Chapter outline

Effectiveness

As with other types of pain, acetaminophen is appropriate alone for mild postoperative pain. A Cochrane Collaboration Review evaluating 47 trials (2561 patients) concluded that single doses of acetaminophen were effective and had few adverse effects for this type of pain, but provided effective analgesia for only one-half of the patients with moderate to severe pain (Toms, McQuay, Derry, et al., 2008). A study of patients following Cesarean section produced similar results, with acetaminophen producing inferior pain relief compared with diclofenac (Siddik, Aouad, Jalbout, et al., 2001). Diclofenac, but not acetaminophen, also produced opioid-dose sparing effects. These studies support the recommendation of acetaminophen for mild pain and NSAIDs alone or in combination with other analgesics, including acetaminophen, for more severe pain (Bradley, Ellis, Thomas, et al., 2007; Cepeda, Carr, Miranda, et al., 2005; Helstrom, Rosow, 2006; Hyllested, Jones, Pedersen, et al., 2002; Issioui, Klein, White, et al., 2002; White, 2002).

Parenteral ketorolac (Toradol) is adequate alone for some moderate-to-severe postoperative pain (Breda, Bui, Liao, et al., 2007; Helstrom, Rosow, 2006). IV ibuprofen (Caldolor) is approved for treatment of acute pain, but clinical experience with this new formulation was sparse at the time of publication (see discussion of IV ketorolac and IV ibuprofen later in the chapter). Cochrane Collaboration Reviews over the years have shown that single doses of the various oral nonselective NSAIDs also produce effective postoperative analgesia alone, with little difference between them (Barden, Edwards, Moore, et al., 2004; Collins, Moore, McQuay, et al., 2000; Forrest, Camu, Greer, et al., 2002; Mason, Edwards, Moore, et al., 2004). One exception is piroxicam. A Cochrane Collaboration Review concluded that there is insufficient evidence to conclude that single doses of this drug provide adequate postoperative analgesia (Moore, Rees, Loke, et al., 2000). Ibuprofen (800 mg) was found to be equianalgesic to acetaminophen (800 mg) plus codeine (60 mg) following ambulatory surgery (Raeder, Steine, Vatsgar, 2001).

Nonselective and COX-2 selective NSAIDs appear to be equally efficacious for postoperative pain (Derry, Barden, McQuay, et al., 2008; Lenz, Raeder, 2008; Rasmussen, Malmstrom, Bourne, et al., 2005; Roy, Derry, Moore, 2007; Schug, 2006; Schug, Manopas, 2007). Etoricoxib (Arcoxia) was found to be superior in overall efficacy compared with acetaminophen plus oxycodone (Chang, Desjardins, King, et al., 2004).

An extensive review of the literature addressing the impact of several different analgesic techniques on patient outcomes concluded that both acetaminophen and NSAIDs used alone reduce pain and opioid requirements (Liu, Wu, 2007a). However, the researchers pointed out that problems with the research design in some of the studies made it difficult to draw concrete conclusions about the impact of the nonopioid analgesic group on postoperative patient-reported outcomes such as quality of recovery and satisfaction.

Perioperative Multimodal Analgesia

The analgesic ceiling effect that characterizes all nonopioids limits the effectiveness of this drug category following major surgical procedures. However, they do provide effective pain relief for a wide variety of major surgical procedures as part of a multimodal regimen that combines drugs with different underlying mechanisms of action (Andersen, Poulsen, Krogh, et al., 2007; Ashburn, Caplan, Carr, et al., 2004; Basse, Billesbolle, Kehlet, 2002; Basse, Hjort Jakobsen, Billesbolle, et al., 2000; Cepeda, Carr, Miranda, et al., 2005; Coloma, White, Huber, et al., 2000; Elia, Lysakowski, Tramer, 2005; Jensen, Kehlet, Lund, 2007; Nemergut, Durieux, Missaghi, et al., 2007; Schug, 2006; Schug, Manopas, 2007). In the perioperative setting, the most common analgesics in a multimodal approach are nonopioids, opioids, local anesthetics, and anticonvulsants.

Combinations of analgesics have been shown to provide greater pain relief than can be achieved with any single analgesic (Busch, Shore, Bhandari, et al., 2006; Cassinelli, Dean, Garcia, et al., 2008; Huang, Wang, Wang, et al., 2008; Merry, Gibbs, Edwards, et al., 2009; Schug, 2006; Tang, Evans, Chaput, et al., 2009). Several studies have shown that the multimodal approach can also result in lower opioid doses and fewer opioid-induced adverse effects than traditional single-agent approaches, particularly when NSAIDs are added to the treatment plan (Chen, Ko, Wen, et al., 2009; Kim, Kim, Nam, et al., 2008; Marret, Kurdi, Zufferey, et al., 2005; White, 2005; Tang, Evans, Chaput, et al., 2009). Although a meta-analysis of seven randomized controlled trials found that acetaminophen combined with morphine patient-controlled analgesia (PCA) produced a significant opioid-sparing effect, this did not result in a lower incidence of opioid-induced adverse effects (Remy, Marret, Bonnet, 2005). Similarly, a larger meta-analysis (33 trials, nearly 3000 patients) that reviewed data to evaluate whether multimodal analgesia with nonopioids plus IV PCA morphine offers advantages over morphine alone found that the addition of acetaminophen reduced 24-hour morphine consumption by an average of 8.3 mg but did not significantly decrease opioid-induced adverse effects (Elia, Lysakowski, Tramer, 2005). This same analysis reported that single doses of nonselective NSAIDs reduced 24-hour morphine consumption by 10.3 mg, postoperative infusions of ketorolac or diclofenac by 18.3 mg, and multiple-dose NSAID regimens by 19.7 mg. Reductions in postoperative nausea and vomiting and sedation were also noted with these NSAIDs. Similar to nonselective NSAIDs, the addition of COX-2 selective NSAIDs allows lower opioid doses, but more research is needed to conclude that this equates to fewer adverse effects (Elia, Lysakowski, Tramer, 2005; Kehlet, 2005; Liu, Wu, 2007a, 2007b; Romsing, Moiniche, Mathiesen, et al., 2005; Staube, Derry, McQuay, et al., 2005). The risk of serious postoperative bleeding was 0% in patients who received placebo or COX-2 selective NSAIDs but increased slightly to 1.7% in patients who received nonselective NSAIDs (ketorolac, diclofenac, ketoprofen) in the previously mentioned meta-analysis (Elia, Lyskowski, Tramer, 2005).

Preemptive Analgesia

In the early 1980s, studies of the spinal cord changes occurring in the context of peripheral afferent input, termed central sensitization (Woolf, 1983), generated interest in the therapeutic potential of interventions that could be implemented before tissue injury to block nociception (pain transmission) (Dahl, Moiniche, 2004; Grape, Tramer, 2007) (see Section I for a discussion of nociception). A multimodal approach (that includes NSAIDs to reduce activation of nociceptors, local anesthetics to block sensory input, and opioids to act within the CNS to interrupt pain) initiated preoperatively and continued intraoperatively and throughout the postoperative course was suggested as ideal preemptive analgesic treatment (Woolf, Chong, 1993). Since then, numerous studies have investigated a wide variety of agents and techniques in an attempt to show a preemptive analgesic effect (Dahl, Moiniche, 2004; Moiniche, Kehlet, Dahl, 2002).

Testing the hypothesis of preemptive analgesia requires comparing the effectiveness of an intervention applied before the surgical incision (experimental group) with the effectiveness of the same or very similar intervention applied only after the surgical incision (control group). The notion that such a simple approach could reduce or possibly prevent postoperative pain stimulated an abundance of research on preemptive analgesia; however, many of the studies had flawed research designs which led to flawed conclusions (Bromley, 2006; Grape, Tramer, 2007; Moiniche, Kehlet, Dahl, 2002; Dahl, Moiniche, 2004). For example, some studies compared preoperative analgesic administration with placebo or no treatment and claimed a preemptive effect when treatment was associated with a subsequent reduction in pain. These and other inaccurate claims of positive results led to an overly optimistic perception of the effectiveness of preemptive analgesia (Grape, Tramer, 2007).

An extensive review of the literature on preemptive analgesia concluded that there was very little evidence that preemptive (preincisional) administration of NSAIDs produced any analgesic benefit when compared with their administration postincision (Moiniche, Kehlet, Dahl, 2002). Similar conclusions were made for IV opioids, ketamine, continuous epidural analgesia, and peripheral local anesthetics. However, an updated review in 2004 found more encouraging results, with 6 of 8 studies published after 2001 showing that NSAIDs produced a preemptive effect (i.e., lower postoperative pain scores or supplementary opioid requirements with preoperative NSAID administration) (Dahl, Moiniche, 2004). For example, a study of patients undergoing ankle fracture surgery (Norman, Daley, Lindsey, 2001) found that those who received IV ketorolac before tourniquet inflation (preemptive) had no increase in pain, and those who received IV ketorolac after tourniquet inflation had significant increases in pain. There were no differences in supplemental opioid consumption, and the preemptive effect was gone within 6 hours. A meta-analysis reviewed 12 randomized controlled trials that compared preincisional with postincisional systemic NSAIDs and concluded that preoperative NSAID administration improved analgesic consumption and time to first rescue dose but not postoperative pain ratings (Ong, Lirk, Seymour, et al., 2005). A more recent randomized, placebo-controlled study of celecoxib showed effective postoperative pain control and improved speed and quality of recovery after major plastic surgery but no advantage to preoperative versus postoperative administration (Sun, Sacan, White, et al., 2008).

The general consensus is that preemptive administration of analgesics does not offer major clinical benefits (i.e., consistent immediate postoperative pain relief or reduced need for supplemental analgesia) (Bromley, 2006; Dahl, Moiniche, 2004; Grape, Tramer, 2007; Kelly, Ahmad, Brull, 2001). However, the disappointing research related to preemptive analgesia does not mean postoperative benefits cannot be realized with aggressive perioperative analgesic interventions. It has been suggested that research and clinical practice should redirect the focus from “preemptive” (timing of a single [most often] conventional intervention) to “protective” analgesia, whereby aggressive, sustained multimodal interventions are initiated preoperatively and continued throughout the intraoperative and postoperative periods (Moiniche, Kehlet, Dahl, 2002; Dahl, Moiniche, 2004). Consistent with this approach are the goals of immediate postoperative pain reduction and prevention of prolonged and pathologic pain (Kelly, Ahmad, Brull, 2001). The key underlying pain management principles are to intervene before the onset of pain, use a multimodal approach, and administer analgesics in the proper dose and manner, on time, and for an adequate duration of time (Kelly, Ahmad, Brull, 2001).

Accelerated Multimodal Postoperative Rehabilitation

Advances in the field of pain management have led to more aggressive use of analgesics, but it is unclear if this has resulted in significant improvements in patient outcomes such as the quality of postoperative recovery and long-term function (Liu, Wu, 2007a). An unacceptable number of surgical patients continue to experience delays in recovery, complications, and the need for extended hospital stays (Kehlet, Wilmore, 2008). An extensive review of research (18 meta-analyses, 10 systematic reviews, 8 randomized controlled trials, and 2 observational database articles) revealed that there is insufficient data to show that high-quality postoperative pain management, such as regional analgesia and IV PCA, impacts the incidence and severity of postoperative complications (Liu, Wu, 2007a). The researchers suggested that improvements will depend on the integration of pain control into a comprehensive postoperative rehabilitation program that includes fluid balance and early mobilization and nutrition.

Patient outcomes have historically been reported as morbidity and mortality data; however, a focus on patient-reported assessments as a subset of morbidity and mortality events may provide unique insight into specific areas that need more intense research and clinical focus (Liu, Wu, 2007a, 2007b). An exhaustive review of the literature evaluated the effect of postoperative analgesia on patient-assessed indicators that included a variety of aspects of analgesia, presence of adverse effects, health-related quality of life, quality of recovery, and patient satisfaction (Liu, Wu, 2007a). The researchers concluded a general lack of high-quality data. They called for the development of validated tools to measure patient-reported outcomes and well-designed research that examines these as the primary study end points.

Establishing the link between good pain management and improvements in patient outcomes will require changes in the way health care is administered (Kehlet, Wilmore, 2008; Liu, Wu, 2007a, 2007b). Traditional practices in perioperative care, such as prolonged bed rest, withholding oral nutrition for extensive periods, and routine use of tubes and drains, are being increasingly challenged and replaced with evidence-based decision making (Pasero, Belden, 2006). This and other factors have led to the evolution of fast track surgery and enhanced postoperative recovery (Kehlet, Wilmore, 2008). In a revi ew of the literature, Kehlet and Wilmore (2008) describe the evidence that supports key principles of implementing what is referred to as accelerated multimodal postoperative rehabilitation. These are outlined in Box 8-1. Continuous multimodal pain relief with nonopioids and other analgesics is integral to this concept.

Tools that can be used to increase evidence-based perioperative pain management practice patterns are emerging. For example, a novel web-based program called PROSPECT (Procedure Specific Postoperative Pain Management) (http://www.postoppain.org), established by an international team of surgeons and anesthesiologists, posts evidence-based recommendations and algorithms to guide the health care team in decision making with regard to pain management according to specific surgical procedures (Pasero, 2007).

Selected Nonopioids and Routes of Administration

Nonopioid analgesics are given most often by the oral route of administration; however, many surgical patients are restricted from oral intake or suffer postoperative nausea and vomiting. These factors make the IV route the primary route of administration in the perioperative setting. Rectal administration is another option. Other novel routes of administration for postoperative analgesia include local infiltration (Coloma, White, Huber, et al., 2000); intraarticular injection (Andersen, Poulsen, Krogh, et al., 2007; Andersen, Pfeiffer-Jensen, Haraldsted, et al., 2007; Toftdahl, Nikolajsen, Haraldsted, et al., 2007); intranasal (Brown, Moodie, Bisley, et al., 2009; Moodie, Brown, Bisley, et al., 2008); and ocular (topical). At the time of publication, an injectable form of diclofenac (Dyloject) was in development for approval in the United States (Colucci, Wright, Mermelstein, et al., 2009). Topical NSAIDs are used for acute pain associated with soft-tissue injury (see Chapter 7), but no research could be found regarding their use for postoperative analgesia. Following is a discussion of selected nonopioids and routes of administration as they relate to their use in the perioperative setting.