Although the exact site and mechanism of action of acetaminophen is not clearly defined,the central nervous system is the active compartment, and it likely involves central COX inhibition and cannabinoidergic effects, along with indirect analgesic serotoninergic effects.10 Pain research efforts over the past 5 decades have not yet yielded many other new analgesics for use in the periop-erative setting. Explanations for this include: a lack of a mechanism-based classification of pain syndromes that makes it difficult to generate testable hypotheses, an inadequate predictive validity of animal models that translate into pain outcomes in humans, and the Food and Drug Administration’s (FDA) requirement of safety and efficacy against placebo,rather than superiority to an active comparator, which contributes to development of “me-too” drugs.11
Preemptive dosing to time the peak pharmacodynamic effect of IV acetaminophen to optimize analgesic effectiveness has been studied clinically. For example, in a study of patients undergoing total abdominal hysterectomy, IV acetaminophen 1 g administered 30 minutes prior to surgical in cision(prior to induction)resulted in a greater reduction in total morphine consumption compared with administering the same dose at the end of surgery just prior to skin closure(reference 2 in Table 1).
Although the exact site and mechanism of action of acetaminophen is not clearly defined,the central nervous system is the active compartment, and it likely involves central COX inhibition and cannabinoidergic effects, along with indirect analgesic serotoninergic effects.10 Pain research efforts over the past 5 decades have not yet yielded many other new analgesics for use in the periop-erative setting. Explanations for this include: a lack of a mechanism-based classification of pain syndromes that makes it difficult to generate testable hypotheses, an inadequate predictive validity of animal models that translate into pain outcomes in humans, and the Food and Drug Administration’s (FDA) requirement of safety and efficacy against placebo,rather than superiority to an active comparator, which contributes to development of “me-too” drugs.11 Preemptive dosing to time the peak pharmacodynamic effect of IV acetaminophen to optimize analgesic effectiveness has been studied clinically. For example, in a study of patients undergoing total abdominal hysterectomy, IV acetaminophen 1 g administered 30 minutes prior to surgical in cision(prior to induction)resulted in a greater reduction in total morphine consumption compared with administering the same dose at the end of surgery just prior to skin closure(reference 2 in Table 1).
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