Multimodal Analgesia for Perioperative Pain Management

Asokumar Buvanendran, MD
Department of Anesthesiology Orthopedic Anesthesia Division Rush Medical College and Rush University Medical Center Chicago, Illinois

Learning Objectives: As a result of completing this activity, the participant will be able to  Explain the importance of initiating early treatment of acute postoperative pain to prevent the consequences  Develop appropriate multimodal regimens for perioperative pain management based on understanding of the pharmacology of adjuvant analgesics  Prescribe the appropriate duration of multimodal analgesic regimens for perioperative pain management with the goal to decrease the use of opioids as the sole agent Author Disclosure Information: Dr. Buvanendran has disclosed that he receives research funding from Pfizer and Cumberland.

ultimodal analgesia is achieved by combining analgesics that act by different mechanisms, resulting in additive or synergistic analgesia with reduced adverse effects secondary to the administration of individual analgesics.1 Opioids have long been the main-

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stay of postoperative analgesia, but the addition of adjuvant medications permits the use of lower doses of opioids while addressing pain by alternative mechanisms. Synergistically or additively, these adjuvants enhance the analgesia provided by opioids and reduce potential adverse effects. In addition, acute opioid tolerance has been described in which high-dose intraoperative opioid administration necessitates increasing postoperative opioid requirements, but this may be avoided by the use of a multimodal perioperative anesthesia and analgesia model.2 Ambulatory surgery encompasses the majority of surgical procedures currently performed in the United States. The number of procedures performed on an ambulatory basis has increased due to improvements in surgical technology, anesthetic techniques, and pharmacology specifically, analgesic agents. There is an increasing trend of performing more painful procedures on an outpatient basis.3 Inadequate management of pain or side effects from medications (such as opioids) can lead to decreased patient satisfaction and delays in discharge. Multimodal analgesia captures the effectiveness of individual agents in optimal dosages that maximize efficacy and minimize side effects. The principles are based on constructing a multimodal analgesia strategy that, in addition to regional or local anesthesia, includes scheduled administration of nonopioid analgesics (e.g., acetaminophen, nonsteroidal antiinflammatory [NSAID] agents, or cyclooxygenase [COX]-2 inhibitors) and using oral opioids only for breakthrough pain (Supplemental Digital Content 1, http:// links.lww.com/ASA/A223; Supplemental Digital Content 2, http://links.lww.com/ASA/A225). These regimens must be tailored to individual patients, keeping in mind the 1

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procedure being performed, side effects of individual medications, and patients preexisting medical conditions. Anesthesiologists are challenged to provide anesthesia and analgesia using the foundations of multimodal analgesia in order for patients to attain rapid recovery and discharge from the hospital.4,5

multimodal analgesia regimen; as availability of intravenous formulations becomes more widespread and anesthesiologists become more comfortable with their administration, their use should increase.

NSAIDs
Inhibition of the cyclooxygenase enzymes (COX-1 and COX-2) and subsequent modulation of the inflammatory response has proved to be an effective means to prevent and treat postoperative pain.9 In the past, there has been concern regarding nonselective COX inhibitors and side effects that include renal toxicity, gastrointestinal toxicity, platelet inhibition, and exacerbation of asthma. COX-2 inhibitors have gained interest as they spare gastrointestinal and renal side effects. However, use of COX-2 inhibitors is not without concern; valdecoxib and rofecoxib were withdrawn from use because of serious side effects. Recent research on celecoxib has defined its efficacy10,11 and safety.11 In addition to decreasing pain scores, celecoxib has been associated with decreased opioid consumption, earlier return of both bowel function11 and physical activity, and increased patient satisfaction. Time to discharge was decreased in groups that received ketorolac (Po 0.05) for ambulatory anorectal procedures.12 Recent meta-analysis examining the use of intravenous ketorolac, even a single dose of 60 or 30 mg, has shown significant reduction in postoperative pain scores and some opioid-sparing adverse effects.13 Newer formulations of ketorolac include an intranasal spray. Compared with placebo, patients receiving intranasal ketorolac had improved pain scores after third molar extraction with bony impaction surgery.14 A randomized controlled trial in patients after abdominal surgery showed that 26% less morphine was consumed in the first 48 hours postoperatively.15 Both studies remarked on the rapid onset of analgesia, which lasted up to 8 hours, and suggested its benefit in ambulatory or fast-track surgery. Local injection of ketorolac was first studied in 2000 and has not been widely used despite oral analgesic-sparing properties, improved quality of recovery, and no effects on postoperative bleeding in one study.15 For patient populations that can tolerate NSAIDs, incorporating them as an oral adjunct has proved to be effective and safe. Local injection or intranasal formulations appear to have properties that make them suitable for further investigation in analgesia regimens for ambulatory surgery.

Multimodal analgesia captures the effectiveness of individual agents in optimal dosages that maximize efficacy and minimize side effects. The principles are based on constructing a multimodal analgesia strategy that, in addition to regional or local anesthesia, includes scheduled administration of nonopioid analgesics (e.g., acetaminophen, NSAIDs, or COX-2 inhibitors) and using oral opioids only for breakthrough pain.

PHARMACOLOGICAL REGIMENS
Aniline Derivatives
Aniline derivatives have mild analgesic, antiinflammatory, and antipyretic properties. The use of these compounds in ambulatory surgery has gained interest of late due to the development of intravenous formulations and the favorable side-effect profiles. Paracetamol, the intravenous equivalent of acetaminophen, became available in 2002 and provides more predictable bioavailability and predictable onset compared with enteral routes of administration. The intravenous formulation of acetaminophen has been demonstrated to spare postoperative opioid use and consequently decrease nausea, vomiting, and sedation. This makes the drug unique and ideal to be the foundation of a multimodal analgesic regimen. Concern still exists for hepatotoxicity associated with aniline derivatives. A prospective study by Gorocs et al.6 demonstrated the safety and efficacy of preoperative paracetamol when given alone or with other systemic analgesics. As a combination, NSAIDs and paracetamol decrease pain scores,7 total opioid consumption, postoperative nausea and vomiting, and sedation. Patients expressed greater satisfaction when the combination of NSAIDs and paracetamol was used versus placebo or acetaminophen alone.7 Paracetamol/ NSAID combinations are also cost-effective, as Issioui et al.8 concluded that it costs only $6.16 to obtain complete satisfaction in one patient. There appears to be much benefit to incorporating aniline derivatives as part of a

Steroids
Preoperative administration of glucocorticoids attenuates peripheral inflammatory pathways and has been shown to decrease postoperative pain for minor surgical procedures.16 Concern regarding side effects of steroid administration, such as gastrointestinal or wound complications, has limited their widespread use.17 In a randomized controlled trial by Coloma et al.,16 dexamethasone (4 mg) administered preoperatively reduced the time to discharge

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with no increase in wound infections. Preoperative or intraoperative administration of glucocorticoids appears to be appropriate timing to obtain the antiinflammatory benefits. The onset of dexamethasone is rapid with duration of action of 24 to 48 hours. When Lunn et al.18 added dexamethasone (16 mg) to a multimodal analgesia regimen (including paracetamol and COX-2 inhibitor), a prolonged analgesic effect was observed. Additional benefits of dexamethasone administration include antiemetic effects. These properties make it an ideal adjunct in the ambulatory or outpatient setting. An extensive review by Salerno and Hermann17 concluded that the literature clearly reflects the safety of short-term use of corticosteroids for acute postoperative analgesia in relatively healthy individuals. Recent data about the effects of a high dose of preoperative methylprednisolone (125 mg) on pain and recovery after total knee arthroplasty showed significant reduction in postoperative pain scores.18

Anticonvulsants
The use of anticonvulsants (g-aminobutyric acid analogues that bind to the a2d subunit of voltage-gated calcium channels) as adjuncts in multimodal regimens has increased in the past decade. Presynaptic voltage-gated calcium channels are up-regulated in the dorsal root ganglia and spinal cord after surgical trauma, which leads to central sensitization.19 Other studies have indicated a decreased incidence of opioid-related side effects (nausea, vomiting, and pruritus) and increased incidence of sedation with the use of anticonvulsants.20 A meta-analysis by Ho et al.21 concluded that a single preoperative dose of gabapentin, 1,200 mg or less, reduces pain scores and opioid consumption in the first 24 hours postoperatively. Continuing administration of gabapentin in addition to a single preoperative dose appears to have benefit; when given for 4 days postoperatively, opioid consumption and some opioid-related side effects were reduced after total knee arthroplasty.22 Pregabalin has shown a more favorable pharmacokinetic profile than gabapentin, including increased bioavailability, longer half-life, and increased potency.23 A single dose of pregabalin (150 mg) demonstrates similar efficacy to gabapentin in reducing postoperative pain and opioid consumption.24 A 50% reduction in 24-hour morphine consumption and decreased nausea and vomiting were observed after a one-time dose of pregabalin (300 mg) in patients undergoing total hip arthroplasty. Buvanendran et al.25 demonstrated that pregabalin (300 mg one-time dose followed by 150 mg twice a day) administered in the perioperative period not only decreases the development of chronic pain, but also improves surgical outcome with greater range of motion after total knee arthroplasty (Supplemental Digital Content 3, http://links. lww.com/ASA/A226; Supplemental Digital Content 4, http://links.lww.com/ASA/A227). Recently, up-regulation of neurotransmitters in the central nervous system cerebrospinal fluid with administration of pregabalin has been

reported in patients undergoing total knee arthroplasty.26 Other studies with single doses of pregabalin (75 or 150 mg) have shown improved immediate postoperative analgesia without opioid-sparing effects.27 Precise dosing of pregabalin is yet undetermined, as higher doses (600 mg), though effective in decreasing postoperative opioid consumption, are associated with an increased incidence of dizziness, blurred vision, and headache. Pregabalin (150 mg), acetaminophen, and celecoxib administered as a multimodal regimen decreased intraoperative and postoperative opioid use in patients undergoing robotic-assisted laparoscopic prostatectomy without causing an increase in somnolence or dizziness.28 A randomized controlled trial by Sen et al.,29 including gabapentin (1,200 mg single dose preoperatively) plus intraoperative ketamine infusion, resulted in lower pain scores, decreased opioid consumption, and less chronic pain after total abdominal hysterectomy. Incorporating anticonvulsants in a multimodal regimen appears to offer not only short-term benefits but also long-term effects, such as decreased development of chronic pain and improved functional outcomes, when continued throughout the immediate postoperative period for certain surgical procedures, including many orthopedic surgeries. While some of the studies cited in this section involve inpatient surgical procedures, the principles can be applied to procedures performed in outpatient settings.

Receptor Antagonists
N-Methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, dextromethorphan, or memantine, have been indicated as possible pharmacological agents to prevent and treat postoperative pain. NMDA receptor antagonists have the ability to treat pain centrally, and possibly preemptively, by limiting central sensitization30,31 (Supplemental Digital Content 5, http://links.lww.com/ ASA/A228). Ketamine has been used more frequently, although side effects such as nausea, vomiting, and delirium are of concern. An effect has been seen with single intravenous boluses and perioperative ketamine infusions. Ketamine infusions have been associated with both opioid sparing32 and improved rehabilitation33 without increased side effects. Other studies demonstrated no effect in reducing pain scores, opioid consumption, or chronic pain in hysterectomy and thoracotomy.34 Memantine, a noncompetitive NMDA receptor antagonist, may prove to be the most applicable for ambulatory surgery. The oral formulation allows ease of administration postoperatively, it is better tolerated, has a longer half-life, and is the most potent NMDA receptor antagonist. It is particularly useful if intravenous ketamine is administered in the perioperative period and oral memantine continued into the postoperative phase in a patient with high risk for developing chronic persistent pain after surgery. Although NMDA receptor antagonists have been shown to have a positive effect on postoperative pain in

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many studies, the appropriate dose and timing have yet to be determined.

a2-Adrenergic Agonists
Stimulation of a2-adrenergic receptors has been known to cause a variety of favorable effects for anesthesiologists, such as analgesia, sedation, and anxiolysis. Clonidine and dexmedetomidine, commonly used a2-agonists, have enteral, intravenous, and transdermal routes of administration. Side effects include bradycardia, hypotension, and excessive sedation. Dexmedetomidine is a highly selective a2-agonist with a short duration of action. An intraoperative infusion reduced volatile anesthetic doses (by 19 to 22%), lessened postoperative opioid needs (by 36 to 42%), decreased nausea and vomiting, and produced a shorter stay in the postoperative anesthesia care unit in patients undergoing laparoscopic bariatric surgery. Prolonged effects (e.g., opioid sparing or shorter hospital stay) were absent, and these findings were attributed to short half-life of dexmedetomidine.35 In patients undergoing laparoscopic gynecological surgery, dexmedetomidine could be used as an alternative to remifentanil in ambulatory surgery because a constant infusion reduced postoperative analgesic requirements, nausea, and vomiting. Use of a2-agonists as adjuncts in regional anesthesia should always be considered, as their safety profile and ability to prolong analgesia has been demonstrated.

associated with activation of the sympathetic nervous system; one thought is that the release of catecholamines enhances excitability of hippocampal NMDA receptors, which may play a role in nociception. Esmolol is a lipophilic, ultrashortacting, b1-selective antagonist that has been studied in ambulatory surgery. Intraoperative esmolol boluses followed by short-term infusions have led to opioid sparing intraoperatively and postoperatively.37,38 However, this opioidsparing effect appears to be limited, lasting as little as 24 hours or as much as 3 days postoperatively. In addition, esmolol has been reported to decrease time to emergence and shorten time to discharge from the recovery room.

Local Anesthetics
Local anesthetics have been found to have multiple mechanism of analgesia, including voltage-gated sodium channel blockade, inhibition of G protein-coupled receptors, and modulation of the inflammatory response.39 In patients undergoing laparoscopic colectomy, an intravenous lidocaine bolus followed by a 24-hour infusion resulted in anesthetic sparing (35% less volatile anesthetic) and greater than 50% reduction in intraoperative and postoperative opioids. In addition, patients receiving lidocaine infusions had earlier return of bowel function and lower postoperative fatigue, resulting in one less day of hospitalization.40 The antiinflammatory effects of lidocaine, with attenuated levels of proinflammatory mediators (IL-6, IL-8, IL-1ra, complement C3a, integrins, and platelet leukocyte aggregates), have been demonstrated by Herroeder et al.40 McCarthy and colleagues reviewed 16 studies with 764 total patients receiving lidocaine infusions. The dosage of lidocaine included boluses of 100 mg (or 1.5 to 2 mg/kg) followed by infusions of 1.5 to 3 mg/kg/h (or 2 to 3 mg/min). They determined a clear benefit in abdominal surgery with less postoperative nausea and vomiting, earlier return of bowel function, earlier ambulation and rehabilitation, and shorter hospitalizations.41 They concluded that a continuous infusion of perioperative lidocaine has a clear advantage in abdominal surgery. Plasma levels of lidocaine during infusions have been measured within a safe (o 5 mg/ mL) range except in one patient, who had a level of 5.8 mg/mL following the initial bolus. However, these infusions seem to be safe as there are no reported cases of central nervous system toxicity in patients undergoing lidocaine infusion.

Through the use of procedure-specific regimens composed of NSAIDs, acetaminophen, and short-acting opioids, many patients will have improved analgesia after mild to moderately painful procedures. The use of steroids, anticonvulsants, and NMDA receptor antagonists should be considered based on the amount of postoperative pain that is anticipated and a patients coexisting medical conditions. Infusions, such as a2-agonists, b-blockers, and local anesthetics, may also prove useful in more painful procedures.
b-Adrenergic Antagonists
The use of b-adrenergic blocking agents as a method of preemptive or preventive analgesia has gained considerable interest in the past 5 years. b-Blockers have been associated with blunting of the sympathetic response, opioid-sparing effects, and anticatabolic properties, yet the exact mechanism of these effects is unknown.36 Incision at the beginning of surgery is

Intraarticular Analgesia
Ease of administration, efficacy in achieving pain relief, and lack of systemic side effects are reasons intraarticular analgesia has become popular for ambulatory surgery. Procedures in which this has been demonstrated include knee and shoulder arthroscopy. However, for every study that demonstrates a positive effect for intraarticular analgesia, there seem to be another that shows the contrary (Supplemental Digital Content 6, http://links.lww.com/ ASA/A232). In addition, reports of chondrolysis after intraarticular injections and infusions have led certain authors to recommend against their use.42

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CONCLUSIONS
Through the use of procedure-specific regimens composed of NSAIDs, acetaminophen, and short-acting opioids, many patients will have improved analgesia after mild to moderately painful procedures (Supplemental Digital Content 7, http://links.lww.com/ASA/A233; Supplemental Digital Content 8, http://links.lww.com/ASA/A235; Supplemental Digital Content 9, http://links.lww.com/ASA/ A236). The use of steroids, anticonvulsants, and NMDA receptor antagonists should be considered based on the amount of postoperative pain that is anticipated and a patients coexisting medical conditions. Infusions, such as a2-agonists, b-blockers, and local anesthetics, may also prove useful in more painful procedures. To facilitate quicker onset of analgesia, new routes of administration (e.g., intranasal ketorolac or ketamine) should become increasingly popular. Their use should also be emphasized, as many have already demonstrated fewer side effects. Advances in pharmacology and equipment should improve the anesthesiologists ability to provide a safe, balanced, multimodal analgesic regimen for a variety of outpatient surgical procedures.
REFERENCES
1. Kehlet H, Dahl JB: The value of multimodal or balanced analgesia in postoperative pain treatment. Anesth Analg 1993; 77:104856. 2. Williams B, Buvanendran A: Non-opioid adjuvants in multimodal therapy for acute perioperative pain. Adv Anesth 2009; 27:11142. 3. Joshi GP: Multimodal analgesia techniques for ambulatory surgery. Int Anesthesiol Clin 2005; 43:197204. 4. Buvanendran A, Thillainathan V: Preoperative and postoperative anesthetic and analgesic techniques for minimally invasive surgery of the spine. Spine 2010; 15:S27480. 5. Buvanendran A, Tuman KJ, McCoy DD, Matusic B, Chelly JE: Anesthetic techniques for minimally invasive total knee arthroplasty. J Knee Surg 2006; 19:1336. 6. Gorocs TS, Lambert M, Rinne T, Krekler M, Modell S: Efficacy and tolerability of ready-to use intravenous paracetamol solution as monotherapy or as an adjunct analgesic therapy for postoperative pain in patients undergoing elective ambulatory surgery: Open, prospective study. Int J Clin Pract 2009; 63:11220. 7. Ong CK, Seymour RA, Lirk P, Merry AF: Combining paracetamol (acetaminophen)with nonsteroidal antiinflammatory drugs: A qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg 2010; 110:11709. 8. Issioui T, Klein KW, White PF, et al.: The efficacy of premedication with celecoxib and acetaminophen in preventing pain after otolaryngologic surgery. Anesth Analg 2002; 94:118893. 9. Buvanendran A, Kroin JS, Tuman KT, et al.: Effects of perioperative administration of a selective cyclooxygenase 2 inhibitor on pain management and recovery of function after knee replacement. A prospective, randomized controlled trial. JAMA 2003; 290: 24118. 10. Sun T, Sacan O, White PF, et al.: Perioperative vs postoperative celecoxib on patient outcome after major plastic surgery procedures. Anesth Analg 2008; 106:9508. 11. White PF, Sacan O, Tufanogullari B, et al.: Effect of short-term postoperative celecoxib administration on patient outcome after outpatient laparoscopic surgery. Can J Anaesth 2007; 54:3428. 12. Grant GM, Mehlisch DR: Intranasal ketorolac for pain secondary to third molar impaction surgery: A randomized, double-blind, placebocontrolled trial J Oral Maxillofac Surg 2010; 68:102531. 13. De Oliveira GS Jr, Agarwal D, Benzon HT: Perioperative single dose ketorolac to prevent postoperative pain: A meta-analysis of randomized trials. Anesth Analg 2012; 114:42433.

14. Singla N, Singla S, Minkowitz HS, Moodie J, Brown C: Intranasal ketorolac for acute postoperative pain. Curr Med Res Opin 2010; 26:191523. 15. Coloma M, White PF, Huber PJ Jr, et al.: The effect of ketorolac on recovery after anorectal surgery: Intravenous versus local administration. Anesth Analg 2000; 90:110710. 16. Coloma M, Duffy LL, White PF, Kendall Tongier W, Huber PJ. Jr: Dexamethasone facilitates discharge after outpatient anorectal surgery. Anesth Analg 2001; 92:858. 17. Salerno A, Hermann R: Efficacy and safety of steroid use for postoperative pain relief. Update and review of the medical literature. J Bone Joint Surg Am 2006; 88:136172. 18. Lunn TH, Kristensen BB, Andersen LO, et al.: Effect of high-dosepreoperative methylpredisolone on pain and recovery after total knee arthroplasty: A randomized, placebo-controlled trial. Br J Anaesth 2011; 106:2308. 19. Woolf CJ: Pain: Moving from symptom control towards mechanismspecific pharmacologic management. Ann Intern Med 2004; 140: 44151. 20. Tiippana EM, Hamunen K, Kontinen VK, Kalso E: Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg 2007; 104:154556. 21. Ho KY, Gan TJ, Habib AS: Gabapentin and postoperative painA systematic review of randomized controlled trials. Pain 2006; 126: 91101. 22. Clarke H, Pereira S, Kennedy D, et al.: Gabapentin decreases morphine consumption and improves functional recovery following total knee arthroplasty. Pain Res Manage 2009; 14:21722. 23. Agarwal A, Gautam S, Gupta D, et al.: Evaluation of a single preoperative dose of pregabalin for attenuation of postoperative pain after laparoscopic cholecystectomy. Br J Anaesth 2008; 101: 7004. 24. Baldini G, Carli F: Anesthetic and adjunctive drugs for fast-track surgery. Curr Drug Targets 2009; 10:66786. 25. Buvanendran A, Kroin JS, Della Valle CJ, et al.: Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: A prospective, randomized, controlled trial. Anesth Analg 2010; 110:199207. 26. Buvanendran A, Kroin JS, Della Valle CJ, Moric M, Tuman KJ: Cerebrospinal fluid neurotransmitter changes during the perioperative period in patients undergoing total knee replacement: A randomized trial. Anesth Analg 2012; 114:43441. 27. Jokela R, Ahonen J, Tallgren M, Haanpa a M, Korttila K: Premedication with pregabalin 75 or 150 mg with ibuprofen to control pain after day-case gynaecological laparoscopic surgery. Br J Anaesth 2008; 100:83440. 28. Trabulsi EJ, Patel J, Vixcusi ER, Gomella LG, Lallas CD: Preemptive multimodal pain regimen reduces opioid analgesia for patients undergoing robotic-assisted laparoscopic radical prostatectomy. Urology 2010; 76:11224. 29. Sen H, Sizlan A, Yanarates O, et al.: A comparison of gabapentin and ketamine in acute and chronic pain after hysterectomy. Anesth Analg 2009; 109:164550. 30. Suzuki M: Role of N-methyl-D-aspartate receptor antagonists in postoperative pain management. Curr Opin Anaesthesiol 2009; 22:61822. 31. McCartney CJ, Sinha A, Katz J: A qualitative systematic review of the role of N-methyl-D-aspartate receptor antagonists in preventative analgesia. Anesth Analg 2004; 98:1385400. 32. Remerand F, Tendre CL, Baud A, et al.: The early and delayed analgesic effects of ketamine after total hip arthroplasty: A prospective, randomized, controlled, double-blind study. Anesth Analg 2009; 109:196371. 33. Loftus RW, Yeager MP, Clark JA, et al.: Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology 2010; 113:63946. 34. Duale C, Sibaud F, Guastella V, et al.: Perioperative ketamine does not prevent chronic pain after thoracotomy. Eur J Pain 2009; 13: 497505. 35. Tufanogullari B, White PF, Peixoto MP, et al.: Dexmedetomidine infusion during laparoscopic bariatric surgery: The effect on recovery outcome variables. Anesth Analg 2008; 106:17418. 36. Collard V, Mistraletti G, Taqi A, et al.: Intraoperative esmolol infusion in the absence of opioids spares postoperative fentanyl

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in patients undergoing ambulatory laparoscopic cholecystectomy. Anesth Analg 2007; 105:125562. 37. Ozturk T, Kaya H, Aran G, Aksun M, Savaci S: Postoperative beneficial effects of esmolol in treated hypertensive patients undergoing laparoscopic cholecystectomy. Br J Anaesth 2008; 100:2114. 38. Chia YY, Chan MH, Ko NH, Liu K: Role of beta-blockade in anaesthesia and postoperative pain management after hysterectomy. Br J Anaesth 2004; 93:799805. 39. Hollmann MW, Durieux ME: Local anesthetics and the inflammatory response: A new therapeutic indication? Anesthesiology 2000; 93:85875.

40. Herroeder S, Pecher S, Schonherr ME, et al.: Systemic lidocaine shortens length of hospital stay after colorectal surgery: A doubleblinded, randomized, placebo-controlled trial. Ann Surg 2007; 246:192200. 41. McCarthy GC, Megalla SA, Habib AS: Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: A systematic review of randomized controlled trials. Drugs 2010; 70:114963. 42. Fredrickson MJ, Krishnan S, Chen CY: Postoperative analgesia for shoulder surgery: A critical appraisal and review of current techniques. Anesthesia 2010; 65:60824.