Agents in common use for ED CS include morphine, fentanyl, and meperidine.
Meperidine may be a poor choice for ED analgesia in general. It causes more histamine release than either morphine or fentanyl. Its primary metabolite, normeperidine, is bioactive and toxic. Normeperidine causes CNS excitation, including tremors, myoclonus, and seizures, effects that are not antagonized by naloxone. Because normeperidine is excreted by the kidneys, it accumulates in renal insufficiency and with repeated doses. 14 Meperidine may also cause a fatal reaction when coadministered with monoamine oxidase inhibitors. This reaction may be excitatory (agitation, rigidity, hyperpyrexia, seizures, and coma) or depressive (respiratory depression, hypotension, and coma). For these reasons, meperidine is considered a second-line agent in the treatment of pain when opioid analgesics are considered.
MORPHINE Morphine is a naturally occurring opioid that is approximately 35 percent protein bound, 77 percent ionized at pH 7.4, and poorly lipid soluble. It therefore is slow to penetrate the blood-brain barrier and, after small bolus injections, 10 to 30 min are required before its peak effects are seen. Doses of 0.2 mg/kg result in peak effects in less than 1 h that may last for 4 to 6 h. It releases histamine and therefore may produce hypotension, especially in preload-dependent patients. Its analgesic effects, and its respiratory depression, have been shown to be potentiated by coadministration of hydroxyzine in postoperative patients; 15 the significance of this finding for ED CS is uncertain, especially since hydroxyzine is not recommended for intravenous (IV) use. Morphine undergoes hepatic glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide; the latter is four times as potent as morphine and has a duration of action approximately double that of its parent. The daughter compounds are renally excreted and accumulate in renal insufficiency.
FENTANYL Fentanyl is a synthetic phenylpiperidine derivative that is approximately 80 to 85 percent protein bound and 92 percent ionized at pH 7.4. However, it is highly lipid soluble, resulting in rapid CNS uptake and an effect onset half-time of 6.4 min. Fentanyl is also distributed into adipose tissue, though, creating a "reservoir" of fentanyl. The size of this reservoir is dose dependent, with higher doses resulting in a progressively increasing duration of effect as the drug is released from tissue stores and then eliminated. Furthermore, distribution from plasma may not result in drug levels below those associated with clinical effects and respiratory depression. Thus, the use of relatively high doses of fentanyl (i.e., in the range of 10 pg/kg) results in greatly prolonged clinical effects and elimination half-times. Fentanyl is metabolized in the liver to inactive compounds.
Fentanyl has been shown to have a low complication rate when used for CS in the ED. Chudnofsky and colleagues noted six cases of respiratory depression (largely in patients who were intoxicated or had received other drugs) and three cases of hypotension among 841 ED patients receiving fentanyl. 16 Respiratory depression occurs at significantly lower fentanyl doses when another respiratory depressant, such as alcohol or midazolam, is present. Chest wall rigidity may occur in a dose-dependent fashion following fentanyl administration; approximately half of healthy volunteers develop chest wall rigidity in response to 15 pg/kg, a dose not usually used in CS in the ED. Rigidity and apnea, however, may occur with even small doses of fentanyl, resulting in respiratory insufficiency. The rigidity is not reliably antagonized by naloxone and may require neuromuscular blockade and intubation to enable adequate ventilation. Fentanyl does not release histamine, which mediates most of the peripheral vascular effects of narcotics, so it rarely produces hypotension.17
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