ACETAMINOPHEN and nonsteroidal antiinflammatory drugs (NSAIDs) have a long history as effective first-line analgesics for postoperative pain. The use of acetaminophen and NSAIDs alone or in combination with other analgesics, such as opioids, anticonvulsants, and local anesthetics, has become more common. This strategy is termed multimodal analgesia. The role of nonopioids in perioperative multimodal pain treatment plans is the focus of this chapter. (See Patient Medication Information Forms III-1 through III-5 on pp. 250-259.)
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.
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).
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).
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).
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.
Ketorolac is the only parenteral nonopioid available in the United States. An abundance of research has shown it to be effective as a first-line analgesic alone for moderate postoperative pain and in combination with other analgesics for more severe pain (Basse, Billesbolle, Kehlet, 2002; Basse, Hjort Jakobsen, Billesbolle, et al., 2000; Ben-David, Swanson, Nelson, et al., 2007; Breda, Bui, Liao, et al., 2007; Chen, Ko, Wen, et al., 2009; Helstrom, Rosow, 2006; Lenz, Raeder, 2008; White, 2002, 2005).
A dose of 30 mg of ketorolac is considered to be roughly equianalgesic to 10 mg of parenteral morphine, which is the standard parenteral postoperative adult morphine dose (Smith, Carroll, Edwards, et al., 2000). However, a large randomized trial of over 1000 patients following a variety of surgical procedures calculated the number of patients who achieved at least 50% reduction in pain intensity 30 minutes after analgesic administration and found that just 50% of those who received an IV morphine infusion (0.1 mg/kg, or approximately 7 mg in a 150 lb patient) and 31% of those who received IV ketorolac (30 mg) met this threshold (Cepeda, Carr, Miranda, et al., 2005). Rescue doses of morphine were given for pain intensity 5 or greater (0 to 10 scale) after the infusions, and fewer rescue doses were required by those who had received the ketorolac infusion. This study reinforces the appropriateness and value of using ketorolac in combination with other analgesics as part of a multimodal pain treatment plan for more severe pain.
Adverse effects associated with ketorolac are dose-dependent. Though 30 mg every 6 hours (120 mg/day maximum) is generally recommended for adults and 15 mg every 6 hours (60 mg/day maximum) for older adults, many clinicians routinely use a lower dose (i.e., 7.5 to 15 mg) or administer the drug less frequently (i.e., every 8 hours) in an effort to minimize adverse effects.
Like opioids, ketorolac doses can be titrated to effect if necessary. An initial loading dose is not necessary and should be avoided. Older adults should be started and maintained on lower doses than those recommended for younger patients. Around-the-clock (ATC) rather than PRN administration of ketorolac is recommended to prevent gaps in analgesia, and the drug should not be used for more than 5 days.
A common misconception is that duration of analgesia will be extended if ketorolac is administered by the intramuscular (IM) rather than the IV route of administration. With the exception of a one-time dose (e.g., office or emergency department (ED) setting) when IV access is not available, there is no advantage or rationale for administering ketorolac by the IM route. Nor is there any advantage to administering one-half of the dose via the IM route and the other half by the IV route, which is another occasional practice. If IV access is available, the drug should be administered by the IV route.
Ketorolac injected into the surgical site was found to produce similar analgesia and a shorter time to discharge compared with IV ketorolac following minor anorectal surgery (Coloma, White, Huber, et al., 2000). Oral ketorolac is reported to be as effective as acetaminophen plus codeine (McCormack, Power, 2009) but is rarely used, likely because more effective options are available.
Intranasal ketorolac was in clinical development at the time of publication and shown to be convenient, effective, and well tolerated for the treatment of acute pain in ambulatory patients (Brown, Moodie, Bisley, et al., 2009; Moodie, Brown, Bisley, et al., 2008). The ketorolac solution is provided in a disposable, multi-dose, metered-spray device that permits patients to self-administer the pain medication. A placebo-controlled study randomized 127 patients to receive 10 mg or 31.5 mg of intranasal ketorolac or intranasal placebo every 8 hours for 40 hours following major surgery (Moodie, Brown, Bisley, et al., 2008). Morphine consumption via IV PCA was significantly less in those who received ketorolac 31.5 mg (37.8 mg) compared with those who received ketorolac 10 mg (54.3 mg) or placebo (56.5 mg). Pain ratings and incidences of pyrexia and tachycardia were also significantly lower in those who received 31.5 mg of ketorolac. Other adverse effects were similar among the groups. The effectiveness of a 30 mg intranasal ketorolac dose was also established in a Phase 3, randomized placebo-controlled trial in which patients were provided a single 30 mg dose of intranasal ketorolac (N = 199) or intranasal placebo (N = 101) prior to a variety of surgical procedures (Brown, Moodie, Bisley, et al., 2009). Those who received ketorolac experienced a significant reduction in pain scores during the first 6 postoperative hours (the study period). Time to first request for analgesia was 3 hours in the ketorolac group compared with 1.3 hours in the placebo group, and morphine consumption via IV PCA was significantly lower with ketorolac.
A parenteral formulation of ibuprofen (Caldolor) was approved in the United States in 2009 for the treatment of fever and acute pain (Medscape Medical News, 2009); however, clinical experience and research were lacking regarding the use of parenteral ibuprofen for pain treatment at the time of publication. The recommended dosing regimen for acute pain treatment is 400 to 800 mg over 30 minutes every 6 hours; fever is treated with a 400 mg dose followed by 400 mg every 4 to 6 hours or 100 to 200 mg every 4 hours as needed (Medscape Medical News, 2009). Adverse effects, contraindications, and precautions are expected to be similar to those of other NSAIDs.
A major advantage of acetaminophen is that it can be administered by multiple routes of administration including the IV route (Bannwarth, Pehourcq, 2003). IV propacetamol, a prodrug that is rapidly metabolized to acetaminophen, has been used for pain management in countries other than the United States for several years. A randomized study of patients undergoing orthodontic surgery compared oral acetaminophen and IV propacetamol and found the latter to have an onset of analgesia of 3 minutes following a bolus dose and 5 minutes following a 15-minute infusion compared with 11 minutes following oral acetaminophen (Moller, Sindet-Pedersen, Petersen, et al., 2005). A dose of 2000 mg of propacetamol was equivalent to 1000 mg of oral acetaminophen. A higher incidence of adverse effects occurred with propacetamol, particularly injection site pain with bolus administration, which was experienced by 90% of the patients. Other adverse effects were dizziness and nausea, again more common with propacetamol bolus than with infusion or oral acetaminophen.
Another study established that 2000 mg of IV propacetamol produced similar pain relief with a faster onset of analgesia than 15 to 30 mg of IV ketorolac post total hip or knee replacement (Zhou, Tang, White, 2001). Other studies have shown an opioid dose-sparing effect with propacetamol, but this did not always result in reduced opioid adverse effects (Aubrun, Kalfon, Mottet, et al., 2003; Hernandez-Palazon, Tortosa, Martinez-Lage, et al., 2001; Lahtinen, Kokki, Hendolin, et al., 2002).
As noted, a major drawback of propacetamol is a high incidence of significant pain at the IV injection site. This is related to acetaminophen’s poor water solubility, instability in solution, and pH of 3.5 (plasma is 7.3 to 7.4). Reconstitution of the drug for clinical use also is associated with mixing errors and a risk of contact dermatitis (Moller, Juhl, Payen-Champenois, et al., 2005). A stable, ready-to-use IV acetaminophen (paracetamol) has been developed to address these disadvantages. At the time of publication, the drug (Acetavance) was undergoing the approval process (Phase III trials) in the United States (http://www.cadencepharm.com/products/apap.html). A randomized controlled study of patients undergoing orthodontic surgery demonstrated infusions of paracetamol (1000 mg) and propacetamol (2000 mg) produced similar pain relief and onset of analgesia (6 to 8 minutes) (Moller, Juhl, Payen-Champenois, et al., 2005). The more significant finding of this study, however, was that none of the patients who received paracetamol infusion experienced injection site pain compared with 49% of the patients who received propacetamol. A randomized study of 151 patients who underwent hip or knee replacement demonstrated significant opioid dose-sparing effects with both paracetamol and propacetamol (Sinatra, Jahr, Reynolds, et al., 2005). As in other studies, the most common adverse effect was local injection pain associated with propacetamol (50%).
The need for nonopioid analgesics that are available in IV formulation and do not increase bleeding time for postoperative pain management served as the impetus for the development and approval in Europe and other countries of the first parenteral COX-2 selective NSAID, parecoxib (Dynastat), a prodrug that is rapidly metabolized to its active form valdecoxib (Malan, Marsh, Hakki, et al., 2003). Parecoxib is reported to produce dose-dependent increases in pain relief and duration of analgesia; 40 mg of parecoxib provided 3 to 4 more hours of pain relief compared with 30 mg of IV ketorolac (Barden, Edwards, McQuay, et al., 2003). In 2005, the manufacturer of IV acetaminophen received a nonapproval letter by the United States Food and Drug Administration (U.S. FDA) that cited concerns about the adverse effects of valdecoxib (see Chapter 6 for discussion of cardiovascular [CV] effects) (U.S. FDA, 2005). At the time of this publication, it was unclear whether or not the manufacturer planned to address the FDA’s concerns.
Although analgesic drugs rarely are administered rectally in adults in the perioperative setting, it is an attractive alternative when oral or parenteral nonopioid analgesics are not an option (Pasero, 2010). Rectal nonopioid administration also may be less costly than parenteral administration (White, 2002). Drawbacks include unreliable drug absorption by the rectal route, and the dislike of this route by some patients and nurses (Schug, Manopas, 2007).
Acetaminophen, aspirin, and indomethacin are available commercially in rectal formulation, and oral nonopioid analgesics can be administered rectally, either by using the intact tablet or by placing the intact or crushed tablet in a gelatin capsule for insertion (Pasero, McCaffery, 1999). (Note that modified-release analgesics should not be crushed.) Because of reduced bioavailability by the rectal route compared with the oral route (80% to 90% of oral bioavailability), higher nonopioid rectal doses may be required (Beck, Schenk, Hagemann, et al., 2000). One study showed that 1000 mg of rectal acetaminophen 4 times daily was too low to produce serum concentrations associated with opioid dose-sparing effects following abdominal hysterectomy (Kvalsvik, Borchgrevink, Hagen, et al., 2003). Maximum plasma concentrations are reached 2 to 3 hours after rectal administration, which is an important consideration when determining optimal time for preoperative administration (i.e., little immediate postoperative value is attained if administered immediately before induction for a 1-hour procedure) (Romsing, Moiniche, Dahl, 2002). Using criteria that excluded patients with known renal dysfunction, asthma, coagulopathy, peptic ulcer disease, or hepatic failure, and those who were receiving long-term NSAIDs or corticosteroids, a randomized controlled trial administered rectal indomethacin 100 mg or placebo to 200 patients 2 hours prior to undergoing open cholecystectomy and found that those who received indomethacin had significantly lower pain scores (VAS) and consumed significantly less opioid than those who received placebo (Bahar, Jangjoo, Soltani, et al., 2010). There were no NSAID-related adverse effects or complications.
Several studies have shown improved pain relief and reductions in opioid consumption with rectal nonopioid analgesics alone (Achariyapota, Titapant, 2008; Bahar, Jangjoo, Soltani, et al., 2010; Ng, Parker, Toogood, et al., 2002; Siddik, Aouad, Jalbout, et al., 2001). A review of randomized controlled trials concluded that rectal acetaminophen combined with NSAIDs was superior to acetaminophen alone, but there was no evidence of superiority when this combination was compared with NSAIDs alone (Romsing, Moiniche, Dahl, 2002). However, methodologic concerns preclude definitive conclusions from this review. Other studies have demonstrated highly effective pain control with combinations of rectal acetaminophen and various NSAIDs or other analgesics (Bannwarth, Pehourcq, 2003; Carli, Mayo, Klubien, et al., 2002; Ng, Swami, Smith, et al., 2008; Romsing, Moiniche, Dahl, 2002).
The recommendation that nonopioid analgesics be routinely administered to surgical patients (Ashburn, Caplan, Carr, et al., 2004) coupled with the lack of availability of parenteral nonopioids in the United States underscores the potential value of the rectal route. However, its use will require a new paradigm of practice—care providers must become familiar with prescribing the rectal administration of analgesics, pharmacists must support the use of this route for analgesic delivery with the necessary drugs and supplies, nurses must become competent in rectal drug administration technique, and patients must be taught the rationale and value of using this route of administration so that it is less objectionable to them (see Section IV for rectal administration technique).
Four topical ocular NSAIDs are approved in the United States for treatment of inflammation and pain after cataract surgery: ketorolac 0.4% (Acular), bromfenac 0.09% (Xibrom), diclofenac 0.1% (Voltaren), and nepafenac 0.1% (Nevanac). All four have been shown to produce safe and effective analgesia after the procedure (Smith, 2005; Lane, Modi, Lehmann, et al., 2007; Walters, Raizman, Ernest, et al., 2007). One study showed that nepafenac, a prodrug, has the greatest ocular bioavailability and the most favorable anti-inflammatory profile compared with the other four (Walters, Raizman, Ernest, et al., 2007). However, another study showed that ketorolac produced significantly better patient satisfaction, compliance, and postoperative pain control when compared with nepafenac (Duong, Westfield, Chalkley, 2007). Other research has supported these findings with ketorolac (Kim, Lo, Hubbard, et al., 2008). Superior control of inflammation was found with ketorolac compared with bromfenac (Bucci, Waterbury, 2008).
A Cochrane Collaboration Review found that two trials demonstrated a positive effect of topical ketorolac on cystoid macular edema (CME), a complication and the most common cause of poor visual outcome after ophthalmic surgery (Sivaprasad, Bunce, Patel, 2005). More recently a 4-week randomized, multicenter study of 278 patients showed 6 cases of CME in patients who received topical steroid alone but none in those who received a combination of topical ketorolac and steroid (Wittpenn, Silverstein, Heier, et al., 2008). Another study showed increased corneal haze and delayed healing with nepafenac compared with ketorolac (Trattler, McDonald, 2007). Further research is required to more clearly establish the role of topical NSAIDs in preventing CME (Kim, Stark, 2008).
Short-term use of nonopioid analgesics is rarely associated with serious adverse effects (Schug, Manopas, 2007). As with long-term use, the patient’s risk factors must be considered when determining whether and which nonopioid analgesics to use in the perioperative setting. See Box 8-2 for prevention and reduction of selected nonopioid analgesic adverse effects in the perioperative setting (see Chapter 6 for an in depth discussion of adverse effects).
NSAID-induced GI toxicity usually is addressed in the literature as an adverse effect resulting from long-term NSAID use; however, GI ulceration can occur with short-term perioperative administration as well (Schug, Manopas, 2007). This is particularly true in individuals with elevated risk for GI toxicity, such as older adults and those with a previous GI complication. The use of the least ulcerogenic nonselective NSAID or a COX-2 selective NSAID if not contraindicated by CV risk is encouraged. The underlying mechanisms, risk factors, and recommendations discussed previously in this section apply to patients in the perioperative setting (see Chapter 6). NSAID-induced GI bleeding as it relates to perioperative NSAID use will be addressed in the following sections.
The possibility of increased bleeding time is of special concern when NSAIDs are used for postoperative pain. Aspirin has an irreversible effect on platelets and will increase bleeding time for up to 7 days after the last dose (i.e., until the damaged platelets are replaced by new ones). For that reason, aspirin therapy is usually discontinued at 1 week or longer before surgery, and aspirin is not recommended for perioperative use (Ashraf, Wong, Ronayne, et al., 2004) (see following section for exceptions). Other nonselective NSAIDs are also sometimes withheld during the perioperative period because of their tendency to prolong bleeding time. However, COX-2 selective NSAIDs (e.g., celecoxib) have no effect on bleeding time and should be considered if not contraindicated by CV risk (Visser, Goucke, 2008). Another option is a nonselective NSAID with minimal effect on bleeding time. These include nabumetone, meloxicam, choline magnesium trisalicylate, magnesium salicylate, and salsalate.
Acetaminophen is another option. As mentioned, it can be given alone or in combination with NSAIDs that have minimal effect on bleeding time. It has been combined with the COX-2 selective NSAID celecoxib as part of an effective multimodal analgesic plan begun preoperatively for total knee arthroplasty (Dorr, Raya, Long, et al., 2008). It is important to note that acetaminophen has been shown to increase INR when administered concomitantly with warfarin (see Chapter 6); however, researchers note that acetaminophen inhibition of thromboxane A2 is less than that of most nonselective NSAIDs, and the likelihood of surgical bleeding as a result of perioperative acetaminophen intake is low (Ashraf, Wong, Ronayne, et al., 2004; Munsterhjelm, Munsterhjelm, Niemi, et al., 2005). Nevertheless, some clinicians call for close monitoring of patients receiving acetaminophen and anticoagulation therapy (Mahe, Bertrand Drouet, et al., 2005, 2006; Ornetti, Ciappuccini, Tavernier, et al., 2005; Parra, Beckey, Stevens, 2007).
Cessation of aspirin prior to surgery is recommended (except in patients with a history of unstable angina in whom cardioprotective aspirin should be continued) (Ashraf, Wong, Ronayne, et al., 2004), but the ideal timing of cessation is unclear. A randomized, placebo-controlled study of 51 healthy volunteers demonstrated no hemostatic defect by or beyond the sixth day after aspirin was discontinued (Cahill, McGreal, Crowe, et al., 2005). This led the researchers to recommend discontinuation of aspirin therapy 5 days preoperatively. Ashraf and colleagues (2004) recommend cessation of aspirin therapy 7 to 9 days before surgery (Ashraf, Wong, Ronayne, et al., 2004).
Sun and colleagues reviewed the research that supports both the risks and benefits of discontinuing cardioprotective aspirin pre–coronary artery bypass surgery and stated that the noted increased risk of hemorrhage when aspirin is not discontinued is supported by research that used aspirin doses well in excess of those used for cardioprotection (i.e., 81 mg) (Sun, Crowther, Warkentin, et al., 2005). However, they caution that further research is required to draw concrete conclusions on the practice of not discontinuing aspirin. They also point out that there is clear evidence that if aspirin is discontinued preoperatively, it should be restarted within 48 hours of surgery to improve graft patency and patient survival.
Patients with peripheral vascular disease are at increased risk for perioperative thrombotic complications, which led researchers to conduct a decision analysis (outcome-focused literature review) of aspirin therapy cessation 2 weeks prior to infrainguinal revascularization surgery compared with continuation of aspirin therapy throughout the perioperative course (Neilipovitz, Bryson, Nichol, 2001). They concluded that preoperative continuation of aspirin therapy in this population decreases perioperative mortality and increases life expectancy and called for further randomized controlled trials to confirm these findings.
Other NSAIDs have reversible effects on platelets, and inhibition of platelet aggregation only lasts as long as it takes to eliminate a sufficient quantity of the drug from the system. Guidelines recommend that nonaspirin nonselective NSAIDs be discontinued 3 to 7 days preoperatively, depending on how long it takes platelet function to normalize (Ashraf, Wong, Ronayne, et al., 2004). Platelets have been found to normalize within 24 hours after cessation of ibuprofen in healthy individuals who stopped the drug after taking it for 7 days (Goldenberg, Jacobson, Manco-Johnson, 2005).
The safety and effectiveness of preoperative administration of nonopioid analgesics with minimal or no effect on bleeding time (see above) alone or as part of a multimodal pain treatment plan that extends into the postoperative period is supported by an abundance of research (Basse, Billesbolle, Kehlet, 2002; Basse, Hjort Jakobsen, Dorthe, et al., 2000; Dorr, Raya, Long, et al., 2009; Huang, Wang, Wang, et al., 2008; Meunier, Lisander, Good, 2007; Recart, Issioui, White, et al., 2003; Schug, 2006; Straube, Derry, McQuay, et al., 2005; Sun, Sacan, White, et al., 2008). As a group, however, nonselective NSAIDs have been identified as a risk factor of severe postoperative bleeding after some surgical procedures, such as tonsillectomy (Marret, Bonnet, 2007; Marret, Flahault, Samama, et al., 2003). Other researchers and clinicians have challenged the strength of the data cited to support this conclusion and question the extent and clinical significance of this risk (Dsida, Cote, 2004; Lake, Khater, 2004). Several other factors, including surgeon skill and operative technique, may be the underlying cause of increased bleeding (Lake, Khater, 2004). A review of the medical records of 1025 patients who underwent laparascopic gastric bypass concluded that preoperative administration of low molecular weight heparin and laparoscopic approach may increase the incidence of bleeding with this procedure (Bakhos, Alkhoury, Kyriakides, et al., 2009).
Attention tends to center on the perioperative use of ketorolac as a primary cause of postoperative GI and incisional bleeding. However, a classic study by Strom and colleagues (35 hospitals, 9900 patients) in which 10,272 courses of parenteral ketorolac were compared with 10,247 courses of a parenteral opioid showed relatively little difference in the risk of GI bleeding, operative site bleeding, and other adverse effects in postoperative patients receiving ketorolac (Strom, Berlin, Kinman, et al., 1996). Other more recent studies also have shown that administration of ketorolac was not associated with significant intraoperative or postoperative blood loss (Cassinelli, Dean, Garcia, et al., 2008; Chin, Sundram, Marcotte, 2007; Diblasio, Snyder, Kattan, et al., 2004; El-Tahan, Warda, Yasseen, et al., 2007). Nevertheless, ketorolac is not recommended as a prophylactic drug prior to major surgery.
The dose of ketorolac is an important factor when considering risk of GI and incisional bleeding. Again, Strom and colleague’s classic study provides insight into this aspect of treatment (Strom, Berlin, Kinman, et al., 1996). The use of ketorolac in patients younger than 65 years at an average dose of 105 mg/day or lower for 5 or fewer days was not associated with a detectable increase in risks. Factors that increased the risk of bleeding in the ketorolac group were advanced age (65 years with significant increase at 75 years), higher doses (120 mg/day or more), and therapy lasting longer than 5 days. Because ketorolac has been shown to provide effective analgesia with parenteral doses as low as 10 mg, the authors recommended using the lowest dose needed to obtain the desired analgesic effect rather than following a specific regimen. A dose of 15 mg parenteral ketorolac given every 6 hours would fulfill the criteria of keeping the dose at less than 105 mg/24 h while providing potentially effective analgesia. As mentioned previously, some clinicians administer doses as low as 7.5 mg, and frequency of dosing can be decreased from every 6 hours to every 8 hours to reduce the total dose and further minimize risk of bleeding.
Shortly after the release of the COX-2 selective NSAIDs, studies revealed an association between their perioperative use and an increase in adverse CV events in patients who had undergone high-risk cardiac surgery. A multicenter study randomized nearly 1700 patients undergoing post coronary artery bypass graft (CABG) to receive IV parecoxib for at least 3 days postoperatively followed by oral valdecoxib through day 10, or IV placebo followed by oral valdecoxib or placebo for 10 days (Nussmeier, Whelton, Brown, et al., 2005). There was a higher rate of myocardial infarction (MI), cardiac arrest, stroke, and pulmonary embolism in those who received parecoxib and valdecoxib. Another multicenter, placebo-controlled 14-day study randomized 462 CABG patients to receive IV parecoxib and oral valdecoxib or placebo after surgery (Ott, Nussmeier, Duke, et al., 2003). Although those receiving parecoxib and valdecoxib experienced very effective pain relief, there was a higher incidence of CV adverse events in these patients, including four deaths caused by MI, cerebral infarction, pulmonary thromboembolism, or sternal wound infection.
As discussed previously, the CV risk associated with use of celecoxib is less than with rofecoxib and valdecoxib (Dajani, Islam, 2008; Joshi, Gertler, Fricker, 2007) and more similar to that of the nonselective NSAIDs (Frampton, Keating, 2007). Nevertheless, these two postoperative studies and others that showed elevated CV risk with NSAIDs in general led to recommendations against the use of any NSAIDs following high-risk open heart surgery (U.S. FDA, 2007). (See Chapter 6 for an explanation of underlying mechanisms and in-depth discussion of CV risk factors and adverse effects.)
Renal toxicity is rarely associated with short-term perioperative acetaminophen use (Shug, Manopas, 2007). A lack of effect on platelet aggregation and low incidence of GI adverse effects make acetaminophen the nonopioid analgesic of choice in individuals with renal insufficiency, advanced chronic kidney disease, and end-stage renal disease (Kurella, Bennett, Chertow, 2003; Launay-Vacher, Karie, Fau, et al., 2005; Leo, 2008). Dose adjustment is not necessary in the presence of these conditions, but caution is recommended when it is used in patients with coexisting liver disease.
Adverse renal effects are also relatively rare in otherwise healthy individuals who are given NSAIDs during the perioperative period. Endogenous renal prostaglandin synthesis does not play a significant role in maintaining optimal glomerular filtration rate (GFR) and renal blood flow in individuals with normal CV, hepatic, endocrine, and renal function who have adequate volume and sodium stores (Helstrom, Rosow, 2006). In these individuals, NSAID-induced renal effects are usually minor and transient (Forrest, Camu, Greer, et al., 2002; Helstrom, Rosow, 2006; Lee, Cooper, Craig, et al., 2007), and there appears to be no difference in these effects between nonselective and COX-2 selective NSAIDs (Helstrom, Rosow, 2006; Launay-Vacher, Karie, Fau, et al., 2005). A Cochrane Collaboration Review could find no cases of renal failure or serious kidney problems in individuals with normal preoperative renal function who were given NSAIDs following surgery in any of the 23 trials (1459 patients) reviewed (Lee, Cooper, Craig, et al., 2007).
In contrast, individuals with acute or chronic volume depletion or hypotension depend on prostaglandin synthesis to maintain adequate renal blood flow (“prostaglandin dependence”) (Helstrom, Rosow, 2006), and NSAID inhibition of prostaglandin synthesis in such patients can cause acute renal ischemia and acute renal failure (ARF) (Helstrom, Rosow, 2006). ARF as a result of hypovolemia is usually reversed when the NSAID is stopped and volume is replenished (Miyoshi, 2001), but it underscores the importance of adequate hydration and maintenance of acceptable blood pressure (BP) before and during NSAID administration.
Patients at increased risk for perioperative ARF and who might be more susceptible to NSAID-induced renal injury include those with cardiac failure, liver cirrhosis, ascites, diabetes, or pre-existing hypertension, and patients being treated with ACE inhibitors (Brater, 2002; Brune, 2003; Forrest, Camu, Greer, et al., 2002; Helstrom, Rosow, 2006; Launay-Vacher, Karie, Fau, et al., 2005). Other risk factors include preexisting renal impairment, advanced age, and left ventricular dysfunction (Helstrom, Rosow, 2006).
Although age alone is not a risk factor for NSAID-induced renal impairment (Brater, 2002), older adults and anyone with risk factors should be assessed frequently for adverse renal effects during perioperative NSAID therapy. ARF can develop with the first NSAID dose in patients with elevated risk, and higher doses carry greater risk (Launay-Vacher, Karie, Fau, et al., 2005).
It is generally recommended that NSAIDs be avoided in patients with chronic renal failure and in any patient with a creatinine clearance below 30 mL/min (Launay-Vacher, Karie, Fau, et al., 2005; Laine, White, Rostom, et al., 2008). Acetaminophen, opioids (e.g., fentanyl), or other analgesics are a better choice in these patients (see Sections IV and V). If NSAID treatment is essential, other risk factors should be eliminated prior to initiating therapy (e.g., correct volume depletion and discontinue potassium-sparing diuretics). NSAIDs with a long half-life can cause persistent decreases in GFR and should be avoided. NSAIDs with a short half-life (e.g., ibuprofen) are preferred because declines in GFR return to baseline levels at the end of the dosing interval (Launay-Vacher, Karie, Fau, et al., 2005).
Although ketorolac is sometimes cited as a cause of perioperative ARF, retrospective data comparing perioperative administration of ketorolac with that of opioids in patients without preexisting risk factors do not show an elevated risk of ARF (Helstrom, Rosow, 2006). One prospective study randomized 11,245 patients undergoing major surgical procedures to receive parenteral and oral doses of ketorolac, ketoprofen, or diclofenac (Forrest, Camu, Greer, et al., 2002). Serious adverse outcomes occurred in 155 patients, which included 10 cases of ARF. Of the 10 who experienced ARF, three received ketorolac, three received ketoprofen, and four received diclofenac. Interestingly, there was no significant increase risk of ARF in patients with preexisting renal insufficiency or congestive heart failure in this study. Adequate hydration is essential before administration of ketorolac to avoid ARF. (See Chapter 6 for renal adverse effects associated with long-term NSAID use.)
The inflammatory process is initiated when bone is fractured, just as it is with any other tissue trauma. Prostaglandins, particularly PGE2, have a central role as mediators in bone healing, providing a balance between bone formation and resorption (Gajraj, 2003; Helstrom, Rosow, 2006). NSAIDs have been used for decades to control pain associated with fracture and for the prevention of heterotropic ossification (see the following section) (Fransen, Neal, 2004; Gajraj, 2003; Helstrom, Rosow, 2006). However, red flags were raised when animal research in the 1980s and 1990s suggested fracture healing might be delayed by NSAID administration (Gajraj, 2003; Helstrom, Rosow, 2006; O’Connor, 2003). Research published in the early 2000s established that COX-2 was indeed essential for fracture healing in animals and that delayed fracture healing and bone ingrowth could occur in animals given NSAIDs (Goodman, Ma, Trindade, et al., 2002; Simon, Manigrasso, O’Connor, 2002; Zhang, Schwarz, Young, et al., 2002). All of this research helped to lay the foundation for the current ongoing controversy over the safety of NSAIDs in humans following fracture and some orthopedic surgical procedures (Einhorn, 2002a, 2002b, 2003a, 2003b; Hochberg, Melin, Reicin, 2003; O’Connor, 2003).
The release of COX-2 selective NSAIDs stimulated animal research comparing the effects of the new NSAIDs and nonselective NSAIDs on bone healing. One study found a higher rate of experimental fracture nonunion with 21 days of daily ketorolac administration (25%) compared with 21 days of daily high-dose parecoxib (8%) (Gerstenfeld, Thiede, Seibert, et al., 2003). A significant finding was that despite evidence of early nonunion, all fractures in both groups showed union by 35 days. A more recent study compared the effects of 7- and 21-day treatments with ketorolac and valdecoxib to evaluate the hypothesis that delays in fracture healing associated with NSAID administration are reversible (Gerstenfeld, Al-Ghawas, Alkhiary, et al., 2007). Seven days of treatment demonstrated a trend for a higher nonunion rate in both NSAID-treated animals compared with controls, but no differences were noted at 35 days. After 21 days of treatment, the valdecoxib-treated group had more nonunions than either the control or the ketorolac-treated group; however, these differences also disappeared by 35 days. The researchers concluded that COX-2 selective NSAIDs inhibit fracture healing more than nonselective NSAIDs and the longer the treatment, the greater the effect; however, prostaglandin levels essential for fracture healing and strength are regained and similar to controls when NSAID treatment is discontinued after 21 days.
Concern has been expressed about the problems in extrapolating animal research to the clinical treatment of humans (Kharasch, 2004), and it has been pointed out that millions of patients have been treated with NSAIDs for fracture-related and other orthopedic pain over many years without an association between their use and impaired bone healing in the clinical setting (Einhorn, 2002a, 2002b). Criticism of the animal research includes the observation that the NSAIDs in experiments were administered for several weeks to months at doses greater than approved or used for acute pain management in humans. Still, researchers have urged practitioners to exercise caution in the use of NSAIDs after fracture until human clinical trials indicate otherwise (O’Connor, 2003; Einhorn, 2003a).
Unfortunately, there are very few well-designed studies that examine the impact of NSAIDs on bone healing in humans. The studies that have been done are retrospective in design and present conflicting findings (Einhorn, 2002b; Einhorn, 2003a; Gerstenfeld, Einhorn, 2004). Retrospective studies are confounded by numerous factors, including surgical technique, bone graft composition, type of fracture, and patient risk factors (Gajraj, 2005; Giannoudis, MacDonald, Matthews, et al., 2000). In addition, there are inherent problems in conducting randomized controlled trials, including the challenge of obtaining the sample size necessary to investigate risk rather than benefit of a treatment (Einhorn, 2003a).
Studies in humans began to focus on NSAID use postspinal fusion following a retrospective study published in 1998 that found an association between postoperative ketorolac and spinal fusion nonunion (Glassman, Rose, Dimar, et al., 1998). This finding was not confirmed, however, by a more recent retrospective review of 405 patients who received ketorolac 30 mg IV every 6 hours for 48 hours or no ketorolac; ketorolac treatment had no significant effect on fusion rates at the 24-month follow-up period (Pradhan, Tatsumi, Gallina, et al., 2008).
There have been no adequate studies evaluating NSAIDs and spinal fusion. In an effort to offer a balanced appraisal of the existing, limited data, Einhorn (2003a) suggests that short-term use of an NSAID after skeletal surgery, for a period less than 2 weeks, probably is safe and might be considered an option unless a patient has a comorbid condition that could negatively impact fracture healing, such as smoking, glucocorticoid use, or metabolic bone disease. Others endorse this view (Helstrom, Rosow, 2006; Langford, Mehta, 2006).
Heterotrophic ossification is pathologic formation of bone in soft tissue. It may be a complication following surgery or trauma. If it occurs after hip surgery, with bone formation in the muscles around the hip, reduced joint mobility ensues (Fransen, Neal, 2004; Gajraj, 2003). Heterotrophic ossification is thought to result when surgery or trauma activates dormant osteoprogenitor stem cells (Helstrom, Rosow, 2006). Approximately one third of individuals who undergo hip replacement experience this complication (Fransen, Neal, 2006).
A Cochrane Collaboration Review of 16 randomized trials and two quasi-randomized trials (4763 patients) concluded that perioperative prophylactic use of an NSAID (other than low-dose aspirin) reduces the risk of heterotrophic bone formation by one-half to two-thirds (Fransen, Neal, 2004). The researchers called for large-scale randomized trials to determine the risks and benefits for all outcomes. A small randomized, placebo-controlled study (N = 23) appeared to confirm the utility of COX-2 selective NSAIDs for this purpose (Buvanendran, Kroin, Berger, 2007). Patients with osteoarthritis (OA) undergoing total hip arthroplasty who received rofecoxib 4 days preoperatively plus a single dose on the morning of surgery experienced a lower incidence of heterotrophic ossification at 6-month follow up than those who received placebo for 4 days preoperatively plus a single rofecoxib dose or placebo on the day of surgery. The authors concluded that preoperative treatment with COX-2 selective NSAIDs is preferable to long-term postoperative nonselective or COX-2 selective NSAIDs, or postoperative irradiation for prevention of heterotrophic ossification.
The processes involved in soft-tissue healing are different from those of bone healing and consist of three distinct phases: Acute, proliferative, and remodeling (Busti, Hooper, Amaya, et al., 2005). The acute phase involves the inflammatory response, characterized by release of prostaglandins and leukotrienes to facilitate hemostasis. The patient experiences symptoms of warmth, swelling, redness, and pain during this phase. Prostaglandins also impact the proliferation phase by influencing the permeability of endothelial cells (Busti, Hooper, Amaya, et al., 2005).
The inhibition of prostaglandins by NSAIDs is the basis for concerns regarding their effect on wound healing. However, similar to the research on NSAIDs and bone healing, research on NSAIDs and soft-tissue healing has been performed entirely in animals, and the doses and duration of NSAID treatment used in the studies are not used to treat pain in patients in the clinical setting (Busti, Hooper, Amaya, et al., 2005). Large randomized controlled studies in humans are needed to confirm the lack of a relationship; however, clinicians should be reassured by the fact that NSAIDs have been used for decades in the perioperative setting as first-line analgesics for all types of postoperative pain without recognition of an increased risk of surgical wound healing complications.
Perioperative multimodal analgesia includes the administration of nonopioid analgesics preoperatively whenever possible and staying on top of pain with scheduled ATC postoperative doses to maximize pain relief with the lowest effective doses. Regular assessment of adverse effects is critical to reducing complications. The overriding principle of administering the lowest effective dose for the shortest time necessary applies in the perioperative setting.