Acute Pain Management in Children

Stacy J. Peterson

Kristen Lynn Labovsky

Steven J. Weisman

Nociception alerts the organism to potential or actual sources of harm. Nociceptive functions are active at birth, even in preterm neonates, and the experience of pain or pleasure has a powerful impact on learning and neurologic development.¹ Fitzgerald and Walker,¹ using neurobiologic studies in infant rats and psychophysical studies in infant humans, showed that the infant nervous system is in many respects hyperresponsive to noxious stimuli compared to the mature nervous system. Infant rats and humans withdraw their limbs from milder mechanical or thermal stimuli compared to older rats or humans. Infant rats and humans develop hyperalgesia following tissue injury, with evidence for spinal sensitization even in preterm neonates.

In the 1980s, there was a growing acceptance that peripheral and spinal mechanisms of nociception are active in preterm and term neonates. Controversy persisted regarding maturation of supraspinal mechanisms and regarding how to view pain as a conscious experience or suffering in neonates. Recent studies have examined correlates of brain activation using nearinfrared spectroscopy, which is sensitive to regional changes in blood flow. A noxious stimulus to the heel (performed for clinically indicated blood sampling) evoked increased signal overlying the contralateral, but not ipsilateral, cerebral cortex, which has been interpreted as a specific pattern of activation not solely dependent on global changes in autonomic arousal and blood pressure. These and other lines of evidence suggest that “painful stimulation reaches the brain” in neonates, although they do not per se establish the nature of pain viewed as conscious experience or suffering in neonates. Additional discussion follows later in the chapter regarding potential consequences of either untreated pain or pain treatment in critically ill neonates.¹

Care of infants and children with acute pain has changed considerably over the past several decades, and available evidence suggests that undertreatment of acute pain has become less prevalent in economically developed countries over this time period.² Changes in practice appear to be the combined result of a series of developments in basic research, clinical trials, and advocacy by parents as well as by clinicians, as listed in Table 50.1.

Pain Assessment in Infants and Children

Assessing pain in infants and children is a fundamental but challenging aspect of pediatric care. Uniform assessment of pain should be part of the standard of care for hospitals and clinics caring for children. Typical adult pain measures are not applicable to preverbal and young children. Infants and very young children are dependent on adult caregivers to adequately interpret their behavior and other signs in determining whether they have pain. Methods of measuring pain in preverbal patients and toddlers (ages 2 and 3 years) generally involve combinations of behavioral observation, such as facial expression, crying, and physiologic parameters. Preschool-age and early school-age children (ages 3 years or 4 to 8 years) are generally able to give some degree of self-report and pain scales in this age group incorporate self-report measures. In the younger group (ages 3 to 4 years), pain may be only be expressed in a binary way (i.e., either present or not present), but by early school age (ages 5 to 6 years), children are generally able to communicate a variety of pain levels.³ Fear and anxiety in children may complicate pain assessment and, in some cases, leads them to either overrate or underrate pain. For this reason, many behavioral scales are taken to be measures of “distress,” which combines pain, fear, and anxiety. For example, a 2-year-old child fearful of having a relatively painless ear examination may appear to have extreme pain based on behavioral measures. A 7-year-old child may deny pain because of the fear of having to receive a “shot” if he admits to having pain. Valid and reliable pain measures have been developed for children based on developmental levels reflecting a child’s ability to communicate and understand concepts of pain. In general, behavioral measures tend to underrate persistent pain relative to self-report.

TABLE 50.1 Factors Possibly Contributing to Increased Awareness of and Treatment of Pain in Infants and Children

Studies demonstrating maturation of nociceptive pathways in infant animals and in infant humans
Clinical trials demonstrating improved outcomes of neonates undergoing surgery under adequate anesthesia
Studies of pain assessment in infants, children, and adolescents
Pharmacologic studies examining pharmacokinetic, pharmacodynamic, and clinical outcomes of analgesics in infants and children
Development of acute pain services in pediatric tertiary centers
Development of regional anesthesia skills and service for infants and children
Advocacy by parents

Pain assessment in infants, neonates, and premature infants is especially challenging. Previously, infants were not thought to be fully capable of experiencing pain, which led in part to inadequate efforts to treat pain in infants. Numerous studies have examined the response of neonates and preterm infants to pain and have shown various response patterns including changes in stress hormones levels; observed behavioral responses; and alterations in heart rate, heart rate variability, oxygen saturation, and other physiologic responses.⁴^,⁵^,⁶^,⁷ Studies have shown that neonates who are subjected to heel lancing for blood sampling consistently swipe the foot being lanced with the unaffected foot, indicating that neonates have the ability to localize to the site of pain.⁸^,⁹ Other data have shown that hospitalized infants display graded responses of heart rate, oxygen saturation, mean arterial pressure, and behavioral state with varying degrees of pain intensity, indicating that infants have the ability to distinguish severity of pain.¹⁰ Pain assessment scales for infants are
typically composite pain scores consisting of behavioral parameters such as facial grimacing, posture, and crying combined with more objective data such as heart rate, blood pressure, and oxygen saturation. Pain ratings may be erroneous in critically ill infants because sepsis, hypotension, respiratory failure, and other conditions will change many of the physiologic and behavioral parameters in composite pain scales. The CRIES; Face, Legs, Activity, Cry, and Consolability (FLACC) scales; and the Premature Infant Pain Profile have been validated for infants and premature infants.¹¹^,¹²^,¹³

Concrete thinking and stages of cognitive and language development of preschool-age children can present difficulties in pain assessment. Many toddlers when ill, hospitalized, or confronted with strangers refuse to cooperate with self-report or formal testing of pain. Involving parents or other familiar caregivers in the assessment of pain for toddlers can provide useful information. Studies comparing parents’ to clinicians’ pain ratings are inconsistent with some showing good agreement but others showing disparities.¹⁴

The Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS) and the Behavioral Observational Pain Scale (BOPS) have been validated for assessing postoperative pain in toddlers and young children.¹⁵^,¹⁶ The FLACC scale is a very widely used scale involving five items, each scored from 0 to 2 to give a composite score ranging from 0 to 10.¹⁷ The FLACC scale has become widely used because it is quick and versatile and its components appear reasonable for a wide range of patient groups, including infants and older patients with developmental disabilities.¹³^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹ A recent review does find evidence to support its use in children aged 2 months to 7 years for postoperative pain as well as in children from ages 4 to 10 years who have cognitive impairment.²¹

Several validated self-report pain scores have been developed for children 4 years and older, including photos or drawings of faces where numerical anchors signify gradations of pain and a slide rule device where increasing color intensity indicates increasing pain intensity.²² Young children are able to differentiate pain intensity when presented with facial expressions, although more than five choices of facial expressions interfere with the child’s ability to reliably indicate pain.²³ Most older school-age children and adolescents have the cognitive and emotional maturity to use adult numerical visual analogue scales; nevertheless, pain, illness, hospitalization, and separation from parents cause some older children and teenagers to regress emotionally, making scales used for younger children, such as faces scale, more applicable. There has been considerable dispute regarding relative merits of different presentations of face-type scales; however, the most widely accepted and validated face-based scale is the Bieri Faces Pain Scale-Revised.²³^,²⁴

Analgesic Pharmacology in Infants and Children

Age-related differences in analgesic pharmacology are explained by a combination of pharmacokinetic and pharmacodynamics factors that vary with development. Neonates and young children have delayed maturation of hepatic enzymes involved in the metabolism of analgesics such as opioids and amide local anesthetics, increasing the risk of drug accumulation and toxicity.²⁵ For example, ester-type local anesthetics are metabolized by pseudocholinesterase. Young infants have significantly less of this enzyme compared to the adult population; therefore, clearance can be decreased and the effect of the local anesthetic is prolonged. Most neonates and young infants will have considerable maturation of the hepatic enzyme systems involved in biotransformation and conjugation by the age of 6 months, although enzyme maturation rates can vary considerably.²⁶ Neonates and young infants have decreased plasma concentrations of albumin and α₁ acid glycoprotein, which leads to decreased protein binding and greater concentrations of unbound, pharmacologically active drug.²⁷ Neonates also have reduced glomerular filtration rates in the first few weeks of life resulting in slower elimination of many drugs and many active metabolites of drugs that have undergone hepatic metabolism which are excreted via the kidneys. A number of specific age-related differences in pharmacokinetics and in drug actions and risks are detailed with each drug class in the following text.

Nonopioid Analgesics

Nonopioid analgesics traditionally refer to aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and selective cyclo-oxygenase (COX) inhibitors. More recently, evidence of analgesic efficacy in adjuvant medications such as gabapentin and pregabalin have expanded the choices of nonopioid analgesics. Several new entities, such as the G protein-related receptor agonists, will provide other nontraditional opioid receptor mediated analgesic choices. Many of the NSAID analgesics were thought of as primarily peripherally active agents; however, analgesia does occur from a combination of peripheral as well as central actions, involving mechanisms in the spinal cord and brain, especially with activation of microglia. Nonopioid analgesics are often first-line drugs used for mild to moderate pain in infants and children because they do not produce respiratory effects and are generally nonsedating.

ONTOGENY OF PROSTANOID BIOSYNTHESIS AND CYCLO-OXYGENASES

A variety of prostanoids are produced during fetal life, and COX inhibition can alter essential functions, including patency of the ductus arteriosus. Recent studies by Ririe and coworkers²⁸ in infant rats suggest that COX-mediated processes in spinal microglia are quite immature at birth. These studies raise the question of whether commonly used analgesics acting on COX isoforms might be ineffective in infants due to this delayed maturation of a prominent site of action.

ASPIRIN AND OTHER SALICYLATES

The use of aspirin in children has diminished significantly, largely due to its association with Reye syndrome. The elimination of aspirin is greatly reduced in infants. In our practice, aspirin is almost never prescribed as an analgesic; its use is confined to situations in which antiplatelet actions are required.

ACETAMINOPHEN

Acetaminophen is the most commonly used analgesic in pediatrics and has been safely used in children of all ages. It is typically used for mild to moderate pain, fever, and can be combined with opioids to provide additional analgesic effect and decreased opioid use. The mechanisms underlying acetaminophen’s analgesic and antipyretic actions remain controversial. Multiple central targets of acetaminophen’s actions have been described, including COX isoenzyme (type 3 as well as type 2) inhibition, endogenous cannabinoid receptors, and nitric oxide pathways.²⁹ Clinically, acetaminophen, by itself, appears to produce minimal gastropathy, minimal effect on platelet function, and much milder anti-inflammatory actions compared to NSAIDs. Acetaminophen, combined with NSAIDs, can produce additional analgesic benefits, with synergism in some models.³⁰ The elimination of acetaminophen is primarily through glucuronidation and sulfation and elimination rates are similar among infants, children, and adults.³¹^,³² Various formulations are available with different concentrations in the United States, although there has been a recent attempt at standardization of dose formulations.³³ Inadvertent dosing errors have led to reports of fulminant hepatic failure among infants and children.³⁴ Typical oral dosing is 10 to 15 mg/kg per dose. The maximum daily dosing is 40 mg/kg/day for premature infants and 75 mg/kg/day for
term infants and children. Rectal dosing can be used for children who are unable to tolerate oral dosing, although absorption of rectal dosing can be variable.³⁵ Maximal concentration after rectal dosing occurs at approximately 2 to 3 hours. Typical rectal dosing is 30 to 45 mg/kg initially, followed by 20 mg/kg every 6 hours.³²^,³⁴ In 2010, the U.S. Food and Drug Administration (FDA) approved the use of intravenous acetaminophen. Peak plasma concentration is reached in 15 minutes following infusion and data show improved pain control with use of the intravenous, with opioid sparing effect.³⁶^,³⁷^,³⁸ There is a role for use of the intravenous form in children who are both nothing by mouth (NPO) and nothing by rectum (NPR), as well as situations where children are NPO alone, given that rectal dosing can lead to discomfort, fear, or anxiety in children beyond infancy.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

NSAIDs are commonly used for mild to moderate pain and for fever control in children. They are often combined with opioids to augment analgesic efficacy and potentially reduce opioid use and opioid side effects. The use of several NSAIDs in postsurgical patients has been shown to reduce opioid use by approximately 30% to 40%.³⁹

NSAIDs produce their anti-inflammatory effect by reversibly inhibiting COX-1 and COX-2 isoforms and inhibiting the conversion of arachidonic acid to prostanoids.⁴⁰ The clearance of ibuprofen, ketorolac, and several other NSAIDs is more rapid in toddlers and preschool children compared to adults.⁴¹

Based on epidemiologic studies and pooled data from clinical trials, NSAIDs have a generally good safety margin in children and infants from roughly age 6 months onward, particularly with short-term use. There are limited safety data on the use of NSAIDs among neonates and young infants. In certain situations, one can consider NSAID use, such as ketorolac, in infants under 6 months, if the risk of using alternate analgesics is felt to be greater than use of an NSAID.⁴²^,⁴³ Indomethacin has been used for closure of patent ductus arteriosus in neonates. Elimination of indomethacin is slower in neonates and has the associated risk of hyponatremia and renal toxicity in this age group.⁴⁴ The incidence of NSAID side effects is quite low in children, when administered for postoperative pain relief. A large-scale study in children administered short-term use of ibuprofen showed a very low overall risk of severe side effects.⁴⁵ The risks of renal and hepatic toxicities are increased in states of decreased renal and hepatic blood flow, such as with significant surgical blood loss or shock. Much of the safety data for long-term use of NSAIDs in children is based on experience in treating juvenile rheumatoid arthritis (JRA).⁴⁶ Long-term use is associated with a higher incidence of mild gastrointestinal distress, but significant gastropathy and gastrointestinal bleeding in children is less common when compared to adults.

Although NSAIDs inhibit platelet aggregation and can prolong bleeding time, clinically significant bleeding is uncommon in healthy children. The use of NSAIDS after tonsillectomy procedures remains somewhat controversial. Children requiring tonsillectomy often have obstructive sleep apnea and are at increased risk of hypoventilation and apnea with opioids, making nonopioid analgesics an attractive alternative. Nausea and vomiting are also common after tonsillectomy, and opioids exacerbate these problems. Life-threatening bleeding can occur after tonsillectomy in the immediate postoperative period and approximately 7 days postoperatively after the patient has been discharged from the hospital.

Two meta-analyses came to different conclusions about the safety of NSAIDs in tonsillectomy. One found no significant increase in bleeding, whereas the other reported a threefold increase in bleeding episodes of sufficient severity to require reoperation.⁴⁷^,⁴⁸ A more recent retrospective chart review did support the findings that postoperative use of ibuprofen did increase posttonsillectomy bleeding.⁴⁹ It is less clear if single dosing of ketorolac during the perioperative period increases the risk of postoperative bleeding in this population. A recent meta-analysis does not show increased risk of posttonsillectomy hemorrhage in children with perioperative ketorolac use.⁵⁰ Despite these concerns, NSAIDs remain commonly used in the posttonsillectomy population worldwide at many institutions both perioperatively and in the postoperative healing period.

An additional concern with NSAID use is impaired bone healing after orthopedic surgeries that involve osteoclast activation and new bone formation.⁵¹ In vitro studies, animal models, and some case-control studies in adults suggest a higher incidence of impaired bone healing and nonunion with NSAID use. However, compared to adults, children are less likely to have impairment of bone formation with similar orthopedic procedures. Even in major procedures such as posterior spinal fusion for scoliosis, perioperative use of NSAIDS appears to be safe and not to result in a higher incidence of nonunion.⁵² For surgeries with lower risk of nonunion, or for selected patients with greater than average risks or side effects from opioids, judicious use of NSAIDs for brief time periods should be considered.

Selective COX-2 inhibitors have the advantage of lower incidence of gastrointestinal symptoms and decreased effect on platelet function compared to traditional NSAIDs in adult patients. The risk of nephropathy with selective COX-2 inhibitors is similar to that of traditional NSAIDs.⁵³ Anti-inflammatory and analgesic effects of COX-2 inhibitors are also similar to those of traditional NSAIDs. COX-2 inhibitors have been associated with cardiovascular complications in adults, with both short- and long-term use. Rofecoxib and valdecoxib have been withdrawn from the market in response to these reports of cardiovascular complications in adults. The cardiovascular risk of COX-2 inhibitors in infants and children remains unclear. The use of COX-2 inhibitors may be considered in children with JRA who experience good analgesia with traditional NSAIDs, but who have significant gastrointestinal symptoms, or in children with bleeding disorders, such as hemophilia or thrombocytopenia, to achieve analgesia with less risk of bleeding than with traditional NSAIDs. Studies of COX-2 inhibitors for analgesia after tonsillectomy are mixed. One study found better analgesia with ibuprofen compared to placebo.⁵⁴ One double-blind randomized controlled trial (RCT) found benefit to use of celecoxib in the posttonsillectomy population with a modest decrease in pain scores in addition to decreased use of acetaminophen.⁵⁵ Some studies suggest that COX-2 inhibitors might be less likely to interfere with active bone formation. Please see Table 50.2 for dosing guidelines of common nonopioid analgesics.

KETAMINE

Ketamine is increasingly used in both acute and chronic pain, especially in the postoperative period. Ketamine has anti-N-methyl-D-aspartate (NMDA) activity, which acts to decrease wind-up, central sensitization, opioid-induced hyperalgesia, and opioid tolerance. Multiple studies in the adult population have shown that ketamine has not only opioid-sparing effects but also analgesic and antihyperalgesic effects.⁵⁶ Literature supporting the use of ketamine in the perioperative period in children is not as clear. A 2016 meta-analysis of perioperative ketamine use in children did not find that ketamine beneficial in decreasing the amount of opioids used postoperatively.⁵⁷ Although the meta-analysis was not favorable, individual studies favor the use of ketamine in the postoperative period. This study showed decreased opioid use and lower pain scores following Nuss procedure in the group that received ketamine in addition to fentanyl.⁵⁸ One study published in 2016 did not find that low-dose ketamine postoperatively in posterior fusion spine surgery in children decreased opioid use postoperatively.⁵⁹ This particular study also did not find benefit in
preventing long-term postoperative pain, although the incidence of persistent postoperative pain in this demographic is not clearly known. It is reasonable to consider use of ketamine in children, particularly in those with difficult to control pain or a history of chronic opioid use. The data for use in adults is well-established and thus is an area that can be further explored in pediatrics.

TABLE 50.2 Dosing Guidelines for Nonopioid Analgesics

	Dose <60 kg	Dose >60 kg
Acetaminophen	10-15 mg/kg q4h PO	650-1,000 mg q4h PO
Acetaminophen	15 mg/kg q6h IV	15 mg/kg q6h IV
Naproxen	5 mg/kg q12h PO	250-500 mg q12h PO
Ibuprofen	6-10 mg/kg q6-8h PO	400-600 q6h PO
Celecoxib	2-4 mg/kg q1h PO	100-200 mg q12h PO
Ketorolac	0.3-5 mg/kg q6-8h IV, not for >5 d	15-30 mg q6-8h IV, not for >5 d
Ketamine	0.1 mg/kg/h IV infusion with titration	0.1 mg/kg/h IV infusion with titration
Gabapentin	15 mg/kg PO preoperative	1 g PO preoperative
NOTE: Dosing guidelines listed herein refer to children > 1 year of age. Maximum dose acetaminophen: 75 mg/kg/day. Further modifications in dosing are required for use of these agents in term and preterm neonates and in infants. Modifications are detailed in the text. IV, intravenous; PO, orally.

ANTICONVULSANTS

The use of anticonvulsants in chronic pain is well established; however, their use in acute pain, especially in children, is not as well established. There is evidence to support perioperative use of gabapentin for spine surgery in children. A study published in 2010 did show benefit to perioperative use of gabapentin 15 mg/kg prior to posterior spine fusion.⁶⁰ Gabapentin (continued at 5 mg/kg three times a day for a total of 5 days) decreased opioid requirements and postoperative pain scores only in the first 48 hours after surgery. Therefore, some clinicians only provide a preoperative oral loading dose. Valproic acid is another anticonvulsant that finds limited use in the acute treatment of pediatric migraine with one study finding approximately 50% of patients receiving significant relief from their headache.⁶¹ There is some evidence to support its efficacy in the treatment of acute migraine; however, the studies are few and also complicated by the fact that valproic acid was not the firstline treatment; thus, other medications, treatments, and factors likely played a role in the reported relief.⁶²

Opioids

Opioids are among the most widely used analgesics for treating moderate to severe pain in infants and children. As with adults, they are extremely useful but require careful patient selection, titrated dosing, and active treatment of side effects.

ONTOGENY OF OPIOID ACTIONS

The ontogeny of opioid actions has been studied in human clinical trials, in case series, and in a number of infant animal models. Infant animal models have provided useful information, although there are marked differences among species in opioid actions. There are age-related differences in analgesia and side effects involving pharmacokinetic and pharmacodynamics differences. Opioids (except for remifentanil) have prolonged actions in neonates and infants due to immature hepatic enzyme systems and immature renal excretion of active metabolites. Effects of hepatic and renal dysfunction on opioid clearance are discussed in a separate section in the following text. Additional factors that influence opioid pharmacokinetics include developmental changes in expression of P-glycoproteins, both in the gastrointestinal tract and in the blood-brain barrier, and changes in protein binding.

Pharmacodynamic studies of opioids in neonates and younger infants have examined analgesia and side effects, with a major emphasis on measures of respiratory depression. These studies are made difficult by a number of factors, including the imprecision inherent in observational pain measures in neonates, on the state dependence of behavioral responses, on the confounding effects of critical illness on measures, and on the variability of painful stimuli. Major sites of opioid actions, including the periaqueductal grey matter and descending pathways of the dorsolateral funiculus, appear immature in infant rats. Conversely, opioids administered systemically or via the epidural route show strong analgesic responses in infant rats at developmental stages corresponding to preterm neonates. In human studies, there are mixed results with use of opioids in studies of procedural pain in neonates, and studies randomly assigning ventilated neonates to receive morphine infusions versus placebo infusions (with both groups receiving morphine for painful procedures) have not shown clear advantages in the morphine infusion groups.⁶³^,⁶⁴

Children who are at particular risk for respiratory depressant effects of opioids include those with tonsillar hypertrophy, obstructive sleep apnea, certain neurologic conditions, and craniofacial abnormalities as well as neonates and young infants. Neonates and infants, particularly premature infants, have an increased risk of apnea and hypoventilation in response to opioids on a pharmacodynamic as well as pharmacokinetic basis. Careful dosing, cardiorespiratory monitoring, and close nursing observation are warranted for neonates and younger infants receiving opioids.

CODEINE

Codeine is an opioid previously used widely to treat mild to moderate pain. It is available as an elixir in pill and parenteral forms. Although it has seen a declining use for pain, it remains commonly used in cough suppressant formulations. For reasons to be detailed in the following text, our opinion is that codeine is in general a suboptimal choice as an analgesic in children in most settings, and we recommend against its use.⁶⁵ Codeine is a prodrug extensively metabolized in the liver. It is demethylated to morphine, which accounts for the analgesic effect.⁶⁶ A study of children undergoing surgery, receiving a fairly large dose of codeine, found that roughly one-third of the subjects generated undetectable blood concentrations of morphine, which would result in no discernible analgesic effect. Conversely, there are genotypes associated with ultrarapid metabolism of codeine to morphine.⁶⁷^,⁶⁸ In these subjects, standard recommended codeine doses can produce apnea. Standard dosing is 0.5 to 1 mg/kg every 4 hours. Dose escalation beyond this range appears to generate a higher incidence of side effects, particularly nausea and vomiting. In standard doses, codeine is a very weak analgesic. Studies in adult patients comparing efficacy of codeine to ibuprofen have shown that 30 to 45 mg codeine has less analgesic effect than 600 mg of ibuprofen. Because of the relatively high incidence of the impaired inability to demethylate codeine and higher incidence of side effects, other oral opioids such as oxycodone, morphine, hydromorphone, and hydrocodone are preferred. Intramuscular (IM) codeine has the double disadvantage of being a weak and inconsistent analgesic delivered by a noxious route.

Codeine is often dispensed in combination with acetaminophen to increase efficacy. When prescribing codeine combined with acetaminophen, care is required to avoid inadvertent administration of toxic doses of acetaminophen, particularly when increased dosages are prescribed for pain or when patients are taking other over-the-counter preparations containing acetaminophen. Codeine is also commonly prescribed as an antitussive.

As of 2013, the FDA has issued a new contraindication for the use of codeine to treat pain or cough in children younger than 12 years as well as a warning against its use the 12- to 18-year-old age group of children who have sleep apnea and/or are obese.⁶⁹

TRAMADOL

Tramadol has both opioid and nonopioid properties. It exists in a racemic mixture where the positive enantiomer has opioid and serotoninergic properties and its negative enantiomer exerts noradrenergic reuptake properties.⁷⁰ Like codeine, it is metabolized to O-desmethyltramadol by the P450 isoenzyme CYP2D6. It exerts its analgesic effect via the µ-opioid as well as acting as a serotonin and norepinephrine reuptake inhibitor. In the United States, it is available only in the oral form. In other countries, it is also available in an intravenous preparation. Although not approved for use in children under the age of 12 years, it is widely used for postoperative pain as well as acute pain in children.⁷¹

Tramadol is also associated with many reports of toxicity in children. Overall, the incidence of these adverse reactions is low, but they do occur. Toxicity for tramadol, like opioids, not only can result in respiratory depression but can also result in seizures.

As of 2017, the FDA has issued new black box contraindication for the use of tramadol to treat pain or cough in children less than 12 years of age. They have also included a contraindication to the use of tramadol in children undergoing tonsillectomy and/or adenoidectomy in patients under the age of 18 years. In addition to these contraindications, a new warning against the of tramadol in the 12- to 18-year-old age group in children with sleep apnea or who are obese is also in place. These were put in place after the recognition of the implications of genetic variability in P450 2D6 metabolism and the potential for life-threatening reactions.⁷²

OXYCODONE

Oxycodone can be used for moderate pain in doses of 0.05 to 0.1 mg/kg every 4 hours and for moderate to severe pain in starting doses of 0.1 to 0.2 mg/kg every 4 hours in infants and children >1 year of age. Less information regarding the use of oxycodone in neonates and small infants is available. Recent review and modeling suggests the use of lower doses in preterm neonate and small infants starting as low as 0.035 mg/kg and increasing to 0.065 mg/kg in term neonates.⁷³^,⁷⁴ Although historically prescribed in smaller doses, oxycodone dosing can be escalated as needed much like any of the socalled strong opioids. Oxycodone is generally well tolerated by children either alone or in combination with acetaminophen. Our impression is that it is associated with fewer side effects than codeine when used to treat moderate to severe pain. Oxycodone is metabolized in the liver to oxymorphone, which is metabolically active.⁷⁵ Because oxymorphone is eliminated by the kidneys, it can accumulate in patients with renal failure. Oxycodone is commonly used in children postoperatively when transitioning from parenteral opioids to oral opioids in preparation for discharge.

A sustained-release preparation of oxycodone (OxyContin) is available for use in the treatment of chronic pain and was approved use in children age 11 to 16 years in 2015. Recently, the trend at our institution is away from the use of long-acting oxycodone for postoperative pain. It has a bioavailability of approximately 60% and reaches peak analgesic effect after 60 to 90 minutes.⁷⁶

MORPHINE

Morphine is often the first-line opioid chosen for parenteral use in children. It has a long track record in pediatrics; it has received extensive pharmacologic study at all age groups; it is inexpensive; and it can be administered via oral, sublingual, intravenous, subcutaneous, rectal, and neuraxial routes.

The duration of morphine’s clinical effects are related in a complex manner to distribution into and out of the central nervous system, hepatic metabolism, and excretion of active metabolites, including morphine 6-glucuronide. Morphine primarily undergoes glucuronidation by the UDP glucuronosyltransferase (UGT) pathway in the liver to morphine-3-glucuronide, which has predominantly excitatory actions, and morphine-6-glucuronide, which has analgesic, sedative, and respiratory depressant actions more potent than morphine.⁷⁷ Because morphine-6-glucuronide is renally eliminated, it can accumulate in patients with renal failure, producing delayed sedation and hypoventilation. In addition, accumulation of morphine 3-glucuronide can contribute to delirium, agitation, and seizures. The elimination half-life of morphine in older children and adults is approximately 3 to 4 hours. The elimination halflife is approximately 7 hours in full-term newborns and even longer in premature infants.⁷⁸^,⁷⁹ Long-acting preparations of morphine, such as MS Contin or KADIAN, are typically used for children with sickle cell pain, cancer pain, and other types of chronic pain.

Dosing of morphine in children, as with all opioids, should be titrated to effect and individualized based on severity of pain, underlying medical conditions, age, side effects, and weight. See Table 50.3 for dosing guidelines for oral and parenteral morphine.

HYDROMORPHONE

Hydromorphone is a commonly used opioid for acute pain management in children for both parenteral and oral use. Like morphine, it is used in children for patient-controlled analgesia (PCA), continuous infusions, oral dosing, intermittent intravenous boluses, and epidural analgesia. Hydromorphone can provide effective analgesia in children with cancer pain and mucositis. In steady-state dosing, hydromorphone is 5 to 6 times more potent than morphine when given intravenously in children.⁸⁰

Although hydromorphone is commonly prescribed to patients with renal insufficiency, this practice is not evidence-based. Hydromorphone is metabolized primarily to hydromorphone-3-glucuronide (H3G) and, to a much lesser extent, hydromorphone-6-glucuronide (H6G) through UGT pathways.⁸¹ These glucuronides can also accumulate in patients with renal insufficiency. Information on metabolism of hydromorphone in neonates and young infants is very sparse.

METHADONE

Methadone is a long-acting opioid with a slow elimination and prolonged duration of analgesia.⁸²^,⁸³ The elimination half-life is highly variable, ranging from 6 to 30 hours. Methadone has a high oral bioavailability of 70% to 100%. Due to these unique properties, methadone is convenient to use as a prolonged duration opioid. Intermittent intravenous dosing at prolonged intervals (e.g., every 4, 6, or 8 hours) can provide a basal level of analgesia similar to that achieved by continuous infusions or frequent intravenous boluses of other opioids.⁸⁴

Methadone is available as an elixir and is often used in place of sustained-release opioid preparations to treat chronic pain in young children or in children unable to swallow pills. Conversely, methadone requires careful titration and vigilance to avoid overdosage, both because of extreme pharmacokinetic variability and for pharmacodynamic reasons detailed in the following text.

Methadone is prepared as a racemic mixture of levo (l-) and dextro (d-) isomers. The l-isomer acts as a µ-receptor agonist; the d-isomer acts as an antagonist at the NMDA receptor in the brain and spinal cord. Antagonism at the NMDA receptors
results in analgesia and reduced hyperalgesia as well as partially reversing tolerance to opioids.⁸⁵

TABLE 50.3 Initial Dosing Guidelines for Opioids

			Parenteral Dosing			Oral Dosing
	Equianalgesic Doses and Intervals		Usual Starting Intravenous or Subcutaneous Doses			Usual Starting Oral Doses and Intervals
Drug	Parenteral	Oral	Child <50 kg	Child >50 kg	Ratio Parenteral to Oral	Child <50 kg	Child >50 kg
Codeine	120 mg	200 mg	NR	NR	1:2	NR	NR
Morphine	10 mg	30 mg (long term)	Bolus: 0.1 mg/kg every 2-4 h	Bolus: 5-8 mg every 2-4 h	1:3 (long term)	Immediate-release: 0.3 mg/kg every 3-4 h	Immediate-release: 15-20 mg every 3-4 h
			Infusion: 0.03 mg/kg/h	Infusion: 1.5 mg/h	1:6 (single dose)	Sustained-release: 20-35 kg, 10-15 mg every 12 h; 35-50 kg, 15-30 mg every 12 h	Sustained-release: 30-45 mg every 12 h
Oxycodone	NA	15-20 mg	NA	NA	NA	0.1-0.2 mg/kg every 3-4 h	5-10 mg every 3-4 h
Methadone^a	10 mg	10-20 mg	0.1 mg/kg every 4-8 h	5-8 mg every 4-8 h	1:2	0.1-0.2 mg/kg every 4-8 h	5-10 mg every 4-8 h
Fentanyl	100 mg (0.1 mg)	NA			NA	NA	NA
			Bolus: 0.5-1.0 mg/kg every 1-2 h Infusion: 0.5-2.0 mg/kg/h	Bolus: 25-50 mg every 1-2 h Infusion: 25-100 mg/h
Hydromorphone	1.5-2 mg	7.5-10 mg	Bolus: 0.02 mg every 2-4 h	Bolus: 1 mg every 2-4 h	1:5	0.05-0.1 mg/kg every 3-4 h	2-4 mg every 3-4 h
			Infusion: 0.006 mg/kg/h	Infusion: 0.3 mg/h
Meperidine^b	75-100 mg	300 mg	NR	NR	1:4	NR	NR
NOTE: Doses are for patients over 6 months of age. In infants under 6 months, initial per kilogram doses should begin at roughly 25% of the per kilogram doses recommended here. Higher doses are often required for patients receiving mechanical ventilation. All doses are approximate and should be adjusted according to clinical circumstances. Recommendations are adapted from previous summary tables, including those of a consensus statement from the World Health Organization and the International Association for the Study of Pain.
^aMethadone requires additional vigilance because it can accumulate and produce delayed sedation. If sedation occurs, doses should be withheld until sedation resolves. Thereafter, doses should be substantially reduced, the interval between doses should be extended to 3 to 12 hours, or both. Electrocardiogram (ECG) for QT interval required. ^bThe use of meperidine should generally be avoided. Can consider use for postoperative shivering.
NA, not applicable; NR, not recommended. Adapted from Berder CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med 2002;347(14):1094-1103. Copyright © 2002 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.