In the perioperative period, NSAIDs are primarily used for their analgesic effect. They may be used alone for mild to moderate pain or in conjunction with narcotics for moderate to severe pain. They are frequently termed “opioid sparing” because their use in combination with opioids has been shown to reduce a patient’s overall opioid requirement while providing an equivalent level of analgesia. Administration of NSAIDs significantly reduces postoperative narcotic requirements in both children and adults. Ketorolac 30 mg IV has been reported to provide equivalent analgesia as morphine 10 mg IV, although more recent studies suggest that morphine may be more effective. Because narcotic doses are reduced, patients receiving NSAIDs experience fewer narcotic-related side effects, including reduced nausea and vomiting and reduced postoperative sedation.

Ketorolac is a nonselective NSAID, and because it can be given IV, it is frequently used in the perioperative period when patients have restricted PO intake. Standard doses are 15–30 mg q6h (or prn); however, doses up to 60 mg and as low as 7.5 mg have been used (Table 15.1). The course of treatment should not exceed 5 days to reduce NSAID-related side effects, particularly renal injury. Recently, IV ibuprofen has become available for injection (via infusion). Standard dosage is 400–800 mg q6h as needed (maximum of 3,200 mg daily).

Orally administered nonselective NSAIDs include ibuprofen and naproxen. These medications are used for their analgesic effects in the perioperative period as well as for long-term management of pain due to multiple causes. They are also frequently used for their antipyretic properties which derive from COX inhibition in the hypothalamus.

The main side effects associated with nonselective NSAIDs are due to inhibition of the COX-1 enzyme. The COX-1 enzyme is active at multiple sites in the body and plays important roles in platelet aggregation, regulation of afferent renal arteriolar tone, and production of gastric mucous. Accordingly, the major side effects of these drugs are bleeding, renal injury, and gastric ulceration. Importantly, inhibition of platelet function is a major limitation to the use of NSAIDs in the immediate postoperative period. There is also concern that the anti-inflammatory effect of NSAIDs inhibits bone healing. For this reason, some clinicians recommend against their use in orthopedic surgery or following a bone fracture.

Because of the side effects characteristic of the nonselective NSAIDs, COX-2 selective inhibitors were developed to provide analgesia without the risks of COX-1 inhibition. Three COX-2 inhibitors were approved for use in the USA: rofecoxib, valdecoxib, and celecoxib. These medications were successful in reducing the risk of gastric ulceration and lacked the antiplatelet effects of traditional NSAIDs. However, rofecoxib and valdecoxib were discontinued from the market in 2004 and 2005, respectively, due to an increased risk of cardiovascular events in patients taking these drugs (coronary vasoconstriction caused by inhibition of prostacyclin production, which is a vasodilator). Celecoxib remains available in the USA, and standard doses for acute pain are 100–200 mg PO BID with the option of a one-time loading dose of 400 mg.

Acetaminophen is another non-opioid analgesic that is effective for mild to moderate pain. While its mechanism of action is not completely understood, it has no significant effect on the COX enzymes at peripheral sites. However, its centrally mediated analgesic effect is likely due to COX inhibition in the CNS in addition to interactions with NMDA receptors, serotonergic pathways, and cannabinoid receptors. Like NSAIDs, the antipyretic effects of acetaminophen are derived from COX inhibition in the hypothalamus.

Acetaminophen has long been available in oral (PO) and rectal (PR) formulations. Oral dosing prior to surgery is effective for postoperative analgesia for short procedures. For patients unable to take medications by mouth, PR formulations were the only available choice until recently. Intravenous acetaminophen was introduced to the USA in 2010 and has quickly become a valuable option for the control of perioperative pain. Like the NSAIDs, IV acetaminophen has opioid-sparing effects. Standard dosing is 1,000 mg IV q6h given as a 15 min infusion. Regardless of the route of administration, the total dose of acetaminophen should not exceed 4 g in 24 h to avoid hepatotoxicity.