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ain Management After Total Joint Arthroplastyitin Goyal, MD,* Amar Parikh, MD,† and Matt Austin, MD*,‡

Pain management following total joint arthroplasty continues to be a growing area ofinterest as surgical techniques and instrumentation improve and allow for potentially morerapid recovery time. A variety of peri/post-operative pain management protocols are usedby arthroplasty surgeons and anesthesiologists with little consensus. However, it is clearthat uncontrolled postoperative pain may result in significant morbidity – including delayedmobilization, poor surgical outcomes, and prolonged hospitalization. In this article thesystemic administration of narcotics, neuraxial anesthesia, peripheral nerve blockade,intra-articular analgesia, and non-opioid oral analgesics for use in the total joint arthro-plasty population are reviewed.Semin Arthro 19:226-230 © 2008 Elsevier Inc. All rights reserved.

KEYWORDS pain, analgesia, hip arthroplasty, knee arthroplasty, total joint replacement, re-gional anesthesia, NSAIDs

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ontemporary developments in orthopedic surgical tech-nique and instrumentation have given arthroplasty sur-

eons the ability to perform traditional procedures througho-called minimally invasive surgery (MIS) approaches thatay result in less soft tissue dissection, smaller incisions,

nd, in some cases, quicker rehabilitation time.1,2 These ad-ances are being made with the goal of accelerating patientecovery through faster mobilization with reduced perioper-tive pain. These surgical advances have been associated withn increased interest in peri- and postoperative pain manage-ent techniques. These improved analgesic methods, rather

han surgical technique, may be responsible for much of theeported success of MIS.3 This progression involves the manyteps that have been made with regard to the comprehensionf pain pathways and the role of perioperative anesthesia inatient recovery. Uncontrolled postoperative pain has beenhown to result in a multitude of consequences, includingelayed mobilization secondary to the inability to activelyake part in physical therapy and rehabilitation, poor surgicalutcomes, and prolonged hospitalization resulting in aboveverage use of health care funds.4 Most of the advances haveeen centered on changes in the management of pain in

Department of Orthopaedic Surgery, Thomas Jefferson University Hospi-tal, Philadelphia, PA, USA.

Department of Anesthesia, Critical Care, and Pain Medicine, Beth IsraelDeaconess Medical Center, Boston, MA, USA.

The Rothman Institute, Philadelphia, PA, USA.ddress reprint requests to Nitin Goyal, MD, Department of Orthopaedic

Surgery, Thomas Jefferson University Hospital, 1015 Walnut Street,Suite 801 Curtis Building, Philadelphia, PA 19107. E-mail: ngoyal1@

tgmail.com

26 1045-4527/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1053/j.sart.2008.08.002

atients after total knee and hip arthroplasty, as postopera-ive pain is clearly a principal factor in mobilization of theseatients inside the hospital.The options available for pain management include the

ystemic administration of narcotics and anti-inflammatoryedications, regional or neuraxial anesthesia, or peripheralerve blockade. Postoperative pain control after arthroplastyas been the subject of intense investigation in recent years.n approach that focuses on “multimodal perioperative reg-

mens” or “comprehensive anesthesia protocols” that incor-orate both regional analgesia with systemic medications haseen recently emphasized.5,6

ystemic Opioid Analgesiahe term opioid refers broadly to the group of compoundselated to opium and it includes all the endogenous andatural/synthetic exogenous derivatives that possess thesenalgesic effects. The analgesic properties of synthetic/natu-al opioid derivatives are produced simply by mimicking thections of endogenous opioids at distinct receptors within theentral nervous system (CNS)—specifically the mu (�),appa (�), and delta (�) receptors. Each class of receptorroduces varying levels of analgesia and cardiovascular, re-piratory, gastrointestinal, and neurologic effects, and eachpioid compound affects the distinct receptors at differingntensities.

The systemic opioid analgesia may be administeredhrough oral, intramuscular, intravenous, or intravenous pa-ient control anesthesia (PCA) routes. Most postoperative to-

al joint arthroplasty medication schedules involve a PCA

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Pain management after total joint arthroplasty 227

evice for 1 to 2 days postoperatively, after which a conver-ion is made to oral pain medications with intravenous orntramuscular opioid boluses given for breakthrough pain.

The PCA device allows the physician to designate anmount of drug that can be self-administered by the patient,ith a lockout interval, maximum dose per hour, and a po-

ential basal infusion rate. The PCA device can usually also berogrammed to allow for the nursing staff to administer bolusoses of the narcotic on a predesignated schedule for break-hrough pain. The opioid choice itself, the patient-adminis-ered dose, and the lockout interval will have a direct impactoth on the effectiveness of the analgesia and potential anal-esic-related complications. Inadequate dosing or a pro-onged lockout interval will result in ineffective analgesia,hereas excessive patient-administered dose or a short lock-ut interval that allows for dosing before the previous doseas taken full effect may result in systemic opioid-related sideffects, including respiratory depression, sedation, and gas-rointestinal effects. A basal infusion rate does not usuallyave a role in an opioid naïve total joint arthroplasty popu-

ation secondary to the potential for narcotic overdosing in annmonitored situation; however, it may play a role in theatient with a severe narcotic dependence before surgery.As there is significant inconsistency within the patient

opulation regarding pain tolerance and effectiveness of nar-otics, the PCA settings may need to be up- or downregulatedo optimize pain control, or the opioid choice may need to bee-evaluated. PCA devices have become the standard forostoperative analgesia in a multitude of populations second-ry to its ease of administration and the patient’s ability to selfitrate for pain control. However, in the total joint arthro-lasty population it is clear that adequate analgesia is notchieved.7,8 The pain in this population is exacerbated withhe movement and ambulation that is encouraged early in theostoperative period. Oftentimes adequate analgesia may bettained, but patients may experience opioid-related side ef-ects that may prohibit early mobilization and potentiallyesult in morbidity. In a study evaluating opioid-related sideffects from intervenous PCA analgesia, Wheeler9 describeastrointestinal effects in 37% of patients, cognitive effects in4%, urinary retention in 16%, pruritus in 15%, and respi-atory depression in 2% of patients. These effects can delayobilization, prolong hospital stay, and have the potential to

esult in significant morbidity.

euraxial Analgesiapinal and epidural neuraxial blocks for perioperative painanagement produce a sensory analgesic effect, a motor

lock, and a sympathetic block that is dependent on themount and concentration of the local anesthetic that is in-used. However, there are clinically significant distinctionshat must be made between spinal and epidural anesthesia.hese distinctions are mostly based on the fact that spinalnesthesia only requires that a small volume of drug be in-used to produce a clinically powerful sensory analgesia. On

he other hand, epidural anesthesia requires that a large vol- t

me of local anesthetic be utilized, which may result in sys-emic complications that are not seen in spinal anesthesia.10

The indication for a neuraxial block is a surgical procedureherein the level of anesthesia that is produced does not

dversely affect the patient such as in the case of total kneend total hip arthroplasty (THA).

Neuraxial analgesia may consist of a local anesthetic, anpioid, or a combination of each to allow a lower concentra-ion of each individual compound while producing a syner-istic effect. Neuraxial opioids tend to produce an enhancednalgesic effect compared with systemic intravenous opioids.pioids in neuraxial analgesia can be given as a single-dose

njection or along with anesthetics in continuous epiduralnfusions. A new single-dose extended release epidural mor-hine for pain control after THA, DepoDur (Endo Pharma-euticals, Chadds Ford, PA), was introduced in 2004. Depo-ur addresses the need for effective extended releasenalgesia without an indwelling catheter. The single-doseherapy provides up to 48 hours of analgesia from a single-ose epidural injection, and it has been shown to provideetter pain control than standard epidural morphine.11

Absolute contraindications to neuraxial block for periop-rative pain management include the patient’s refusal, theatient’s inability to remain motionless during the block ad-inistration, and an elevated intracranial pressure. Relative

ontraindications include either intrinsic or iatrogenic co-gulopathy, critical hypovolemia, prior spine operations,orbid obesity, and skin/soft tissue infection at the location

f the anticipated needle insertion.12

Neuraxial anesthesia has several physiologic effects. Neu-axial blocks often produce an effective sympathectomy,hich causes venous/arterial vasodilation resulting in a de-

rease in total peripheral resistance, resulting in a decreasedean arterial blood pressure and a decreased heart rate. This

s often compensated for in the operating room by adminis-ration of volume to maintain the mean arterial blood pres-ure. This reduces blood loss and decreases thrombogenesisecondary to increased flow.10 Neuraxial blocks may causeastrointestinal effects such as nausea/vomiting in up to 20%f patients secondary to the unopposed parasympathetictimulation of the gastrointestinal tract.13 Other potential se-ious complications include spinal headache, neurogenicladder, infection, and epidural hematoma.12

egional Blockadeeripheral nerve blocks for orthopedic surgical proceduresrovide effective analgesia. Lower extremity regional blocksre less widely employed than in the upper extremities sec-ndary to the experience with epidural and spinal anesthesiaechniques in the lower extremity.14

Before arthroplasty, regional blocks are generally directedt one or more of three areas: psoas compartment block (pos-erior lumbar plexus) (PCB), femoral nerve block (FNB), andciatic nerve block (SNB). Peripheral nerve blockade can bettained by a single-dose injection or can be maintained by aontinuous infusion catheter. The effectiveness of each of

hese blocks for THA and total knee arthroplasty (TKA) has

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228 N. Goyal, A. Parikh, and M. Austin

een controversial, with variable results reported in the liter-ture.15-19

The hip joint is supplied by branches of the lumbar andacral plexus, although the distribution of each nerve rootikely has anatomic variation within the population. Based onhe innervation of this region, blocks for postoperative painelief after THA typically involve either a PCB alone, or a PCBn conjunction with SNB. The contribution of the PCB andNB are not well defined.16-18,20 However, several institutionsave made PCB infusion catheters part of the standard pro-ocol for postoperative pain control after THA.5 In a prospec-ive, randomized, double-blinded study comparing intrave-ous PCA with single-injection of FNB or PCB after THA, theNB was shown to provide no analgesic advantage except for

ust after extubation, and the PCB was an effective analgesicor the first 4 postoperative hours.15 It must be noted that thisas a single-dose injection and not a continuous infusion.Based on the extremity innervation, generally after TKA,

ostoperative regional blocks consist of either a PCB or anNB with or without an SNB. The psoas block must be com-ined with an SNB for anesthesia of the entire lower extrem-

ty.14 PCB may be placed through a variety of approachesposterior/perivascular). There is a risk of epidural, subarach-oid, or intravascular injection. There is also a risk of periph-ral nerve damage and a unilateral sympathetic block.

The femoral nerve block is typically used in conjunctionith other peripheral blocks to enhance anesthesia of the

ower extremity. Secondary to the proximity of the femoralrtery/vein to the femoral nerve there is a theoretical risk ofntravascular injection of the block and hematoma formation,lthough the femoral artery and nerve are located in distinctheaths approximately 10 mm apart. Peripheral nerve dam-ge is also a potential complication of this regional block,lthough rare.

Because of its vast sensory innervation to the posteriorhigh and the complete leg/foot below the knee except for theedial portion supplied by the saphenous nerve, an SNBay be utilized along with an FNB/saphenous nerve block formultitude of procedures involving the lower extremity. TheNB can be a technically challenging block to perform, butide effects of the SNB do not differ from the PCB/FNB—ematoma formation and nerve damage being the most note-orthy.

ntra-articular Analgesiantra-articular continuous infusion catheters have recentlyecome popular for outpatient surgery. The classic intra-rticular continuous infusion pump is a spring-loaded sy-inge that has the potential to deliver up to 100 mL of anes-hetic at a constant rate of 2 mL/h. It has been demonstratedo provide excellent pain relief after shoulder surgery21 andas been utilized for knee arthroscopy.22,23

The theoretical advantage of an intra-articular infusionatheter is the ability to decrease the amount of narcoticequirement postoperatively while reducing systemic com-

lications. However, in a study comparing intra-articular ver- m

us epidural anesthesia for postoperative pain relief afterKA, significantly more acetaminophen, proxoyphene, andetolorac were used by patients with the intra-articular cath-ter and prolonged wound drainage was more common inatients with the catheter compared with patients with thepidural.12

The benefit of intra-articular injections has yet to be dem-nstrated for TKA.24-26 Morgan,27 in a randomized double-lind study, recently evaluated the use of continuous localnesthetic infusions at iliac crest bone-graft sites and foundo difference in perceived pain or narcotic use between theroup that received the continuous local anesthetic infusionnd the group that did not. It appears that the effectiveness ofntra-articular continuous infusion catheters in total joint ar-hroplasty patients is thus far unproven.

onopioid Oral Analgesicshe use of nonopioid analgesics on a regular dosing schedule

n the postoperative pain regimen can produce an additivend synergistic analgesic effect while reducing opioid use andubsequently minimizing the negative opioid-related side ef-ects By utilizing these agents a multimodal approach to at-ack pain may be taken, in that the site of nociception in theeripheral tissues may be addressed directly, rather than onlycting at CNS locations. However, these analgesics have theirwn distinct side effect profile that must be taken into ac-ount before use, including questionable effects on boneealing, bleeding, and gastrointestinal side effects.

onsteroidalnti-inflammatory Drugs

onsteroidal anti-inflammatory drugs (NSAIDs) produce an-inociceptive and analgesic effects by causing the inhibitionf cyclooxygenase (COX) pathways in both the CNS and theeripheral tissues. The mechanism of action of NSAIDS isrimarily through blocking two prostaglandin productionathways—via inhibition of two distinct COX enzymes.28

he inhibition of the COX-2 isoenzyme is what produces thenalgesic and anti-inflammatory effects of NSAIDS. TheOX-1 enzymatic pathway is primarily involved in produc-

ion of prostaglandin E2 (PGE2). PGE2 works as a vasodilatornd plays an important role in gastric mucosal protection asell as playing a key role in diuresis/natriuresis in the kidney.he COX-1 pathway also plays a key role in the synthesis of

hromboxane A2 from arachidonic acid. Thromboxane A2 is aentral part of the pathway of platelet aggregation and hemo-tasis and, therefore, COX-1 inhibition can lead toward in-reased bleeding.29 The COX-2 pathway is primarily con-erned with the production of prostaglandins that affect painnd fever.

Conventional NSAIDs have a structure that allows them toind easily into the receptor sites of both the COX-1 andOX-2 enzymes, so as to bring forth their analgesic andnti-inflammatory effects along with their gastrointestinal

ucosa effect and bleeding properties. On the other hand,

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Pain management after total joint arthroplasty 229

he selective COX-2 inhibitors possess a bulky side chain thatinds to the COX-2 enzymes binding site with greater affin-

ty, thus selectively inhibiting the COX-2 enzyme. When in-roduced, the COX-2 inhibitors were a leap forward in painanagement, and they have been shown to be as effective, ifot more effective than the nonspecific NSAIDs in the man-gement of pain associated with osteoarthritis, rheumatoidrthritis, and acute soft tissue trauma.30,31 Because of thebsence of antiplatelet activity and the reduced gastrointesti-al side effects, COX-2 specific NSAIDs can be administered

n the immediate postoperative period without the increasedisk of perioperative bleeding that is associated with the non-elective NSAIDs.32 The utilization of COX-2 inhibitors in theostoperative period has already been shown to have a re-arkable opioid-sparing effect in major orthopedic proce-ures.33

One of the concerns with both the nonselective and selec-ive COX-2 NSAIDs has been the effect on bone healing, ashere are conflicting animal studies that may show that theOX inhibitors delay bone healing. In these studies NSAIDsre given over long periods of time (months) and in doseshat are not approved in the United States for the treatment ofcute postoperative pain. In a recent study by Reuben andkman34 evaluating COX-2 inhibition and spinal fusion, noffect was seen on the rate of nonunion at the time of 1 yearollow up, while it was found that celecoxib resulted in sig-ificant reduction in postoperative pain and opioid con-umption. Furthermore, in addition to their analgesic effects,OX-2 inhibitors have also been shown to play a role inrevention of heterotopic ossification.35

cetaminophenhe exact mechanism of action of acetaminophen is not wellefined, but it is perceived to act predominantly centrally,ossibly resulting in its analgesic effects by increasing theain threshold, potentially through a prostaglandin-medi-ted pathway in the central nervous system.36 The side effectrofile of acetaminophen is very limited and, therefore, canave a broad use in postoperative pain. Acetaminophenhould be given on a scheduled dosing rather than on an “aseeded” dosing schedule so as to exploit its full analgesicotential. Many opioid medications, including oxycodone,ave oral preparations that include acetaminophen alreadyor an additive analgesic effect.

regabalinn recent reports, pregabalin (Lyrica, Pfizer, New York, NY)a gabapentin analogue) has been suggested to have a place inhe treatment of postoperative pain. Pregabalin and its ana-ogues have traditionally been targeted for use in neuropathicain, for which they are thought to reduce the hyperexcit-bility of the dorsal horn neurons that is initiated by the tissueamage. Recently, particular interest has been given to pre-abalin and its potential use in the postoperative setting be-ause its action is unique and distinct from those of opioids

nd NSAIDs. In a review of the role of pregabalin in the i

anagement of postoperative pain published by Dahl andoworkers37 in 2004 they found statistically significant dif-erences in pain relief and pain intensity difference in post-perative pain comparing pregabalin and placebo. Furthertudies must be conducted to evaluate the role of pregabalinn the postoperative total joint arthroplasty population.

ultimodal Therapyultimodal analgesic therapy refers to the utilization of aultifaceted approach to pain management, with the goal ofaximizing the desired characteristics and minimizing thenwanted side effects of each agent. The use of a variety ofistinct analgesic agents often leads to synergistic effects, al-

owing the use of smaller medication dosages, resulting ineduced undesired effects.4 As some of the most prominentnd limiting side effects are associated with opioid agents,uch of multimodal therapy is focused on minimizing peri-

perative opioid consumption and achieving optimal painontrol through the use of regional/neuraxial analgesia alongith nonopioid analgesic agents as well as low-dose opioids.

re-emptive Analgesiare-emptive analgesia is an analgesic administration beforehe onset of pain. The goal of this analgesic administrationefore the onset of noxious stimuli is to prevent central sen-itization to the pain that can result in magnification of painerception. The efficacy of pre-emptive analgesia, especially

n the total joint population, continues to be a controversialssue.

onclusiont is clear that the failure to provide adequate analgesia post-peratively from total joint arthroplasty can impede earlyhysical therapy and rehabilitation, delay mobilization, andesult in a prolonged hospital admission that could poten-ially produce a variety of morbidities. Advances in under-tanding of pain pathways, and more aggressive approachesoward treating postoperative pain in this population, alongith pharmacological progress, have allowed us the tools toetter control this pain.The evidence indicates that a multimodal approach to an-

lgesia in the total joint arthroplasty patient population is theanner in which we can maximize analgesia while minimiz-

ng the associated negative side effects.38 The utilization of aombined regimen—a regional/neuraxial block, along withOX-2 nonsteroidal anti-inflammatory drugs, gabapentinnalogues, and acetaminophen, with low-dose opioids is po-entially the most effective way to exploit the synergy of eachgent while continuing to use smaller doses and avoiding theegative effects. The use of a neuraxial versus a regional blockay depend on the institution and the experience of the

nesthesiologist performing the procedure, as the rate of un-uccessful blocks can rise significantly with inexperience.dditionally, the role of “pre-emptive” analgesia in patients

n the postoperative period after a total joint arthroplasty

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230 N. Goyal, A. Parikh, and M. Austin

ppears to be undefined at the current time. Undoubtedly inecent years several strides have been made in the optimiza-ion of pain control after total joint arthroplasty, and futureesearch will likely further delineate pain pathways and an-lgesia methods to maximize control.

eferences1. Waldman BJ: Minimally invasive total hip replacement and periopera-

tive management: Early experience. J South Orthop Assoc 11(4):213-217, 2002

2. Wenz JF, Gurkan I, Jibodh SR: Mini-incision total hip arthroplasty: Acomparative assessment of perioperative outcomes. Orthopedics 25:1031-1043, 2002

3. Nuelle DG, Mann K: Minimal incision protocols for anesthesia, painmanagement, and physical therapy with standard incisions in hip andknee arthroplasties: The effect on early outcomes. J Arthroplasty 22:20-25, 2007

4. Reuben SS, Sklar J: Pain management in patients who undergo outpa-tient arthroscopic surgery of the knee. J Bone Joint Surg Am 82A:1754-1766, 2000

5. Hebl JR, Kopp SL, Ali MH, et al: A comprehensive anesthesia protocolthat emphasizes peripheral nerve blockade for total knee and total hiparthroplasty. J Bone Joint Surg Am Suppl 87:63-70, 2005

6. Horlocker TT, Kopp SL, Pagnano MW, et al: Analgesia for total hip andknee arthroplasty: A multimodal pathway featuring peripheral nerveblock. J Am Acad Orthop Surg 14:126-135, 2006

7. Capdevila X, Barthelet Y, Biboulet P, et al: Effects of perioperativeanalgesic technique on the surgical outcome and duration of rehabili-tation after major knee surgery. Anesthesiology 91:8-15, 1999

8. Choi PT, Bhandari M, Scott J, et al: Epidural analgesia for pain relieffollowing hip or knee replacement. Cochrane Database Syst Rev 3:3-71, 2003

9. Wheeler M, Oderda GM, Ashburn MA, et al: Adverse events associatedwith postoperative opioid analgesia: A systematic review. J Pain 3:159-180, 2002

0. Brown D: Spinal, Epidural, and Caudal Anesthesia, in Miller R (ed):Miller’s Anesthesia. Elsevier, Philadelphia, PA, 1192-1212, 2005

1. Viscusi ER, Kopacz D, Hartrick C, et al: Single-dose extended-releaseepidural morphine for pain following hip arthroplasty. Am J Ther 13:423-431, 2006

2. DeWeese FT, Akbari Z, Carline E: Pain control after knee arthroplasty:Intraarticular versus epidural anesthesia. Clin Orthop 392:226-231,2001

3. Carpenter RL, Caplan RA, Brown DL, et al: Incidence and risk factorsfor side effects of spinal anesthesia. Anesthesiology 76:906-916, 1992

4. Sharrock N, Beckman J, Inda E, et al: Anesthesia for Orthopedic Sur-gery, in Miller R (ed): Miller’s Anesthesia. Elsevier, Philadelphia, PA,1769-1794, 2005

5. Biboulet P, Morau D, Aubas P, et al: Postoperative analgesia after total-hip arthroplasty: Comparison of intravenous patient-controlled anal-gesia with morphine and single injection of femoral nerve or psoascompartment block. A prospective, randomized, double-blind study.Reg Anesth Pain Med 29:102-109, 2004

6. Capdevila X, Macaire P, Dadure C, et al: Continuous psoas compart-ment block for postoperative analgesia after total hip arthroplasty: Newlandmarks, technical guidelines, and clinical evaluation. see comment.Anesth Analg 94:1606-1613, 2002

7. Fournier R, Van Gessel E, Gaggero G, et al: Postoperative analgesia with“3-in-1” femoral nerve block after prosthetic hip surgery. Can J Anaesth45:34-38, 1998

8. Singelyn FJ, Gouvemeur JM: Postoperative analgesia after total hiparthroplasty: i.v. PCA with morphine, patient-controlled epidural an-

algesia, or continuous “3-in-1” block? A prospective evaluation by our

acute pain service in more than 1,300 patients. J Clin Anesth11:550-554, 1999

9. Szczukowski MJ Jr, Hines JA, Snell JA, et al: Femoral nerve block fortotal knee arthroplasty patients: A method to control postoperativepain. J Arthroplasty 19:720-725, 2004

0. Stevens RD, Van Gessel E, Flory N, et al: Lumbar plexus block reducespain and blood loss associated with total hip arthroplasty.see comment.Anesthesiology 93:115-121, 2000

1. Savoie FH, Field LD, Jenkins RN, et al: The pain control infusion pumpfor postoperative pain control in shoulder surgery. Arthroscopy 16:339-342, 2000

2. De Andres J, Bellver J, Barrera L, et al: A comparative study of analgesiaafter knee surgery with intraarticular bupivacaine, intraarticular mor-phine, and lumbar plexus block. Anesth Analg 77:727-730, 1993

3. Jaureguito JW, Wilcox JF, Conn SJ, et al: A comparison of intraarticularmorphine and bupivacaine for pain control after outpatient knee ar-throscopy: A prospective, randomized, double-blinded study. Am JSports Med 23:350-353, 1995

4. Klasen JA, Opitz SA, Melzer C, et al: Intraarticular, epidural, and intra-venous analgesia after total knee arthroplasty. Acta Anaesthesiol Scand43:1021-1026, 1999

5. Mauerhan DR, Campbell M, Miller JS, et al: Intra-articular morphineand/or bupivacaine in the management of pain after total knee arthro-plasty. J Arthroplasty 12:546-552, 1997

6. Ritter MA, Koehler M, Keating EM, et al: Intra-articular morphineand/or bupivacaine after total knee replacement. J Bone Joint Surg Br81:301-303, 1999

7. Morgan SJ, Jeray KJ, Saliman LH, et al: Continuous infusion of localanesthetic at iliac crest bone-graft sites for postoperative pain relief: Arandomized, double-blind study. J Bone Joint Surg Am 88:2606-2612,2006

8. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of actionfor aspirin-like drugs. Nat New Biol 231:232-235, 1971

9. Cheng JC, Siegel LB, Katari B, et al: Nonsteroidal anti-inflammatorydrugs and aspirin: A comparison of the antiplatelet effects. Am J Ther4:62-65, 1997

0. Emery P, Zeidler H, Kvien TK, et al: Celecoxib versus diclofenac inlong-term management of rheumatoid arthritis: Randomised double-blind comparison. Lancet 354:2106-2111, 1999

1. Kivitz A, Eisen G, Zhao WW, et al: Randomized placebo-controlledtrial comparing efficacy and safety of valdecoxib with naproxen inpatients with osteoarthritis. J Fam Pract 51:530-537, 2002

2. Robinson CM, Christie J, Malcolm-Smith N: Nonsteroidal antiinflam-matory drugs, perioperative blood loss, and transfusion requirementsin elective hip arthroplasty. J Arthroplasty 8:607-610, 1993

3. Reuben SS, Fingeroth R, Krushell R, et al: Evaluation of the safety andefficacy of the perioperative administration of rofecoxib for total kneearthroplasty. J Arthroplasty 17:26-31, 2002

4. Reuben SS, Ekman EF: The effect of cyclooxygenase-2 inhibition onanalgesia and spinal fusion. J Bone Joint Surg Am 87:536-542, 2005

5. Banovac K, Williams JM, Patrick LD, et al: Prevention of heterotopicossification after spinal cord injury with COX-2 selective inhibitor (ro-fecoxib). Spinal Cord 42:707-710, 2004

6. Aronoff DM, Oates JA, Boutaud O: New insights into the mechanism ofaction of acetaminophen: Its clinical pharmacologic characteristics re-flect its inhibition of the two prostaglandin H2 synthases. Clin Phar-macol Ther 79:9-19, 2006

7. Dahl JB, Mathiesen O, Moiniche S: ‘Protective premedication’: an op-tion with gabapentin and related drugs? A review of gabapentin andpregabalin in in the treatment of post-operative pain. Acta AnaesthesiolScand 48:130-136, 2004

8. Hebl JR, Kopp SL, Ali MH, et al: A comprehensive anesthesia protocolthat emphasizes peripheral nerve blockade for total knee and total hip

arthroplasty. J Bone Joint Surg Am Suppl 87:63-70, 2005