Pediatric Pain Management: A Review

Abstract

Although the occurrence of pain in hospitalized children is common, assessment and treatment of pain presents unique challenges to practitioners who care for pediatric patients. Knowledge of drug mechanisms as well as metabolic differences in infants and children compared with adults is necessary for the successful treatment of acute and chronic pain syndromes. Recent reports of adverse events in children receiving both opioid and non-opioid analgesics have prompted re-examination of some long standing pain medication regimens and prescribing practices. We review advances in diagnosis and management of pain in pediatric populations.

Background

The incidence of pain is common among neonates, infants, and children, with an estimated 33–82% of hospitalized pediatric patients experiencing moderate to severe pain, especially following surgery or other painful procedures.¹ Despite this, it has long been recognized that pain in pediatric populations is poorly assessed and undertreated or mismanaged, leading to adverse patient outcomes (both long-term and short-term) and increased healthcare expenditures. Attempts to improve analgesia through education include designation of pain as the fifth vital sign and the Children are at increased risk for adverse drug effects from analgesic therapy if proper vigilance and monitoring are neglected. Analgesics and anesthetics are responsible for the majority of adverse drug effects in hospitalized children. application of the World Health Organization (WHO) pain ladder. Although originally intended to guide management of cancer pain, it has been expanded to other mechanisms of acute and chronic pain.² (See Figure 1) Many pain management strategies, both pharmacologic and non-pharmacologic, are available to practitioners for the treatment of acute pain and procedural pain in children.³ Management of chronic pediatric pain due to conditions such as musculoskeletal pain, recurrent abdominal pain, headaches, vaso-occlusive crises, and cancer is complex, and often requires a multidisciplinary approach and is beyond the scope of this paper.⁴

Figure 1.

WHO pain ladder modified for acute and assorted chronic pain²

Pain Assessment

Timely and accurate assessment of pain in hospitalized children is important to diagnosis and management, improving patient satisfaction and clinical outcomes, as well as reducing distress during subsequent hospitalizations and painful interventions.³ Pediatric pain assessment tools are difficult to validate because it is often impossible to distinguish pain from other causes of distress in children. There are many age-appropriate tools available for assessing pain in pediatrics.⁵ In general, self-report methods are useful in children at least five to six years old.⁶ Visual analog scales such as those used for adults can be used in children age 8 and above, and include face scales such as the Oucher Pain Scale™ and Wong-Baker Faces Scale.⁷ (See Figure 2) The Oucher™ uses actual photographs of children’s facial expressions. Five different ethnic posters are available: African-American, Asian, Caucasian, First Nations, and Hispanic. Line drawings show the spectrum of facial expression in the Wong-Baker scale. These scales are more appropriate in younger children. The Oucher™ is not valid in children less than three years of age. Self-report tools are not useful for many children because of age, cognitive impairment, or language/cultural barriers. In these situations, use of observational measures of behavior and physiologic parameters such as heart rate, blood pressure, facial expressions, crying, and body posturing is recommended.⁶ Autistic patients are frequently described as insensitive to pain. A recent study using objective measures suggests that their response may be greater and recovery delayed compared to normal children when assessed by behavioral and physiologic scales.⁸

Figure 2.

Pharmacology of Pain Medication in Pediatrics

Although afferent pain pathways are thought to be mature by 26 weeks gestational age, pediatric dosing regimens for analgesic drugs are complicated by age-related differences in drug metabolism. Differences in body water composition, metabolic rate, and plasma protein binding often offset each other to produce minimal change in dosage. However, immaturity of metabolic pathways and clearance mechanisms frequently require prolonged intervals between recommended doses.³ Adult metabolism may not be achieved until adolescence. However, the majority of the increase occurs in the first year of life.

Medications

Traditional Non-Opioid Analgesics

Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDS) are among the most commonly prescribed medications during pediatric hospitalizations for control of mild to moderate pain.⁹ NSAIDS inhibit cyclo-oxygenase (COX) enzymes and reduce inflammatory mediators in peripheral tissues. NSAIDs are largely free of side effects commonly associated with opioids.¹⁰ The mechanism of acetaminophen is less completely understood but is believed to involve multiple pain pathways. Some studies describe benefit to combining acetaminophen and NSAIDS for the treatment of post-surgical pain in adults or children post-tonsillectomy. ^{10, 11} Combination therapy is associated with better post-operative pain scores, fewer side effects, and improved patient satisfaction. Although these drugs are recommended for mild to moderate pain, they are useful adjuncts in the management of moderate to severe pain. (See Table 1 for recommended dosing.) A large meta-analysis in children documents significant opioid sparing for both NSAIDS and acetaminophen in the treatment of moderate to severe pain.¹²

Table 1.

Non-Opioid Analgesics

Drug	Route	Age	Dose	Frequency
Acetaminophen
Acetaminophen	Oral	< 10 days	10–15 mg/kg	Q6 hrs
Acetaminophen	Oral	NB > 10 days	10–15 mg/kg	Q4–6hrs
Acetaminophen	Oral	Infants & Children < 12 yrs	10–15 mg/kg	Q4–6hrs
Acetaminophen	Oral	Children ≥ 12 yrs	10–15 mg/kg	Q4–6hrs
Acetaminophen	Rectal	< 10 days	30 mg/kg	Q8hrs
Acetaminophen	Rectal	NB > 10 days	30 mg/kg	Q6–8hrs
Acetaminophen	Rectal	Infants & Children < 12 yrs	20 mg/kg	Q4–6hrs
Acetaminophen	Rectal	Children ≥ 12 yrs	325–650 mg	Q4–6hrs
Acetaminophen	Intravenous	2–12 yrs	12.5mg/kg or	Q4hrs
Acetaminophen	Intravenous	2–12 yrs	15 mg/kg	Q6hrs
NSAIDS
Aspirin*	Oral		10–15 mg/kg	Q4hrs
Ibuprophen	Oral		5–10 mg/kg	Q6hrs
Naproxen	Oral		5–6 mg/kg	Q12hrs
Ketorolac	Intravenous		0.5 mg/kg
Ketorolac	Intramuscular		1.0 mg/kg

^*Do not use in children with acute febrile illness due to risk of Reye’s syndrome

Acetaminophen is available over-the-counter in liquid formulations and chewable tablets with variable concentrations alone or in combination with other medications. These inconsistencies increase the risk of accidental overdose. Intentional ingestion of acetaminophen by children accounts for roughly half of pediatric acetaminophen overdoses requiring hospitalization and treatment.¹³ Acetaminophen has a narrow therapeutic index and overdose produces accumulation of the toxic metabolite N-acetyl-pbenzoquinoneimine (NPQI) that damages hepatic tissues, and may result in acute liver failure or even death. Maximum safe daily dose varies with age (See Table 2). The FDA has recently recommended that acetaminophen concentration in liquid formulations be standardized to 160 mg/5 mL and that any acetaminophen-containing medication be clearly labeled.¹⁴ Prior to the introduction of intravenous acetaminophen, rectal administration of acetaminophen (40 mg/kg loading dose) was common in infants and children unable or unwilling to take oral formulations, but rectal dosing is associated with delayed onset, variable uptake, and prolonged clearance.¹⁵

Table 2.

Maximum Daily Dose Oral or Rectal Acetaminophen³

Age	Dose
Children	100 mg/kg/day
Infants	75 mg/kg/day
Term & preterm neonates ≥ 32 weeks post conceptual age	60 mg/kg/day
Preterm neonates 28–32 weeks	40 mg/kg/day

In 2011, intravenous acetaminophen (Ofirmev, Cadence Pharmaceuticals, San Diego, CA) was approved in the United States for the treatment of fever and mild to moderate pain in children greater than two years of age. Unfortunately, there have been numerous reports of ten-fold overdoses of intravenous acetaminophen resulting from dosages being calculated in milligrams (mg) but administered in milliliters (mL) of the 10 mg/mL intravenous solution.^{16, 17} The recommended dosing of intravenous acetaminophen for children between ages two and twelve is 12.5 mg/ kg Q4 hours, or 15 mg/kg Q6 hours, not to exceed 750 mg per dose or 75 mg/kg per day.¹⁸

There are three types of NSAIDs available for pediatric use: salicyclates, traditional NSAIDS, and COX 2 inhibitors. Aspirin, ibuprophen and naproxen are available over-the-counter and in liquid form. Indomethacin and Celebrex® are available only by prescription. Celebrex is a COX2 inhibitor that has no liquid formulation. Use of aspirin in the setting of fever/acute illness has been abandoned because of the risk of Reye Syndrome in children. Aspirin, indomethacin, and Celebrex are prescribed for the control of chronic pain associated with rheumatoid arthritis.

Some studies demonstrate no difference in efficacy between NSAIDs and acetaminophen for the management of mild pediatric pain. Other reports support improved analgesia with NSAIDs.³ Similarly, some studies indicate a greater degree of opioid sparing with NSAIDs.¹² Common adult NSAID risks, such as gastrointestinal bleeding and renal insufficiency, are rare in children during short term usage in the absence of known gastrointestinal or renal pathology. Patients and care givers should be advised against taking or administering these medications on an empty stomach.

Ketorolac is a non-selective COX inhibitor that may be given intravenously or intramuscularly and is especially useful in hospitalized patients.^{19, 20} Ketorolac may be relatively contraindicated in patients at risk for bleeding due to its inhibition of platelet function. It has been used safely in many surgical patients after hemostasis has been achieved. Based on reports of adverse events, its use is limited after tonsillectomy and some orthopedic procedures. Intramuscular dose (1 mg/kg) is double the recommended intravenous dose (0.5 mg/kg).

Opioids

A variety of opioid medications (See Table 3 for recommended dosing) are available for the treatment of pain in pediatrics and are recommended by the WHO in combination with non-opioid analgesics for the treatment of moderate to severe pain resulting from acute and chronic pain syndromes as well as post surgical pain.^2,21 Although effective, opioid analgesics are associated with undesirable side effects (e.g., nausea, pruritis, ileus, urinary retention, sedation, and respiratory depression). Neonates are at especially high risk for central respiratory depression because hepatic enzymes, renal function, and hypoxic respiratory drive are immature and less efficient than in adults.³

Table 3.

Opioid Analgesics in Infants ≥ 6 Months and Children³

Drug	Route	Dose	Frequency
Codeine	Oral	0.5–1.0 mg/kg	Q3–4hrs
Codeine	Intramuscular	0.3–0.5 mg/kg	Q4–6hrs
Fentanyl	Intravenous	0.5–1.0 mcg/kg	Q1–2hrs
Fentanyl	Intranasal	1.5 mcg/kg	May repeat x1 at 10 minutes
Fentanyl	Intranasal 2nd dose	0.75–1.5 mcg/kg
Hydrocodone	Oral	0.1–0.15 mg/kg	Q3–4hrs
Hydromorphone	Oral	40–80 mcg/kg	Q3–4hrs
Hydromorphone	Intravenous	10–20 mcg/kg	Q2–4hrs
Meperidine	Oral	2–3 mg/kg	Q2–3hrs
Meperidine	Intravenous	0.8–1.0 mg/kg	Q2–3hrs
Methadone	Oral	0.1–0.2 mg/kg	Q6–8hrs
Methadone	Intravenous	0.1 mg/kg	Q6–8hrs
Morphine	Oral	0.3 mg/kg	Q3–4hrs
Morphine	Intravenous	0.1 mg/kg	Q2–4hrs
Oxycodone	Oral	0.1–0.2 mg/kg	Q3–4hrs

It is recommended that acetaminophen and opioids be prescribed separately so that acetaminophen can be administered regularly (e.g., every four to six hours) and oral opioid preparations can be reserved for breakthrough pain and give on an as-needed basis (pro re nata). There are four commonly prescribed pediatric oral opioids: codeine, hydrocodone, oxycodone, and morphine. While morphine is the gold standard for analgesia, it has a relative low oral bioavailability. Morphine and oxycodone are active drugs and do not require biotransformation to produce analgesia. Codeine and hydrocodone are prodrugs without significant analgesic properties and require metabolism by hepatic cytochrome P450 (CYP) enzymes to achieve clinical benefit.

In May 2013, the FDA issued a black box warning for codeine following outpatient tonsillectomy and adenoidectomy in children. A cluster of three reported deaths in this population appeared in 2012. Subsequent FDA investigation revealed an additional seven deaths and three overdoses since 1969. Codeine remains in widespread use despite these reports and knowledge of marked differences in clinical effect.²² Inter-individual variability in expression of the CYP2D6 allele of the CYP enzyme system leads to different rates of metabolism of codeine. Poor metabolism varies from 10% in the Caucasian population to 30% in the Chinese population.¹² The greatest risk for ultra-rapid metabolism, 16–28%, occurs in the Arabic and North African populations.¹² Other ethnic groups show less than 10% incidence of this genetic feature. Patients who metabolize codeine slowly may experience little to no analgesic effect from the drug, while ultra-rapid metabolizers may be at risk for respiratory depression from resulting high blood levels of morphine.

Similar to codeine, hydrocodone is also a prodrug that uses the CYP2D6 enzyme to produce its active form, hydromorphone.^{23, 24} The dearth of case reports about pediatric overdose with hydrocodone may simply reflect the historical preference for codeine. All commercial liquid formulations of hydrocodone contain other drugs: acetaminophen, ibuprophen or pseudoephedrine. Oxycodone is an active drug and more effective than most of its metabolites. The CYP3A4 enzyme is its major metabolic pathway. However, a small proportion of this drug is also handled by the CYP2D6 enzyme. Ultra-rapid metabolizers may not achieve adequate analgesia for the expected duration. Slow metabolizers demonstrate an increased incidence of side effects. The FDA has issued a black box warning for oxycodone based on drug interactions. Macrolide antibiotics, antifungal agents and antiviral agents inhibit the CYP3A4 enzymes and can enhance opioid side effects. There is an adult case report of inability to achieve adequate analgesia in a CYP2D6 slow metabolizer.²⁵ The Toronto Hospital for Sick Children has removed codeine from its formulary and recommended morphine as the primary oral analgesic for children because it does not rely on any cytochrome reactions.²⁶ Oxycodone and codeine are all available as individual drugs or in combination with acetaminophen. Recently, the FDA recommended limiting the dose of acetaminophen in fixed drug combination tablets to 325 mg because acetaminophen overdose may be an inadvertent side effect of therapeutic opioid dosing.

The most commonly prescribed parenteral opioid analgesics in pediatric hospitalizations are fentanyl and morphine.⁹ Hydromorphone, meperidine, and methadone can also be used. Intermittent intramuscular dosing has been replaced by intravenous administration, either bolus administration on demand or through patient controlled analgesia (PCA). Children receiving PCA should be monitored with continuous pulse oximetry +/− end-tidal carbon dioxide measurement. PCA is widely used for post-surgical pain in adults, and has also been validated in pediatric patients as young as six years of age.³ Treatment should be individualized and adding a background basal infusion to demand doses is controversial due to the possible increased risk of hypoxia, especially during sleep. Allowing nursing staff or care givers to administer PCA doses (so called nurse-controlled or parent-controlled analgesia) may be appropriate for infants or children who are unable or unwilling to operate a PCA pump, but requires additional education in order to prevent overdoses and respiratory depression. The presence of comorbidities or concurrent use of sedatives is associated with an increased risk of adverse drug events. Meperidine is not routinely used for PCA because of the risk of accumulation of the toxic metabolite normeperidine. The long half life of methadone does not make it a good choice for PCA either. Intranasal fentanyl, 1–2 mcg/kg, is an alternative to achieve rapid analgesia in the hospitalized child who does not have intravascular access.

Non-Traditional Analgesics

Several drugs classically used in the operating room are migrating to other locations where children require analgesia and sedation. Nitrous oxide inhalation was embraced by pediatric dentists decades ago to facilitate painful dental care in children. More recently it is being used throughout pediatric hospitals to provide analgesia for needle sticks and other minor procedures. It provides analgesia, anxiolysis and some amnesia within 3-5 min of starting inhalation. It has no odor or taste. Most locations limit the inspired concentration of nitrous oxide to 50%. Special education about the safe delivery of medical gases is necessary for personnel.

Ketamine was originally developed as an anesthetic agent but is used more commonly, at lower doses (0.25–0.5 mg/kg intravenous), for sedation and analgesia in children. It is often administered intramuscularly (1–3 mg/kg) in patients with learning and behavioral disabilities because it is rapidly effective and requires minimal patient cooperation. Ketamine is effective orally (3–5 mg/kg) either alone or in combination with midazolam. Ketamine is a central sympathetic nervous system stimulant and may produce mild hypertension and tachycardia. Unlike opioids, it does not produce respiratory depression or decrease airway tone.

The primary indication for dexmedetomidine is sedation but analgesia is a desirable side effect. Dexmedetomidine does not depress respiration or airway reflexes. Transient bradycardia or mild hypertension can be observed with bolus administration. Traditional regimens for continuous intravenous infusion use a loading dose, 1 mcg/kg, delivered over 10 minutes followed by lower dose, 0.5 mcg/kg/hr continuous infusion. Mild hypotension +/− bradycardia may be observed during the maintenance phase. It can be easily be treated by dose reduction. The uses for dexmedetomidine in children are expanding.²⁷ Intranasal delivery of dexmedetomidine is effective at a dose of 1–2 mcg/kg.

Local Anesthesia

Needle sticks are one of the most common painful procedures in children. There are both chemical and mechanical methods to diminish pain. Stimulation of both cold and vibration nerves can block transmission of painful impulses.²⁸ Application of ice alone or vapocoolant spray is inexpensive & effective. A commercial product, Buzzy®, provides both cold and vibration and can be purchased without a prescription.

The topical application of local anesthetics can significantly reduce pain and increase IV placement success rates. The two most commonly used products are eutectic mixture of local anesthetics (EMLA) and lidocaine 4% in liposomes (LMX4). EMLA is a creamy mixture of lidocaine and prilocaine that is placed over the injection site and covered with an occlusive dressing for 45–60 minutes. Blanching and venospasm can produce difficulty with venipuncture. EMLA is a prescription product. Beware of potential prilocaine overdose when used in young infants or on broken skin. LMX4 is equally effective and available OTC. It has a more rapid onset (20–30 minutes) compared to EMLA, and must also be protected with an occlusive dressing. The anesthetic effect also dissipates more rapidly. LMX does not produce vasoconstriction, which may improve the conditions for IV placement. Solutions of lidocaine, tetracaine and epinephrine (TAC, LET, LAT) may be directly applied to larger wounds before repair to provide analgesia.

Summary

There is a wide variety of effective pharmacologic treatments for pain in children. Children are at increased risk for adverse drug effects from analgesic therapy if proper vigilance and monitoring are neglected. Analgesics and anesthetics are responsible for the majority of adverse drug effects in hospitalized children.³³ It is also critical to not only assess the child’s pain but to reassess after the delivery of therapy.¹ It is equally important to not let fear of adverse effects to impede delivery of adequate pediatric analgesia.

Biography

Frederick T. O’Donnell, MD, (above) and Kathleen R. Rosen, MD, are both at the University of Missouri Department of Anesthesiology and Perioperative Medicine in Columbia, Missouri.

Contact: odonnellf@health.missouri.edu