pub110.pdf

Review Article

Clinical/Research Fellow in Anesthesia

†Professor of Anesthesia, Department of An-esthesia, University of Toronto

Address correspondence and reprint re-quests to Dr. Chung at the Department ofAnesthesia, Toronto Western Hospital, 399Bathurst St., EC 2–046, Toronto, Ontario,Canada M5T 2S8. [Email: [email protected]].

This paper is partially sponsored by Pharma-cia Corporation, Skokie, IL.

Received for publication March 22, 2001;revised manuscript accepted for publicationJuly 23, 2001.

Multimodal Analgesia forPostoperative Pain Control

Fengling Jin, MD,* Frances Chung, FRCPC†Department of Anesthesia, Toronto Western Hospital, University Health Network,University of Toronto, Toronto, Ontario, Canada

Pain is one of the main postoperative adverse outcomes. Single analgesics, either opioid ornonsteroidal antiinflammatory drugs (NSAIDs), are not able to provide effective pain reliefwithout side effects such as nausea, vomiting, sedation, or bleeding. A majority of doubleor single-blind studies investigating the use of NSAIDs and opioid analgesics with orwithout local anesthetic infiltration showed that patients experience lower pain scores, needfewer analgesics, and have a prolonged time to requiring analgesics after surgery. Thisreview focuses on multimodal analgesia, which is currently recommended for effectivepostoperative pain control. © 2001 by Elsevier Science Inc.

Keywords: Analgesia: multimodal; anesthesia: regional block, complications;nonsteroidal antiinflammatory drugs.

Introduction

Postoperative pain is one of the main postoperative adverse outcomes causingdistress to patients,1 prolonging stays in ambulatory care units,2 and increasingthe incidence of unanticipated admissions after surgery.3 Single analgesicsalone, either opioid or nonsteroidal antiinflammatory drugs (NSAIDs), are notable to provide effective pain relief for most moderate or severe pain, andmoreover, they are associated with side effects such as nausea, vomiting,sedation, or bleeding,.2,4,5

Multimodal analgesia is currently recommended for effective postoperativepain control.6,7 Multimodal analgesia is achieved by combining different anal-gesics that act by different mechanisms (e.g., opioids, NSAIDs, and localanesthetics), resulting in additive or synergistic analgesia, lower total doses ofanalgesics, and fewer side effects.8 The use of multimodal analgesia decreasespain scores and/or the requirement for postoperative analgesics in differentsurgical procedures.7–18 This review focuses on the effect of multimodal analge-sia on postoperative pain management and the recovery profile of adult surgicalpatients undergoing ambulatory or major surgical procedures.

Multimodal Analgesia

It has been suggested that multimodal analgesia is a rational approach to painmanagement and is more effective (Table 1).4,19 The aim of multimodalanalgesia combinations is to reduce postoperative pain. Theoretically, multimo-dal analgesia is achieved by a combination of opioids, and regional blocks whichattenuate the pain-related signals in the central nervous system (CNS), andNSAIDs, which act mainly in the periphery to inhibit the initiation of pain

Journal of Clinical Anesthesia 13:524–539, 2001© 2001 Elsevier Science Inc. All rights reserved. 0952-8180/01/$–see front matter655 Avenue of the Americas, New York, NY 10010 PII S0952-8180(00)00320-8

signals. Animal studies also demonstrate the synergisticeffect between NSAIDs and opioids, and certain otheranalgesics in clinical pain states.20 Many studies haveshown additive and/or synergistic effects, with reductionsin pain scores or postoperative analgesic requirements inhumans and animals7–12,14–18,21–27. Therefore, multimodalanalgesia should be given to control postoperative pain.

Opioids

Opioids are the most effective analgesics, especially formoderate-to-severe postoperative pain.28 Their effects aremediated by opioid receptors in the CNS that attenuatepain-related signals. Peripheral opioid receptors also canprovide analgesic effects in humans.29 The potency ofindividual opioids correlates with their affinity for theirrespective receptors.30 However, the side effect profile ofopioids, which includes nausea/vomiting, sedation, ileus,constipation, and respiratory depression, should be con-sidered when using large doses of these drugs.2,5,31

NSAIDs

Nonsteroidal antiinflammatory drugs (NSAIDs) haveproved to be valuable in the management of postoperativepain because of their opioid-sparing actions32 and antiin-flammatory effects. NSAIDs achieve their hyperalgesia-suppressing effect by reducing the concentration of pros-taglandins peripherally and centrally, and through severalother peripheral and central mechanisms.33–35 Cyclic pros-taglandins are produced by the cyclooxygenase-catalyzedoxidation of arachidonic acid.

The Cyclooxygenase Pathway

The cyclooxygenase (COX) pathway represents one of themajor routes for oxidative metabolism of arachidonic acid.

NSAIDs inhibit cyclooxygenases, a group that comprisestwo enzymes: COX-1 and COX-2. The two COX enzymesare very similar in structure, but they have a crucialdifference in amino acid sequence at their active site.36,37

Most COX-1 is constitutively expressed and involved inhomeostasis, whereas COX-2 is inducible and involved inpathways of pain and inflammation.35,38,39 Prostaglandinsproduced through metabolism of arachidonic acid byCOX-1 are essential for maintaining the integrity of thegastric mucosa, and allowing normal platelet aggregation,and kidney function.38

COX-2-Specific Inhibitors

Inhibition of COX-1 by NSAIDs results in the reduction ofmucosal prostaglandin cytoprotective functions, in somecases leading to gastric erosions and ulcers.35,40–43 Incontrast, inhibition of COX-2 produces analgesia withfewer adverse effects, particularly gastric erosions, ulcer-ations, and bleeding (lack of effect on platelet aggregationtimes).41,42,44–47 However, some studies have shown thatCOX-2 inhibition may delay gastric ulcer healing.48–50

For acute pain relief, studies with the first two COX-2specific inhibitors to be developed (celecoxib and rofe-coxib) have shown that these two drugs have similaranalgesic effects compared with ibuprofen or aspirin inpostdental surgery patients.51–53 In more long-term stud-ies, celecoxib has demonstrated sustained antiinflamma-tory and analgesic activity similar to both diclofenac54 andnaproxen55 in rheumatoid arthritis patients, with a lowerincidence of gastrointestinal (GI) ulceration and GI ad-verse events in both studies.

Celecoxib is available only in an oral formulation. Aparenteral form of a new COX-2 specific inhibitor iscurrently under development. Parecoxib has already dem-onstrated excellent analgesic and antiinflammatory activi-ties in patients with postoperative dental pain.*,†,56,57 Ithas also been shown to be effective as an analgesicpostgeneral gynecologic surgery in a 24-hour study withketorolac and morphine sulphate as comparators.‡ In a7-day study of parecoxib and ketorolac in elderly patients,parecoxib was associated with similar GI effects to placebo,with significantly fewer gastric and duodenal erosions andulcers than ketorolac.58

Finally, a 10-day study of the effects of celecoxib and

*Kuss M, Mehlisch D, Bauman A, Baum D, Hubbard R: Analgesicactivity of single IV doses of parecoxib, a COX-2-specific inhibitor,and Toradol in postoperative dental pain [Abstract]. 9th WorldCongress on Pain, Vienna, Austria, August 2000. Abstract number249.†Mehlisch D, Kuss M, Bauman A, Baum D, Hubbard R: Onset andduration of analgesia of intramuscular doses of parecoxib, a newparenteral COX-2 inhibitor, in postoperative dental pain [Abstract].9th World Congress on Pain, Vienna, Austria, August 2000. Abstractnumber 250.‡Langand F, Turpin M, Waller P, Kuss M, Hubbard R, LeComte D: Acomparative analgesic efficacy study of parecoxib, a new COX-2specific inhibitor, on post-gynecologic surgery patients [Abstract].19th Annual Scientific Meeting of American Pain Society, Atlanta,GA, November 2000. Abstract number 814.

Table 1. Recommended Approach to Analgesia in PatientsUndergoing Surgical Procedures

Minor surgeryWound infiltration with local anestheticPeripheral nerve blockade with local anestheticOral or parenteral NSAIDsOral opioid with or without acetaminophen forBreakthrough pain

Intermediate surgeryWound infiltration with local anestheticPeripheral nerve blockade with local anestheticIntravenous PCA opioidOral or parental NSAIDsSingle-injection intrathecal or epidural opioid

Major surgeryWound infiltration with local anestheticPeripheral nerve blockade with local anestheticEpidural local anesthetic and opioidOral or injectable NSAIDsSystemic opioid (intravenous, intermittent, or PCA)

NSAIDs � nonsteroidal antiinflammatory drugs; PCA � patient-controlled analgesia. From Reference4. Reproduced with permission.

Postoperative pain management: Jin and Chung

525J. Clin. Anesth., vol. 13, November 2001

naproxen on platelet function demonstrates clearly thatcelecoxib does not interfere with normal mechanisms ofplatelet aggregation and hemostasis, and had no effect onbleeding times.59 This finding is of particular importanceto patients undergoing surgery; an effective analgesic notassociated with increased risk of hemorrhage is a usefultool for the surgeon.

For patients at high risk for gastropathy (such as theelderly60), COX-2 specific inhibitors provide useful alter-natives to existing analgesic therapies. However, the safetyprofile of COX-2 specific inhibitors in postoperative pa-tients requires further study.61–63

The timing of NSAID administration has been exam-ined extensively in studies investigating the concept ofpreemptive analgesia. This concept suggests that the useof analgesics before surgery will attenuate the centralneural effects of the “injury barrage” induced by c-fiberprimary afferents as a result of surgical incision andsubsequent noxious intraoperative events.64,65 This mini-mization of central sensitization is hypothesized to yieldreduced postoperative pain intensity and/or reduced post-operative analgesic consumption. Preemptive analgesiahas been effective in animals or human volunteers; how-ever, clinical evidence has been either controversial or hasfailed to support the notion following surgery.33,66–70

Regional Block or Wound Infiltration

Regional block, or wound infiltration, can provide bothintraoperative and postoperative pain analgesia. Infiltra-tion of local anesthetics into the wound inhibits thetransmission of nervous signals from damaged tissue andreduces neurogenic inflammation by blockade of the axonreflex and sympathetic efferent.71 Preoperative nerveblock or wound infiltration with local anesthetics candecrease the inflammatory reaction, reduce pain intensity,and decrease the usage of analgesics intraoperatively andpostoperatively in human studies.70,72,73 Neuraxial block-ade reduces postoperative mortality and decreases theodds of deep vein thrombosis by 44%, pulmonary embo-lism by 55%, transfusion requirements by 50%, pneumo-nia by 39%, and respiratory depression by 59%.74

Neuraxial blockade is highly recommended as part of thepain armamentarium and should be used whenever pos-sible.

Multimodal Analgesia: Outcomes in AmbulatorySurgical Patients

Multimodal analgesia is highly recommended in ambula-tory anesthesia. Table 2 and Table 3 summarize the ran-domized, controlled trials of multimodal analgesia inambulatory anesthesia.

Systemic Opioids and/or NSAIDs With or Without LocalAnesthetic Infiltration or Intraarticular (IA) Block

Systemic opioids and/or NSAIDs combined with localanesthetic infiltration or IA block were also a means of

effective pain relief after ambulatory surgical procedures.Table 2 summarizes the available data from double-blindor single-blind studies investigating the systemic use ofcombinations of NSAIDs and opioid analgesics with orwithout local anesthetic infiltration or IA block. Thisapproach was particularly useful for controlling moderateor even severe pain in patients who underwent ambulatorygynecologic procedures, breast lump excision, and lapa-roscopic cholecystectomy. Eleven of 14 studies demon-strated a decrease in pain score and/or postoperativeanalgesic requirements6,7,10,12,16,18,72,75–78. In most of thestudies, local anesthetic infiltration together with systemicopioids or NSAIDs resulted in a significant improvementin analgesia compared with either drug alone. Combina-tions of systemic opioids and/or NSAIDs with local anes-thetic infiltration or IA block improved recovery by lower-ing the incidence of postoperative nausea and vomiting(PONV), shortening the discharge time from the postan-esthesia care unit (PACU ) and day surgery unit (DSU),and allowed patients to be cared for more easily.6,7,72,75,77

Therefore, systemic opioids and NSAIDs plus local orregional anesthesia should be considered when patientsexperience severe postoperative pain.

Not all studies investigating multimodal analgesia dem-onstrated an improvement in analgesia or recovery pro-file. The patients in one study who did not show thebenefit of combined IP bupivacaine and a preoperativesingle dose of diclofenac in postoperative pain controlafter laparoscopic cholecystectomy, had a very low painscore (2 or lower), and were given large doses of cycli-morph and co-proxamol postoperatively.79 Systemic intra-venous (IV) fentanyl and ketorolac significantly loweredthe requirement for intraoperative fentanyl,80 but did nothave a better effect on postoperative pain managementcompared with either drug alone. Tylenol #3®, whichcontains hydrocodone and acetaminophen, was only moreeffective than placebo but not better than ketorolac. Inaddition, this effect was seen only in patients undergoingknee arthroscopy rather than laparoscopic tubal liga-tion.78 The reason might be that placebo was used in thefirst instance, and then ketorolac was continued in thisstudy.78 Moreover, hydrocodone and acetaminophen wereassociated with a higher incidence of dizziness.78 Otherstudies did not show any enhancement in recovery pro-file.12,18,80

Although three of 14 studies did not show the benefit ofmultimodal analgesia in outpatients, most studies provedthat local or regional blocks plus systemic opioids andNSAIDs provided effective pain control with improvedrecovery profile. Therefore, multimodal treatment withlocal or regional block plus systemic opioids and NSAIDsis highly recommended.

Combined Use of Local Anesthetics and Analgesics inKnee Arthroscopy, Inguinal Hernia, or Hand Surgeries

The efficacy of combinations of local anesthetics, opioids,and NSAIDs in wound infiltration; intraarticular, IV re-gional anesthesia; and axillary blocks for postoperative

Original Contributions

526 J. Clin. Anesth., vol. 13, November 2001

pain in knee arthroscopy, inguinal hernia, or hand sur-geries has been extensively investigated in randomized,

controlled trials (Table 3). Twenty of 23 studies demon-strated that combinations of local anesthetics and opioids

Table 2. Combined Systemic Opioids and/or NSAIDs, and/or Local Anesthetic Infiltration in Ambulatory Surgery

StudySample

Size Type of Surgery Treatment Control

Postop-erativePainScore

Postop-erative

AnalgesicsRecoveryProfile

Smith et al.(1992)18

60 Knee arthroscopy IV and IM intraopketorolac � IAbupivacaine

Ketorolac orbupivacaine

2/2 2/2 z

Morrow et al.(1995)76

60 Knee arthroscopy IA bupivacaine � IMintraop piroxicam

IA saline � IMpiroxicam afterinduction

2 2

White et al.(1997)78

65 Knee arthroscopy PO hydrocodone-acetaminophen

PO ketorolac orplacebo firstdose then POketorolac

7/2 Dizziness 1intreatmentgroup

Chan et al.(1996)10

100 Breast lumpexcision

Preop and postopdiclofenac �bupivacaine infiltrationon closure

Diclofenac orbupivacaine orsaline

2/2/22

7

Nehra et al.(1995)16

200 Inguinal hernia Ilioinguinal block �papaveretum-aspirin

Block orpapaveretum-aspirin orsaline

7/2/22

7/2/22

Ben-David et al.(1995)75

70 Inguinal hernia Preop local anestheticinfiltration � IMketorolac

Preop localanesthetic �ketorolacwoundinfiltration orlocal anestheticinfiltration �IV ketorolac orPO ketorolacor saline

2/2/2/22

2/2/2/22

1 easy tocare for inparentalketorolacgroups

Ding et al.(1993)80

109 Gynecologicsurgery

IV fentanyl � ketorolac Fentanyl or IVketorolac

7/7 7/7 7

Fiddes et al.(1996)12

59 Laparoscopictubal ligation

Lidocaine subserosalinjection at the cornualend of the fallopiantubes � rectaldiclofenac

Saline � rectaldiclofenac

2 2 7

Eriksson et al.(1996)7


Lidocaine gel on clips �preop and postopketoprofen

Lidocaine gel orsaline

2/22

2/22 PONV 2homereadiness1

Van Ee et al.(1996)77


PO preop ketoprofen �bupivacaine infiltrationof mesosalpinx

PO ketoprofenor bupivacaineinfiltration

2/2 2/2 Dischargetime 2

White et al.(1997)78


PO hydrocodone-acetaminophen

PO ketorolac orsaline first dosethen POketorolac

7/7 Dizziness 1intreatmentgroup

Michaloliakouet al. 6 (1996)

49 Laparoscopiccholecystectomy

Preop meperidine �ketorolac � preincisionbupivacaine �bupivacaine atgallbladder site

Saline 2 2 Nausea 2anddischargetime fromPACU andDSU 2 intreatmentgroup

Johnson et al.(1999)79


Rectal preop diclofenac� bupivacaine atgallbladder site

Saline �bupivacaine atgallbladder site

7 7

Bisgaard et al.(1999)72


IV intraop ketorolac �postop rectalparacetamol �preincision bupivacaine� bupivacaine atgallbladder site

IV intraopketorolac �postop rectalparacetamol �saline

2 2 Nausea 2

Data indecipherable, IV � intravenous, IM � intramuscular, intraop � intraoperative, IA � intraarticular, preop � preoperative, postop � postoperative,PONV � postoperative nausea and vomiting, PACU � postanesthesia care unit, DSU � day surgery unit,7: Remains the same,2: Decrease,1: Increase.



or NSAIDs in these settings decreased pain scores and/orpostoperative analgesic requirements13,17,73,81–97 com-pared with placebo therapy. In addition, some studies

demonstrated a better analgesic effect with combinationtherapy than with a single analgesic17,81,85–88-90,92,,93. How-ever, other studies failed to show the advantages of com-

Table 3. Combined Local Anesthetics, and Analgesics in Infiltration or Intraarticular (IA), Intravenous (IV), and Axillary Blocks inAmbulatory Surgery

StudySample



Postop-erative


Khoury et al.(1992)86

33 Kneearthroscopy

IA bupivacaine �morphine

IA bupivacaine orIA morphine

2/2 2/2

McSwiney et al.(1993)87

40 Kneearthroscopy


Saline or IAbupivacaine orIA morphine

22/22

2/7/7

Allen et al.(1993)85

120 Kneearthroscopy


IA morphine or IAbupivacaine

2/7 2/7 7

Joshi et al.(1993)88

40 Kneearthroscopy


IA morphine or IAbupivacaine �IA saline

7/2/2 7/2/2

Heine et al.(1994)90

31 Kneearthroscopy


IA bupivacaine 2 2 7

Boden et al.(1994)89

38 Kneearthroscopy


IA bupivacaine orIA morphine orSaline

7/7/2 7/7/2

7

Haynes et al.(1994)13

40 Kneearthroscopy


IA bupivacaine orIA morphine orsaline

7/7/2 7/1/7

mobilizationwas slower insaline group

Laurent et al.(1994)99

58 Kneearthroscopy


IA bupivacaine 7 7

Reuben et al.(1995)17

80 Kneearthroscopy

IA ketorolac �IA bupivacaine

ketorolac or IAbupivacaine

2/2 2/2

Gupta et al.(1999)81

100 Kneearthroscopy

Ketorolac � IAmorphine

IA saline or IAmorphine or IAketorolac

2/2/2 7/7/7


50 Kneearthroscopy

IA bupivacaine �IA clonidine

IA bupivacaine orIA clonidine

7/7 2/7


100 Reconstructionof ACL


IA bupivacaine �IV morphine orIA bupivacaineor IA morphine

7/7/2 7/7/2

Rasmussen et al.(1998)73

60 Meniscectomy IA bupivacaine �morphine �methylpredni-solone

IA bupivacaine �IA morphine orsaline

2/22 2/22 convalescence1

Ben-David et al.(1996)83

32 Inguinal hernia Ketorolac �bupivacaineinfiltration

Bupivacaineinfiltration orketorolacinfiltration orsalineinfiltration �IM ketorolac

7/7/2 7/7/2

Tverskoy et al.(1996)98

18 Inguinal hernia Bupivacaine �ketamineinfiltration

Bupivacaineinfiltration

7 7

Connelly et al.(1997)95

30 Inguinal hernia Local lidocaine� ketorolacinfiltration

Local lidocaineinfiltration � IVketorolac

2 inmovement

2 7

Tverskoy et al.(1998)82

20 Inguinal hernia Lidocaine �fentanylinfiltration

Lidocaineinfiltration �IM fentanyl

2 7

(continued on next page)



bination therapy over single analgesics,98,99 and severalstudies showed that different ways of using combinationtherapy led to different results in postoperative painmanagement.82,83,95 Not only was the combination of localanesthetics and opioids studied, but the combination ofother medications such as clonidine or ketamine and localanesthetics was also investigated. The results showed thatcombining local anesthetic and clonidine significantlyprolonged both the time until patients required analgesicsand also the amount of analgesic medication re-quired.92,100 In one study, incisional injection of bupiva-caine and ketamine did not show a decrease in visualanalog (VAS) pain score or the need for rescue painmedication, but the duration of local anesthetic effect wassignificantly prolonged, by more than 100 minutes.98

Although the advantages in pain management wereobvious, only one study reported that the time to mobili-zation was slower in the control group.13 Convalescence inarthroscopic meniscectomy surgical patients was en-hanced with the combined use of bupivacaine, morphine,and methylprednisolone, which played an important role

in antiinflammatory treatment.73 Most studies in kneearthroscopy, inguinal hernia, or hand surgeries did notshow that combining local anesthetics and analgesicsreduces the incidence of side effects or shortens thelength of hospital stay. One study even showed that largerdose of meperidine (�30 mg) with lidocaine used inaxillary brachial plexus worsened the side effects of seda-tion, dizziness, and PONV.93

In general, multimodal analgesia can improve postop-erative pain management. Patients experience lower painscores, and/or need fewer analgesics, and/or have aprolonged time to requiring analgesics after surgery if theyare given multimodal analgesia. Theoretically, the recov-ery profile in terms of discharge time from hospital andmobilization should be improved. However, only a fewstudies demonstrated this advantage for multimodal anal-gesia6,7,13,72,73,75,77. Some studies did not show any benefiton recovery profile12,18,41,80,85,89,90,94–96. In addition, somestudies did not even observe the recovery da-ta10,16,17,76,79,81–84,86–88,91,97–100. Therefore, further studiesof multimodal analgesia should not only investigate the

Table 3. (Continued)

StudySample



Postop-erative


Reubenet al.(1996)96

60 Carpal tunnel ortenolysissurgery

Lidocaine �ketorolac (60mg) IVRA �lidocainewoundinfiltration

Lidocaine IVRA �lidocaine �ketorolac woundinfiltration orLidocaine IVRA� lidocainewoundinfiltration

7/2 7/2 7

Steinberget al.(1998)94

70 Hand Lidocaine �ketorolac (�20mg) IVRA

Lidocaine �ketorolac(�10mg) IVRAor saline �lidocaine IVRA

2/2/2 2/2/2

7


45 Carpal tunnelor tenolysissurgery

Lidocaine �clonidine IVRA

Lidocaine IVRA orLidocaine IVRA� clonidine IV

2/2 2/2


60 Carpal tunnelor tenolysissurgery

Lidocaine �meperidine(�30 mg)IVRA

Lidocaine �meperidine(�20 mg) orLidocaine �saline

2/2 2/2 Sedation 1Dizziness 1postoperativenausea andvomiting 1

Bourkeet al.(1993)97

40 Hand Lidocaine �morphineaxillarybrachial plexusblock

Lidocaine axillarybrachial plexusblock � IVmorphine

7 2 7

Singelynet al.(1996)100

80 Hand Mepivacaine �clonidineaxillarybrachial plexusblock

Mepivacaineaxillary brachialplexus block

7 7 7

ACL � anterior cruciate ligament, IM � intramuscular, IVRA � intravenous regional anesthesia. 7 � remains the same, 2 � decrease, 1 �increase.



effectiveness in pain management, but also observe therecovery profile, which is another important aspect ofambulatory anesthesia.

In summary, multimodal analgesia could be used forrelieving postoperative pain in ambulatory surgical pa-tients. For patients undergoing laparoscopic gynecologicprocedures or laparoscopic chelecystectomy, shoulder,breast lump resection, reconstruction of anterior cruciateligament surgical procedures, local or regional use ofanesthetic plus systemic NSAIDs and systemic opioidswould be the choice. For knee arthroscopy, inguinalherniorrhaphy, and hand surgeries, local or regional useof anesthetics and opioids plus NSAIDs would provideeffective pain control. Opioids could be used for break-through pain. Table 4 shows ways to approach multimodalpain therapy.

Multimodal Analgesia: Outcomes in Inpatients

Systemic Use of Combinations of NSAIDs and OpioidAnalgesics

Combined use of systemic opioids and NSAIDs relievedpostoperative pain more effectively than single-drug regi-mens9,68,101–123 (Table 5). In addition, some studies demon-strated a benefit in recovery profile of shortened duration ofischemic attack, and decreased incidence of PONV, sedation,and respiratory depression68,101,102,104,109,110,112,114,115. Fur-thermore, the side effects of NSAIDs, such as gastritis, pepticulceration, and depression of renal function, were not signif-icantly higher compared with patients who did not useperioperative NSAIDs.68,102–123 Only one study reported thatthe incidence of hemorrhage was increased with the use ofindomethacin.113 However, cautious use of NSAIDs is sug-gested in patients with a history of upper GI bleeding, renaland liver impairment, hypovolemia, and older age.8,114

One study showed that �-cyclodextrin piroxicam ad-ministered po plus continuous tramadol–propofol infu-sion significantly lowered the requirement for intraopera-tive propofol, although there was not a decrease in painscore and the requirement of analgesics.124 Combined useof acetaminophen and oxycodone or hydrocodone andibuprofen was reported to increase somnolence and post-operative nausea and vomiting.123 Ileus was reported intwo patients undergoing cesarean section or lower abdom-inal surgery who took acetaminophen/oxycodone. Thisdrug combination provided better analgesia than didibuprofen alone or placebo, but less analgesia than brom-fenac sodium alone.105 In general, combinations of sys-temic opioids and NSAIDs for major surgical procedurehave been showed to be more rational and effective.

Epidural Combinations of Local Anesthetics and Opioids

Epidural anesthesia not only provides intraoperative anal-gesia, but can also control postoperative pain in majorsurgical procedures.125 Morphine enhances pain reliefand the spread of sensory analgesia during continuousepidural bupivacaine infusion.126,127 The analgesic effi-cacy of epidural combinations of local anesthetics andopioids has been investigated in randomized, controlledstudies (Table 6). Almost all studies showed that combina-tion therapy provided better analgesic efficacy than didbupivacaine alone.126,128–140 Epidural combinations offentanyl and morphine also improved pain managementin postgastrectomy patients. In addition, combining localanesthetic with clonidine or ketamine showed an en-hanced effect on pain relief, although more studies arerequired to prove their efficacy and safety.129,136

Adverse effects of combination therapy reportedranged from limb weakness, increased vomiting, slowerrecovery of bowel movement, and respiratory depressionand hypotension128,131,132,136,138,141,142. However, somestudies demonstrated that combination therapy hastenedrecovery in respiration, and decreased the incidence ofhypotension and emetic episodes.130 Therefore, morestudies are required to investigate the issue of postopera-tive recovery and adverse effects of combination therapy.

Combined Use of Wound Infiltration, or Regional Block,or Neuroaxial Block with Systemic NSAIDs, and/orOpioid Analgesics

Wound infiltration provides both intraoperative and post-operative analgesia (Table 7). First of all, combined use ofincisional local anesthetic infiltration and NSAIDs, and/oropioid analgesics decreased the pain score or the require-ment of analgesics,143–152 compared with morphine orketorolac alone. Secondly, incisional bupivacaine can en-hance the analgesic effect of epidural bupivacaine andmorphine in upper abdominal surgical patients.145

Thirdly, epidural use of local anesthetics and opioids hadbetter analgesic effect with decreased vomiting and seda-tion.143,146 Finally, epidural or spinal local anestheticsand/or morphine combined with opioids or NSAIDs also

Table 4. Approach to Multimodal Pain Therapy in AmbulatoryAnesthesia

Is the patient already in pain?If so, preoperative analgesia, such as NSAIDs should be started

in the preoperative period.Can I perform a peripheral or regional block?Nerve block, neuraxial blocks.What agents can I give at the beginning of, and during, the

operation?Short-acting opioid, NSAIDs (rectal diclofenac, IV ketoralac,

or tenoxicam), acetaminophen at the induction by rectalsuppository, or IV propacetamol.

What can be given at termination of surgery?Wound infitration with bupivacaine or ropivicaine, IA local

anesthetics and/or opioid, epidural analgesia with localanesthetic, opioids, or ketamine.

What can be given for pain in the PACU?Short-acting opioid, NSAIDs, acetaminophen.What can I give postoperatively?Acetaminophen, NSAIDs, codeine, oxycodone.

NSAIDs � nonsteroidal antiinflammatory drugs, IV � intravenous,IA � intraarticular, PACU � postanesthetic care unit. From refer-ence19. Reproduced with permission.



Table 5. Systemic Use of Combinations of Nonsteroidal Antiinflammatory Drugs (NSAIDs) and Opioid Analgesics for PostoperativeAnalgesia in Inpatients After Major Surgical Procedures

StudySample


Postoper-ativePainScore

Postoper-ative


Segstro et al.(1991)116

50 Orthopedic Postop rectalindomethacin �PCA/IV morphine

Placebo � PCA/IV, morphine

2 2 7

Kinsella et al.(1992)106

75 Orthopedic Postop IM ketorolac� IM morphine

Placebo � IMmorphine

2 2 7

Park et al.(1996)109

44 Orthopedic Preop and postopclonidine PO �PCA/IV morphine

PO placebo �PCA/IVmorphine

7 2 Sedation 1 andPONV 2 intreatmentgroup

Beattieet al.(1997)102

174 Orthopedic Postop IV ketorolac� PCA/IVmorphine

IV saline � PCA/IV morphine

2 2 Duration ofcardiacischemia 2

Fletcher et al.(1997)68

64 Orthopedic propacetamol � IVketoprofen �PCA/IV morphine

Saline orpropacetamol orketoprofen �PCA/IVmorphine

2/2/2 2/2/2 1 respiratorydepressionepisode insaline group


80 Orthopedic IV ketorolac �PCA/IV morphine

PCA/IV saline �morphine

2 2 Sedation 1 insaline group


70 Orthopedic IV ketorolac (�7.5mg) � PCA/IVmorphine

Saline or IVketorolac (�5mg) � PCA/IVmorphine

2/2 2/2 Sedation 1 insaline group

Reasbeck et al.(1982)113

90 Majorabdominal

Postop rectalindomethacin �IM morphine

Placebo � IMmorphine

2 2 Hemorrhage 1in treatmentgroup

Hodsman et al.(1987)104

65 Abdominal Postop IMdiclofenac �PCA/IV morphine


2 2 pCO2 1 incontrol group

Sevarino et al.(1992)117

35 Lowerabdominal

Postop IM ketorolac� PCA/IVmorphine


7 2

Gillies et al.(1987)101

61 Upperabdominal



2 2 pCO2 1 insaline group

Burns et al.(1991)103

67 Upperabdominal



2 2 7

Sevarino et al.(1994)118

62 Lowerabdominal



2 7

Watanabe et al.(1994)122

80 Cholecystectomy Buprenorphine �rectalindomethacin

Rectalbuprenorphineor rectalindomethacin orplacebo

7/2/2 7/2/2 7

Turner et al.(1994)121

50 Cholecystectomy Intraop and postoprectalindomethacin �PCA/IV pethidine

Saline 2 2 7

Parker et al.(1994)110

210 Lowerabdominal

Postop IV ketorolac� IV morphine/meperidine

IV saline �morphine/IVmeperidine

2 2 Antiemetic drugs,sedation anddiscomfort1in saline group

(continued on next page)



provided better analgesia for major surgical proceduresthan these techniques alone.143–145,148

Regarding the improvement of recovery profile, how-ever, only one study demonstrated that preincisional para-vertebral block lowered the pain score and analgesicrequirement with improved postoperative pulmonaryfunctions for thoracic surgical patients.150 Another studyof thoracic surgical patients, in which intercostal block wascombined with IV morphine and postoperative intramus-cular ketorolac, did not show a significant advantage ofmultimodal analgesia.153 The requirement for analgesiawas decreased only in the first 6 hours postsurgery, butcumulative consumption of analgesics was no different

from the placebo group at 72 hours.147 In addition,ketamine IV supplement to epidural bupivacaine for renalsurgical patients resulted in a higher incidence of sedationwith no benefit for postoperative analgesia.154 Althoughintraarticular bupivacaine and morphine had a superioranalgesic effect in postoperative arthroscopic proceduresthan did single drug alone, this effect was not demon-strated in knee replacement procedures.155 The reasonmight be that the dose of morphine used in this study (1mg) was sufficient for arthroscopy, but not large enoughfor knee replacement, and the wound drain might haveresulted in loss of drug.155

In general, multimodal analgesia with combined local

Table 5. (Continued)

StudySample


Postope-rativePainScore

Postop-erative

Analgesics Recovery Profile

Blackburn et al.(1995)9

60 Lowerabdominal

Postop IV ketorolacinfusion � PCA/IV morphine

Saline 2 2 7

Plummer et al.(1996)111

108 Lowerabdominal

Preop and postopPO ibuprofen �PCA/IV morphine

Placebo 2 7 7

Johnson et al.(1997)105

238 Cesarean sectionand lowerabdominal

Acetaminophen �PO oxycodone

Bromfenac sodiumor ibuprofen orplacebo

1/2/2 2/1/1in timeforremedica-tion

2 ileus inAcetaminophen� oxycodonegroup

Sunshine et al.(1997)120


Hydrocodone � POibuprofen

Ibuprofen orplacebo

2/22 1/11in timeforremedi-caton

Somnolence1 incombinationgroup

Lauretti et al.(1997)124

48 Minorabdominal

Preop PO beta-cyclodextrinpiroxicam �continuoustramadol-propofolinfusion

Saline � propofolinfusion

7 Time forrescueanalgesic1

7

Sia et al.(1997)119

60 Cesarean section Preop rectaldiclofenac � IVmorphine infusion

Saline � IVmorphineinfusion

2 2 7

Wideman et al.(1999)123


Hydrocodone �PO ibuprofen

Hydrocodone oribuprofen orplacebo

2/2/22

1/1/11 intime forremedica-tion

PONV 1 inhydrocodone �ibuprofengroup

Olofsson et al.(2000)108

50 Cesarean section Postop rectaldiclofenac � PCAketobemidone

PCA saline �ketobemidone

2 2 7

Liu et al.(1993)107


Preop � postop IMketorolac � IVfentanyl

IV saline �fentanyl

2 2 7

Ready et al.(1994)112

207 Major surgery Postop IV ketorolac� PCA/IVmorphine

Saline � PCA/IVmorphine

2 2 Vomiting andfever 1 insaline group

Postop � postoperative, PCA � Patient-controlled analgesia, IV � intravenous, IM � intramuscular, preop � preoperative, PO � per PONV �postoperative nausea and vomiting, pCO2 � partial pressure of carbon dioxide, Intraop � intraoperative.7 � remains the same,2 � decrease,1 � Increase.



Table 6. Epidural Combinations of Local Anesthetics and Opioids for Postoperative Analgesia After Major Surgical Procedures

StudySample

size Type of surgery Treatment ControlAnalgesicefficacy Duration Complication

Cullen et al.(1985)130

81 Majorabdominal

Bupivacaine �morphine

Nonepiduralor salineorbupivacaine

1/1/1 72 Recovery of respiration wasquicker in treatmentgroup

Hjortso et al.(1986)126

20 Majorabdominal


Bupivacaine 1 16 7 patients withdrew fromcontrol group due to thewide segment sensoryblock

Logas et al.(1987)134

53 Thoracic Bupivacaine �morphine

Morphineorbupivacaineor salineor IMmorphine

7/1/1/11

72 One respiratory depressionepisode in B group

Lee et al.(1988)133

60 Lowerabdominal

Bupivacaine �diamorphine

Bupivacaineordiamorphine

1/1 21 One motor block in Bgroup

Scott et al.(1989)140

20 Upperabdominal


Bupivacaine 1 16 7

George et al.(1991)132

25 Thoracic Bupivacaine �fentanyl

Fentanyl 1 in first24 hours

48 One limb weaknessepisode in B�F group

Asantila et al.(1991)128

60 Lowerabdominal


Morphineorbupivacaine

7/1 24 Vomiting 1 and recoveryin bowel movementslower in treatment andmorphine groups

Badner et al.(1991)142

30 Orthopedic Bupivacaine �fentanyl

Fentanyl 7 48 One respiratory depressionepisode andhypotension, one slightmotor weakness episodein B�F group


30 Majorabdominal

Bupivacaine �fentanyl

Fentanyl orbupivacaine

1/1 24 One limb weakness in Bgroup and another onein study group


30 Majorabdominaland thoracic


Fentanyl 7 48 Two motor weaknessepisodes in B�F group

Mourisse et al.(1992)135

50 Thoracic Bupivacaine �sulfentanil

Bupivacaineorsulfentanil

1/1 72 One orthostatichypotension episode inB and One orthostatichypotension episode inS group

Dahl et al.(1992)139

24 Majorabdominal


Morphine 1 inmobilizationandcough

48 7


39 Abdominal andthoracic


Fentanyl 1 48 4 leg weakness episodes inB�F group

Tanaka et al.(1997)137

120 Major upperabdominal

Fentanyl �morphine

Morphine 1 24 7

Paech et al.(1997)136

92 Lowerabdominal

Bupivacaine �fentanyl �clonidine

Bupivacaine�fentanyl

1 24 BP 2, emetic episodes 2in the treatment group

Chia et al.(1998)129

91 Major thoracicandabdominal

Bupivacaine �morphine �ketamine

Bupivacaine�morphine

1 72 7

IM � intramuscular, BP � blood pressure. 7 � remains the same, 2 � decrease, 1 � increase.



Table 7. Combined Use of Wound Infiltration and/or Epidural and/or Nonsteroidal Antiinflammatory Drugs (NSAIDs), and/orOpioid Analgesics for Postoperative Analgesia After Major Surgical Procedures

StudySample

SizeType ofSurgery Treatment Control

PostoperativePain Score

PostoperativeAnalgesics

RecoveryProfile

Moiniche et al.(1994)148

42 Knee and hiparthroplasty

Epiduralbupivacaine/morphine � oralpiroxicam

IM/IVmorphine �acetaminophen

2 2 7


75 Kneereplacement

Morphine � IAbupivacaine

IA bupivacaineor IAmorphine

7/7 7/7 7

Scott et al.(1994)144

26 Hysterectomy IM diclofenac �epiduralbupivacaine

IM saline �epiduralbupivacaine

2 7

Dahl et al.(1994)143

32 Cholecystectomy Preop ibuprofen �incisionalbupivacaine�bupivacaine �epidural morphine

Preopibuprofen �incisionalbupivacaine�IV morphine

2 7 Vomiting 1in controlgroup

Bartholdy et al.(1994)145

49 Upperabdominalsurgery

Incisional bupivacaine� bupivacaine �epidural morphine

Bupivacaine �epiduralmorphine

7 at rest andcough 2 atmobilization

2


21 Upperabdominal

Bupivacaine �epidural fentanyl

Morphine PCA 2 2 vomiting,sedation2

Pavy et al.(1995)149

30 Cesareansection

Postop rectalindomethacin �intrathecalmorphine

Placebo �intrathecalmorphine

2 2 7

Rosaeg et al.(1997)152

40 Cesareansection

Intrathecal morphine� incisionalbupivacaine �ibuprofen � POacetaminophen

Morphine PCA 2 early bowelmobility

Wittels et al.(1998)151

20 MinilaparotomyBupivacaineinfiltration ofthe uterinetubes andmesosalpinx� intraopketorolac

Saline infiltration �intraop ketorolac

2 2

Ilkjaer et al.(1998)154

60 Renal surgery IV ketamine �epiduralbupivacaine

Saline IV �epiduralbupivacaine

7 7 Sedation 1inketaminegroup

Kavanagh et al.(1994)147

30 Thoracic Preop indomethacin� morphine IV �intraop bupivacaineintercostal block

Saline 7 2 7

Richardson et al.(1994)150

56 Thoracic Periop rectaldiclofenac �morphine �preincisionalparavertebralblock

Saline 2 2 Postoppulmonaryfunction2 incontrolgroup

Power et al.(1994)153

75 Thoracic Postop IM ketorolac� bupivacaineintercostal block

Saline �bupivacaineintercostalblock

7 7

IM � intamuscular,7: Remains the same,2: Decrease,1: Increase. IV � intavenous, IA � intraarticular, PCA � patient-controlled analgesia,PO � per os, oral administration, intraop � intraoperative, periop � perioperative, postop � postoperative.



anesthesia infiltration or block and systemic opioids orNSAIDs provided better analgesic effect for most majorsurgical procedures. Whether multimodal analgesia canimprove the convalescence period is still unclear; only afew studies have focused on this area. One study proposesthat the multimodal approach—in terms of preoperativeinformation, attenuation of stress, dynamic pain relief,early mobilization, enteral nutrition, and administrationof various growth factors in certain high-risk patients—willenable accelerated postoperative surgical recovery.156 Nev-ertheless, effective postoperative pain relief has beneficialphysiologic effects on different organ systems during thepostoperative period and plays an important role in im-proving postoperative outcome.157,158

In summary, multimodal analgesia should be a routinepractice to control postoperative pain in inpatients (Table1). For major vascular, abdominal, thoracic, knee and hipreplacement surgical procedures, neuraxial block withlocal anesthetics and/or opioids can provide effectiveintraoperative and postoperative pain control. Combinedgeneral and epidural anesthesia should be highly recom-mended for major surgery procedures. For neurologicsurgical procedure such as cranial or spinal surgical pro-cedures, in which nerve or regional block cannot beadministrated, or for intermediate surgeries such as lowerabdominal surgical procedures, or for patients who arenot willing to have neuraxial blocks, systemic use ofcombinations of preoperative or intraoperative NSAIDsand PCA morphine could be used. Combined use ofwound infiltration, or nerve block with systemic NSAIDs,or opioids could provide effective pain control for inpa-tients after minor surgical procedures such as laparoscopyor inguinal herniorrhaphy.

Economic Impact

Some studies have demonstrated that multimodal analge-sia combined with preoperative education, enforced mo-bilization, and nutrition decreases postoperative morbid-ity in terms of PONV and pain, and shortened the hospitalstay.6,73,158–164 One study reported reduced hospital costsfor knee and hip replacement surgical patients.165 Studiesin the treatment of rheumatoid arthritis show that non-specific NSAIDs were cost-effective for patients who wereat low risk for developing side effects. However, forpatients at high risk, such as elderly patients, the COX-2specific inhibitors are likely to be more cost-effective.166

Further studies are needed to clarify these issues.

Conclusion

Multimodal analgesia is a promising approach to control-ling postoperative pain, both for outpatients who haveminor surgical procedures and for inpatients undergoingmajor surgical procedures. Different techniques are ap-propriate to different procedures. Perioperative NSAIDsand wound infiltration and block are more suitable forminor ambulatory surgical procedures. For patients whoexperience severe pain, combined systemic opioids,NSAIDs, and epidural analgesics or wound infiltration or

block can provide more effective pain control. Multimodalanalgesia has a great potential to enhance the postopera-tive recovery period.

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