Multimodal Analgesia for PerioperativePain Management

Asokumar Buvanendran, MDDepartment of AnesthesiologyOrthopedic Anesthesia Division

Rush Medical College and Rush University Medical CenterChicago, Illinois

Learning Objectives:As a result of completing this activity, the participantwill be able to� Explain the importance of initiating early treat-

ment of acute postoperative pain to prevent theconsequences

� Develop appropriate multimodal regimens forperioperative pain management based on under-standing of the pharmacology of adjuvant analgesics

� Prescribe the appropriate duration of multimodalanalgesic regimens for perioperative pain manage-ment with the goal to decrease the use of opioids asthe sole agent

Author Disclosure Information:Dr. Buvanendran has disclosed that he receivesresearch funding from Pfizer and Cumberland.

Multimodal analgesia is achieved by combininganalgesics that act by different mechanisms,resulting in additive or synergistic analgesia with

reduced adverse effects secondary to the administration ofindividual analgesics.1 Opioids have long been the main-

stay of postoperative analgesia, but the addition ofadjuvant medications permits the use of lower doses ofopioids while addressing pain by alternative mechanisms.Synergistically or additively, these adjuvants enhance theanalgesia provided by opioids and reduce potential adverseeffects. In addition, acute opioid tolerance has beendescribed in which high-dose intraoperative opioid admin-istration necessitates increasing postoperative opioid re-quirements, but this may be avoided by the use of amultimodal perioperative anesthesia and analgesia model.2

Ambulatory surgery encompasses the majority of sur-gical procedures currently performed in the United States.The number of procedures performed on an ambulatorybasis has increased due to improvements in surgicaltechnology, anesthetic techniques, and pharmacology—specifically, analgesic agents. There is an increasing trendof performing more painful procedures on an outpatientbasis.3 Inadequate management of pain or side effects frommedications (such as opioids) can lead to decreased patientsatisfaction and delays in discharge. Multimodal analgesiacaptures the effectiveness of individual agents in optimaldosages that maximize efficacy and minimize side effects.The principles are based on constructing a multimodalanalgesia strategy that, in addition to regional or localanesthesia, includes scheduled administration of non-opioid analgesics (e.g., acetaminophen, nonsteroidalantiinflammatory [NSAID] agents, or cyclooxygenase[COX]-2 inhibitors) and using oral opioids only for break-through pain (Supplemental Digital Content 1, http://links.lww.com/ASA/A223; Supplemental Digital Content2, http://links.lww.com/ASA/A225). These regimens mustbe tailored to individual patients, keeping in mind the

1

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procedure being performed, side effects of individualmedications, and patients’ preexisting medical conditions.Anesthesiologists are challenged to provide anesthesia andanalgesia using the foundations of multimodal analgesia inorder for patients to attain rapid recovery and dischargefrom the hospital.4,5

Multimodal analgesia captures the effective-

ness 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 DerivativesAniline derivatives have mild analgesic, antiinflammatory,and antipyretic properties. The use of these compounds inambulatory surgery has gained interest of late due to thedevelopment of intravenous formulations and the favor-able side-effect profiles. Paracetamol, the intravenousequivalent of acetaminophen, became available in 2002and provides more predictable bioavailability and pre-dictable onset compared with enteral routes of admin-istration. The intravenous formulation of acetaminophenhas been demonstrated to spare postoperative opioid useand consequently decrease nausea, vomiting, and sedation.This makes the drug unique and ideal to be the foundationof a multimodal analgesic regimen. Concern still exists forhepatotoxicity associated with aniline derivatives. A pro-spective study by Gorocs et al.6 demonstrated the safetyand efficacy of preoperative paracetamol when given aloneor with other systemic analgesics. As a combination,NSAIDs and paracetamol decrease pain scores,7 totalopioid consumption, postoperative nausea and vomiting,and sedation. Patients expressed greater satisfaction whenthe combination of NSAIDs and paracetamol was usedversus placebo or acetaminophen alone.7 Paracetamol/NSAID combinations are also cost-effective, as Issiouiet al.8 concluded that it costs only $6.16 to obtain com-plete satisfaction in one patient. There appears to be muchbenefit to incorporating aniline derivatives as part of a

multimodal analgesia regimen; as availability of intra-venous formulations becomes more widespread and anes-thesiologists become more comfortable with theiradministration, their use should increase.

NSAIDsInhibition of the cyclooxygenase enzymes (COX-1 andCOX-2) and subsequent modulation of the inflammatoryresponse has proved to be an effective means to preventand treat postoperative pain.9 In the past, there has beenconcern regarding nonselective COX inhibitors and sideeffects that include renal toxicity, gastrointestinal toxicity,platelet inhibition, and exacerbation of asthma. COX-2inhibitors have gained interest as they spare gastro-intestinal and renal side effects. However, use of COX-2inhibitors is not without concern; valdecoxib and rofe-coxib were withdrawn from use because of serious sideeffects. Recent research on celecoxib has defined itsefficacy10,11 and safety.11 In addition to decreasing painscores, celecoxib has been associated with decreasedopioid consumption, earlier return of both bowel func-tion11 and physical activity, and increased patient sat-isfaction.

Time to discharge was decreased in groups that receivedketorolac (Po0.05) for ambulatory anorectal proce-dures.12 Recent meta-analysis examining the use of intra-venous ketorolac, even a single dose of 60 or 30 mg, hasshown significant reduction in postoperative pain scoresand some opioid-sparing adverse effects.13 Newer for-mulations of ketorolac include an intranasal spray. Com-pared with placebo, patients receiving intranasal ketorolachad improved pain scores after third molar extraction withbony impaction surgery.14 A randomized controlled trialin patients after abdominal surgery showed that 26%less morphine was consumed in the first 48 hours post-operatively.15 Both studies remarked on the rapid onset ofanalgesia, which lasted up to 8 hours, and suggested itsbenefit in ambulatory or fast-track surgery. Local injectionof ketorolac was first studied in 2000 and has not beenwidely used despite oral analgesic-sparing properties, im-proved quality of recovery, and no effects on postoperativebleeding in one study.15 For patient populations that cantolerate NSAIDs, incorporating them as an oral adjuncthas proved to be effective and safe. Local injection or in-tranasal formulations appear to have properties that makethem suitable for further investigation in analgesia regi-mens for ambulatory surgery.

SteroidsPreoperative administration of glucocorticoids attenuatesperipheral inflammatory pathways and has been shown todecrease postoperative pain for minor surgical proce-dures.16 Concern regarding side effects of steroid admin-istration, such as gastrointestinal or wound complications,has limited their widespread use.17 In a randomized con-trolled trial by Coloma et al.,16 dexamethasone (4 mg)administered preoperatively reduced the time to discharge

2 Buvanendran

with no increase in wound infections. Preoperative orintraoperative administration of glucocorticoids appearsto be appropriate timing to obtain the antiinflammatorybenefits. The onset of dexamethasone is rapid with dura-tion of action of 24 to 48 hours. When Lunn et al.18 addeddexamethasone (16 mg) to a multimodal analgesia regimen(including paracetamol and COX-2 inhibitor), a pro-longed analgesic effect was observed. Additional benefitsof dexamethasone administration include antiemeticeffects. These properties make it an ideal adjunct in theambulatory or outpatient setting. An extensive reviewby Salerno and Hermann17 concluded that ‘‘the literatureclearly reflects the safety of short-term use of cortico-steroids for acute postoperative analgesia in relativelyhealthy individuals.’’ Recent data about the effects of ahigh dose of preoperative methylprednisolone (125 mg) onpain and recovery after total knee arthroplasty showedsignificant reduction in postoperative pain scores.18

AnticonvulsantsThe use of anticonvulsants (g-aminobutyric acid analoguesthat bind to the a2d subunit of voltage-gated calciumchannels) as adjuncts in multimodal regimens has in-creased in the past decade. Presynaptic voltage-gated cal-cium channels are up-regulated in the dorsal root gangliaand spinal cord after surgical trauma, which leads tocentral sensitization.19 Other studies have indicated adecreased incidence of opioid-related side effects (nausea,vomiting, and pruritus) and increased incidence of seda-tion with the use of anticonvulsants.20 A meta-analysis byHo et al.21 concluded that a single preoperative dose ofgabapentin, 1,200 mg or less, reduces pain scores andopioid consumption in the first 24 hours postoperatively.Continuing administration of gabapentin in addition to asingle preoperative dose appears to have benefit; whengiven for 4 days postoperatively, opioid consumption andsome opioid-related side effects were reduced after totalknee arthroplasty.22

Pregabalin has shown a more favorable pharmaco-kinetic profile than gabapentin, including increased bio-availability, longer half-life, and increased potency.23 Asingle dose of pregabalin (150 mg) demonstrates similarefficacy to gabapentin in reducing postoperative painand opioid consumption.24 A 50% reduction in 24-hourmorphine consumption and decreased nausea and vom-iting 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 mgone-time dose followed by 150 mg twice a day) admin-istered in the perioperative period not only decreases thedevelopment of chronic pain, but also improves surgicaloutcome with greater range of motion after total knee ar-throplasty (Supplemental Digital Content 3, http://links.lww.com/ASA/A226; Supplemental Digital Content 4,http://links.lww.com/ASA/A227). Recently, up-regulationof neurotransmitters in the central nervous system cere-brospinal fluid with administration of pregabalin has been

reported in patients undergoing total knee arthroplasty.26

Other studies with single doses of pregabalin (75or 150 mg) have shown improved immediate postoperativeanalgesia without opioid-sparing effects.27 Precise dosingof pregabalin is yet undetermined, as higher doses(600 mg), though effective in decreasing postoperativeopioid consumption, are associated with an increasedincidence of dizziness, blurred vision, and headache.

Pregabalin (150 mg), acetaminophen, and celecoxibadministered as a multimodal regimen decreased intra-operative and postoperative opioid use in patients under-going robotic-assisted laparoscopic prostatectomy withoutcausing an increase in somnolence or dizziness.28 Arandomized controlled trial by Sen et al.,29 includinggabapentin (1,200 mg single dose preoperatively) plus in-traoperative ketamine infusion, resulted in lower painscores, decreased opioid consumption, and less chronicpain after total abdominal hysterectomy. Incorporatinganticonvulsants in a multimodal regimen appears to offernot only short-term benefits but also long-term effects,such as decreased development of chronic pain and im-proved functional outcomes, when continued throughoutthe immediate postoperative period for certain surgicalprocedures, including many orthopedic surgeries. Whilesome of the studies cited in this section involve inpatientsurgical procedures, the principles can be applied to pro-cedures performed in outpatient settings.

Receptor AntagonistsN-Methyl-D-aspartate (NMDA) receptor antagonists,such as ketamine, dextromethorphan, or memantine, havebeen indicated as possible pharmacological agents to pre-vent and treat postoperative pain. NMDA receptor an-tagonists have the ability to treat pain centrally, andpossibly preemptively, by limiting central sensitization30,31

(Supplemental Digital Content 5, http://links.lww.com/ASA/A228). Ketamine has been used more frequently, al-though side effects such as nausea, vomiting, and deliriumare of concern. An effect has been seen with single intra-venous boluses and perioperative ketamine infusions.Ketamine infusions have been associated with both opioidsparing32 and improved rehabilitation33 without increasedside effects. Other studies demonstrated no effect in re-ducing pain scores, opioid consumption, or chronic pain inhysterectomy and thoracotomy.34

Memantine, a noncompetitive NMDA receptor antag-onist, may prove to be the most applicable for ambulatorysurgery. The oral formulation allows ease of admin-istration postoperatively, it is better tolerated, has a longerhalf-life, and is the most potent NMDA receptor antago-nist. It is particularly useful if intravenous ketamine is ad-ministered in the perioperative period and oral memantinecontinued into the postoperative phase in a patient withhigh risk for developing chronic persistent pain after sur-gery. Although NMDA receptor antagonists have beenshown to have a positive effect on postoperative pain in

3Multimodal Analgesia

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

a2-Adrenergic AgonistsStimulation of a2-adrenergic receptors has been known tocause a variety of favorable effects for anesthesiologists, suchas analgesia, sedation, and anxiolysis. Clonidine and dex-medetomidine, commonly used a2-agonists, have enteral,intravenous, and transdermal routes of administration. Sideeffects include bradycardia, hypotension, and excessive se-dation. Dexmedetomidine is a highly selective a2-agonistwith a short duration of action. An intraoperative infusionreduced volatile anesthetic doses (by 19 to 22%), lessenedpostoperative opioid needs (by 36 to 42%), decreasednausea and vomiting, and produced a shorter stay in thepostoperative anesthesia care unit in patients undergoinglaparoscopic bariatric surgery. Prolonged effects (e.g., opioidsparing or shorter hospital stay) were absent, and thesefindings were attributed to short half-life of dexmedetomi-dine.35 In patients undergoing laparoscopic gynecologicalsurgery, dexmedetomidine could be used as an alternative toremifentanil in ambulatory surgery because a constant in-fusion reduced postoperative analgesic requirements, nau-sea, and vomiting. Use of a2-agonists as adjuncts in regionalanesthesia should always be considered, as their safety pro-file and ability to prolong analgesia has been demonstrated.

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 patient’s coexisting medical conditions.

Infusions, such as a2-agonists, b-blockers,

and local anesthetics, may also prove

useful in more painful procedures.

b-Adrenergic AntagonistsThe use of b-adrenergic blocking agents as a method of pre-emptive or preventive analgesia has gained considerable in-terest in the past 5 years. b-Blockers have been associated withblunting of the sympathetic response, opioid-sparing effects,and anticatabolic properties, yet the exact mechanism of theseeffects is unknown.36 Incision at the beginning of surgery is

associated with activation of the sympathetic nervous system;one thought is that the release of catecholamines enhancesexcitability of hippocampal NMDA receptors, which mayplay a role in nociception. Esmolol is a lipophilic, ultrashort-acting, b1-selective antagonist that has been studied in ambu-latory surgery. Intraoperative esmolol boluses followed byshort-term infusions have led to opioid sparing intra-operatively and postoperatively.37,38 However, this opioid-sparing effect appears to be limited, lasting as little as 24 hoursor as much as 3 days postoperatively. In addition, esmolol hasbeen reported to decrease time to emergence and shorten timeto discharge from the recovery room.

Local AnestheticsLocal anesthetics have been found to have multiple mecha-nism of analgesia, including voltage-gated sodium channelblockade, inhibition of G protein-coupled receptors, andmodulation of the inflammatory response.39 In patients un-dergoing laparoscopic colectomy, an intravenous lidocainebolus followed by a 24-hour infusion resulted in anestheticsparing (35% less volatile anesthetic) and greater than 50%reduction in intraoperative and postoperative opioids. In ad-dition, patients receiving lidocaine infusions had earlier returnof bowel function and lower postoperative fatigue, resulting inone less day of hospitalization.40 The antiinflammatory effectsof lidocaine, with attenuated levels of proinflammatory me-diators (IL-6, IL-8, IL-1ra, complement C3a, integrins, andplatelet leukocyte aggregates), have been demonstrated byHerroeder et al.40 McCarthy and colleagues reviewed 16studies with 764 total patients receiving lidocaine infusions.The dosage of lidocaine included boluses of 100mg (or 1.5 to2mg/kg) followed by infusions of 1.5 to 3mg/kg/h (or 2 to3mg/min). They determined a clear benefit in abdominal sur-gery with less postoperative nausea and vomiting, earlier re-turn of bowel function, earlier ambulation and rehabilitation,and shorter hospitalizations.41 They concluded that a ‘‘con-tinuous infusion of perioperative lidocaine has a clear ad-vantage in abdominal surgery.’’ Plasma levels of lidocaineduring infusions have been measured within a safe (o5mg/mL) range except in one patient, who had a level of 5.8mg/mLfollowing the initial bolus. However, these infusions seem tobe safe as there are no reported cases of central nervous systemtoxicity in patients undergoing lidocaine infusion.

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

4 Buvanendran

CONCLUSIONS

Through the use of procedure-specific regimens composedof NSAIDs, acetaminophen, and short-acting opioids,many patients will have improved analgesia after mild tomoderately painful procedures (Supplemental DigitalContent 7, http://links.lww.com/ASA/A233; SupplementalDigital Content 8, http://links.lww.com/ASA/A235; Sup-plemental Digital Content 9, http://links.lww.com/ASA/A236). The use of steroids, anticonvulsants, and NMDAreceptor antagonists should be considered based on theamount of postoperative pain that is anticipated and apatient’s coexisting medical conditions. Infusions, such asa2-agonists, b-blockers, and local anesthetics, may alsoprove useful in more painful procedures. To facilitatequicker onset of analgesia, new routes of administration(e.g., intranasal ketorolac or ketamine) should becomeincreasingly popular. Their use should also be emphasized,as many have already demonstrated fewer side effects.Advances in pharmacology and equipment should improvethe anesthesiologist’s ability to provide a safe, balanced,multimodal analgesic regimen for a variety of outpatientsurgical procedures.

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5Multimodal Analgesia

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