Chapter 77. The Role of Nonopioid Analgesic Techniques in the Management of Postoperative Pain

An increasing number of complex operations are being performed on an outpatient basis for which the use of conventional opioid-based IV patient-controlled analgesia (IVPCA) and central neuraxial (spinal and epidural) analgesia are not practical techniques for pain management. For that and other reasons, effective treatment of acute postsurgical pain presents unique challenges for practitioners.1 This expansion of outpatient surgery requires a perioperative analgesic regimen that is highly effective, has minimal side effects, is intrinsically safe, and can be easily managed away from the hospital or surgical center.2

Adequacy of postoperative pain control is one of the most important factors in determining when a patient can be safely discharged from a surgical facility and has a major influence on the patient's ability to resume the normal activities of daily living.3 Perioperative analgesia has traditionally been provided by opioid analgesics. However, extensive use of opioids is associated with a variety of perioperative side effects [eg, ventilatory depression, drowsiness and sedation, postoperative nausea and vomiting (PONV), pruritus, urinary retention, ileus, constipation] that can delay hospital discharge.4 Intraoperative use of large bolus doses or continuous infusions of potent opioid analgesics may actually increase postoperative pain as a result of their rapid elimination or the development of acute tolerance.5 In addition, it has been suggested by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) that excessive use of postoperative opioid analgesics leads to decreased patient satisfaction. Partial opioid agonists (eg, tramadol) are also associated with increased side effects (eg, nausea, vomiting, ileus) and patient dissatisfaction compared with those reported for both opioid6 and nonopioid7,8 analgesics.

Therefore, in order to minimize the adverse effects of analgesic medications, anesthesiologists and surgeons are increasingly turning to nonopioid analgesic techniques as adjuvants for managing pain during the perioperative period. Multimodal, or “balanced,” analgesic techniques involving the use of smaller doses of opioids in combination with nonopioid analgesic drugs [eg, local anesthetics, ketamine, acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs)] are becoming increasingly popular approaches to preventing pain after surgery (Table 77–1).9–11 This review will discuss recent evidence supporting the use of nonopioid analgesic drugs and techniques for facilitating the recovery process during the perioperative period.

The routine use of peripheral nerve blocks and wound infiltration with long-acting local anesthetics as an adjuvant to local, regional, and general anesthetic techniques can improve postoperative pain management after a wide variety of surgical procedures (Table 77–2).4 When administered before surgery, these simple techniques can also decrease anesthetic and analgesic requirements during surgery, as well as reduce the need for opioid-containing analgesics postoperatively. More effective pain relief in the early postoperative period, as a result of the residual sensory block produced by local anesthetics, facilitates recovery by enabling earlier ambulation and discharge home (ie, “fast-track” recovery).12–14 In addition, use of local anesthetic-based techniques for preventing pain can decrease the incidence of PONV because of their opioid-sparing effects. However, these techniques are most effective for superficial procedures, and the duration of analgesia is only 6–8 h.

Blockade of the ilioinguinal and iliohypogastric nerves significantly decreases opioid analgesic requirements in both children and adults undergoing inguinal herniorrhaphy by providing 6–8 h of postoperative pain relief.15,16 Similarly, a subcutaneous ring block of the penis provides effective perioperative analgesia for circumcision.17 Local anesthetic infiltration of the mesosalpinx significantly decreases pain and cramping after laparoscopic tubal ligation.18 Simple instillation of local anesthetic after removal of the gallbladder also reduced right upper quadrant and shoulder pain.10,19 Pain after arthroscopic shoulder surgery was decreased significantly by a suprascapular nerve block,20 and pain after knee surgery was minimized with a femoral nerve block.21 However, more complete perioperative analgesia for painful shoulder and knee procedures requires use of interscalene brachial plexus,22 and combined femoral, obturator, lateral femoral cutaneous, and sciatic nerve23 blocks, respectively. Although additional preparation time may be required when major peripheral nerve blocks are performed before surgery, these techniques can offer significant advantages over general and spinal anesthesia with respect to pain control in the postoperative period.12,13,22,23

It has been suggested that performing neural blockade with local anesthetics before surgical incision prevents the nociceptive input from altering excitability of the central nervous system by preemptively blocking the N-methyl-d-asparate- (NMDA) induced “wind up” phenomena and subsequent release of inflammatory mediators.24 The concept of preemptive analgesia, or treating postoperative pain by preventing establishment of central sensitization, seems intuitively logical. However, the clinical relevance of preemptive analgesia has been questioned. Only a small number of well-controlled clinical studies have demonstrated any benefit of pre- vs postincisional analgesic administration.25,26 A quantitative systematic review by Møiniche and colleagues27 stated that evidence is still lacking to support the claim that the timing of single-dose or continuous postoperative pain treatment is critically important in the management of postsurgical pain. These investigators concluded that there was no convincing evidence that preemptive treatment with centrally or peripherally administered local anesthetics, NSAIDs, opioid analgesics, or ketamine offers any advantage with respect to postoperative pain relief when compared with a similar analgesic regimen administered after the surgical incision.27 Nevertheless, preincisional local anesthetic administration offers an obvious advantage over infiltration at the end of surgery because it can provide supplemental intraoperative analgesia as well as effective analgesia in the early postoperative period after emergence from anesthesia.

Preincisional infiltration of the surgical wound site with local anesthetics, combined with general anesthesia, is clearly superior to general or spinal anesthesia alone in reducing postoperative pain.28,29 For example, preincisional infiltration of the tonsillar bed with bupivacaine decreased the intensity of both constant pain and pain on swallowing fluids for up to 5 days after tonsillectomy procedures.29 Paracervical block with 0.5% bupivacaine also reduced pain and the need for opioid analgesics after vaginal hysterectomy under general anesthesia.30 Preincisional ilioinguinal–iliohypogastric nerve block not only improves perioperative pain control for inguinal hernia repair, but reduces the need for oral opioid-containing analgesics in the postdischarge period.16 Although local infiltration can reduce incisional pain after laparoscopic cholecystectomy,31–34 some investigators have actually reported that infiltration of the trocar sites at the end of surgery provided better pain relief than when the local anesthetic was given before incision.32 The overall analgesic efficacy of trocar wound infiltration after laparoscopic surgery remains controversial.35

Although preincisional infiltration of the operative site with local anesthetics remains popular for reducing the perioperative opioid analgesic requirement, other simpler local anesthetic delivery systems (eg, topical applications) have been described.36–40 Topical analgesia with a lidocaine aerosol was effective in decreasing both pain and the opioid analgesic requirement after inguinal herniorrhaphy in adults,36 and instillation of 0.25% bupivacaine before surgical closure compared favorably with an ilioinguinal–iliohypogastric nerve block in children undergoing hernia repair.37 Furthermore, the simple application of topical lidocaine jelly or ointment, as well as eutectic mixture of local anesthesia (EMLA) cream, have been shown to be as effective as peripheral nerve blocks or parenteral opioids in providing pain relief after outpatient circumcision.38–40 Use of a 5% lidocaine patch has also been reported to be effective in providing peripheral analgesia.41 However, further studies are needed to define the role (if any) of this analgesic device in the postoperative period.

Intracavitary instillation of local anesthetics is another simple, yet effective, technique for providing pain relief during the early postoperative period after laparoscopic and arthroscopic procedures. For example, when 80 mL of lidocaine 0.5% or bupivacaine 0.125% was administered intraperitoneally at the start of the laparoscopic procedure, it significantly reduced postoperative scapular pain and the need for opioid analgesic during the first 48 h after surgery.42 Compared with a control group receiving saline, use of intraperitoneal bupivacaine 0.5% (15–30 mL) also led to a larger percentage of patients going home on the day of surgery (79% vs 43%).43 However, other studies involving intraperitoneal administration of local anesthetics during laparoscopy report inconsistent effects on postoperative pain and the need for opioid analgesics.44–54 Some investigators have suggested that the beneficial effects of intraperitoneal bupivacaine are transient and have little effect on patient recovery.49 Furthermore, when bupivacaine was injected at the preperitoneal fascial plane during extraperitoneal laparoscopic hernia repair, it also failed to reduce postoperative pain.55 Subfacial infiltration with bupivacaine 0.5% at the trochar and incision sites reduced pain and the length of stay after laparoscopic nephrectomy procedures.56 Yndgaard and coworkers57 demonstrated that subfascially administered lidocaine was significantly more effective than subcutaneous injection in reducing pain after inguinal herniotomy. It is obvious that the location, volume, and timing of the local anesthetic administration are key factors in determining efficacy of intraperitoneal instillation in preventing pain after both superficial and laparoscopic surgery.19,43,53

Analogous to intraperitoneal administration, intrapleural instillation of local anesthetic solutions has been reported to improve pain control after laparoscopic surgery.58–66 Some investigators report that interpleural bupivacaine produced more effective analgesia than intraperitoneal bupivacaine66 and compared favorably with epidural bupivacaine58 after laparoscopic cholecystectomy. Compared with standard opioid analgesics, intrapleural bupivacaine achieved better pain relief and greater improvement in postoperative pulmonary function.59,64 In contrast, Oxorn and Whatley65 reported that postoperative pulmonary mechanics were worsened after intrapleural bupivacaine. Adverse effects on pulmonary function (due to muscle weakness) and the risk of systemic local anesthetic toxicity (due to rapid systemic absorption) are the major concerns with this technique.66,67 Although intercostal nerve blocks can also improve pain relief after cholecystectomy procedures, this does not necessarily lead to improved pulmonary function.68

Local anesthetics are also commonly injected into joint spaces to provide analgesia during and after arthroscopic procedures.69,70 In a placebo-controlled study, intraarticular instillation of 30 mL of 0.5% bupivacaine reduced opioid requirements and facilitated early mobilization and discharge after knee arthroscopy.70 In a follow-up study, a combination of intraarticular bupivacaine and systemic ketorolac (60 mg) further decreased pain in the early postoperative recovery period.71 In addition to the local anesthetics, a wide variety of other adjuvants (eg, morphine, ketorolac, triamcinolone, and clonidine) have also been injected into the intraarticular space to decrease postarthroscopic pain.72–77 Small-dose intraarticular morphine (0.5–1 mg), combined with bupivacaine, appears to provide the longest lasting and most cost-effective analgesia after knee arthroscopy.76,77 Although administering intraarticular morphine before knee surgery was reported to provide a longer duration of analgesia and greater opioid-sparing effects than when it was given at the end of surgery,77 the clinical advantage of preemptive intraarticular local anesthetic administration remains controversial.27

Although local anesthetic supplementation decreases the severity of incisional pain in the early postoperative period, many patients still experience significant pain when the local anesthetic effect wears off. Therefore, continuous78,79 or intermittent perfusion80,81 of the surgical wound (or peripheral nerve) with local anesthetic solutions has been reintroduced as a way of extending local anesthetic-induced incisional pain relief into the postoperative period. In a recent study by White and associates82 infusion of 0.5% bupivacaine (4 mL/h) at the median sternotomy site reduced postoperative pain and opioid analgesic requirement after cardiac surgery. As a result of the opioid-sparing effect, these patients recovered bowel and bladder function more rapidly. Similarly, wound instillation with 0.2% ropivacaine (5 mL/h) improved pain control after spine fusion surgery.83 These continuous local anesthetic infusion techniques can be modified to allow for patient-controlled local anesthetic administration after surgery.84,85

Investigators have failed to find consistent improvement in pain scores or opioid-sparing effects when the local anesthetic was infused at the incision site after abdominal surgery.57,86–88 Efficacy of local anesthetic infusion systems is enhanced when the catheter is placed at the subfacial level or near a peripheral nerve. For example, a continuous popliteal-sciatic nerve block provides improved postoperative analgesia, decreased opioid use, and enhanced patient satisfaction after painful foot and ankle surgery.89,90 Similarly, a continuous infraclavicular brachial plexus block provides highly effective pain control after discharge in patients undergoing shoulder surgery.91 Although continuous local anesthetic infusions with concomitant IVPCA capability appears to be superior to a continuous infusion alone for prolonging nerve blocks,92,93 many patients elect not to use the IVPCA function on their electronic pumps.91

When using a continuous local anesthetic infusion, analgesic efficacy is influenced by a wide variety of factors in addition to location to the catheter system, including the concentration and volume of the local anesthetic solution,82 as well as the accuracy and consistency of the pumps.94 The use of a disposable, nonelectronic infusion system may offer advantages over the electronic pump because its simplicity minimizes the need for trouble shooting.95 However, accuracy of the infusion rate of the nonelectronic pumps can change over time.94 Temperature changes also influence the infusion rate of elastomeric pumps, and battery life is a limiting factor for the electronic pumps.94 With these catheter delivery systems, the risk of infection appears to be small. However, bacterial colonization of the catheter is a common occurrence.96 Patient satisfaction and comfort when using these delivery systems outside the hospital is high, and over 90% of the patients are comfortable removing the catheter at home.97 Finally, combining local anesthetic infusion techniques with other analgesic modalities as part of multimodal analgesic therapy further improves pain control throughout the perioperative period.98

Peripheral nerve block techniques are simple, safe, and highly effective approaches to providing perioperative analgesia. Use of long-acting local anesthetics for neural blockade techniques involving the upper (eg, interscalene brachial plexus block) and lower (eg, femoral-sciatic nerve block) extremities can facilitate an earlier discharge after major shoulder and knee reconstructive procedures, respectively.99,100 Availability of long-acting local anesthetics that claim less toxicity and greater selectivity with respect to sensory and motor blockade (eg, ropivacaine) may further enhance the benefits of local anesthetic supplementation after both major and minor surgery.

Although ropivacaine 0.2% provides better pain relief with less motor impairment than lidocaine 1% for continuous interscalene brachial plexus block,101 its clinical advantages relative to equipotent concentrations of bupivacaine are less well established. Addition of adjuvants (eg, epinephrine, clonidine) that can prolong postoperative analgesia and facilitate recovery when using central and peripheral nerve blocks may be of greater clinical importance.102,103 Interestingly, a more recent study104 found that clonidine's use as an adjunct to ropivacaine as part of a continuous perineural infusion technique failed to reduce postoperative pain and oral analgesic usage or improve the patient's quality of sleep after upper extremity surgery when compared with the local anesthetic alone. Although pain control can be improved after orthopedic procedures by continuously infusing local anesthetic solutions,89,90,105–107 availability of longer acting local anesthetic suspensions and “delayed release” formulations containing liposomes or polymer microspheres may minimize the need for continuous infusion catheter delivery system in the future.

Oral NSAIDs have long been used for treating nonsurgical pain syndromes because of their well known antiinflammatory, antipyretic, and analgesic properties. When parenteral preparations of NSAIDs (eg, ketorolac, ketoprofen, diclofenac) became available, these drugs were more widely used in the management of acute perioperative pain. NSAIDs block the synthesis of prostaglandins by inhibiting cyclooxygenase (COX) types I and II, thereby reducing production of mediators of the acute inflammatory response. By decreasing the inflammatory response to surgical trauma, NSAIDs have been alleged to reduce peripheral nociception. Studies also suggest that the central response to painful stimuli is modulated by NSAID-induced inhibition of prostaglandin synthesis in the spinal cord.27

Early reports suggested that parenteral NSAIDs possessed analgesic properties comparable to those for traditional opioid analgesics108–110 without opioid-related side effects.111,112 Compared with the partial opioid agonist tramadol, diclofenac produced better postoperative pain relief with fewer side effects after cardiac surgery.8 When administered as an adjuvant during outpatient anesthesia, ketorolac was associated with improved postoperative analgesia and patient comfort compared with fentanyl and the partial opioid agonist, dezocine.112,113 Other investigators reported that ketorolac provided postoperative pain relief similar to that of fentanyl, but was associated with less nausea and somnolence, as well as an earlier return of bowel function.114 In most studies, use of ketorolac has been associated with a less frequent incidence of PONV than the opioid analgesics. As a result, patients tolerate oral fluids and are fit for discharge earlier than those receiving only opioid analgesics during the perioperative period. Of interest, ketorolac (30 mg q6h) was superior to a dilute local anesthetic infusion (bupivacaine 0.125%) in supplementing epidural IVPCA hydromorphone in patients undergoing thoracotomy procedures.115 Furthermore, it has been found that the injection of ketorolac (30 mg) at the incision site in combination with local anesthesia resulted in significantly less postoperative pain, a better quality of recovery, and earlier discharge compared with local anesthesia alone.116 In fact, evidence exists for both a peripheral and central analgesic action of NSAIDs.117 However, when ketorolac was substituted for, or combined with, fentanyl during minor gynecologic and laparoscopic procedures, beneficial effects of the NSAID were reduced.118,119

Using shock wave lithotripsy to evaluate the effect of NSAIDs on visceral pain, diclofenac produced only a marginal opioid-sparing effect.120 However, when diclofenac (1 mg/kg IV) was administered before arthroscopic surgery, it was associated with similar pain scores to fentanyl (1 mcg/kg IV).121 Preoperative diclofenac (50 mg) also decreased pain and the opioid analgesic requirements for 24 h after laparoscopic surgery.122 Similarly, preoperative administration of ketorolac to patients undergoing laparoscopic cholecystectomy119 decreased postoperative opioid requirements and improved some ventilatory variables during the early postoperative period. A perioperative ketorolac infusion (2 mg/h) also improved the quality of postoperative pain relief after abdominal surgery.123 Ketorolac (30 mg IV) produced comparable analgesia to tramadol (100 mg IV), but with a 68% decreased incidence of PONV after maxillofacial surgery.124 Of interest, diclofenac (1 mg/kg) is alleged to be a more cost-effective alternative to ketorolac (0.5 mg/kg).125,126

When diclofenac was administered preoperatively to pediatric patients, the incidence of both restlessness and crying, as well as the postoperative opioid requirements, were less than in patients treated with acetaminophen.127 Similarly, oral ketorolac (1 mg/kg) was superior to small-dose acetaminophen (10 mg/kg) for pain in children undergoing bilateral myringotomy procedures.128 In children undergoing inguinal hernia repair,129 ketorolac (1 mg/kg IV) compared favorably with caudal bupivacaine 0.2% with respect to pain control and postoperative side effects. In addition, ketorolac-treated children had an improved recovery profile, including less vomiting, shorter times to voiding and ambulation, and earlier discharge home. Intraoperative administration of ketorolac as an adjuvant to general anesthesia in pediatric patients provided postoperative analgesia comparable to morphine with less PONV.130 When ketorolac or morphine is administered for pain control in pediatric patients, ketorolac-induced analgesia develops more slowly but lasts longer.131

Oral or rectal administration of NSAIDs is also effective and less costly in the prophylactic management of surgical pain.132 For example, when oral naproxen was administered before laparoscopic surgery, postoperative pain scores, opioid requirements, and time to discharge were significantly reduced.133 Furthermore, premedication with oral ibuprofen (800 mg) was associated with superior postoperative analgesia and less nausea than with fentanyl (75 mcg IV) after laparoscopic surgery.134 However, the more important role for oral NSAIDs may be in the postdischarge period. Ibuprofen liquigel (400 mg PO) was significantly more effective than celecoxib (200 mg PO) in treating pain after oral surgery.135 Ibuprofen (5 mg/kg PO) compared favorably with rofecoxib (0.625 mg/kg PO) for minimizing postoperative pain when used in combination with acetaminophen (20 mg/kg) prior to tonsillectomy procedures.136 When used as part of a multimodal analgesic technique consisting of alfentanil, lidocaine, and ketorolac,137 oral ibuprofen (800 mg q8h) was equianalgesic to paracetamol 800 mg in combination with codeine 60 mg (q8h) during the first 72 h after discharge and resulted in better global patient satisfaction and less constipation than opioid-containing oral analgesics. Ibuprofen (400 or 600 mg PO) appears to produce comparable analgesia to the combination tramadol (75–112.5 mg) and acetaminophen (650 or 975 mg) for acute postoperative pain relief.138 To achieve the optimal benefit of using NSAIDs in the perioperative period, these compounds should be continued during the postdischarge period as part of a preventative pain management strategy.98

Despite the obvious benefits of using NSAIDs in the perioperative period, controversy still exists regarding their use because of the potential for gastrointestinal mucosal damage and renal tubular and platelet dysfunction.139 Although some studies have found increased blood loss and risk of reoperation when ketorolac was administered to children undergoing tonsillectomy procedures,140,141 a recent systematic review of the literature suggested that the evidence supporting an increase of bleeding was equivocal at best.142

In an effort to minimize the potential for operative site bleeding complications, as well as gastrointestinal damage, associated with the classic nonselective NSAIDs such as ketorolac and diclofenac, the more highly selective COX-2 inhibitors are increasingly being used as nonopioid adjuvants for minimizing pain during the perioperative period (Table 77–3).143 Early clinical studies in surgical patients evaluated the use of celecoxib, rofecoxib, and valdecoxib as preventative analgesics when administered for oral premedication.144–148 Rofecoxib (50 mg PO) produced more effective and sustained analgesia than celecoxib (200 mg PO) after spinal surgery.144 Celecoxib (200 mg PO) was equivalent to acetaminophen (2 g PO) when administered before otolaryngologic operations.145 However, the analgesic efficacy of celecoxib is dose-related, and 400 mg is the currently recommended dose for prevention of acute pain.146 Rofecoxib (50 mg PO) produced significantly more effective analgesia than acetaminophen (2 g PO), and the pain relief was more sustained in the postdischarge period.147 Premedication with rofecoxib also facilitated recovery by reducing postoperative pain and improving the quality of recovery from the patient's perspective.148 It has also been suggested that the long-acting rofecoxib is more cost-effective than celecoxib in the perioperative period.149 In a recent study,143 a single preoperative dose of rofecoxib (25–50 mg PO) produced a 44–59% reduction in the PCA morphine requirement after major abdominal surgery.150 However, clinical studies suggest a more sustained benefit can be achieved when the drug is administered both before and after surgery.148,151 The recent withdrawal of rofecoxib from the market by its manufacturer because of an increased risk of cardiovascular side effects following prolonged use (>16 months) has led investigators to begin reevaluating other COX-2 inhibitors in the perioperative period.

Valdecoxib has been introduced recently for the prevention of postoperative pain, with doses of 20 to 40 mg reducing the opioid requirement by 25 to 50% after elective surgery.152,153 In patients undergoing oral surgery and bunionectomy, premedication with valdecoxib 40 mg appears to produce the optimal analgesic effect in the postoperative period.152 Valdecoxib is as rapidly acting and effective as oxycodone in combination with acetaminophen, but has a longer duration of action and fewer side effects when used for the management of pain after oral surgery. Valdecoxib (40 mg PO) was alleged to be even more effective than rofecoxib (50 mg PO) in treating pain after oral surgery.154

A parenterally active COX-2 inhibitor, parecoxib (a prodrug which is rapidly converted to valdecoxib), has been investigated as an alternative to the parenteral NSAIDs.155–157 However, to achieve equianalgesia with the IV prodrug, a higher dose may be required than of the orally active drug valdecoxib. Parecoxib is similar pharmacokinetically to both celecoxib and valdecoxib. Preliminary studies suggested that parecoxib (40–80 mg IV) is as effective and longer acting than ketorolac (30 mg IV) in reducing pain after oral158 and laparotomy surgery.159 Both preoperative and postoperative administration of this COX-2 inhibitor resulted in significant opioid-sparing effects, reduced adverse effects, and improved the quality of recovery and patient satisfaction with their postoperative pain management.152,160 Unfortunately, a recent study in patients undergoing cardiac surgery suggested that perioperative use of parecoxib and valdecoxib as part of a 14-day analgesic treatment regimen increased adverse events, including sternal wound infections.161 Another recent study found that when parecoxib (40 mg IV) was given at induction of anesthesia, it was less effective than ketorolac (30 mg IV) after tonsillectomy procedures.141 A new more highly selective COX-2 inhibitor, etoricoxib (120 mg PO), provided rapid and long-lasting pain relief after dental surgery.162 A recent study also suggested that etoricoxib was associated with fewer side effects than a standard opioid-containing oral analgesic. Current evidence suggest that the newer COX-2 inhibitors appear to offer minimal advantages over the first-generation COX-2 inhibitors and the nonselective NSAIDs.163,164

In addition to the growing controversy regarding the potential adverse cardiovascular risks of the COX-2 inhibitors, many orthopedic surgeons are also concerned about the negative influence of these compounds (as well as the traditional NSAIDs) on bone growth.165,166 Since COX-2 activity appears to play an important role in bone healing,167–169 some orthopedic surgeons have recommended that these drugs be avoided in the early postoperative period.164,165 Since the effect on bone growth is dose-dependent and reversible,166 COX-2 inhibitors should only be used for 3 to 5 days in the early postoperative period. Although several review articles on the COX-2 inhibitors have recently been published,163,170–172 the question remains as to whether these compounds truly overcome the perceived limitations of the nonselective NSAIDs.173

Acetaminophen (also known as paracetamol) is perhaps the safest and most cost-effective nonopioid analgesic when it is administered in analgesic dosages. Although both parenteral and rectal acetaminophen produce analgesic effects in the postoperative period, concurrent use with an NSAID is superior to acetaminophen alone.145,147 The addition of acetaminophen (1 g, q4h) to PCA morphine improved the quality of pain relief and patient satisfaction after major orthopedic procedures.174 Although Watcha and colleagues128reported minimal analgesic-sparing effects after a 10 mg/kg oral dose of acetaminophen, Rusy and coworkers140 found that a larger dose (35 mg/kg PR) was as effective as a ketorolac (1 mg/kg IV) in reducing pain after tonsillectomy procedures and was associated with less postoperative bleeding. Subsequently, Korpela and associates175 demonstrated that the opioid-sparing effect of rectal acetaminophen was dose-related up to 60 mg/kg. The optimal dosing regimen for acetaminophen in children appears to consist of a preoperative initial dose of 30 to 40 mg/kg followed by a maintenance dose of 15 to 20 mg/kg every 6–8 h during the early postoperative period.176 In adults, acetaminophen 2 g orally was equivalent to celecoxib 200 mg, but less effective than celecoxib 400 mg, rofecoxib 50 mg, or ketoprofen 150 mg in preventing pain after ambulatory surgery.145–147

An IV formulation of a prodrug of acetaminophen, propacetamol, has been administered to adults as an alternative to ketorolac in the perioperative period.177,178 Propacetamol reduced IVPCA morphine consumption by 22% to 46% in patients undergoing major orthopedic surgery.179,180 However, in patients undergoing cardiac surgery, propacetamol (2 g IV q6h for 3 days) failed to enhance analgesia, decrease opioid usage, or reduce adverse side effects in the postoperative period.181 Propacetamol has become a popular adjuvant to opioid analgesics for postoperative pain control in Europe; however, this drug may soon be replaced when an investigational IV formulation of acetaminophen becomes available for clinical use.182 Rectal acetaminophen (1.3 g) has also been successfully used as an adjuvant to NSAIDs and local anesthetics as part of a multimodal fast-tracking surgery recovery protocol.183 Given the adverse effects associated with both NSAIDs and COX-2 inhibitors in patients with preexisting cardiovascular disease, acetaminophen may assume a greater role in postoperative pain management in the future.184

Ketamine is a unique IV anesthetic with analgesic-like properties that has been used for both induction and maintenance of anesthesia,185 as well as an analgesic adjuvant during local anesthesia.186,187 As a result of its well-known side effect profile (Table 77–4), ketamine fell into disfavor in the late 1980s. However, adjunctive use of small doses of ketamine (0.1–0.2 mg/kg IV) appears to be associated with opioid-sparing effects, a less frequent incidence of adverse events and greater patient and physician acceptance.188 Several studies have described the use of small-dose ketamine in combination with local anesthetics or opioid analgesics.189–199 However, when ketamine (1 mg/mL) was combined with morphine (1 mg/mL) for IVPCA after major abdominal surgery, it did not significantly improve pain relief and was associated with increased side effects (eg, vivid dreaming) compared with the opioid alone.191 A recent study192 supports use of an IVPCA morphine–ketamine combination in a 1:1 ratio with a lockout interval of 8 min for pain control after major orthopedic procedures. Further studies are obviously needed to clarify ketamine's role as a supplemental analgesic.

Administration of ketamine (4–18 mcg/kg/min) in combination with propofol (30-90 mcg/kg/min) obviated the respiratory depression produced by commonly used sedative–opioid combinations, while producing positive mood effects after surgery, and may even provide for an earlier recovery of cognitive function.186,187 In addition, a single bolus dose of ketamine (0.1–0.15 mg/kg IV), during surgery has been reported to produce significant opioid-sparing effects after painful orthopedic and intraabdominal procedures without increasing the incidence of side effects.194–200 Ketamine (0.1 mg/kg IM) reduced swallowing-evoked pain after tonsillectomy procedures in children receiving a multimodal analgesic regimen.198 Small doses of epidural ketamine (20–30 mg) enhanced epidural morphine-induced analgesia after major upper abdominal surgery.199 Although it was alleged that ketamine possesses preemptive analgesic effects as a result of its ability to inhibit central NMDA receptors,200 well-controlled clinical studies have failed to demonstrate significant preemptive analgesic effects.201,202 Interestingly, a modest dose of ketamine (250 mcg/kg) after surgery was alleged to improve analgesia in the presence of opioid-resistant pain.203 Acute tolerance to opioid-induced analgesia leading to long-lasting hyperalgesia may be prevented by repeat doses of this NMDA antagonist.204

Small doses of the S(+) and R(–) isomers of ketamine have been administered both IV and epidurally in an effort to decrease injury-induced hyperalgesia. Although S(+) ketamine (0.5 mg/kg IV followed by 0.125 to 1 mcg/kg/min) failed to improve pain control after arthroscopic knee surgery,205 epidural S(+) ketamine (0.25 mg/kg) enhanced ropivacaine-induced analgesia after total knee arthroplasty.206 Interestingly, transdermal nitroglycerin (5 mg) has been alleged to enhance the spinal analgesia produced by epidural S(+) ketamine (0.1–0.2 mg/kg).207 Consistent with an early comparative clinical study involving the ketamine isomers.208R(-) ketamine (1 mg/kg IV) produced only a short-lasting analgesic effect in the postoperative period.209

Dextromethorphan, another NMDA receptor antagonist that inhibits wind-up and NMDA-mediated nociceptive responses in dorsal horn neurons, has been alleged to enhance opioid, local anesthetic, and NSAID-induced analgesia. Premedication with dextromethorphan (150 mg PO) reduced the IVPCA morphine requirement in the early postoperative period after abdominal hysterectomy procedures, but failed to produce prolonged beneficial effects on wound hyperalgesia.210 In patients undergoing laparoscopic cholecystectomy or inguinal herniorrhaphy procedures, dextromethorphan (90 mg PO) improved well-being and reduced analgesic consumption, pain intensity and sedation, as well as thermal-induced hyperalgesia.211 Preincisional administration of dextromethorphan (40–120 mg IM) provided some evidence of preemptive analgesia in patients undergoing laparoscopic cholecystectomy and upper abdominal surgery.212,213 Perioperative dextromethorphan (40–90 mg IM) reduced the opioid requirement or improved pain control (or both) after modified radical mastectomy.214 Interestingly, in patients undergoing knee surgery, dextromethorphan (200 mg q8h) failed to significantly improve pain management.215 Compared with ibuprofen (400 mg PO), dextromethorphan (120 mg PO) was significantly less effective in providing postoperative analgesia and was associated with increased nausea in the preoperative period.216 In patients undergoing knee replacement surgery with epidural anesthesia, dextromethorphan (40 mg IM) also failed to produce any preemptive analgesic effect, but did enhance pain control in the postoperative period.217

Other NMDA antagonists are being actively investigated in the perioperative setting. Preoperative amantadine (200 mg IV) failed to enhance postoperative analgesia in patients undergoing abdominal hysterectomy procedures.218 However, a more recent study reports that perioperative amantadine reduced the IVPCA morphine requirement after radical prostatectomy surgery.219 Further clinical studies are clearly needed to better define the role of noncompetitive NMDA receptor antagonists in the perioperative setting.

The α2-adrenergic agonists, clonidine and dexmedetomidine, produce significant anesthetic and analgesic-sparing effects. Premedication with oral and transdermal clonidine decreased the IVPCA morphine requirement 50% after radical prostatectomy surgery.220 Clonidine also improved and prolonged central neuroaxis221,222 and peripheral nerve blocks223 when administered as part of multimodal analgesic regimens. For example, epidural infusion of clonidine in combination with ropivacaine improved analgesia after major abdominal surgery in children.224 Adding intrathecal clonidine (0.075 mg) to local anesthesia provided excellent analgesia for up to 8 h after urologic surgery.225 Although clonidine (4 mcg/kg IV over 20 min) failed to reduce the IVPCA morphine requirement after lower abdominal surgery in adults, it did reduce pain, nausea, and vomiting while improving patient satisfaction with their pain relief.226 However, when used to treat postoperative pain, clonidine (0.3 mg IV) was apparently ineffective.227

Dexmedetomidine is a pure α2-agonist that also reduces postoperative pain and the opioid analgesic requirement.228 However, its use was associated with increased postoperative sedation and bradycardia. When used for premedication before IV regional anesthesia,229 dexmedetomidine (1 mcg/kg IV) reduced patient anxiety, sympathoadrenal responses, and intraoperative opioid analgesic requirement. Compared with propofol (75 mcg/kg/min), dexmedetomidine (1 mcg/kg followed by 0.4–0.7 mcg/kg/h) had a slower onset and offset of sedation, but was associated with improved analgesia and reduced morphine use in the postoperative period.230 Administration of dexmedetomidine (1 mcg/kg followed by 0.4 mcg/kg/h) was also associated with a 66% reduction in IVPCA morphine use in the early postoperative period after major inpatient surgery.231

A diverse array of nonopioid pharmacologic compounds (eg, adenosine,232,233 droperidol,234 magnesium,235 neostigmine,236 gabapentin237,238) used during the perioperative period have been alleged to possess analgesic-sparing properties. Although such effects of these compounds have not been extensively evaluated and their use for acute postoperative pain management is considered investigational, the preliminary findings are nonetheless intriguing. For example, use of an adenosine infusion as an alternative to an opioid analgesic (remifentanil) for controlling acute autonomic responses during lower abdominal surgery resulted in a significant reduction in both postoperative pain scores and the requirement for opioid analgesics.232

Gabapentin (a structural analog of γ-aminobutyric acid; GABA) is an anticonvulsant that has proven useful in the treatment of chronic neuropathic pain and may also be a useful adjuvant in the management of acute postoperative pain.237–242 For example, premedication with gabapentin (1.2 g PO) reduced postoperative analgesic requirement significantly without increasing side effects.237 When gabapentin (1.2 g) was continued for 10 d after breast surgery238 it reduced the postoperative opioid analgesic requirement and movement-related pain; however, the overall incidence of chronic pain was unaffected. Recent studies by Dierking and colleagues,239 Turan and coworkers,240 and Rorarius and associates241 suggested that the improvement in postoperative pain control with gabapentin was not necessarily associated with a decrease in opioid-related side effects. Pregabalin, a related compound, has also been reported to possess analgesic potential comparable to ibuprofen in treating acute dental pain.242 This review article discussed the potential role of gabapentin and pregabalin in “protective premedication.” Magnesium, a divalent cation, is also assumed to possess antinociceptive effects. For example, Kara and colleagues235 reported that perioperative magnesium (30 mg/kg IV followed by an infusion of 0.5 g/h) yielded a significant reduction in the postoperative analgesic requirement after abdominal hysterectomy. A bolus dose of magnesium (50 mg/kg IV) at induction of anesthesia also led to improved pain control and better patient satisfaction with less opioid medication after major orthopedic surgery.243 However, magnesium (50 mg/kg IV) failed to produce opioid-sparing effects after open cholecystectomy procedures.244 In addition, a nonopioid multimodal analgesic regimen that included magnesium produced comparable postoperative pain relief with fewer side effects than fentanyl in obese patients undergoing gastric bypass surgery.245 However, other investigators have failed to demonstrate a beneficial effect of magnesium (30–50 mg/kg followed by 10–15 mg/kg/h) with respect to reducing postoperative pain or the need for opioid analgesics.246 Of interest, intrathecal magnesium was reported to prolong fentanyl analgesia.247

Neostigmine, a cholinesterase inhibitor, has been reported to possess analgesic properties when doses of 10 to 200 mcg were administered in the subarachnoid or epidural spaces.236,248 Although peripherally administered neostigmine failed to produce postoperative analgesia, epidurally administered neostigmine (1 mcg/kg) produced more than 5 h of pain relief after knee surgery.249 Neostigmine (10 mcg/kg) also enhanced epidural local analgesia.250 Both epidural (60 mcg) and spinal (1–5 mcg) neostigmine enhanced morphine-induced neuraxial analgesia.251–254 In patients undergoing knee replacement surgery with intrathecal bupivacaine, adjunctive use of neostigmine (50 mcg) was alleged to produce better postoperative analgesia than morphine (300 mcg).255 In addition, transdermal nitroglycerin enhanced spinal neostigmine-induced postoperative analgesia without increasing perioperative side effects.256 However, epidural neostigmine (75–300 mcg) alone produced only modest analgesia after cesarean delivery.257 The primary adverse effects associated with neuraxial neostigmine appear to be mild sedation257 and PONV (15–30%).237,253

Cannabinoids have been reported to reduce hyperalgesia and drug-induced allodynia. However, clinical studies have failed to demonstrate any evidence of postoperative analgesia.258,259 A new antiinflammatory drug, inositol triphosphate, reduced postoperative pain and the need for opioid analgesics after cholecystectomy surgery.260 However, additional well controlled clinical trials are needed with all of these novel adjunctive drugs.

Nonpharmacologic “electroanalgesic” techniques [eg, transcutaneous electrical nerve stimulation (TENS), acupuncture-like transcutaneous electrical nerve stimulation, percutaneous neuromodulation therapy] can also be useful adjuvants to pharmacologic compounds in the management of acute postoperative pain.261 Given the inherent side effects produced by both opioid and nonopioid analgesics (see Table 77–4), it is possible that the use of nonpharmacologic approaches will assume a more prominent role in the future management of acute postoperative pain.262

Clinical studies suggest that electroanalgesia can reduce opioid analgesic requirements up to 60% after surgery.263,264 In addition to reducing pain and the need for oral analgesics, Jensen and coworkers265 reported a more rapid recovery of joint mobility after arthroscopic knee surgery. When used as an adjuvant to pharmacologic analgesia, TENS reduced the intensity of exercise-induced pain and facilitated ambulation after abdominal surgery.266 In reviewing the medical literature, Carroll and associates267 found conflicting results regarding the effect of TENS on the requirement for opioid analgesic medication and the quality of postoperative pain relief. Studies suggest that the location, intensity, timing, and frequency of electrical stimulation are all important variables influencing the efficacy of electroanalgesic therapies.263,264,268 More recent studies have confirmed the importance of these variables in achieving improved pain relief with TENS therapy.269

Of interest, simple (mechanical) intradermal needles placed in the paravertebral region before abdominal surgery reduced postoperative pain and the opioid analgesic requirement, as well as PONV.270 However, a “minute sphere”-induced acupressure technique (in which 1-mm stainless steel spheres are applied at known analgesic acupoints) failed to relieve pain after major abdominal surgery.271 Other nonpharmacologic approaches that have been used as analgesic adjuvants in the perioperative period include cryoanalgesia,272 ultrasound,273 laser stimulation,274 and hypnotherapy. However, well-controlled clinical studies are needed to establish benefits of these nonpharmacologic modalities on postoperative pain and patient outcomes after surgery.

In summary, as more extensive and painful operations (eg, laparoscopic cholecystectomy, adrenalectomy, and nephrectomy procedures, as well as prostatectomy, laminectomy, shoulder and knee reconstructions, hysterectomy) are performed on an outpatient or short-stay basis, the use of multimodal perioperative analgesic regimens involving nonopioid analgesic therapies will likely assume an increasingly important role in facilitating the recovery process and improving patient satisfaction.4 Pavlin and colleagues275 recently confirmed the importance of postoperative pain on recovery after ambulatory surgery. Moderate-to-severe pain prolonged recovery room stay by 40 to 80 min. Use of local anesthetics and NSAIDs decreased pain scores and facilitated an earlier discharge home. Additional outcome studies are needed to validate the beneficial effect of these nonopioid therapeutic approaches with respect to important recovery variables (eg, resumption of normal activities [dietary intake, bowel function], return to work). Although many factors other than pain per se must be controlled in order to minimize postoperative morbidity and facilitate the recovery process,1 pain remains a major concern of all patients undergoing elective surgical procedures.276

Opioid analgesics continue to play an important role in the management of moderate-to-severe pain after surgical procedures. However, adjunctive use of nonopioid analgesics will likely assume a greater role as minimally invasive (“key hole”) surgery continues to expand.2,4 In addition to the local anesthetics, NSAIDs, COX-2 inhibitors, acetaminophen, ketamine, dextromethorphan, α2-agonists, gabapentin, magnesium, and neostigmine may all prove to be useful adjuncts in the management of postoperative pain in the future. Adjunctive use of droperidol234 and glucocorticoid steroids277,278 also appears to provide beneficial effects in the postoperative period. Use of analgesic drug combinations with differing mechanisms of action as part of a multimodal regimen will provide additive (or even synergistic) effects with respect to improving pain control, reducing the need for opioid analgesics and facilitating the recovery process.279 Safer, simpler, and less costly analgesic drug delivery systems are needed to provide cost-effective pain relief in the postdischarge period as more major surgery is performed on an ambulatory (or short-stay) basis in the future.

The optimal nonopioid analgesic technique for postoperative pain management would therefore not only reduce pain scores and enhance patient satisfaction, but also facilitate earlier mobilization and rehabilitation by reducing pain-related complications after surgery. Recent evidence suggests that this goal can be best achieved by using a combination of preemptive techniques involving both centrally and peripherally acting analgesic drugs and devices.