headaches in children are not associated with serious underlying intracranial pathology or organic disease. A thorough history and physical examination are essential and should include a careful neurologic with funduscopic examination. A psychosocial history is also beneficial in helping to determine whether family stressors or maladaptive behaviors might play a causative role in reinforcing pain behaviors. A history of personality changes, visual disturbances, fever, and headaches associated with neurologic deficits are signs that neuroimaging is indicated. Chronic progressive headache or focal symptoms on neurologic examination warrant neuroimaging to investigate for structural abnormalities or malignancies. The routine use of diagnostic studies is not indicated when the clinical history reveals no associated risk factors and the child's examination is normal.⁵

Treatment for headaches in children includes the use of both pharmacologic and nonpharmacologic therapies. Patient and family education should be provided, along with reassurance that a most worrisome cause of headaches is unlikely and that reevaluation will be ongoing. Often, a diary will be kept by the patient, documenting the characteristics of the headaches, medications tried, diet, and stress level at the time of onset to identify aggravating factors. Modifications or any disruptions to the patient's lifestyle such as increasing physical activity as the patient can tolerate it, improving school attendance, and restoring sleep hygiene are important. In addition, cognitive-behavioral interventions can alleviate headache pain and promote functional and adaptive behavior.

Combinations of analgesics, antiemetics, and 5-HT serotonin agonists are commonly used abortive migraine therapies for children. Nonsteroidal anti-inflammatory drugs (NSAIDs) are often first-line agents for migraines, tension headaches, and combined headaches.⁶ Patients should be instructed about proper dosing, as excessive use of NSAIDs, acetaminophen, and combination drugs such as Fioricet can cause rebound headaches.⁷ Systematic reviews of NSAIDs among adult patients report little difference in their clinical effectiveness. However, parenteral NSAIDs such as ketorolac are often used in patients with persistent vomiting who cannot tolerate oral intake. In a randomized crossover study, ibuprofen was found to be more effective than acetaminophen for interruptive therapy.⁷ Ibuprofen in suspension form is commonly used for abortive headache therapy in children who are unable to swallow pills. The recommended pediatric doses are between 6 and 10 mg/kg, taken orally. The 5-HT serotonin agonists, such as sumatriptan, zolmitriptan, and rizatriptan, have been shown to be effective abortive therapies in patients with severe migraines.^8-10 Chronic opioid use is generally not recommended for the treatment of recurrent or chronic headaches.¹¹

Antidepressants, beta-blockers, and anticonvulsants are frequently used for prophylactic migraine therapy. Low-dose tricyclic antidepressants, such as amitriptyline and nortriptyline, may provide effective migraine prophylaxis. Typical starting dose in children is 0.2 mg/kg, administered at bedtime, to promote improved sleep. The doses are titrated, based on the clinical response and any side effects the patient may experience. Trazodone has been shown to be more effective than placebo in a crossover trial but should be avoided in teenaged boys because of the potential for priapism.¹² Propranolol is often used in doses of 1 to 2 mg/kg daily; however, controlled studies in pediatric headache management have shown equivocal results.^13,14 Gabapentin 5 to 10 mg/kg/day, with a maximum dose of 2400 to 3600 mg, is commonly prescribed for patients with chronic headache. Several studies have shown positive clinical results from treatment with calcium channel blockers. Coenzyme Q10 supplement 25 to 300 mg/day can be effective in the prevention of migraine.¹⁵ Occipital nerve blocks and botulinum toxin injection can control some intractable headaches.

Nonpharmacologic therapies and treatments for chronic headache in children include cognitive-behavioral therapy, biofeedback, relaxation, guided imagery, self-hypnosis, family therapy, and acupuncture. Evidence supports the effectiveness of biobehavioral headache management, when compared to pharmacologic agents, for certain types of headaches in children.^14,16 Through biofeedback, guided imagery, and progressive muscle relaxation, patients learn to shift their cognitive focus away from the pain, thereby decreasing their experience of pain. These skills reduce stress and anxiety, which are precipitating factors in many children with headaches. Cognitive-behavioral strategies help patients improve coping skills, return to school, recognize maladaptive behaviors, and reinforce more functional lifestyles. Acupuncture may be a valuable tool for patients with frequent, episodic, or chronic tension-type headaches.¹⁷ Available studies suggest that acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment and has fewer adverse effects.¹⁸

CHEST PAIN

Chest pain in children and adolescents is a common presenting symptom in emergency rooms, general pediatric practices, and pediatric pain clinics. Because chest pain is often an ominous symptom among adults, it causes much distress to children and their parents. It is, however, not commonly associated with heart disease in children. Of 67 patients referred to a pediatric cardiology clinic with chest pain, only 6% were found to have underlying cardiac disease.¹⁹ The most common causes of chest pain in children include costochondritis, idiopathic causes, muscle pain from coughing, and other musculoskeletal causes.^20,21 Additional causes of chest pain in children include slipping rib syndrome and abdominal and gastroesophageal disease.²²

A thorough medical history and physical examination help identify cardiac symptoms. Selbst and colleagues found that organic causes of chest pain in children were more common when associated with abnormal findings on physical examination or when symptoms were present in a younger child.²⁰ A history of syncope, presyncopal episodes, or a history of palpitations warrants further evaluation. Gastroesophageal reflux or esophageal spasm may cause referred pain in the chest.

In the absence of worrisome findings on history or physical examination, education and reassurance that heart disease is not a likely cause for the pain are helpful in resolving the symptoms in the long term.^19,23 A trial of NSAIDs may be helpful for patients with musculoskeletal causes such as costochondritis. Nonpharmacologic therapies such as physical therapy, transcutaneous electrical nerve stimulation (TENS), heat, and relaxation therapies are helpful for many pediatric patients experiencing chest pain.

FUNCTIONAL ABDOMINAL PAIN

Abdominal pain is a common painful condition in infants, children, and adolescents. Functional abdominal pain (FAP) is recurrent episodic pain with no evidence of structural or inflammatory origin.²⁴ It is a common condition among school-aged children. Several studies report that up to 25% of school-aged children experience recurrent abdominal pain, with the highest prevalence among girls.²⁵ Many children with FAP can maintain normal activities; the patients seen at pediatric pain clinics are typically those with more severe patterns of pain and disability. In most cases, there is no clear identifiable cause of FAP in school-aged children.^25,26

A number of clinical characteristics distinguish benign FAP from other types of childhood abdominal pain. In general, children with FAP are between 4 and 16 years of age, experience episodic abdominal pain interspersed with pain-free periods, and are otherwise thriving and medically well. Children with FAP frequently describe diffuse periumbilical pain that is poorly localized. It rarely radiates to the back or chest. Pain is often worse at night but rarely awakens the child from sleep. Many children experience other chronic symptoms, such as headaches, nausea, and dizziness.

In the majority of cases, FAP is functional, which refers to the lack of an identifiable biochemical, structural, or other organic cause. However, the lack of a readily identifiable cause does not imply psychogenic origin. Most children with FAP are generally medically and psychologically well.²⁷ A subgroup of patients will have a recognizable underlying disease, such as lactose intolerance, constipation, ureteropelvic junction obstruction, inflammatory bowel disease, or endometriosis.^28-32 For many children, however, an underlying etiology is not diagnosed. Some studies suggest that FAP may be a precursor to irritable bowel syndrome (IBS) in adults, and that some children and adolescents may progress to meet the standardized criteria for IBS as adults.^33,34 In a study of 200 children with recurrent abdominal pain, somatic causes were found in 26%. Laxative therapy was successful in 46%, resulting in nearly all patients with functional abdominal pain becoming pain free. Eventually, 99% became pain free using a therapeutic intervention protocol.³⁵

The diagnosis of FAP should be based on thorough history, physical examination, and review of symptoms. A psychosocial history is essential to learn how the child and family cope with pain and to identify issues, such as school avoidance and reinforcers of pain. A history of fever, weight loss, growth failure, rash, or other symptoms of systemic illness should prompt further investigation of organic causes.^36,37 Occurrence of persistent pain or recurrent abdominal pain in children younger than 4 years of age is also of concern. Physical examination should include a rectal examination with stool guaiac, evaluation for undescended testes, hernias, and abdominal masses. Findings on history and physical examination suggesting a possible underlying organic disorder should serve as a guide to laboratory and diagnostic testing. In general, extensive routine screening tests such as endoscopies, barium studies, and other radiographic studies are of low yield, particularly when there are no specific clinical suspicions from history or physical examination. In addition to careful history and physical examination, baseline complete blood count, sedimentation rate, and urinalysis are reasonable screening tests to help rule out occult organic disease. A family history of inflammatory bowel disease in a child with chronic abdominal pain warrants further laboratory and possibly diagnostic testing. In children who experience chronic persistent abdominal pain rather than the more characteristic episodic pain of FAP, laparoscopy identifies treatable conditions in a high percentage of cases.^38,39 In a study of 104 children with FAP, parents were randomly assigned and trained to interact with their children according to one of three conditions: attention, distraction, or no instruction. Parents of the pain patients rated distraction as having greater negative impact on their children than attention.⁴⁰

A significant component of treatment is education and reassurance that no serious organic illness is likely. It should be emphasized that the child's pain is genuine and that clinical reassessments will be ongoing. Treatment is based on improving function and reducing maladaptive pain behaviors through emphasis on cognitive-behavioral therapies.^41-44 Underlying anxiety or depression should also be addressed. A return to school and participation in normal family and social activities is essential. Extensive diagnostic testing and referrals to multiple subspecialists may heighten patient and parental anxiety and reinforce a patient's “sick role.” Although the study indicated no significant difference between amitriptyline and placebo after 4 weeks of treatment,⁴⁵ tricyclic antidepressants are commonly used. Antispasmodics are sometimes used; however, there are limited data on the efficacy of drug therapy. The routine use of pain medications should be avoided. Hypnotherapy can be used for children with FAP.⁴⁶

Longitudinal studies show that only 30% of children with FAP have resolution of pain within 5 years and 25% to 50% continue to experience symptoms as adults. Walker and colleagues found that in a 5-year follow-up, only 1 in 31 children with FAP was eventually diagnosed with a definable “organic” disease.⁴⁷ A meta-analysis of 10 controlled studies regarding the effectiveness of psychological therapies for pain reduction in children with recurrent abdominal pain showed that psychological therapies are effective in treating children with chronic abdominal pain.⁴⁸

PELVIC PAIN

Endometriosis is a common cause of pelvic pain among adolescents, affecting 45% to 70% of adolescents with chronic pelvic pain.^49,50 In general, endometriosis affects women of reproductive age, but adolescent girls can experience pain from endometriosis prior to the onset of menses. Laufer and colleagues studied adolescent patients with chronic pelvic pain which was unresponsive to conservative medical treatment using oral contraceptives and NSAIDs and determined that 70% of patients had endometriosis upon diagnostic laparoscopy.⁴⁹ A variety of other medical conditions such as painful musculoskeletal disorders, constipation, urologic conditions, and irritable bowel syndrome may present as chronic pelvic or abdominal pain.

Many adolescent patients with endometriosis report both cyclic and acyclic pelvic pain. Some patients experience more severe pain at midcycle and with menstruation, but many will experience pain throughout the month. There is evidence to suggest that the severity of endometriosis seen on laparoscopy does not necessarily correlate with the severity of pain.⁵¹

Treatment of chronic pelvic pain and endometriosis can include hormonal suppression of endometriosis, surgical treatment, effective pain control, and minimizing disability. Hormonal therapy with oral contraceptives and gonadotropin-releasing hormone (GnRH) agonists suppress the growth of endometriosis and inhibit progression of disease. Surgical resection of endometriosis has been shown to provide both immediate and long-term relief from chronic pelvic pain.

Chronic pelvic pain in female adolescents can lead to significant disability. Over 90% of adolescent women with chronic pelvic pain referred to the Pain Treatment Services at Boston Children's Hospital have been diagnosed with endometriosis. A comprehensive approach consisting of biobehavioral therapy, physical therapy, acupuncture, and selected medication trials has been helpful for many patients. As with the treatment of recurrent abdominal pain, emphasis is placed on school attendance, participation in social and family activities, and recognition of maladaptive behaviors. Patients should be evaluated for other conditions in addition to endometriosis that may contribute to pelvic pain, such as constipation, irritable bowel symptoms, and urolithiasis. Medication trials of tricyclic antidepressants may be helpful, particularly for patients with sleep disorders, although there are few data on efficacy. Opioids are rarely used for long-term treatment. There is evidence to suggest that an integrated approach to chronic pelvic pain with attention to organic causes as well as psychosocial factors early in the course of treatment may improve long-term outcome.⁵²

NEUROPATHIC PAIN

Neuropathic pain conditions in children are most commonly a result of postsurgical nerve injury, extremity trauma, malignancies, complex regional pain syndromes, and congenital and traumatic amputation. Diabetic peripheral neuropathy and trigeminal neuralgia seen in adult patients are rarely seen in children. Clinical features of neuropathic pain in children include allodynia, hyperpathia, and hyperalgesia to noxious, mechanical, and thermal stimuli. Some children will also experience autonomic dysregulation and motor weakness. Children often have difficulty describing neuropathic pain, and report pain that is “strange” or “weird.”

A thorough history and physical examination, including a careful neurologic examination, is essential when evaluating a child with neuropathic pain. A broad-based evaluation may provide clues to less common causes of neuropathic pain such as underlying cancer, neurodegenerative disorders, and metabolic diseases. Nerve conduction studies are insensitive to abnormalities of C and A-δ fibers, and therefore may be normal in patients with certain neuropathic pain conditions. Quantitative sensory testing (QST), which assesses thermal and vibratory thresholds, may be especially useful in evaluating pediatric patients because it is painless and does not require the use of sedation.⁵³

The use of medications in the treatment of neuropathic pain in children is based on data extrapolated from adult studies. Randomized controlled studies of tricyclic antidepressants have shown effectiveness in treating neuropathic pain conditions in adults, including diabetic neuropathy and postherpetic neuralgia.^54-57 Nortriptyline and amitriptyline are antidepressants most commonly used in children, although desipramine is sometimes a useful alternative if excessive sedation is experienced with other tricyclic antidepressants. Because children metabolize tricyclic antidepressants more efficiently than adults, twice-daily dosing is sometimes necessary, with a larger portion of the dose administered in the evening to improve sleep disturbances and minimize daytime somnolence. As a result of rare case reports of sudden death attributed to cardiac dysrhythmia in children treated with tricyclics, a thorough cardiac history, physical examination, and baseline electrocardiogram are recommended prior to initiation of therapy.⁵⁸ Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are occasionally used in the treatment of neuropathic pain; however, additional studies are needed to determine efficacy. SSRIs can be useful for patients who have neuropathic pain associated with depressed mood or anxiety.

Adult clinical trials have shown effectiveness of anticonvulsants such as carbamazepine, phenytoin, valproic acid, and gabapentin for the treatment of various neuropathic pain conditions.^59-61 Gabapentin has a lower side effect profile and fewer severe adverse effects than other anticonvulsants, and monitoring of serum levels is not necessary. The most frequent side effects include dizziness and somnolence. Gabapentin may also be effective in the treatment of mood disorders.

The 5% lidocaine transdermal (Lidoderm) patch is safe for neuropathic pain. It penetrates the skin to act locally on dysfunctional nerve fibers. The patch measures 10 × 14 cm and contains 700 mg of lidocaine mixture with a nonwoven polyethylene backing. The patch can be cut to the desired size. A 12-hour-on and 12-hour-off schedule is recommended with a maximum of three patches at a time applied to intact skin at or beside the area of the neuropathic pain.⁶² Most patients who are responsive to the Lidoderm patch experience relief within a few days of application. A trial of 2 weeks is recommended.

The use of opioids in the treatment of neuropathic pain remains controversial. Some evidence supports their ineffectiveness in treating neuropathic pain or their effectiveness only at doses that produce intolerable side effects.⁶³ Other studies suggest that opioids can provide effective pain relief in patients with neuropathic pain from cancer, limb amputation, and other causes without producing unremitting side effects.^64,65 In general, the use of opioids in selected patients with neuropathic pain not caused by cancer or other terminal illnesses should include a treatment plan emphasizing ongoing cognitive-behavioral therapy and maintenance of school and peer activities.

COMPLEX REGIONAL PAIN SYNDROMES

Complex regional pain syndrome type 1 (CRPS 1) is a condition characterized by persistent neuropathic limb pain with cyanosis, coldness, swelling, atrophy, or other signs of neurovascular abnormalities without an associated nerve injury. Complex regional pain syndrome type 2 (CRPS 2) refers to this clinical syndrome with a definable nerve injury.

The clinical presentation of CRPS in children differs from that in adults. Most children with CRPS are female with a lower limb affected. In the adult presentation, gender differences are not significant and upper and lower extremities are equally affected. CRPS in children occurs most frequently at 10 to 12 years of age and rarely before the age of 6 years. In a report by Wilder and colleagues of 70 children with CRPS, each of the subjects was able to identify a specific injury prior to developing symptoms, and some developed similar symptoms in a second extremity without additional injury.⁶⁶ Many patients experienced eating disorders and were involved in highly competitive sports, such as ballet and gymnastics.

Conservative treatment with aggressive physical therapy and cognitive-behavioral therapy results in marked improvement of symptoms in children with CRPS.^67,68 A noninvasive approach with physical therapy, TENS, and cognitive-behavioral therapy was effective in improving function and reducing pain scores in over 50% of patients.⁶⁶ Other studies have emphasized sympathetic blockade.⁶⁹ A prospective, randomized, controlled trial by Lee and colleagues⁷⁰ showed that most children had clinical improvement with a regimen that emphasized physical therapy and cognitive-behavioral therapy.

The approach at the Boston Children's Hospital includes an initial outpatient trial of active physical therapy and cognitive-behavioral therapy. Physical therapy is based on a rehabilitative approach involving desensitization techniques, weight-bearing exercises, and a gradual return to function. Cognitive-behavioral interventions typically include biofeedback training, relaxation techniques, and family and individual counseling. Education of both patients and parents is essential regarding the nonproductive nature of pain with CRPS and instructing that movement of the affected limb will ultimately diminish pain and dysfunction. Regular school attendance and participation in family and peer activities is emphasized. Often, a home diary that records pain scores and measures of function helps track response to therapy.

Commonly used medications in the treatment of CRPS in children include antidepressants, anticonvulsants, local anesthetic-like drugs, and opioids. There is significant individual variation in response to medication trials. Opioids are used in a selected group of patients. Sympathetic blockade is reserved for patients who do not improve with outpatient therapy and who continue to experience significant pain and limitations of limb mobility. Sympathetic blockade is also used for patients who have severe circulatory impairment with ischemic complications. Typically, sympathetic blockade is performed using continuous catheter techniques, combined with an intensive rehabilitative 5- to 7-day hospitalization.

Over the past 15 years, more than 650 children with CRPS have been treated at the Boston Children's Hospital. Over 85% of patients have experienced pain reduction and improvement in limb function. Less than 5% of patients have received spinal cord stimulation trials or implantations. Fewer than 1% over the past 15 years have received operative or chemical sympathectomies. In all cases, the patients who underwent sympathectomies did so to preserve limb circulation rather than for pain control.

AMPUTATION PAIN

Historically, it was assumed that children who have congenital absence of a limb or who experienced amputation early in life rarely experience phantom sensations. However, results of several case studies suggest that most children with limb amputations, as well as burn patients, do experience phantom sensations and pain.^71-74 In a retrospective study of children who had undergone amputation, Krane and Heller determined that 100% of patients reported phantom sensations and 75% experienced phantom pain.⁷¹ A study by Melzack and colleagues⁷² showed that approximately 20% of patients who had congenital limb absence and 50% of patients who had amputations at an early age experienced phantom limb sensations. There is some evidence to suggest that the children who receive chemotherapy prior to amputation are more likely to experience phantom limb pain than children with amputations who were not exposed to chemotherapy.⁷⁵

Children describe a variety of phantom sensations such as persistent itching, burning, pain, or a perception of the presence of the missing limb. Some patients will experience allodynia and dysesthesia of the stump.

Studies of tricyclic antidepressants, anticonvulsants such as gabapentin and clonazepam, and opioids have shown effectiveness in treating amputation pain; however, there are limited data on the best treatment among adult and pediatric amputees.⁷⁶ Medication trials, biobehavioral techniques, physical rehabilitation, and the early use of prosthesis have been helpful for many patients.⁷⁶ Studies examining whether preoperative neurologic blockade reduces the severity or incidence of phantom pain have shown inconsistent results.^77-79

CYSTIC FIBROSIS

Patients with cystic fibrosis (CF) suffer a variety of recurrent and chronic pains, particularly as lung disease becomes more advanced.⁸⁰ Recurrent chest pain is common and may occur from chest wall muscle strain, costochondritis, and spontaneous pneumothorax. Severe coughing may produce painful rib fractures that can significantly compromise respiratory function. Frequent headaches can be caused by sinus disease or by the intense contraction of muscles caused by coughing. As respiratory function declines with advanced disease, hypercarbia and hypoxia can contribute to headaches.⁸⁰ Other causes of pain in patients with CF include back pain from compression fractures, arthritis pain, and abdominal pain from pancreatitis.^81,82

Treatment of recurrent and chronic pain of CF should provide optimal analgesia without further impairing respiratory function. Opioids may provide effective pain relief without inducing excessive sedation and respiratory depression in selected patients.⁸⁰ Because patients with CF frequently experience constipation with opioid use, laxatives should be used early in the course of treatment. Selective COX-2 inhibitors may provide analgesia without causing respiratory depression and constipation and cause less risk of hemoptysis than conventional NSAIDs. Continuous thoracic epidural infusions can provide effective analgesia for rib fractures or pneumothoraces and for postoperative pain control. Intercostal blockade is preferred less than epidural analgesia because of short duration of effect and a considerable risk of pneumothorax.

SICKLE CELL PAIN

Sickle cell pain ranges from acute vaso-occlusive episodes to chronic, daily pain. Acute painful episodes are characterized by an abrupt and usually unpredictable onset of severe ischemic pain. Vaso-occlusive episodes typically produce pain in extremities, chest, lower back, and abdomen and may be caused by a variety of factors such as infection, dehydration, hypoxia, and acidosis. Often, there is no obvious cause. Acute episodes of pain account for most hospitalizations and emergency room visits. In a prospective study, Platt and colleagues reported that 5% of patients with sickle cell hemoglobinopathy experienced over 30% of all painful episodes and that the patients with the highest rates of painful episodes tended to die earlier than the patients with lower rates of painful episodes.⁸³ Chronic pain may develop as episodic pain and become more frequent and severe, ultimately resulting in persistent daily pain. Bone infarction or necrosis may result in debilitating chronic pain conditions such as aseptic necrosis of the hip, vertebral compression fractures, and chronic low back pain.

Home management of vaso-occlusive episodes is encouraged through the use of NSAIDs and orally administered opioids. Day treatment programs may provide effective alternatives to hospitalizations or emergency room visits for some patients.⁸⁴ Hospitalization is necessary for patients who are unable to tolerate oral opioids because of vomiting or for patients with severe, escalating pain requiring rapid control with intravenous analgesics. Patient-controlled analgesia enables patients to rapidly titrate opioids according to the wide fluctuations in pain intensity common in vaso-occlusive episodes. A low-dose basal opioid infusion, in addition to on-demand doses, may provide effective analgesia, particularly during severe episodes of pain. However, there is some evidence that this regimen may increase the risk of hypoxemia at night.⁸⁵ Continuous epidural analgesia can provide effective analgesia and maintenance of respiratory drive in patients with acute chest syndrome.⁸⁶ It has not been established how frequently epidural analgesia should be chosen for patients with frequent, painful episodes. Self-report pain scales should be used as much as possible for pain assessment. Close nursing observation and monitoring is necessary, especially for patients at risk for opioid-induced respiratory depression and hypoxemia.

A multidisciplinary approach to sickle cell pain integrates pharmacologic therapy and cognitive-behavioral techniques to provide effective pain control, maintenance of normal functioning, and optimal quality of life. There is often excessive concern among HCPs and families about addiction to opioids, which has led to inadequate analgesia in some cases. Education is necessary regarding the use of opioids, home management strategies, and avoidance of precipitating factors of painful episodes. Cognitive-behavioral treatment such as biofeedback, hypnosis, guided imagery, and family therapy can improve coping mechanisms and prevent maladaptive behaviors.⁸⁷

SUMMARY

A central component of the treatment of pain and distress in children is an in-depth understanding of pediatric diseases and the psychological and social dynamics involved in treatment of chronic pain conditions. Analgesics and specialized techniques should be combined with lifestyle changes and nonpharmacologic approaches to provide optimal care. Additional prospective clinical trials are necessary in the understanding and treatment of chronic pain conditions in children. The multidisciplinary pediatric pain service would allow pediatric patients and family to be seen in a single visit by a number of pain specialists, including pain physician, child psychologist, physical therapist, and complementary medical therapy providers. This comprehensive approach for pediatric pain management would allow pediatric pain patients to obtain optimal care with the least disruption for patients and their families.

REFERENCES

INTRODUCTION

The prognosis of cancer in children has improved dramatically over the past 40 years. Unlike many adult cancers, pediatric malignancies are often responsive to initial aggressive chemotherapy, radiation, and surgery. Currently, the estimated survival rate for a child (age 0-19) with cancer is 80%. However, these therapies often produce acute and chronic pain problems, such as mucositis, graft versus host disease (GVHD), peripheral and central neuropathic pain, phantom limb pain, prolonged postdural puncture headache, radiation dermatitis, and visceral hyperalgesia. Although treatment-related pain generally exceeds tumor-associated pain in pediatric cancer patients, tumor-associated pain is prevalent and may involve bone, viscera, nerves, and other tissues. In the most common diagnostic category of pediatric cancer, leukemia, presenting in children 2 to 6 years of age, bone pain is secondary to rapid growth of precursor cells in the bone marrow. In adolescents, malignant bone tumors and lymphomas produce most tumor-related pain. The most common solid tumor diagnosed during childhood, central nervous system (CNS) tumor, may induce headache caused by increased intracranial pressure (ICP).

Following the often successful treatment protocols for children with cancer, there is increasing risk of delayed and chronic complications of treatment, such as secondary malignancies, skeletal disorders, cardiac and pulmonary insufficiency, neurocognitive disability, and pain. At present, the estimated number of childhood cancer survivors in the United States is greater than 300,000, and there is a 75% risk of a chronic health disorder 30 years postdiagnosis. Early recognition and treatment of medical and psychological issues in children treated for cancer are a public health care concern.

As the assessment of pain in children is guided by the child's cognitive and behavioral development and individualized coping skills,¹ the treatment of cancer pain in children should involve a multidimensional approach that uses medications for pain and symptom management and also cognitive-behavioral interventions and other nonpharmacologic therapies. This approach provides optimal pain control and addresses patients’ complex emotional needs related to grief and sense of loss.

TREATMENT-RELATED PAIN

In contrast to adults, children with cancer experience pain more frequently related to aspects of cancer treatment. This is in part because of higher rates of remission in children after initial chemotherapy induction and improved long-term survival rates in childhood cancers.^1,2

Procedures such as bone marrow biopsies and aspirates, lumbar punctures, and central venous line insertions are common sources of distress and pain in children with cancer. Pain related to the treatment of cancer includes painful mucositis, amputation pain, and painful neuropathies from surgery and chemotherapeutic agents.

Every attempt should be made to minimize distress, fear, and pain in children undergoing brief needle procedures and more invasive procedures because traumatic experiences with initial procedures make subsequent procedures more distressing. Treatment of procedure-related pain is combination of cognitive-behavioral interventions, local anesthesia, conscious sedation, and general anesthesia.

Evidence supports the use of cognitive-behavioral strategies in the management of procedure-related pain in children with cancer. Guided imagery, progressive muscle relaxation, and hypnosis can direct patients’ focus away from pain and the procedure to reduce their experience of pain, fear, and discomfort. Young children or those with developmental deficiencies, however, may not have the cognitive abilities to use these strategies. Explaining the procedure in age-appropriate terms can gain the child's trust and confidence.

Local anesthetics and conscious sedation combined with cognitive-behavioral strategies can make procedures less terrifying for children. Traditional agents utilized as topical anesthetics for pediatric needlestick procedures include eutectic mixture of local anesthetics (EMLA), various lidocaine formulations, and vapocoolants. Newer agents and novel drug-delivery systems include lidocaine/tetracaine heating patches and pressurized lidocaine delivery systems (J-Tip, Zingo). Application of topical anesthetics to overlying intravenous (IV) catheter-insertion sites or lumbar puncture sites can decrease pain from needle insertion into the skin. This allows less painful infiltration of local anesthetics deep to the dermis. For more invasive procedures or for children who experience significant distress during brief needle procedures, conscious sedation or general anesthesia should be used. Conscious sedation is a level of sedation in which a child is comfortable but is able to maintain airway reflexes and spontaneous ventilation. Conscious sedation is often performed by pediatric subspecialists and is widely used for bone marrow aspirates or biopsies, lumbar punctures, and central venous line removals (Table 66-1). Consultation with a pediatric anesthesiologist is indicated for more invasive procedures or for children with certain risks of conscious sedation, such as airway anomalies, obstructive sleep apnea, and significant gastroesophageal reflux disease.

Centers that provide care for children with cancer often have a two-tiered approach in which specific procedures are performed under conscious sedation by pediatric subspecialists, such as oncologists and radiologists. Sedation protocols guide the choice of sedative, dosing, monitoring, and indications when a pediatric anesthesiologist is required. For young infants, or for patients with specific cardiac, neurologic, or airway diseases that increase risk, sedation or general anesthesia by pediatric anesthesiologist is indicated.

Mucositis is painful mucosal inflammation and necrosis caused by chemotherapy or radiation therapy. Although mucositis is a self-limiting condition in most patients, it causes significant pain and distress in children. Mucositis associated with bone marrow transplantation can be especially prolonged and painful. Topical therapies such as diphenhydramine, viscous lidocaine, antacids, and sucralfate may be used to provide symptomatic relief; however, there is little evidence to support efficacy. Patient-controlled analgesia (PCA) is frequently used in addition to topical agents. Some children, however, continue to experience significant pain despite aggressive opioid dosing. PCA permits dose titration and treatment of acute exacerbations associated with mouth or perineal care. Several studies have shown lower pain scores, fewer side effects, and lower opioid use in treating mucositis with PCA compared with staff-controlled analgesia.³

Vincristine is an antineoplastic agent associated with peripheral neuropathies such as sensory deficits, gastrointestinal dysmotility, and paresthesias. Some children treated with vincristine experience burning neuropathic pain of the lower extremities. Additional studies are needed to determine the best treatment strategy; however, opioids, tricyclic antidepressants (TCAs), and anticonvulsants are often used. In most patients, symptoms improve gradually but may recur with repeated use of vincristine. Chemotherapeutic agents associated with potential neuropathic pain include cisplatin, etoposide, and paclitaxel.

TUMOR-RELATED PAIN

Most children experience tumor-related pain at initial diagnosis. A survey by Miser and colleagues showed that 62% of children reported pain prior to receiving an initial diagnosis of cancer.⁴ Additional studies show that 25% of outpatient pediatric patients with cancer report experiencing daily pain.⁵ Tumors can produce different types of pain through stretch or involvement of bone, viscera, nerves, and other tissues. Leukemia can produce constant, aching bone pain caused by proliferation of malignant cells in marrow causing compression of the marrow space. Bone pain can also result from metastasis of solid tumors to localized areas of bone. The involvement of lymphoma, leukemia, and neuroblastoma in solid viscera such as spleen and liver can cause abdominal pain by distension and capsular stretch. Tumors can spread to plexuses, peripheral nerves, or the epidural space, causing lancinating and sometimes refractory neuropathic pain. Children with brain tumors and increased ICP often present with headaches and, in some cases, focal neurologic signs or seizures. Spinal cord tumors or the extension of tumors into the intrathecal space typically cause back or neck pain.⁶

The assessment of pain in children with cancer can be challenging. Children with inadequately treated cancer pain may withdraw from their environment and may erroneously appear comfortable to health care providers (HCPs). Pain assessment scales developed to assess acute pain frequently underrate pain when used to assess persistent cancer pain. Physiologic signs such as blood pressure and heart rate may habituate with persistent pain. Gauvain-Piquard and colleagues designed an observational pain scale specifically for young children with cancer that includes depression and anxiety-like descriptors often reported by patients.⁷

Cancer pain is often best treated using a multidisciplinary approach that combines the aggressive use of pharmacologic agents, psychosocial support, cognitive and behavioral therapy, and nerve blocks. The World Health Organization (WHO) has developed an analgesia ladder to guide physicians in treating cancer pain. A study of children with terminal malignancies showed that over 90% of patients had effective pain relief when managed according to standard escalations based on WHO guidelines.⁸ According to this treatment guide, non-opioid analgesics such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) are a “Step 1” therapy. Selective COX-2-inhibitors may be used for children with platelet dysfunction or for children who experience gastric side effects with NSAIDs. Weak opioids, such as low-dose oxycodone, often combined with acetaminophen are “Step 2” in managing mild pain. Recommended oral dosing of oxycodone is 0.5 to 1 mg/kg every 4 hours. Patients tend to experience more nausea and other side effects with higher doses of codeine compared with other opioids. In addition, some patients lack sufficient enzyme activity to O-demethylate codeine to morphine, causing a marked reduction in analgesic effect.⁹ Dosing of acetaminophen and opioid combination preparations is usually limited by the maximum recommended acetaminophen dose. Weak opioids have a “ceiling effect” whereby escalation of dose typically causes increased side effects without improving analgesic effect. Strong opioids such as morphine, hydromorphone, and fentanyl used for moderate to severe pain, or worsening pain are “Step 3.”

With progression of cancer pain, μ-opioid agonists are the cornerstone of treatment (Table 66-2). Oral dosing of opioids is preferable where possible. Regular scheduled dosing of opioids should be used for patients who have continued pain in order to avoid breakthrough pain. Morphine is the most widely used opioid for treating cancer pain in children. Younger infants have an increased risk of hypoventilation with opioids because of both pharmacokinetic factors, such as diminished hepatic conjugation, and pharmacodynamic factors, such as immature ventilatory reflex response to hypoxemia and hypercapnia. A typical starting dose for immediate-release morphine in opioid-naïve patients is 0.3 mg/kg orally every 4 hours. Sustained-release preparations of morphine and oxycodone are frequently used and are effective alternatives to frequent dosing of short-acting agents. A significant number of children are unable to swallow pills, which limits the use of sustained-release preparations in these patients.

Methadone has a prolonged duration of action because of slow hepatic metabolism. The elimination half-life of methadone is approximately 19 hours, and the oral bioavailability ranges from 60% to 90%. Elixir preparations are therefore useful for children with continued pain who are unable to swallow pills. Intermittent IV dosing can provide sustained analgesia without the need for a continuous infusion pump or PCA device.¹⁰ Because of the prolonged effect and a slow but variable clearance, the dose-response to methadone can be variable.

Methadone dosing is also complicated because it is a combination drug: the l-isomer is a μ-opioid and the d-isomer of methadone is an antagonist at the N-methyl-D-aspartate (NMDA) subgroup of glutamate receptors.¹¹ NMDA receptor antagonists have been shown to prevent tolerance to opioids. The result is that methadone shows incomplete cross-tolerance, meaning that its relative potency for both analgesia and respiratory depression compared with other opioids is much greater in opioid-tolerant patients than in opioid-naïve patients.^12,13 Because of incomplete cross-tolerance and variable dose-response, frequent assessment and careful titration of methadone is necessary to avoid oversedation and hypoventilation. After adequate analgesia is achieved, the dose of methadone should be reduced or the dosing interval extended to avoid drug accumulation.

Hydromorphone is similar to morphine in onset of action and duration; it is used as an alternative when patients experience dose-limiting side effects with morphine. In a double-blind, randomized, crossover trial comparing morphine with hydromorphone in PCA for children with mucositis, hydromorphone was well tolerated and had an approximate potency ratio of 6:1 relative to morphine.

Meperidine is most commonly used for rigors following the administration of amphotericin or blood products. Normeperidine, the major active metabolite of meperidine, can cause dysphoria, CNS excitation, and seizures, thus limiting the use of meperidine in the management of pain in children.

Fentanyl is approximately 50 to 100 times as potent as morphine. It is frequently used for brief needle procedures because of its rapid onset and short duration of action caused by rapid redistribution. However, with continuous infusions or multiple dosing, the clinical duration of action becomes significantly more prolonged. Fentanyl is commonly used in PCA for children who have excessive side effects from morphine.

Mixed μ-agonists/antagonists and agonists with activity at κ (kappa) receptors, including buprenorphine, butorphanol, and nalbuphine, have limited use in the treatment of cancer pain compared with μ-agonists. Some of these agents may exhibit a ceiling effect with escalated doses, can cause dysphoria, and can precipitate withdrawal in opioid-tolerant patients. Buprenorphine provides prolonged analgesia and may be a useful agent in countries with limited access to μ-agonists.

ROUTES OF OPIOID ADMINISTRATION

The optimal route of analgesic administration varies in children with cancer. Oral administration of opioids is convenient and relatively easy; however, some children are either unwilling to swallow pills or unable to tolerate oral drugs because of painful swallowing from mucositis, vomiting, or lethargy associated with terminal disease. Oral analgesics are generally not effective for rapidly escalating pain. In these patients, other routes of administration such as IV, subcutaneous, or transdermal are indicated.

Intravenous administration allows for rapid titration in the setting of moderate to severe fluctuating pain. Many children with cancer have indwelling venous catheters, which can facilitate opioid administration. PCA is widely used in children to manage cancer pain and is useful for both inpatients and outpatients. Nurse-controlled analgesia (NCA) is used for infants or toddlers or those who are unable to press the PCA button. In a palliative care setting, parents often participate in PCA dosing. The use of parent-controlled analgesia in the nonpalliative care setting is more controversial.¹⁴ If parent-controlled analgesia is to be considered in a nonpalliative care setting, we would advocate formal programs for parent education and standardized protocols for respiratory depression. Morphine is the most commonly used drug in PCA; however, hydromorphone and fentanyl are frequently used alternatives. The addition of a basal infusion appears to provide more consistent analgesia and can promote restful sleep when used at night.

Subcutaneous opioid infusions can be used for children who have limited IV access.^15,16 Typically, a 22- or 24-gauge catheter or butterfly needle is inserted in the subcutaneous tissue of the chest or abdomen, with the site changed every 3 to 7 days as needed. Concentrated solutions of morphine or hydromorphone are most commonly used. PCA, NCA, continuous infusions, and intermittent boluses can be administered through subcutaneous catheters.

Transdermal fentanyl patches can provide continuous opioid delivery without the need for IV access or PCA devices. Since steady state is reached in approximately 12 to 24 hours after initial patch application, titration by other routes is usually necessary during this time. Transdermal fentanyl patches are not useful for patients who have fluctuating pain intensity. The lowest dose available in the United States is 25 μg per hour, which may be excessive for some children, particularly for opioid-naïve patients.

MANAGEMENT OF OPIOID SIDE EFFECTS

The successful use of opioids in the treatment of cancer pain requires aggressive management of side effects (Table 66-3). Unremitting nausea, vomiting, and pruritus can be as distressing as pain to some children. Constipation should be anticipated and can be prevented and treated through the early use of stimulant laxatives. 5HT-3 antagonists, antihistamines, and phenothiazines can be effective for opioid-induced nausea in children. Pruritus can be treated with antihistamines or by switching to a different opioid. Sedation can be troublesome to patients as well as parents. The daytime use of dextroamphetamine or methylphenidate can provide additional analgesia and can allow patients to be more alert and interactive during the day. A trial of a different opioid should be considered in managing opioid-induced side effects because patients may experience fewer side effects with one opioid versus another. In general, tolerance to nausea, sedation, and pruritus develops within 1 to 2 weeks after initial opioid dosing. A recent retrospective study of parents’ recollections following care of children with terminal malignancy suggested that nonpainful symptoms, including sedation, fatigue, dysphoria, and sleep disturbances, were as important sources of suffering as pain itself.¹⁷ Attention should be directed toward improving methods for management of these symptoms.

ADJUVANT MEDICATIONS

Children with cancer can experience neuropathic pain from tumor invasion of nerves, chemotherapeutic agents, postsurgical trauma, and radiation. Neuropathic pain can range from mild symptoms to severe, lancinating pain that can be refractory to opioids and other medications (see Part 5, Section A: Neuropathic Pain). There is a subgroup of patients with neuropathic pain for whom opioids do provide effective analgesia. In other patients, however, doses of opioids that improve pain also cause intolerable side effects. Tricyclic antidepressants are used frequently in children to treat neuropathic pain; however, additional studies are needed to determine efficacy in children. Nortriptyline and amitriptyline are most commonly used. Typically, a bedtime dose is started and titrated according to clinical response and side effects. Plasma levels can help guide titration. A baseline electrocardiogram should be obtained to screen for rhythm disturbances prior to initiating TCAs. Intravenous administration of amitriptyline has been used for patients who cannot tolerate oral routes.¹⁸ Selective serotonin reuptake inhibitors (SSRIs) are considered less effective for treating neuropathic pain; however, they are associated with fewer side effects than TCAs. Some children experience good analgesic effect with SSRIs, which may be especially helpful for patients with pain and depressed mood. SSRIs have shown some efficacy for patients with depression-related fatigue and those with fibromyalgia.

Anticonvulsants such as gabapentin, valproate, phenytoin, and carbamazepine are used for the treatment of neuropathic pain and are considered to be particularly effective for lancinating, paroxysmal pains. Gabapentin is usually well tolerated and, unlike other anticonvulsants, does not require monitoring of serum blood levels.

Corticosteroids are used as adjuvant analgesics for selected types of cancer pain such as headaches caused by increased ICP, spinal cord compression, and metastatic bone pain.¹⁹ Dexamethasone effectively penetrates cerebral spinal fluid and is most frequently used for pain relief from brain tumors and spinal cord compression. Prolonged use of corticosteroids can result in immunosuppression, mood and behavior disturbances, and fractures.

REGIONAL TECHNIQUES FOR CANCER PAIN MANAGEMENT IN CHILDREN

Despite aggressive opioid dose escalation, some children with cancer experience intractable pain, particularly as the disease becomes widely metastatic. Regional blockade and neurodestructive procedures may be helpful for selected patients with refractory neuropathic pain, unremitting bone pain, severe chest or abdominal pain, and tumor involvement of the spine.^20-22 Pharmacologic, nonpharmacologic, and adjuvant therapies should be optimized when considering interventional approaches.

For pain that is below the umbilicus, we have found most success by placement of subarachnoid catheters. The subarachnoid route provides great flexibility in escalating local anesthetic dosing without producing toxic plasma levels. We prefer placement of thoracic epidural catheters for pain in upper abdominal and higher dermatomes. Epidural tumor involvement may result in technical difficulty in placing epidural catheters and may interfere with adequate spread of local anesthetics. Most children will require general anesthesia or deep sedation. Fluoroscopic guidance and use of contrast solution ensure proper catheter placement and determine spread of local anesthetics. Tunneling of the catheters facilitates skin care and prevents dislodgement. We generally tunnel catheters at initial placement rather than use the two-step process of a temporary catheter followed by an implanted catheter commonly used for adult patients.

The choice of neuraxial solution should be individualized and based on the nature and site of pain, location of catheter tip, and side effects with consideration of a child's additional symptoms, such as excessive sedation and air hunger. In our experience, local anesthetics applied to an appropriate dermatologic location provide improved analgesia; neuraxial opioids alone rarely provide sufficient improvement in therapeutic index relative to systemic opioids. If neuraxial opioids produce persistent pruritus, nausea, ileus, or urinary retention, clonidine may be useful because it provides synergistic analgesia with neuraxial local anesthetics and does not typically produce the side effects of neuraxial opioids. In home care of children with subarachnoid or epidural infusions, it is essential that families have the resources to manage issues related to the catheters, pumps, infusions, and side effects that may occur.

Neurolytic blockade is less commonly used in children with cancer pain; however, it can provide excellent analgesia for some children in terminal stage of the disease. Celiac plexus blockade can provide dramatic pain relief for children with upper abdominal pain caused by tumor involvement of viscera.^23,24

NEURODEGENERATIVE DISEASES

A number of neurologic and neuromuscular diseases in children cause chronic pain, physical and cognitive impairments, and a shortened life span. Although there is a wide spectrum of clinical expression, children with these diseases require long-term symptom management, palliative care, and end-of-life care. For example, children with Duchenne muscular dystrophy and spinal muscle atrophy have intact cognition but have varying degrees of motor impairment. Some children will experience slowly progressive muscle weakness whereas others suffer from profound motor devastation, cardiomyopathy, and early death. Tay-Sachs disease causes severe cognitive and motor impairments and death early in life.

A number of factors make symptom management and palliative care challenging in these patients. A disease may have a variable prognosis and an unpredictable clinical course, which makes long-term care decisions difficult. Cognitive and motor impairments can make diagnosis of causes of pain, agitation, and distress difficult. Children may have persistent screaming and agitation without a clearly identifiable cause, which can be extremely distressing to parents and caregivers. Common causes of pain are usually excluded first, such as hip dislocations and gastrointestinal reflux. Therapeutic trials of opioids and sedatives are often used, but many patients have unremitting agitation. Baclofen and anticonvulsants trials are used with varying success.

Improved methods of assisted ventilation enable children with myopathies to have enhanced quality of life and improved life span. Some children require nasal or mask positive pressure devices only at night, without the need for a tracheostomy. However, as motor weakness progresses, many children will require more invasive mechanical ventilation. The decision to provide ventilatory support for patients with advanced neuromuscular disease is invariably difficult and must take into account individual variation. If the decision is made to forgo assisted ventilation, opioids and anxiolytics may have a role in the treatment of terminal air hunger.

CYSTIC FIBROSIS

Cystic fibrosis (CF) is a multisystem disease that affects the pancreas, lung, liver, sinuses, and sweat glands. The associated chronic obstructive lung disease, however, causes the most pain and suffering. There has been considerable increase in life-expectancy of patients with CF. Lung transplantation and heart-lung transplantation offer hope of improved quality of life; however, hope is limited by a shortage of organ donors and a significant early mortality caused by infection and acute rejection.

Patients with CF suffer from a variety of pain and distressing symptoms. A study by Ravilly and colleagues reported that many patients with advanced disease experience daily pains, including headaches and chest pain.^25,26 Chronic hypoxemia and hypercarbia and frequent strain of head and neck muscles from violent coughing contribute to chronic daily headaches. In addition, chronic sinusitis can exacerbate headaches.

Chest pain is a common symptom and can be caused by intercostal muscle strain from coughing and an increased work of breathing. Patients may experience severe chest pain from pneumothoraces or fracture ribs from violent coughing episodes.

Patients with CF die from progressive respiratory failure. In the final stages of life, patients experience a spectrum of distressing symptoms. Fatigue, air hunger, severe dyspnea, headache, and chest pain are predominant symptoms in children with advanced lung disease. Most patients experience daily headaches and chest pain in the final 6 months of life. Opioids can provide relief; however, they may exacerbate headaches by increasing hypercarbia. Benzodiazepines may help reduce anxiety associated with dyspnea in some patients. Sleep is often disturbed because of air hunger and anxiety and may be improved with use of TCAs at bedtime. Tetracyclics, such as trazodone, may be useful if anticholinergic effects of TCAs are bothersome.

Terminal care of patients with advanced disease varies. Prior to the possibility of lung transplantation, patients in our institution died in an in-patient adolescent unit. With the hope of transplantation, many patients in our institution now die in the intensive care unit awaiting a transplant.²⁶ Many of our patients fear suffocation and intractable pain and choose to be in a hospital setting for end-of-life care rather than home care. Other centers report higher patient preference for end-of-life care at home.²⁷

TERMINAL CARE

Home care, hospices, or hospital-based programs are chosen by patients and families for end-of-life care. The choice is an individual one based on several factors, including the level of care required, the degree of support for families and caregivers, and the connection to pediatric subspecialists. Home care can provide a secure and comfortable environment for children, free from the anxiety associated with hospital care. Optimal care requires careful individual planning for availability of supplies and medications, with ongoing support from nurses, physicians, and pharmacists. Some children and families develop close connections with subspecialists and HCPs at tertiary care institutions throughout the course of the child's illness and prefer to remain in this environment in the terminal stage of disease.

Although free-standing hospices are commonly used in adult palliative care, they are used less often for children. More commonly, the choices are among home care, comfort-oriented care at their tertiary pediatric center, and comfort-oriented care at a local community hospital. Where pediatric hospices are available, they often combine care of children with advanced cancer, care of infants and children with advanced HIV disease who lack family support, and respite care or end-of-life care for children with neurodegenerative disorders.

Children with cancer, neurodegenerative conditions, and other life-threatening diseases require individualized treatment plans (ITPs) for symptom management through the use of pharmacologic agents, regional techniques, and psychological support. Consideration for quality of life is necessary in all stages of disease. For the terminal stage, optimal care should emphasize patient comfort in an emotionally and spiritually supportive environment, which may include home, hospital, or hospice care.

REFERENCES

INTRODUCTION

It is well known that we are an aging society with 20% of the population reaching 65 years or older by the year 2030.¹ Older Americans have more chronic conditions such as osteoarthritis, atherosclerosis, cancer, and diabetes, contributing to increased health care costs, one-third of the total annual health budget today. In the older patient population, pain is the most common symptom noted when consulting a physician.² There are multiple sites and causes of these painful conditions, including lower back (40%), arthritis (24%), previous fractures (14%), and neuropathies (11%).³

Despite the well known association of aging and chronic painful conditions, pain remains underreported and undertreated. Reasons for undertreatment are related to fear, bias, and education from health care providers (HCPs) and from patients themselves. Patients often believe that pain is inevitable, a normal part of aging, and they fear adverse effects from treatment. They are apprehensive about underlying cancer and addiction to analgesics. Health professionals may mistakenly believe that older patients have a higher pain tolerance and fail to inquire about pain. Many of the chronic conditions manifesting pain in older patients are not curable; however, there must be a focus on the management of the pain associated with these chronic conditions.

The American Geriatrics Society and American Medical Directors Association have published guidelines for the assessment, treatment, and monitoring of chronic pain in older patients, advocating individualized pain management, which is vital to patients with multiple underlying chronic diseases.^4,5 A number of treatment modalities have been demonstrated to be effective for older persons. Pharmacologic and nonpharmacologic options should be considered in the context of the patient's beliefs, goals, and desires. Combining these options helps keep drug effects lower.⁶ With advancement in research and newer treatment options, regimens can target chronic pain while addressing comorbid conditions specific to the older patient.

This chapter will explore pain in the older patient. We address the neurophysiology, assessment of pain in cognitively intact and non-intact patients, and psychosocial issues associated with pain in this clinical population. Traditional treatments including pharmacologic and nonpharmacologic treatments are discussed; complementary and alternative methods for pain treatment, as well as extended care facilities and pain at the end of life, are also reviewed.

PAIN AND AGING

Age-related functional, structural, and biochemical changes of the pain pathways have been reported.⁷ The effects of age on the human brain are extensive, involving changes in structure, neurochemistry, and function.⁸ Excitatory and inhibitory mechanisms in the nervous system exert differential effects that contribute to the experience of pain and depend on complex communications among neural systems. There is strong evidence of progressive, age-related loss of serotonergic and noradrenergic neurons in the dorsal horn, suggesting impairment of the pain inhibitory system.^9,10 Functional consequences of structural age-related changes are difficult to extrapolate because of the highly integrated nature of pain processing; however, several patterns have emerged from the literature. Unmyelinated and myelinated peripheral nerves decrease with age, and increasing age shows signs of related damage or degeneration of sensory fibers.^11,12 Neurotransmitters of primary sensory nerves, substance P, and calcitonin gene-related protein are found at lower levels with increasing age, reflecting a reduction in the density or functional integrity of nociceptive nerves.¹³

Decreased acuity for pain may place older people at greater risk of tissue damage.¹⁴ Despite these changes, age does not produce a change in the pain stimulus-response curve.¹⁵ Reports of increasing pain with age occur when stimuli are intense or persist for longer periods. The widely held belief that older persons do not experience pain with the same intensity as younger persons is not supported by the literature. Increased pain threshold to noxious thermal, mechanical, and electrical stimuli with age has been shown in more than 40 studies, yet there was no agreement among studies. An increased pain threshold could result in less time between the alerting pain and the onset of tissue injury, which puts the older patient at greater risk.

Nerves that have been injured by trauma or disease can become more sensitive. Older persons are more likely to have slow resolution of peripheral sensitization despite tissue healing that leads to prolonged pain states not seen in younger persons. In addition to their prolonged time to heal, older persons are more likely to demonstrate slower resolution of hyperalgesia.¹⁶ Under circumstances where pain is likely to persist, older persons are especially vulnerable to the negative impacts of pain.

PAIN ASSESSMENT IN THE OLDER PATIENT

Assessment of pain in the older patient is difficult because patients commonly have physical limitations with loss of vision and hearing, and some patients present with cognitive impairments or dementia. Nevertheless, these patients have need of adequate pain assessment as they have many sources and reasons for pain related to aging. Taking the time to teach the older patient how to use the assessment scale and use of a pain assessment scale that meets the patient's needs can provide a fairly accurate rating for pain intensity.

Older patients who have pain may fear the pain they are experiencing because it means a disease is progressing or is a new disease. Many older patients want to be seen as good patients and feel that the pain they are having is just a part of the aging process and do not report pain concerns. Pain can also be a threat to independent living, leisure activities, and self-esteem, leaving patients feeling less worthwhile if they admit to having pain every day.¹⁷

Creation of a sense of trust is important to obtain the salient information needed for a good pain assessment. Reassuring the patient that he or she needs to report pain and that the reports of pain will be respected can go a long way in determining the best way to treat the patient's pain.

The basic elements of pain assessment can be used effectively with the older person. Asking the patient about the location and duration of the pain, intensity, description, aggravating or alleviating factors, functional impairment, and cognitive impairment can provide the base for the assessment.^17,18 In the older patient cognitive impairment and functional impairment may be key indicators for pain. Pain may be interfering with sleep, which may make it much more difficult for patients to concentrate and may cause the patient to appear disheveled in appearance or seem confused.¹⁷

Most cognitively intact older persons can use the numeric rating scale (NRS) based on ratings of 0-no pain to 10-worst pain possible. A systematic review found that single item pain ratings were a reliable and valid measure of pain intensity.¹⁹ The NRS is best used to determine if pain interventions have been successful in reducing pain levels. If the patient reports a decreased pain rating of 2 points on the NRS or 30%, the decrease is considered to be clinically significant.²⁰ If using a written pain assessment scale, using off-white paper with larger, bolder print will make it easier for the older patient to see what is written.

When the older patient has chronic pain, a comprehensive pain assessment tool such as the brief pain inventory (BPI) or the McGill Pain Questionnaire (MPQ) not only can help determine the intensity of the pain but also provide information on activity and pain medications as well as determine descriptions. One helpful element of these tools is the use of a pain diagram where the patient can mark the location of the pain on a body diagram.¹⁷

There are pain assessment scales using pain behaviors that have been developed to assess pain in patients who cannot self-report pain. Before using a behavioral scale recommendations include asking the patient to self-report the pain intensity, attempting to identify any potential causes of pain, taking time to observe the patient especially with movement, asking the family or caregivers about behaviors that would indicate pain, and attempting an analgesic trial to see if the behaviors resolve.^18,21

Behaviors identified as indicating pain include vocalizations, facial grimacing, bracing, rubbing, restlessness, vocal complaints such as moaning, changes in interpersonal behaviors such as resisting care and being disruptive, and changes in mental status such as confusion, irritability, and distress.^22,23,24

Although the behavioral tools we are currently using to assess pain in the older patient are not as good as they will be with more research, they provide a method for assessment of pain in the nonverbal older patient. A behavioral tool currently used is the Modified FLACC scale, which uses facial expression, restlessness, and body tension that are rated using a 0 to 10 pain intensity composite rating. The Pain Assessment in Advanced Dementia Scale (PAINAD) is a behavioral tool designed for use with Alzheimer patients. The tool uses breathing, negative vocalizations, facial expression, body language, and consolability that is rated to derive a 0 to 10 pain intensity rating.²⁵ Additional pain assessment tools for older persons include Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC), Functional Pain Scale (FPS), and Dolophus-2.¹⁸

PSYCHOSOCIAL ISSUES ASSOCIATED WITH PAIN IN THE OLDER PERSON

Older patients with pain can feel depressed, isolated, and at risk for loss of independence. If pain is not adequately treated, older patients may find that they cannot function as well as they did prior to the onset of pain. Overall functionality can be impaired, resulting in deconditioning. Some older patients feel that pain is just a part of normal aging. Although patients may have a higher number of comorbidities that can produce painful conditions such as diabetic neuropathy, they should be afforded the opportunity for pain management to reduce pain and the unwanted effects of unrelieved pain.

Financial concerns also impact the way older patients report and treat pain. Patients who cannot afford clinic visits and medications will have untreated pain that can heavily impact functionality. This can lead to undertreated or untreated pain that results in depression, anxiety, decreased socialization, disturbed sleep, impaired ambulation, increased health care utilization and subsequent costs, impaired cognition, and altered nutrition.^24,26 Assessment of older patients for depression and other psychosocial effects at clinic visits can help pinpoint the effects of untreated pain and identify patients’ needs.

TREATMENT OF OLDER PEOPLE WITH PAIN BASED UPON PATHOPHYSIOLOGY

Choosing treatment options for older patients requires considerations such as mental capacity to comprehend how to take medications, impaired kidney and liver functions where medication clearance may be affected, and age-related differences in muscle-to-fat ratios that may affect the binding ability of medications.¹⁷ Absorption of medication may be slowed by increased gastric pH, decreased intestinal blood flow, and delayed gastric emptying.²⁶

In studies comparing the efficacy and tolerability of opioids with both younger patients and those older than 65 years of age, findings indicate that older patients responded as well as, if not better than, younger patients when fentanyl, morphine, and buprenorphine were used.²⁷ For patients with cognitive impairment or difficulty with compliance, a sustained-release preparation is recommended although aging may cause higher concentrations of drug at the receptor sites, delayed elimination of the drug, and bizarre or atypical reactions to pain medications.²⁷

Differences in medication utilization in older patients include

• A wide variety of comorbid diseases and potential for polypharmacy that can cause medication interactions resulting in increased adverse effects.

• Decrease in hepatic and renal function that can affect the rate of elimination, drug half-life, and onset of action related to decreased liver mass, decreased microsomal enzyme activity, and decreased hepatic blood flow.

• A 30% to 40% reduction in elimination of medications metabolized by the liver.

• Reduced glomerular filtration rates can increase the half-life of drugs eliminated through the kidneys.

• Age-related decrease in body water and increased body fat can cause a decrease in volume distribution of lipophilic drugs such as fentanyl and increase the volume of distribution of hydrophilic drugs such as morphine.^17,26,28

The best base to use for medication choices is the World Health Organization (WHO) analgesia ladder. Although originally designed to treat cancer pain, the ladder has been used in many other settings successfully.²⁹ There are three steps of the ladder divided by the level of pain the patient is reporting (Fig. 67-1).

• Step 1 consists of medications for mild pain, intensity levels 1 to 3. Recommended medications include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). For older patients the use of acetaminophen and NSAIDs can be contraindicated if comorbidities such as liver impairment or cardiovascular risk factors are present. Because older patients can have changes in liver function, decreasing the maximum recommended dose of acetaminophen that can be used daily to 2000 mg is an option. For older patients who are using aspirin as a cardiac prophylaxis, NSAIDs such as naproxen and diclofenac can interfere with the inhibitory effects of the aspirin.^30,31 Higher doses of NSAIDs in older persons are associated with increased risk of gastrointestinal bleeding.³²

• Step 2 consists of medications for mild to moderate pain, intensity levels 4 to 6. Recommended combination medications include acetaminophen combined with hydrocodone, oxycodone, or codeine. Additionally, oxycodone alone, oxymorphone, tramadol, and tapentadol are listed on this step of the ladder.

Older patients can tolerate opioids but must have careful monitoring for adverse effects and toxicity; doses may have to be adjusted downward to accommodate the patient's ability to tolerate adverse effects such as sedation, nausea, and dizziness. Tapentadol, a medication combining an opioid action with an antidepressant, can lower seizure threshold and has adverse effects such as sedation, nausea, and somnolence, making it more difficult to use in the older patient^17,33

• Step 3 consists of pure opioids for moderate to severe pain, or pain intensity levels 7 to 10. Recommended medications include morphine, hydromorphone, fentanyl, and methadone. Older patients can tolerate these medications, but doses must be adjusted carefully for opioid-tolerant patients, and for opioid-tolerant individuals there should be careful monitoring for oversedation, nausea, and constipation.

In addition to the medications on the WHO analgesia ladder, there are medications specifically suited to older individuals. Targeted topical analgesics such as analgesic balms, creams, and patches can be used alone or as added pain relief options. Lidocaine patches with 5% lidocaine have been shown to be effective for postherpetic neuralgia and may help low back pain as well. Capsaicin cream can be used for neuropathic pain. Its main action is regression of C fibers in peripheral nerve endings. More recently, NSAIDs have been made into patches and gels that can be used on localized areas of pain such as sprains and strains for the patches and large joints such as knees for the gels. Older patients like this option as it gives them more control over pain relief.

Older patients may exhibit adverse effects of opioids, including respiratory depression, constipation, urinary retention, nausea and vomiting, dizziness, confused thinking, and sedation. Frequent and close monitoring of older patients using opioids is recommended as well as use of a laxative regimen for patients who are prescribed opioids.

Recommendations for use of pain medication for older patients:

• Use shorter-acting medications at the onset of therapy to determine if any adverse effects will occur.

• Reduce the beginning opioid dose by 25% to 50% to decrease the potential for oversedation.

• When patients have consistent and persistent pain, schedule medications to reduce the need for breakthrough or additional medication.

• Carefully monitor patients who are started on opioids at least daily if not more frequently.³⁴

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Older persons like using complementary and alternative medicine (CAM) for pain relief. A home remedy such as ice, heat, or an over the counter analgesic cream, can give them more control and be cost effective. The most common conditions for which patients use CAM include back pain, neck pain, joint pain, arthritis, and headache.³⁵ In primary care many practitioners do not ask about CAM therapies but about 40% of patients volunteer this information at office visits.³⁶ Complementary methods for pain relief are those that the patient uses with standard treatment, whereas alternative therapies are those that the patient uses in place of standard therapy.³⁷

Two of the most common CAM therapies used are heat and cold. Using a heat pack can increase circulation to the affected area, decrease stiffness, and relieve muscle spasms.¹⁷ A Cochrane review found little support for the use of heat and cold applications to treat low back pain.^38,39 Many older patients prefer heat to cold as they find the cold sensation uncomfortable.

Other types of CAM are attractive to the older patient. Massage may help muscle pain while providing relaxation. Older patients can benefit from physical therapy for reconditioning and improving balance.^24,26 Acupuncture can be used for pain related to fibromyalgia, osteoarthritis, and cancer.^40,41 The older patient can also benefit from movement therapy such as yoga or Tai Chi that improves functionality, balance, flexibility, and range of motion.

Some older patients can use cognitive behavioral strategies to relieve pain although others find them too difficult to master. Relaxation, imagery, meditation, and biofeedback can help reduce pain. Relaxation exercises can be provided using tapes, breathing exercises, or in class settings. The Arthritis Self Management Program (ASMP) provides techniques that older patients can use to reduce pain. Recommended techniques include education, cognitive restructuring, physical activity, problem solving, relaxation, and development of communication skills to interact with health care professionals.⁴² For older patients the value of relaxation and cognitive behavioral techniques is an improved sense of well-being and higher scores on quality of life scales.⁴¹

EXTENDED CARE FACILITIES

There are about 20,000 nursing homes in the United States caring for almost 2 million older persons who are typically poor and very disabled. The average length of stay in a nursing home is about 2 years, 20% of individuals stay for longer than 5 years, and 20% of discharges are secondary to death. The goals of nursing home care vary widely from short-term rehabilitation, to short-term hospice care, to long-term custodial care. It has been estimated that for each resident in a nursing home, there are three more similarly disabled persons living at home relying on family caregivers and community resources for their health and dependency needs.¹⁷

Extended care facilities vary greatly in the amount of health care they may provide. Because of regional differences, categories of care in these facilities differ dramatically, which makes generalizations difficult. Most of what is known about health care in long-term care facilities has come from data generated in nursing homes where undertreatment of pain has been reported to be as high as 85%.¹⁷ Similar to outpatient care, treatment may be withheld due to concerns about falling, diminished cognition, addiction, and constipation. Depression, anxiety, decreased socialization, sleep disturbance, impaired ambulation, and increased health care utilization are associated with the presence of pain in older people.¹⁷ Deconditioning, gait disturbances, and falls result from poor pain management.

Pain is often overlooked, in part because identification of pain requires specific assessment skills not utilized by many long-term care facilities. Cognitively impaired older persons are even more at risk. In a study done by Won, 74% of a demented, older long-term care population suffered from inadequately treated pain.²² Although cancer is a source of severe distress among patients and for staff, it is not nearly as common as arthritis and other musculoskeletal sources. Major causes of pain include low back pain, crystal-induced arthropathies, leg cramps, headaches, and claudication. Despite liberal treatment of cancer pain, an analysis of Medicare and Medicaid data showed that 25% of nursing home residents with severe cancer pain did not receive analgesic medication.³

Unique challenges are present in pain management for older residents in extended care facilities not seen in younger patients. The spectrum of complaints, manifestations of distress, and differential diagnosis is often difficult and challenging. Recovery from illness is less dramatic and slower to occur. Many of the medical problems are irreversible and expectations for cure or recovery lead to disappointments. Despite the progressive and incurable nature of many conditions in older residents, the discomfort or disability they produce can often be modified. Aggressive testing or complicated treatment is less important than comfort and effective symptom management, especially near the end of life.¹⁷

Assessment of acute and chronic pain is complicated by incomplete medical records and lack of access to laboratories, x-rays, and consultants. Transportation for medical workup results in missed meals, medications, and social interactions. For some patients, the alternative is referral to the emergency department, hospitalization, and repetition of tests that have substantial risk for these frail residents.¹⁷

Nursing homes are already highly burdened by local, state, and federal policies that regulate licensure and eligibility for reimbursement. Most of the care is delivered by nursing assistants with little or sometimes no formal medical education. Physicians see patients monthly and with an often unorganized staff where turnover can exceed 150% per year. Physicians often play a minor role in directing resources and quality improvement in many facilities. Despite Joint Commission for Accreditation of Health Care Organizations (JCAHO) adoption of pain indicators in its review process, only 5% of nursing homes submit themselves for JCAHO review. JCAHO is not required or substituted for yearly state licensure surveys or Medicaid and Medicare surveys.¹⁷

CONCLUSION

Pain in older patients is often underreported, underdiagnosed, and undertreated. Clinicians who care for patients receiving long-term care services must establish a treatment plan that is reasonable given the limited resources and skills available. Treatment must address the root cause of the pain as well as its severity, while taking into account comorbid conditions and concomitant medications. A pharmacologic regimen for older patients must combine sufficient analgesia, and be simplified as much as possible yet have safety precautions. Long-acting medications should be used whenever possible to provide longer durations of comfort and fewer doses for nurses or other caregivers to administer. The primary goal must be to control pain and prevent suffering. Extended care facilities must adopt contingency plans for pain management. These plans will prevent delays in pain care during medication changes or dosage adjustments. Nonpharmacologic strategies require further investigation for this highly disabled population. In an elderly population, that goal should be combined with safety considerations to avoid adverse effects that may not occur as often in younger patients. As the need for health systems for frail older persons continues to grow, it is our most important obligation to provide comfort and effective pain control appropriate for these new settings.

REFERENCES