Systemic Pharmacologic Agents

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ACETAMINOPHEN Acetaminophen is a commonly used analgesic and antipyretic that is useful for mild pain and as an adjunct for moderate pain in combination with codeine. Acetaminophen is rapidly absorbed from the gastrointestinal tract and is distributed throughout most body tissues. The plasma half-life is 1.25 to 3 h, but may be increased by liver disease and following overdosage. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites.

ASPIRIN Salicylates such as aspirin exhibit analgesic, anti-inflammatory, and antipyretic activity, and inhibit platelet aggregation. There is a strong association between Reye's syndrome and the use of aspirin in children, but the pathogenesis has not been determined. Aspirin must be used with caution, if at all, in children. Dehydrated patients who are more susceptible to salicylate toxicity even in therapeutic doses. The FDA advises that aspirin not be used in children with varicella or influenza.

NSAIDs Ibuprofen is a racemic mixture of two isomers. It has anti-inflammatory, antipyretic, and analgesic properties. The analgesic effect is related to inhibition of prostaglandin synthesis. It is used for children over six months of age as an alternative to acetaminophen. The most frequent adverse effects involve gastrointestinal (GI) tract irritation and renal dysfunction. Renal failure has been reported. Dehydrated patients are at higher risk for renal failure. There is a rare association with aseptic meningitis and severe hepatic reactions. Safety and efficacy have been established for children over six months of age.

Ketorolac is a pyrrolizine carboxylic acid derivative. It is an anti-inflammatory, antipyretic, and potent analgesic agent with similar actions and side effect profile to other NSAIDs, with slightly less GI irritation when given IV/IM than for oral NSAIDs. Overall, ketorolac has a lower incidence of side effects and longer duration of action than morphine. It acts peripherally, does not affect opiate receptors, and does not cause respiratory depression. Ketorolac is the only IV NSAID approved by the FDA. It may be used in combination with opioids, but has an opioid-sparing effect. Thus, smaller opioid dosages may provide adequate pain relief. It should not be admixed in the same syringe as opiates or hydroxyzine due to incompatibilities. Ketorolac also has good oral bioavailability, but has not been shown to be more efficacious than less expensive NSAID oral preparations. There is limited data on the use in children less than 16 years of age. In addition to GI irritation and platelet effects, ketorolac has been reported to adversely effect renal function, particularly in the dehydrated patient. Additionally, an increased risk of renal failure in patients on diuretics has been reported. Because ketorolac is highly protein-bound, it should be used cautiously in the presence of other protein-bound drugs such as warfarin. Interactions with renal clearance of lithium resulting in increased lithium levels have been reported. There is potential for cumulative adverse effects if ketorolac is combined with aspirin or other NSAIDs. There have been reports of bronchospasm and anaphylactoid reactions in adults. Duration of ketorolac therapy should not exceed five days.

OPIOIDS Narcotic or opioid medications remain the mainstay of analgesic pharmacotherapy for severe pain. Opioids include the phenanthrene derivatives (e.g., morphine, codeine, and hydromorphone), the phenylpiperidine derivatives (e.g., meperidine and fentanyl) and the diphenylheptane derivative (methadone). Close clinical and physiologic monitoring is essential with the use of opioids in the pediatric ED patient, as is an understanding of the relationship between level of pain, narcotic dose, and conscious state. Opioids in general have analgesic effects at lower doses than those required for sedation. A detailed discussion of opioid drugs is outlined in Chap..34.

Morphine remains the gold standard opioid for the management of moderate to severe acute pain; it is widely used and easily reversed with naloxone. Its oral bioavailability is poor. Infants less than three months old are particularly sensitive to its respiratory depressant effects.

Hydromorphone (Dilaudid) is a hydrogenated ketone of morphine. It is well absorbed following oral, rectal or parenteral administration. It has a more rapid onset and a shorter duration of action than morphine when given orally. Side effect profile is similar to morphine but less marked.

Meperidine is a synthetic derivative of morphine and is one-tenth as potent an analgesic per milligram of drug. Onset and duration of action is shorter than morphine and meperidine has slightly better oral bioavailability. Normeperidine (6- M-desmethylmeperidine) is a toxic meperidine metabolite excreted through the kidney. Normeperidine is a cerebral irritant that can cause effects ranging from dysphoria and irritability to convulsions. Because of its unique toxicity, meperidine is contraindicated in patients with impaired renal function and in those receiving antidepressants of the monamine oxidase inhibitor class. These effects have been observed even in young, otherwise healthy patients who were given sufficiently high doses of normeperidine. Therefore, meperidine should be reserved for very brief courses in otherwise healthy patients who have demonstrated an unusual reaction or allergic response during treatment with other opioids, such as morphine or hydromorphone.

Fentanyl is a short-acting synthetic opioid, 80 to 100 times as potent as morphine. When administered intravenously it has a rapid onset of action of less than 1 min and a short duration of action (15 to 30 min), due to its high lipid solubility and rapid redistribution. The major ED role for fentanyl is as an analgesic component for conscious sedation. In infants, it is less of a cardiovascular and respiratory depressant than morphine, and causes less histamine release, but the respiratory depressant effect may lag behind the analgesic effect. Fentanyl is associated with an idiosyncratic reaction of chest wall rigidity. This is more likely to occur with a high bolus dosing (5 pg/kg), but can occur with lower dosing (1 to 2 pg/kg). Small infants, less than 6 months of age, are at greater risk. The management approach for chest wall rigidity includes: naloxone 0.001 to 0.01 mg/kg or neuromuscular blockade (succinylcholine 2 mg/kg, or rocuronium 0.6 to 1.0 mg/kg, or pancuronium 0.1 mg/kg) and mechanical ventilation with 100 percent oxygen. Given the high concentration of fentanyl, exercise caution to avoid inadvertently flushing a residual bolus of the drug remaining in the IV line.

The new oral transmucosal fentanyl citrate (OTFC) (Oralet) preparation is a raspberry-flavored fentanyl-impregnated lozenge that allows administration of an opioid through oral transmucosal absorption. This nonthreatening "needleless" mode of drug delivery has been demonstrated in recent years to be an efficacious and safe method for inducing conscious sedation in children undergoing diagnostic or therapeutic procedures that are painful, such as bone marrow aspiration, laceration repair, gynecologic examination, and fracture reductions.6 The transdermal fentanyl patch currently has no role in ED acute pain management. Steady-state levels are not reached until 12 to 24 h, and the subdermal depot remains for 24 h after the patch is removed.

Codeine is readily absorbed from the gastrointestinal tract, and a very useful agent in the ED for adjunct oral pain therapy with acetaminophen. Codeine can be given IM, but IV administration is not recommended due to a higher side-effect profile. At therapeutic doses, the analgesic effect reaches a peak within two hours and persists between four and six hours. The plasma concentration does not correlate with brain concentration or relief of pain. Codeine crosses the blood-brain barrier, is found in fetal tissue and breast milk, but is not bound to plasma proteins. The plasma half-life is about 2.9 h. The elimination of codeine is primarily by the kidneys, and about 90 percent of an oral dose is excreted by the kidneys within 24 h of dosing.

ADJUNCTS Benzodiazepines have sedative, anxiolytic, amnestic, and muscle-relaxant properties. They have no analgesic action. They are adjuncts for acute pain management in the child over the age of 10 years where anxiety or muscle spasm is a prominent feature. Benzodiazepines can be given IV, orally, or rectally. Benzodiazepines are discussed in detail in the following sedation section.

Hydroxyzine is an Hrreceptor antagonist that is indicated for anxiety and allergic pruritus; it also has sedative properties. Hydroxyzine has no analgesic action. It is available in oral and IM preparations (dosage 0.5 mg/kg oral or IM); IV administration is not recommended. It should be considered as a second-line drug to benzodiazepines, and IM injections generally should be avoided for pain-control medications. Promethazine (Phenergan) is also an H rreceptor antagonist, with sedative, anxiolytic, and antiemetic properties, in addition to providing relief of minor allergic conditions. It is not recommended for children less than two years of age. Promethazine can be given orally, rectally, IV (slowly), or IM. The evidence to support a synergistic analgesic effect of H -,-antagonists with opioids is limited, and they may potentiate the sedative effects of opioids.

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