Evolving Concepts in Perioperative Analgesia

Preemptive analgesia

The types of acute and chronic pain (discussed earlier), and analgesic strategies to resolve them, are diagrammed in Figure 1. An evolving concept in perioperative pain management is the use of preemptive analgesia (Figure 1).(9,30) The pain and inflammation that result from surgery normally cause increased prostaglandin production and sensitization. If analgesia is administered before painful stimuli and tissue damage, hypersensitivity can be circumvented and hyperalgesia and central sensitization prevented.(9,30) Accordingly, the use of longacting analgesic agents before surgery can avert the establishment of a sensitized state in the peripheral nervous system, greatly diminishing the degree and persistence of postoperative pain.

Figure 1. Analgesic strategies for pain management. The temporal progression of pain and approaches (and their argets) to the initiation and maintenance of analgesia. Arrows show effector pathways (dotted lines indicate lower efficacy). Adapted with permission from Kissin I. Preemptive analgesia. Anesthesiology 2000;93:1138-1143.(30)

Balanced analgesia

Balanced analgesia uses a combination of topical anesthetics, opioids, and NSAIDs to improve analgesic efficacy and safety.(31,32) In perioperative settings, this strategy should be used whenever possible as it has the advantage of decreasing the doses and thereby the adverse effects of each drug. While opioid-sparing, balanced analgesia provides enhanced pain relief compared with opioids or local anesthetics alone.(23)

COX-2-selective inhibitors have been shown to be efficacious in the prevention of hyperalgesia when used postoperatively as part of a balanced approach to analgesia. Their tolerability and the nonadditive nature of the dose-related adverse effects of opioids make the COX-2-selective inhibitors a particularly useful resource in combination with opioids.(6)

Though there are many analgesic choices for treating pain in general, there are fewer choices and more limitations when using analgesics in the perioperative setting. A multitude of factors come into play when a patient needs pain relief for a surgical procedure and concerns about hepatic, cardiac, and renal function are paramount. Also, patients often cannot take drugs orally and may benefit from preoperative longer-acting analgesic agents and analgesic adjuvants. Additionally, in the case of invasive surgery, platelet aggregation should not be compromised, unless risk of thrombosis signals a specific need for antithrombotic agents. Bleeding is a concern with the use of nonselective NSAIDs, and so, they are usually discontinued prior to surgery. Ketorolac presents particular concerns due to its renal effects: it may cause volume depletion and precipitate renal failure and is, therefore, contraindicated for preoperative analgesia. Despite the benefit of nonselective NSAIDs as part of a balanced analgesic regimen, their potential adverse effects may ultimately compromise pain relief. This obstacle to nonselective NSAID use may be effectively overcome with the use of COX-2-selective inhibitors.(33)

COX-2-Selective Inhibitors in Preemptive Analgesia

In the perioperative setting, preemptive analgesia can be achieved with NSAIDs, COX-2-selective inhibitors, acetaminophen, and longer-acting opioids such as codeine and propoxyphene. COX-2-selective inhibitors, or coxibs, offer advantages over nonselective NSAIDs due to their lack of COX-1 inhibition. They do not affect platelet function nor do they increase the risk of bleeding, and they are associated with less GI toxicity than nonselective NSAIDs. COX-2-selective inhibitors lack the serious side effects of opioids and complement other analgesic agents. These factors, combined with their duration of action, have prompted studies of their use in preemptive analgesia.

Acute pain

Adequate relief of acute pain may be dependent on several factors such as time to onset of analgesia, maximum analgesic effect, and duration of analgesic effect. Several key studies of coxibs in acute pain are summarized in Table 2. Relevant conclusions are briefly detailed here.

Table 2: Summary of Acute Pain Studies of COX-2-Selective Inhibitors

R = randomized; DB = double blind; PC = placebo controlled; PG = parallel group; AC = active comparator; IM = intramuscular; IV = intravenous; BID = twice daily.
*P ² ≤.006.
†P <.05.
‡P <.001.
§P <.001; P < .003; P < .001, respectively.
¶ P ≤.05.

Primary dysmenorrhea is caused by prostaglandin- induced uterine hyperactivity and is usually treated with nonselective NSAIDs. The pain associated with dysmenorrhea is similar to perioperative pain, particularly that of abdominal surgery, and lasts about 72 hours. As it is associated with both acute and recurring pain, dysmenorrhea requires analgesic relief on a cyclical basis. Concerns about GI toxicity from the effects of longterm nonselective NSAID use are justified.

Rofecoxib is indicated for the treatment of dysmenorrhea and, at doses of 25 mg or 50 mg, provided analgesic relief comparable to naproxen (550 mg BID) in 127 women with a history of primary dysmenorrhea.(34) The main endpoints used in the study were total pain, difference in pain intensity over an 8-hour period, patient global evaluation, and time to remedication.

Patients frequently receive nonselective NSAIDs for acute pain associated with dental surgery. A study of rofecoxib 50 mg (n = 50) and ibuprofen 400 mg (n = 51) for pain after oral surgery, compared with placebo (n = 50), assessed efficacy by evaluating pain intensity and pain relief at 12 intervals during a 24-hour period.(35) Additional primary assessments included the TOPAR8, which represents the time-weighted pain-relief score up to 8 hours.(35) Rofecoxib and ibuprofen both resulted in significantly better TOPAR8 scores than placebo (P <.05), but patients randomized to rofecoxib had longer lasting pain relief compared with the ibuprofen group (P = .039). Fewer patients (28%) receiving rofecoxib took rescue medication within the 24- hour period compared with those receiving ibuprofen (82.4%). Notably, tolerability was greatest for rofecoxib.(35)

Another study of pain due to molar excision evaluated rofecoxib (50 mg) and celecoxib (200 mg), each compared with ibuprofen, through the 24-hour period following surgery.(36) Rofecoxib had analgesic effects on all measures that were superior to celecoxib, including overall analgesic effect (TOPAR8), time to onset of pain relief, peak pain relief, and duration of effect. Notably, and as shown in other studies, rofecoxib had analgesic efficacy comparable to ibuprofen but with longer duration (P <.05) (Figure 2).(36)

Figure 2. Mean (± SE) pain relief (PR) in patients experiencing moderate to severe postoperative dental pain over the 24 hours after dosing with rofecoxib 50 mg, ibuprofen 400 mg, celecoxib 200 mg, or placebo. Patients who used rescue medication are included (last observation carried forward). Reprinted with permission of the publisher. From Malmstrom K et al. Comparison of rofecoxib and celecoxib, two cyclooxygenase-2 inhibitors, in postoperative dental pain: a randomized, placebo- and active-comparator-controlled clinical trial. Clin Ther 1999; 21:1653-1663. Copyright 1999 by Exerpta Medica Inc.(36)

A similar double-blind, randomized study of postoperative dental pain compared the efficacy of rofecoxib 50 mg with codeine 60 mg plus acetaminophen 600 mg in 393 patients.(37) The overall analgesic effect of rofecoxib was greater than that of codeine/acetaminophen for TOPAR8 (P <.001), as was the patient global assessment of response to therapy (PGART) at 6 hours (P < .001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen, but the peak analgesic effect was significantly greater in the rofecoxib group (P < .001). As seen in other studies, duration of analgesic effect was greater with rofecoxib. More patients in the codeine/acetaminophen group experienced adverse events overall (P < .05) and nausea in particular (P < .001) compared with rofecoxib.(37)

In a study of intramuscularly or intravenously administered NSAID for postoperative dental pain, the experimental parenteral coxib, parecoxib, was compared with the nonselective NSAID ketorolac. 38 Although generally comparable on all experimental measures (time-specific pain intensity, pain relief, time to onset of analgesia, and time to use of rescue medication), parecoxib effected a longer duration of analgesia than did ketorolac (P ² .05).(38)

Studies show that, for commonly employed regimens, rofecoxib is superior to placebo and comparable to commonly used nonselective NSAIDs, and codeine plus acetaminophen, by many of the criteria for determining overall analgesic efficacy. Similar results may hold for parecoxib compared with ketorolac. Time to onset, peak effect, and duration of analgesia are important factors.

Celecoxib has been recently approved for acute pain: 400 mg followed by 200 mg every 12 hours as needed.(39) Another oral coxib, valdecoxib, was recently approved for osteoarthritis, rheumatoid arthritis, and menstrual pain.(40)

Katz WA. Cyclooxygenase-2-selective inhibitors in the management of acute and perioperative pain. Cleve Clin J Med 2002;69:SI65-75.