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Analgesic Medications
Insufficient knowledge about the pharmacology of analgesic medications in the pediatric age group has led to inadequate treatment of pediatric pain partly related to the fluctuating pharmacokinetic and pharmacodynamics properties of analgesics during development.
Although all analgesic medications have undergone thorough pharmacologic investigation in adults, similar studies have not always been performed in children. Only since 2001 has the Food and Drug Administration (FDA) required studies of all new pharmaceuticals in the pediatric population. All of the medications discussed in this chapter gained FDA approval before this time.
Pharmacokinetic Considerations
Because of the physiologic changes that occur between infancy and adulthood, the pharmacokinetics of many medications administered to pediatric patients differ from those of adults. Differences in body compartment composition, plasma protein binding capacity, enzyme and renal function, metabolism, and respiratory function result in varied medication absorption, distribution, metabolism, clearance, and response.
Drug absorption in the pediatric patient differs from adults in many ways. The gastric pH of an infant is relatively less acidic leading to a potential for decreased bioavailability of orally administered medications that are weakly acidic. On the other hand, there is a similar potential for an increase in the bioavailability of weakly alkaline oral medications. Infants also demonstrate prolonged gastric emptying and abbreviated intestinal transit time, which can delay the absorption of medications. Biliary and pancreatic enzymatic function are not fully developed initially, and resultantly neither is the pediatric patient’s ability to solubilize and absorb drugs, which are lipophilic and rely on these functions. Because of the increased hydration of the epidermis, greater perfusion to subcutaneous regions, and greater body surface area to body mass ratio, transdermal applications may be absorbed more rapidly in the pediatric patient. Furthermore, a reduction in blood flow to skeletal muscle provides for a theoretical risk in delayed absorption of intramuscular medications.
The percentage of free drug available for action in the serum relies on the extent to which it is bound to plasma proteins. In neonates, there is a reduction in protein binding compared with older children and adults. This is because of several factors. First, there is a decreased amount of albumin produced in the neonatal period. This factor, in combination with a qualitative difference in the albumin itself, leads to a decrease in both the effectiveness and occurrence of protein binding. Second, the level of alpha-1-acid glycoprotein is markedly decreased in infancy. Opioids and local anesthetics are heavily bound to these proteins, and deficiency leads to increased plasma levels of unbound drug. This causes a potential increase in not only analgesic effect, but also potential for increased respiratory and neurologic depression, and cardiotoxicity. Conversely, there are various disease states that are associated with increased levels of alpha-1-acid glycoprotein, including burns, malignancy, infection, and trauma. This leads to increased drug binding and subtherapeutic effects at normal medication dosages.
Body composition also changes the way in which the pediatric patient responds to medications. The total body water percentage of an infant is 85% which decreases to 60% total body composition by adulthood. In the pediatric patient, this equates to an increased volume of distribution, an increased duration of action, and an increased dosing interval required for many water-soluble drugs. Muscle and fat proportions in the neonate are significantly decreased compared with the older patient, which results in decreased amount of drug uptake into these pharmacodynamically inactive sites. This results in higher drug concentrations at active sites, and a potential for supratherapeutic drug levels. Finally, the relative increase in blood flow to the neonatal brain and immature blood-brain barrier can lead to increased drug concentrations in the brain.
Metabolism plays a critical role in the termination of action of medications into hydrophilic, metabolically inactive compounds, which can then be excreted primarily by the kidneys and—to a lesser degree—by the biliary system. There are two stages of metabolism that occur primarily at the liver. Phase I metabolism includes oxidation, reduction, hydrolysis, and hydroxylation reactions. The most important enzyme family in this stage is the cytochrome P450 system, which is a mixed oxidase system that uses nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen. This system is responsible for the reduction and oxidation of many medications including acetaminophen, nonsteroidal antiinflammatory diseases (NSAIDs), and opioids. Phase II metabolism uses glucuronidation, sulfation, and acetylation reactions to increase the water solubility of a drug, thus converting parent molecules into more polar, water-soluble, inactive metabolites. These drugs may then undergo renal excretion.
Hepatic enzymes are severely deficient at birth but rapidly develop and approach adult levels by a few months of age. This development continues, and between approximately 2 and 6 years of age, hepatic function actually exceeds that of an adult. It then declines to again reach levels similar to those of adulthood by puberty. However, during this period of increased function, the patient may require increased dosing, shorter interval dosing, and higher infusion rates to accomplish equianalgesic effects. Metabolism can also be influenced by pressure gradients within the body compartments themselves. For instance, hypotension or increase in intraabdominal pressure—as can be seen in an infant in the immediate postoperative period status postclosure of an omphalocele—may result in a decrease in renal and hepatic blood flow and, therefore, a decrease in the function of the kidneys and liver, respectively.
Excretion of water-soluble metabolites and, to a lesser extent, parent compounds is primarily completed by the renal system. In neonates, the glomerular filtration rate is decreased, which can lead to an accumulation of these products. This can result in metabolite-associated toxicity with many drugs. An example is the highly potent metabolite of normeperidine, which can lead to seizure activity in the patient with renal impairment.
When administering opioids to pediatric patients, respiratory function must be considered to avoid potential issues with atelectasis, airway obstruction, and respiratory failure. Pediatric patients have an increased work of breathing secondary to compliant chest walls, poor respiratory muscle tone, smaller caliber airways, compliant laryngeal and tracheal cartilage, and decreased presence of fatigue-resistant, type 1 muscle fibers. Furthermore, their respiratory drive is diminished, especially in the neonatal period, as the ventilatory response to carbon dioxide and oxygen is decreased. When combined with their significantly increased relative oxygen consumption, typically negligible doses of opioids can result in a decrease in respiratory drive that can result in hypoventilation, hypercarbia, acidosis, respiratory arrest, and cardiac arrest.
Antipyretic, Analgesic, and Nonsteroidal Antiinflammatory Drugs
Cyclooxygenase (COX) inhibitors used for pain in pediatric patients include acetaminophen and NSAIDs. They are used to treat mild to moderate pain and can be used concomitantly with opioids in treatment of severe pain. Unlike opioid analgesics, these medications do not have the unwanted side effects of respiratory depression and sedation. They also have little to no dependence and abuse potential.
COX is an enzyme that is responsible for the metabolism of arachidonic acid into prostanoids, including prostaglandins and thromboxanes ( Fig. 33.1 ). These substances contribute to pain via sensitization of peripheral nerve endings. They also act as vasodilators, contributing to erythema and swelling associated with the inflammatory response.
There are two isozymes of cyclooxygenase. COX-1 is found in tissues throughout the body, in the presence or absence of disease. It plays an integral role in the mediation of physiologic functions such as gastric mucosa protection, renal blood flow regulation, and platelet aggregation. It is inhibition of this isozyme that is associated with the negative effects attributed to COX inhibitors (including gastric ulceration, coagulation disturbance, renal blood flow compromise, and bronchoconstriction). COX-2 is the inducible isozyme, which is produced by the cell in response to trauma or inflammation. It is inhibition of this enzyme that is responsible for the therapeutic effects of COX inhibitors.
The majority of COX inhibitors are nonselective, preventing the action of both COX-1 and COX-2, thus interfering with desirable physiologic effects in addition to those that are associated with inflammation. The development of COX-2 inhibitors, such as celecoxib and rofecoxib, has provided the antiinflammatory and analgesic benefits of nonselective COX inhibitors without contributing to gastric ulceration and other undesired associated effects. These medications are not yet well studied in pediatric patients.
Acetaminophen is the most common antipyretic and analgesic medication currently used in pediatrics. This drug came to the forefront in pediatric pain management in the 1980s, when aspirin was determined to be a contributing factor to Reye syndrome. Acetaminophen quickly gained traction as one of the primary analgesic medications because of its relatively low side-effect profile and its analgesic and antipyretic efficacy. The effects of acetaminophen are thought to be exclusively mediated by central COX inhibition, and thereby the negative effects of peripheral COX inhibition commonly associated with NSAIDs are avoided. However, acetaminophen offers no peripheral antiinflammatory action.
Though optimal analgesic plasma concentrations are variable and not well-defined, antipyretic effects of acetaminophen are seen at 10 to 20 μg/mL. This therapeutic range is accomplished at oral doses of 10 to 15 mg/kg at 4-hour dosing intervals. With oral dosing, peak effects are noted at 30 minutes after administration. Rectal bioavailability is much lower and more variable and for these reasons it is used less at the author’s institution. However, initial rectal dosing of 35 to 45 mg/kg will achieve therapeutic range with peak effect at 2 to 3 hours. Because of the delayed effect of rectal acetaminophen, the dosing interval is increased to every 6 to 8 hours. After initial administration, subsequent rectal dosages of 10 mg/kg are sufficient. The maximum daily dose relies on the patient’s age, ranging from 40 mg/kg in premature neonates of 28 to 32 weeks of age to 75 mg/kg in children and adults.
Acetaminophen is also available in IV form, which is dosed similar to the oral form. Although IV administration results in more predictable pharmacodynamics and pharmacokinetics with 50% higher cerebrospinal fluid (CSF) peak concentration compared to oral or rectal administration, evidence of significant benefit of IV over oral acetaminophen dosing is lacking except in specific circumstances, such as during gastrointestinal compromise where absorption via oral dosing may not be possible.
At therapeutic doses, the metabolism of acetaminophen is primarily hepatic, yielding primarily nontoxic, inactive metabolites that can be excreted by the kidneys. This is accomplished via three pathways: glucuronidation (45%–55%), sulfate conjugation (20%–30%), and N-hydroxylation and dehydration, typically followed by glutathione conjugation. The last pathway results in an intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is potentially toxic and the primary culprit for the destructive effects seen in acetaminophen overdose. At usual doses, NAPQI is detoxified by glutathione conjugation and minimal amounts are oxidized by the cytochrome P450 pathway. In the setting of overdose, the glutathione pathway is overwhelmed and oxidation is enhanced. This leads to high levels of oxidation byproducts, which are associated with fulminant hepatic failure and necrosis. The treatment for acetaminophen overdose is N-acetylcysteine (NAC), which serves to replenish glutathione reserves and thereby enhance nontoxic metabolism.
Aspirin (acetylsalicylic acid) is the oldest NSAID. It is an irreversible inhibitor of COX-1 and is a modifier of COX-2 activity. Because of its association with Reye syndrome—a rare disorder characterized by brain and liver damage—it is not often used in pediatrics except in certain populations, such as those with juvenile rheumatoid arthritis and various other rheumatic diseases. Oral dosing of aspirin is 10 to 15 mg/kg every 4 hours with a maximal daily dose of 90 mg/kg.
There are many other NSAIDs with little variability among their benefit and side-effect profiles ( Fig. 33.2 ). These are selected based on desired dosing interval and the patient’s fasting status. Ibuprofen is the most widely used NSAID in pediatric patients. It is available in multiple pediatric formulations and has few adverse effects. Oral dosing is 15 mg/kg for a single dose, with decreased repeated doses of 10 mg/kg. For a maximum of 40 mg/kg per day. The dosing interval for repeated doses is every 6 hours. Naproxen has a longer half-life than ibuprofen and is dosed at 5 to 10 mg/kg PO every 8 to 12 hours up to a maximum daily dose of 20 mg/kg. The safety of naproxen in neonates is not well established.
Ketorolac is unique in that it is currently the only nonsteroidal antiinflammatory drug in the United States that is available for oral, intramuscular, and intravenous dosing. This medication should be used for no longer than 5 days because of risk for gastric ulceration and hemorrhage and renal dysfunction. Because of its effect on platelet function, it should be avoided in patients at high risk for issues with bleeding. Ketorolac is dosed at 0.5 mg/kg every 6 hours with a maximum of 30 mg per dose, and the maximum daily dose is the lesser of 120 mg or 2 mg/kg.
Ketamine
Ketamine is a phencyclidine derivative that is used most commonly as a dissociative anesthetic at doses of 1 to 5 mg/kg IV (see also Chapter 19). Potent analgesia is demonstrated at subanesthetic doses (0.25–0.5 mg/kg IV), and it can be administered in oral, IV, intramuscular, or rectal form. It is useful in pain settings in which there is a large neuropathic component. In high doses, ketamine can be given orally or intramuscularly to induce general anesthesia when IV access is not an option, such as in pediatric patients who are severely behaviorally challenged. In addition to providing anesthesia and analgesia during short, stimulating procedures, ketamine can be administered as a prolonged infusion that can result in analgesic effects for up to 3 months after discontinuation.
Ketamine provides its analgesic effects primarily by antagonism of the N-methyl-D-aspartate (NMDA) receptor ( Fig. 33.3 ).
It is also thought to enhance descending neurologic inhibition and cause antiinflammatory effects at central sites. This compound possesses a high affinity for central muscarinic receptors and exerts significant cholinergic effects.
Opioids
Opioids are the primary treatment for moderate to severe nociceptive pain. Although they are still used for neuropathic pain, they are not as effective. Opioids exert their effect by binding centrally to both pre- and postsynaptic cell membranes. Upon agonistic binding to an opioid receptor, G-protein coupled calcium channels are deactivated. This deactivation results in a decrease in intracellular calcium ( Fig. 33.4 ).
At the same time, G-protein coupled potassium channels are activated, which leads to hyperpolarization of the neuron’s cell membrane. Combined, there is a decrease in calcium-related activity. Presynaptically, this results in a decrease of excitatory neurotransmitter release (substance P and glutamate). Postsynaptically, there is an associated increase in induction of spinal adenosine release. These neurotransmitters are paramount to pain signal transmission, and a strong analgesic effect is the result.
Opioids act on a variety of specific receptors. The μ receptor—named because of its affinity for morphine—is located predominantly in the cerebral cortex, thalamus, periaqueductal gray matter, and substantia gelatinosa of the spinal cord. This receptor is responsible for supraspinal analgesia, dysmotility, bradycardia, dependence, respiratory depression, and sedation. Systemic action is primarily caused by supraspinal μ receptors while neuraxial opioids work additionally on μ and κ receptors, which are located in the substantia gelatinosa of the spinal cord.
There are various other opioid receptors, including the κ receptor, which is associated with analgesia and sedation, respiratory depression, hallucinations, miosis, dysphoria, and, by inhibition of antidiuretic hormone, diuresis. The δ receptor contributes to analgesic and antidepressant effects, convulsions, and physical dependence. It is also thought to be associated with modulation of μ-mediated respiratory depression. Other receptor subtypes contribute to opioid effects to a lesser extent.
Most opioids undergo extensive first-pass hepatic metabolism before reaching systemic circulation, resulting in reduced bioavailability. Opioids are generally lipophilic, which allows crossing of cell membranes to the desired site of action. However, this decreases the ability of the compound to be renally excreted. For this reason, metabolism is necessary, rendering the molecule more hydrophilic and amenable to excretion by the kidneys. This is accomplished by phase I and II metabolism, as mentioned above (see also Chapter 2). In the case of opioids, phase II is primarily accomplished by the process of glucuronidation, catalyzed by uridine diphosphate glucuronosyltransferase (UGT), which results in the highly hydrophilic opioid metabolite. This by-product is then easily excreted by the kidneys.
Opioids can be classified by their potency, means of derivation (naturally occurring, semisynthetic, or synthetic), or by their mechanism of action. The latter is perhaps the most useful, and includes the following classifications: agonists, partial agonists, mixed agonist-antagonists, or pure antagonists. Agonists bind to the receptor of interest and result in a change of cellular function, resulting in the characteristic pharmacologic effect. Agonists include drugs such as morphine, meperidine, hydromorphone, methadone, oxycodone, codeine, fentanyl, and remifentanil. Partial agonists, such as buprenorphine, bind to the receptor and cause a less-than-maximal response than full agonism.
Conversely, antagonists bind to the receptor, prevent binding of the agonist, and result in the antagonism of the pharmacologic effects of the agonist. Opioid antagonists include naloxone, naltrexone, and nalmefene. Mixed agonist-antagonists demonstrate agonistic and antagonistic effects when they bind to multiple receptor subtypes, and include nalbuphine and pentazocine.
There are many side effects associated with opioid medications. Nausea and vomiting are common and associated with the rostral spread of the opioid to the medullary vomiting center. It is important to consider the clinical context and rule out potentially dangerous causes of these signs and symptoms, such as hypotension secondary to sympathectomy associated with neuraxial techniques. When appropriate, multiple therapies can be effective, such as opioid rotation, phenothiazines, 5-HT3 antagonists (such as ondansetron), antihistamines, various antipsychotics at low doses, and anticholinergic medications.
Urinary retention is another unwanted, dose-independent side effect of opioids. It is more commonly associated with neuraxial than systemic opioid administration but frequently occurs in either setting. The mechanism for urinary retention involves parasympathetic outflow inhibition at the sacral spinal cord resulting in increased urinary bladder capacitance and decreased tone of the detrusor muscle involved in bladder emptying. This is addressed with continuous or intermittent catheterization, or with low-dose naloxone administration.
Opioid-associated pruritus is histamine independent and mediated by opioid receptors in the brainstem at the level of the trigeminal nucleus. For this reason, the pruritus is frequently most concentrated in the distribution of the trigeminal nerve. Treatment can include naltrexone, naloxone, mixed agonist-antagonist opioids, or serotonin antagonists. Though frequently used, antihistamines offer relief only to the extent of providing sedation.
Constipation and miosis are the two opioid-related side effects most resistant to tolerance. Opioid therapy requires bowel prophylaxis in both the acute and chronic setting. If constipation is left untreated, ileus may result.
The most dangerous side effect of opioids is respiratory depression. Concomitant administration of medications with the side effect of sedation can lead to an increased risk for severe respiratory depression. At the population-based level, benzodiazepines are highly correlated with opioid-associated overdose mortality. Even medications such as gabapentin which are not known respiratory depressants by themselves but rather are described as sedating, have been shown to increase respiratory depression when given with opioids. Opioid analgesic response and level of side effects are highly variable by individual, and careful monitoring and appropriate titration on a patient-to-patient basis is paramount to avoiding these unwanted, potentially lethal effects.
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