Pediatric Pain Management

The Newborn and Infant

There are several behavioral distress scales for the infant and young child, mostly emphasizing the patient's facial expressions, crying, and body movement. Facial expression measures appear most useful and specific in neonates. Autonomic and vital signs can indicate pain, but because they are nonspecific, they may reflect other processes, including fever, hypoxemia, and cardiac or renal dysfunction ( Table 76.3 ).

The Older Child

Children age 3-7 yr become increasingly articulate in describing the intensity, location, and quality of pain. Pain is occasionally referred to adjacent areas; referral of hip pain to the thigh or area above the knee is common in this age range. Self-report measures for children this age include using drawings, pictures of faces, or graded color intensities. Children ≥8 yr can usually use verbal numerical rating scales or visual analog pain scales (VAS) accurately ( Fig. 76.2 ). Verbal numerical ratings are preferred and considered the gold standard; valid and reliable ratings can be obtained from children ≥8 yr. The numerical rating scale (NRS) consists of numbers from 0-10, in which 0 represents no pain and 10 represents very severe pain. There is debate about the label for the highest pain rating, but the current agreement is not to use the phrase “worst pain possible,” because children can always imagine a greater pain. In the United States, regularly documented pain assessments are required for hospitalized children and children attending outpatient hospital clinics and emergency departments (EDs). Pain scores do not always correlate with changes in heart rate or blood pressure.

The Cognitively Impaired Child

Measuring pain in cognitively impaired children remains a challenge. Understanding pain expression and experience in this population is important, because behaviors may be misinterpreted as indicating that cognitively impaired children are more insensitive to pain than cognitively competent children. Children with trisomy 21 may express pain less precisely and more slowly than the general population. Pain in children with ASD may be difficult to assess because these children may be both hyposensitive and hypersensitive to many different types of sensory stimuli, and they may have limited communication abilities. Although self-reports of pain can be elicited from some children who are cognitively impaired, observational measures have better validation among these children. The Noncommunicating Child's Pain Checklist—Postoperative Version is recommended for children up to 18 yr. Maladaptive behaviors and reduction in function may also indicate pain. Children with severe cognitive impairments experience pain frequently, mostly not because of accidental injury. Children with the fewest abilities experience the most pain.

Acetaminophen, Aspirin, Nonsteroidal Antiinflammatory, and Coxib Drugs

Acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) have replaced aspirin as the most commonly used antipyretics and oral, nonopioid analgesics ( Table 76.4 ).

Acetaminophen , a generally safe, nonopioid analgesic and antipyretic, has the advantage of intravenous (IV), rectal, and oral routes of administration. Acetaminophen is not associated with the gastrointestinal (GI) or antiplatelet effects of aspirin and NSAIDs, making it a particularly useful drug in patients with cancer. Unlike aspirin and NSAIDs, acetaminophen has only mild antiinflammatory action.

Acetaminophen toxicity can result from a large single dose or cumulative excessive dosing over days or weeks (see Chapter 77 ). A single massive overdose overwhelms the normal glucuronidation and sulfation metabolic pathways in the liver, whereas long-term overdosing exhausts supplies of the sulfhydryl donor glutathione, leading to alternative cytochrome P-450 (CYP)–catalyzed oxidative metabolism and the production of the hepatotoxic metabolite N -acetyl- p -benzoquinone imine (NAPQI). Toxicity manifests as fulminant hepatic necrosis and failure in infants, children, and adults. Drug biotransformation processes are immature in neonates, very active in young children, and somewhat less active in adults. Young children are more resistant to acetaminophen-induced hepatotoxicity than are adults as a result of metabolic differences; sulfation predominates over glucuronidation in young children, leading to a reduction in NAPQI production.

Aspirin is indicated for certain rheumatologic conditions and for inhibition of platelet adhesiveness, as in the treatment of Kawasaki disease. Concerns about Reye syndrome have resulted in a substantial decline in pediatric aspirin use.

The NSAIDs are used widely to treat pain and fever in children. NSAIDs are nonselective cyclooxygenase (COX) inhibitors, that is, drugs that nonselectively block the activity of both COX-1 (found in gastric mucosa and platelets) and COX-2 (active in inflammatory pathways and cortical renal blood flow regulation) enzymes that synthesize prostaglandins. In children with juvenile idiopathic arthritis, ibuprofen and aspirin are equally effective, but ibuprofen is associated with fewer side effects and better drug adherence. NSAIDs and coxibs used adjunctively in surgical patients reduce opioid requirements (and therefore opioid side effects) by as much as 35–40%. Although NSAIDs can be useful postoperatively, they should be used as an adjunct to, not as a substitute for, opioids in patients with acute, moderate to severe pain.

Ketorolac, an IV NSAID, is useful in treating moderate to severe acute pain in patients who are unable or unwilling to swallow oral NSAIDs. U.S. Food and Drug Administration (FDA) recommendations limit ketorolac to 5 consecutive days of administration. IV ibuprofen (Caldolor) is FDA approved for the management of pain and fever in infants and children >6 mo of age. Adverse effects of NSAIDs are uncommon but may be serious when they occur, including inhibition of bone growth and healing; gastritis with pain and bleeding; decreased renal blood flow that may reduce glomerular filtration and enhance sodium reabsorption, in some cases leading to tubular necrosis; hepatic dysfunction and liver failure; inhibition of platelet function; and an increased incidence of cardiovascular events in patients predisposed to stroke and myocardial infarction. Although the overall incidence of bleeding is very low, gastric bleeding is the most common cause of mortality related to this class of analgesics. NSAIDs should not be used in the child with a bleeding diathesis or at risk for bleeding or when surgical hemostasis is a concern, such as after tonsillectomy. The drug class is usually not used in the setting of bone healing, except perhaps in the 1st few days after surgery. Renal injury from short-term use of ibuprofen in euvolemic children is quite rare; the risk is increased by hypovolemia or cardiac dysfunction. The safety of both ibuprofen and acetaminophen for short-term use is well established (see Table 76.4 ).

Coxib drugs available in the United States are limited to oral celecoxib, whereas in Europe and elsewhere parenteral parecoxib and oral rofecoxib are available. Parecoxib was not FDA approved, whereas rofecoxib was approved and withdrawn from marketing due to concern of enhanced risk of heart attack and stroke in high-risk adults, which has subsequently been found to be associated with all the coxibs and all the NSAID drugs as well. The coxib drugs are selective COX-2 enzyme inhibitors; therefore they are effective antiinflammatory and analgesic molecules that generally do not result in platelet inhibition or bleeding, or in gastric inflammation or ulceration, findings that may be seen with the nonselective COX inhibitors in the NSAID class. However, coxib drugs do inhibit regulation of cortical renal blood flow, and therefore carry the same risk of renal toxicity and acute tubular necrosis, particularly in the setting of low cardiac output states or dehydration. Celecoxib is therefore an appropriate primary or adjunctive analgesic to use in children after surgery, children with gastric mucosal pathology, or oncology patients in whom concern for hemostasis contraindicates conventional NSAIDs.

Opioids

Opioids are analgesic substances either derived from the opium poppy ( opiates ) or synthesized to have a similar chemical structure and mechanism of action ( opioids ). The older, pejorative term “narcotics” (narcotic analgesics) should not be used for these agents because it connotes criminality and lacks pharmacologic descriptive specificity. Opioids are administered for moderate and severe pain, such as acute postoperative pain, sickle cell crisis pain, and cancer pain. Opioids can be administered by the oral, rectal, oral transmucosal, transdermal, intranasal, IV, epidural, intrathecal, subcutaneous (SC), or intramuscular (IM) route. Regardless of route of administration, the site of action is at mu (µ) opioid receptors in the peripheral nervous system, spinal cord, brainstem, and higher CNS centers. Historically, infants and young children have been underdosed with opioids because of concern about significant respiratory side effects. Once thought to represent infants' particular sensitivity, the opioids' respiratory depressant effects are now known to result from infants' lower metabolic clearance of opioids and higher blood levels with frequent dosing. With proper understanding of the pharmacokinetic and pharmacodynamics of opioids, children can receive effective relief of pain and suffering with a good margin of safety, regardless of pharmacokinetic maturity, age, or size ( Tables 76.5 to 76.8 ).

Opioids act by mimicking the actions of endogenous opioid peptides, binding to receptors in the brain, brainstem, spinal cord, and to a lesser extent in the peripheral nervous system, and thus leading to inhibition of nociception. Opioids also bind to µ receptors in the pleasure centers of the midbrain, particularly in genetically susceptible individuals, a factor responsible for the euphoric effect in some individuals as well as the predilection to psychological dependence and addictive behavior. Opioids also have dose-dependent respiratory depressant effects when interacting with the µ-opioid receptors in the respiratory centers of the brainstem, depressing ventilator drive and blunting ventilatory responses to both hypoxia and hypercarbia. These respiratory depressant effects are increased with co-administration of other sedating drugs, particularly benzodiazepines or barbiturates.

Optimal use of opioids requires proactive and anticipatory management of side effects (see Table 76.7 ). Common side effects include sedation, constipation, nausea, vomiting, urinary retention, and pruritus. Tolerance usually develops to the side effect of nausea , which typically subsides with long-term dosing, but nausea may require treatment with antiemetics, such as a phenothiazine, butyrophenones, antihistamines, or a serotonin receptor antagonist such as ondansetron or granisetron. Pruritus and other complications during patient-controlled analgesia with opioids may be effectively managed by low-dose IV naloxone.

The most common, troubling, but treatable side effect is constipation . Patients who take opioids for chronic pain for long periods predictably develop tolerance to the sedative and analgesic effects of opioids over time, but tolerance to constipation does not occur, and constipation remains a troublesome and distressing problem in almost all patients with long-term opioid administration. Stool softeners and stimulant laxatives should be administered to most patients receiving opioids for more than a few days. Osmotic and bulk laxatives are less effective, usually producing more distention and discomfort. A peripherally acting opiate µ-receptor antagonist, methylnaltrexone, promptly and effectively reverses opioid-induced constipation in patients with chronic pain who are receiving opioids daily. Methylnaltrexone is approved for use as either an injectable or oral formulation, but only the SC injection is commercially available, which most children will object to receiving. Naldemedine and naloxegol are other agents with actions similar to methylnaltrexone. A novel laxative, lubiprostone , is a colonic chloride channel inhibitor that impairs water reabsorption in the colon and is very effective for opioid-induced constipation.

Media and government attention the “opioid epidemic” has reasonably led to scrutiny of the prescription of opioids to children, and recent FDA approval of opioid formulations for children has raised alarm and criticism by some vocal critics of the use of opioids for medical purposes. Thus, one of the potent barriers to effective management of pain with opioids is the fear of addiction held by many prescribing pediatricians and parents alike. Pediatricians should understand the phenomena of tolerance, dependence, withdrawal, and addiction (see Table 76.5 ). Opioid addiction is the result of the complex interplay of genetic predisposition, psychiatric pathology, and social forces, including poverty, joblessness, hopelessness, and despair. The dramatic increase in the amount of opioid abuse and overdoses and opioid-related deaths since 2001 has been largely restricted to the adult white population age 30-55 yr, not in children or adolescents. A longitudinal study of children and adolescents treated for medical reasons with opioids found that there was no increased risk of the development of substance abuse, at least until their mid-20s. Other epidemiologic studies have shown a negligible increase in opioid overdoses and deaths in the black and Latino populations, but rather a relationship to the unemployment rate. Thus the rational short- or even long-term use of opioids in children does not lead to a predilection for or risk of addiction in a child not otherwise at risk because of genetic background, race, or social milieu.

It is equally important for pediatricians to realize that even patients with recognized substance abuse diagnoses are entitled to effective analgesic management, which often includes the use of opioids. If legitimate concerns exist about addiction in a patient, safe effective opioid pain management is often best managed by specialists in pain management and addiction medicine. Table 76.9 outlines the U.S. Centers for Disease Control and Prevention (CDC) opioid recommendations for chronic pain (primarily in adults).

There is no longer a reason to administer opioids by IM injection. Continuous IV infusion of opioids is an effective option that permits more constant plasma concentrations and clinical effects than intermittent IV bolus dosing, without the pain associated with IM injection. The most common approach in pediatric centers is to administer a low-dose basal opioid infusion, while permitting patients to use a patient-controlled analgesia (PCA) device to titrate the dosage above the infusion ( Fig. 76.3 ) (see Chapter 74 ). Compared with children given intermittent IM morphine, children using PCA reported better pain scores. PCA has several other advantages: (1) dosing can be adjusted to account for individual pharmacokinetic and pharmacodynamic variation and for changing pain intensity during the day; (2) psychologically the patient is more in control, actively coping with the pain; (3) overall opioid consumption tends to be lower; (4) therefore fewer side effects occur; and (5) patient satisfaction is generally much higher. Children as young as 5-6 yr can effectively use PCA. The device can also be activated by parents or nurses, known as PCA-by-proxy (PCA-P), which produces analgesia in a safe, effective manner for children who cannot activate the PCA demand button themselves because they are too young or intellectually or physically impaired. PCA overdoses have occurred when well-meaning, inadequately instructed parents pushed the PCA button in medically complicated situations, with or without the use of PCA-P, highlighting the need for patient and family education, use of protocols, and adequate nursing supervision.

Because of the high risk of adverse side effects (respiratory depression), the FDA has issued contraindications for the pediatric use of codeine and tramadol ( Table 76.10 ).

Local Anesthetics

Local anesthetics are widely used in children for topical application, cutaneous infiltration, peripheral nerve block, neuraxial blocks (intrathecal or epidural infusions), and IV infusions ( Table 76.11 ) (see Chapter 74 ). Local anesthetics can be used with excellent safety and effectiveness. Local anesthetics interfere with neural transmission by blocking neuronal sodium channels. Excessive systemic dosing can cause seizures, CNS depression, and (by cardiac and arteriolar sodium channel blockade) hypotension, arrhythmias, cardiac depression, and cardiovascular collapse. Local anesthetics therefore require a strict maximum dosing schedule. Pediatricians should be aware of the need to calculate these doses and adhere to guidelines.

Topical local anesthetic preparations do not generally result in measurable systemic blood levels and can reduce pain in diverse circumstances: suturing of lacerations, placement of peripheral IV catheters, lumbar punctures, and accessing indwelling central venous ports. The application of tetracaine, epinephrine, and cocaine results in good anesthesia for suturing wounds but should not be used on mucous membranes. Combinations of tetracaine with phenylephrine and lidocaine-epinephrine-tetracaine are equally as effective, eliminating the need to use a controlled substance (cocaine). EMLA, a topical eutectic mixture of lidocaine and prilocaine used to anesthetize intact skin, is frequently applied for venipuncture, lumbar puncture, and other needle procedures. A 5% lidocaine cream (Elemax) is also effective as a topical anesthetic.

Lidocaine is the most commonly used local anesthetic for cutaneous infiltration. Maximum safe doses of lidocaine are 5 mg/kg without epinephrine and 7 mg/kg with epinephrine. Although concentrated solutions (2%) are commonly available from hospital pharmacies, more dilute solutions (0.25% and 0.5%) are equally as effective as 1–2% solutions. The diluted solutions cause less burning discomfort on injection and permit use of larger volumes without achieving toxic doses. In the surgical setting, cutaneous infiltration is more often performed with bupivacaine 0.25% or ropivacaine 0.2% because of the much longer duration of effect; maximum dosage of these long-acting amide anesthetics is 2-3 mg/kg and 3-4 mg/kg, respectively.

Neuropathic pain may respond well to the local application of a lidocaine topical patch (Lidoderm) for 12 hr/day ( Table 76.12 ). Peripheral and central neuropathic pain also may respond to IV lidocaine infusions, which may be used in hospital settings for refractory pain, complex regional pain syndromes, and pain associated with malignancies or the therapy of malignancies, such as oral mucositis following bone marrow transplantation. In these patients, 1-2 mg/kg/hr should be administered, and the infusion titrated to achieve a blood lidocaine level in the 2-5 µg/mL range, with use of twice-daily therapeutic blood monitoring. Table 76.13 outlines approaches to central neuropathic pain.