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Apollo Medicine 2012 DecemberVolume 9, Number 4; pp. 323e335 Review Article

Pain management in total knee replacement

Raju Vaishyaa,*, Ajaz Majeedb

aProfeMathu*CorreReceivCopyrihttp://d

ABSTRACT

Total knee replacement (TKR) is one of the most commonly done surgical procedures, with over 150,000 total kneereplacements and THR performed annually in England and Wales in the National Health Service (NHS). In Indiaalthough clear-cut data is not available but the incidence is increasing. In the US, 431,000 TKRs are performed yearlyand the utilization of TKR has increased over the last two decades, especially among younger patients .TKR may beassociated with severe post-operative pain. The International Association for the Study of Pain (IASP) has definedpain as “an unpleasant sensory or emotional experience associated with actual or potential tissue damage, ordescribed in terms of such damage”. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO)has made adequate pain management a priority and has deemed monitoring pain as the “fifth” vital sign.

Copyright © 2012, Indraprastha Medical Corporation Ltd. All rights reserved.

Keywords: International association for the study of pain, Deep vein thrombosis, Nosocomial infection

Total knee replacement (TKR) is one of the most commonlydone surgical procedures, with over 150,000 total kneereplacements and THR performed annually in England andWales in the National Health Service (NHS).1 In Indiaalthough clear-cut data is not available but the incidence isincreasing. In the US, 431,000 TKRs are performed yearly2

and the utilization of TKR has increased over the last twodecades, especially among younger patients.3 TKR may beassociated with severe post-operative pain. The InternationalAssociation for the Study of Pain (IASP) has defined pain as“an unpleasant sensory or emotional experience associatedwith actual or potential tissue damage, or described in termsof such damage”.4 The Joint Commission onAccreditation ofHealthcare Organizations (JCAHO) has made adequate painmanagement a priority and has deemed monitoring pain asthe “fifth” vital sign.5

BACKGROUND

TKRmay result in severepost-operative pain usually requiringhospitalization from 5 to 10 days to provide effective anal-gesia.This prolongedhospital stay and relative immobilization

ssor, Senior Consultant, bDNB student, Department of Orthopaedra Road, New Delhi 110076, India.sponding author. Tel.: þ91 9810123331, email: raju.vaishya@gmai

ed: 9.8.2012; Accepted: 27.8.2012; Available online 5.9.2012ght � 2012, Indraprastha Medical Corporation Ltd. All rights reservedx.doi.org/10.1016/j.apme.2012.08.012

of the patient in bed may invite nosocomial infection and deepvein thrombosis (DVT). In addition to causing unnecessarydistress and discomfort during the post-operative period,poorly managed post-operative pain can have negative conse-quences for long-term surgical outcomes.Adequate post-oper-ative pain relief following TKR is very important to optimalpost-operative recovery (Table 1). The faster that mobilizationand rehabilitation can progress, the better the ultimate outcomewill be. Adequate pain control post-operatively should allowearlier patient mobilization with the aim of increasing strengthand proprioception and decreasing the incidence of the devel-opment of thromboembolism. In complicated cases, prolongedimmobility due to pain can cause the development ofmuscularcontractures or atrophy that eventually cause the developmentof long-term functional impairments (Table 2). Adequatemanagement of post-operative pain still poses a significantchallenge to healthcare, as demonstrated by a review of theliterature which concluded that approximately 60% of patientsexperienced severe pain and approximately 30% patientsexperienced moderate pain after surgery.6 In a recent studyat the Avon Orthopedic Center, 58% of TKR patients reportedmoderate or severe pain on the first post-operative day.7

ics & Joint Replacement Surgery, Indraprastha Apollo Hospitals,

l.com

.

Table 1 Advantages of adequate analgesia in TKR.

324 Apollo Medicine 2012 December; Vol. 9, No. 4 Vaishya and Majeed

Current pharmaceutical pain relief options for TKR painhave limitations due to associated side effects, often requiringadditional treatment for them. Unfortunately, there are veryfewpainmanagementoptionsavailable thatcanprovidea treat-ment that is both non-invasive and without side effects. Sideeffects of theopiate painmedication include lethargy, sedation,respiratory depression, nausea, vomiting, numbness, weak-ness, urinary retention, hypotension and digestive discomfort,including gastro paresis and constipation. Opioids may alsoalter mood negatively and/or induce euphoria. The side effectsof non-steroidal anti-inflammatory agents (NSAIDS) includegastric upset, sometimes predisposing symptoms leading topeptic ulcers. COX-2 inhibitors have been found to increase

Table 2 Effect of inadequate analgesia in TKR.

risk of heart attack while overdoses can lead to liver damage.Navigating these side effects amongst the co-morbidities andpotential drug interactions with concurrent medications inthe elderly population is typically problematic.

PAIN PERCEPTION

Pain is generated because of local inflammation and nervedamage due to trauma or temperature change, during TKR.Tissue insult causes local release of inflammatory mediatorssuch as bradykinin, prostaglandins, substance P, and hista-mine. Receptors detect changes in pain and temperature andinitiate afferent signals in the peripheral nervous systemthrough unmyelinatedCfibers ormyelinatedAfibers. Signalsreach the dorsal root ganglion and synapse in the dorsal hornof the spinal cord. At this juncture, spinal modulation of theafferent signals occurs through opioids, a2 agonists, and N-methyl-D-aspartate (NMDA) receptor antagonists. Neuro-transmission is further modulated by other substances suchas gamma-aminobutyric acid (GABA). From here, spinotha-lamic tracts carry ascending signals, where further centralmodulation can occur in supraspinal modulatory centers.4

The various agents used as part of amultimodal strategy affectnociceptors and different regions of common pain pathwaysto achieve an overall reduction in perceived pain (Fig. 1).

Assessment of pain

In the assessment of pain intensity, various rating scaletechniques are used. The most commonly used forms are:

The category rating scales (Fig. 2)(e.g. none, mild, moderate, severe, unbearable or 1e5).

The visual analog scales (VAS) (Fig. 3)The VAS has been shown to be more sensitive to changeand is therefore more widely used. These scales may alsobe incorporated into pain diaries.

McGill pain questionnaire (MPQ) (Melzack, 1975)(78 pain adjectives arranged into 20 groups further arrangedinto sets of words describing sensory aspects of the quality ofpain).

POST-OPERATIVE PAIN CONTROL AFTERTOTAL KNEE REPLACEMENT

Traditionally, acute post-operative pain following TKR hasbeen managed with:

Fig. 1 Pain pathways and multimodal analgesic therapy.

Pain management in TKR Review Article 325

1. Peripheral nerve blocks2. Epidural analgesia3. Parental (IV) analgesia (e.g., patient-controlled

analgesia)4. Multimodal analgesia5. Local infiltration analgesia (LIA)

Peripheral nerve blocks

Innervation of the knee jointKnowledge about the innervation of the knee joint is impor-tant in performing a peripheral nerve block. Innervation ofthe knee joint (Fig. 4) is derived from (i) femoral nerve viathe branch to vastus medialis (anterior aspect of the joint

Fig. 2 Category rating scale.

capsule); (ii) sciatic nerve via genicular branches of bothtibial and common peroneal components (posterior aspectof the joint capsule and all of the intra-articular structures);and (iii) obturator nerve by a branch from its posterior divi-sion that accompanies the femoral artery through adductorMagnus into the popliteal fossa. Cutaneous innervation ofthe anterior aspect of the knee is supplied by the femoralnerve. The obturator nerve supplies the skin on the medialaspect of the knee in less than 40% of people.

Peripheral nerve blocksPeripheral nerve blocks with a local anesthetic have beenused commonly in total joint replacements (Table 3).Patients undergoing TKR may have a femoral nerve block

Fig. 3 VAS scale.

326 Apollo Medicine 2012 December; Vol. 9, No. 4 Vaishya and Majeed

and/or a sciatic nerve block. Peripheral nerve blocks may becontinuous or administered as a one-time dose. Continuousperipheral nerve blocks provide the most effective andlong-lasting analgesia with fewer side effects whencompared with PCA morphine or continuous epidural anal-gesia. Potential side effects include nerve damage anda lack of muscle control in the immediate rehabilitationperiod. Local infection due to an indwelling catheter hasbeen reported in between 0% and 3% of cases.8 Compari-sons have shown that one-time blocks fail to provide theprolonged relief of continuous blocks, with no differenceafter the first four to 6 h following a total joint arthroplasty.9

Kardash et al administered one-time doses of bupivacaineand epinephrine in the form of a femoral nerve block or

Fig. 4 Innervation of lower limb.

obturator nerve block, or gave a placebo, to patients treatedwith total knee arthroplasty.10 All patients were concur-rently receiving multimodal pain agents. Results showedthat an obturator block was no different from the placebo,and the femoral nerve block lowered only pain scores,not morphine consumption. In another study, Ozen et alcompared the so-called three-in-one femoral nerve block(femoral nerve, lateral femoral cutaneous nerve, and obtu-rator nerve blocks) with the use of no block in patientsundergoing total knee arthroplasty.11 Less consumption ofpatient-controlled opioid analgesia and lower visual analogscale (VAS) pain scores were recorded for the three-in-onefemoral nerve block cohort. In another investigation,patients receiving the nerve block were able to undergofaster rehabilitation than the cohort patients receivingpatient-controlled analgesia with morphine.12 A peripheralnerve block with continuous infusion provides analgesiasuperior to that resulting from a one-time injection.13

Most studies in the literature support the use of a continuousperipheral nerve block in multimodal pain management. Ameta-analysis by Richman et al demonstrated significantlyimproved pain control (p < 0.05) in patients receivinga peripheral nerve block compared with that associatedwith opioid analgesia alone.14 According to Fowler et al,peripheral nerve blocks have a side-effect profile that ismore desirable than that of epidural analgesia while main-taining a similar level of pain relief.15 Peripheral nerveblocks created less urinary retention and hypotension inthat study. Patients treated with a unilateral nerve blockhad less restriction of movement than those who receivedepidural analgesia. The primary concern about the use ofperipheral nerve blocks is the development of late neurolog-ical sequelae, including permanent nerve damage. A recentinvestigation of over 6000 patients was performed toexamine these complications.16 While 0.5% of patientsdeveloped nerve symptoms post-operatively, the incidenceof symptoms related to the peripheral nerve block wasonly 0.04%. A meta-analysis of peripheral nerve blockstudies done between 1995 and 2005 revealed a 0.34% inci-dence of symptomatic post-operative neuropathy withfemoral nerve blocks64. The best combination of peripheralnerve blocks and choice of local anesthetic solution forcontinuous infusion following total knee arthroplasty iscurrently unknown.

Table 3 Features of peripheral nerve blocks.

Nerve block Advantages Disadvantages

Femoral nerve block d Easy to performd Good efficacyd Less side effectsd Faster rehabilitation

d Neurovascular injuryd Localization

Sciatic nerve block d Combined with femoral nerve blockprovide adequate analgesia with less side effects

d Time consuming procedureto give two simultaneous blocks

d Sciatic nerve injuryd Isolated block not adequate

Obturator nerve block d Adding obturator block to sciatic andfemoral nerve blocks improve analgesia

d Localization difficultd Inadequate analgesia, if performed alone

Lumbosacral block d Better than femoral nerve block becauseit blocks the femoral, obturator, and lateralfemoral cutaneous nerves more reliably

d Facilitate earlier mobilization

d Difficult to perform

Pain management in TKR Review Article 327

Femoral nerve blockThe knee is innervated by the femoral nerve, which is thelargest branch of the lumbosacral plexus. The femoral nervesupplies about 80% of the sensation in the knee. Thefemoral nerve supplies the motor contraction of the iliacus,pectineus, and anterior thigh muscles. The femoral nervealso supplies the cutaneous and articular branches to thefront and inner thigh, leg and foot, and hip and knee.Femoral nerve block has a high success rate and carriesa low risk of complications. However, proximal spread oflocal anesthetic to the other branches of the lumbar plexusis unreliable. Single-shot femoral nerve block using a long-acting amide local anesthetic will provide analgesia to theanterior aspect of the knee for up to 24 h, although the inci-dence of profound motor block of the quadriceps muscleswill be unacceptably high if large volumes of concentratedlocal anesthetic agents are used.

The benefit of using a continuous femoral nerve block tocontrol pain after total knee replacement surgery has beentested and proven to be effective. By using this methodfor pain control, fewer narcotic medications will be neededto control the pain. By using fewer narcotics there will befewer side effects.

AdvantagesContinuous femoral nerve block is technically simple toperform with a low incidence of side effects. The infusionis continued for 48e72 h before catheter removal andpatients are allowed to mobilize during this time providedthey have adequate motor power and proprioception.Several recent studies have confirmed that the analgesicefficacy of this technique is equivalent to both continuousepidural analgesia and continuous lumbar plexus blockfollowing total knee arthroplasty; however, continuous

femoral nerve block was associated with fewer side effectsthan the other techniques.17 Ozen et al (2006) found that theuse of a FNB led to a reduction in post-operative opioidadministration and its associated side effects.

Sciatic nerve blockPain behind the knee is a problem for a significant propor-tion of patients who only receive femoral nerve blockbecause all of the intra-articular structures are innervatedby the tibial nerve. The benefit of adding a sciatic nerveblock to a femoral nerve block has become the subject ofdebate in regional anesthesia circles.

AdvantagesSingle-shot sciatic nerve block combined with femoral nerveblock will provide analgesia for up to 24 h.When performingthe block using a nerve stimulator, success rates are highest ifinversion (tibial and peroneal nerve) or plantar flexion (tibialnerve) of the foot is elicited. The combination of continuousfemoral and sciatic nerve blocks has been shown to providesuperior analgesia with less PONV when compared to otheranalgesic techniques.

DisadvantagesThe potential disadvantages of adding a continuous sciaticblock to continuous femoral nerve block are increasedtime required to perform two continuous blocks and thepotential problems mobilizing patients post-operativelybecause of more extensive motor block. The practical alter-native is to use continuous femoral nerve block combinedwith single-shot sciatic nerve block.

Lumbar plexus blockIt has been suggested that lumbar plexus (Fig. 5) block maybe better than femoral nerve block because it blocks the

Fig. 5 Anatomy of lumbar plexus.

328 Apollo Medicine 2012 December; Vol. 9, No. 4 Vaishya and Majeed

femoral, obturator, and lateral femoral cutaneous nervesmore reliably. However, there is little evidence from clin-ical trials to support this hypothesis. Continuous lumbarplexus block is a logical and effective technique that hasbeen shown to improve analgesia and facilitate earliermobilization following total knee arthroplasty comparedwith single-shot lumbar plexus block.18 Again, the combi-nation of a sciatic nerve block should be considered.

Obturator nerve blockThe addition of a separate obturator block to a femoral orlumbar plexus block is contentious. Femoral nerve blockhas been shown to spare the obturator nerve in as many as50% of patients, contrasting with lumbar plexus blockwhen the obturator nerve is missed in<10%. It is interestingto note that a comparative study of continuous lumbar plexusand continuous femoral nerve block found no difference inanalgesia. On the other hand, there is some evidence thatadding a single-shot obturator block to single-shot sciaticand femoral nerve blocks may improve analgesia.19

Epidural analgesia

Administration of epidural analgesia/anesthesia is one of themost popular techniques used in TKR surgery as it is associ-ated with improved pain control compared with thatprovided by patient-controlled analgesia.20 In a directcomparison with patient-controlled analgesia with

morphine, epidural analgesia was found to decrease the dura-tion of post-operative inpatient rehabilitation.21 Analgesicagents delivered to the epidural space can be administeredcontinuously or as a single dose. Typically, an opioidcombined with epinephrine is administered during adminis-tration of epidural anesthesia. Epinephrine, through localvasoconstriction, reduces opioid absorption and leads toa relatively higher local concentration of the opioid agentand greater analgesia from the local anesthetic. Ketaminecan also be added as a synergistic agent. Side effects ofepidural injection include hypotension and decreased motorfunction. Newer extended-release one-time dosage formula-tions consisting of a single epidural injection of morphinemay relieve problems associated with catheter malfunction.Casati et al followed patients who received epidural0.125% levobupivacaine through a catheter for 72 hfollowing total knee arthroplasty.22 All patients also receivedpatient-controlled analgesia with morphine. As comparedwith a group that received only patient-controlled morphinepost-operatively, those who received the levobupivacainehad better pain scores and decreased morphine consumptionover the 3 days for which the epidural was maintained. Mostimportantly, no decrease in motor function was noted, whichminimized loss of physical therapy. Förster and Rosenbergstudied the effect of adding clonidine to a fentanyl epiduralinfusion and reported a decrease in morphine consumptioncompared with that by patients who had not received theclonidine additive.23 The only problem was an averagedrop in blood pressure of 5 mmHg and an average drop inthe pulse rate of 3 beats per minute in the clonidine group.Another relatively recent advancement includes the avail-ability of microsomal delivery technology that allowsepidural delivery of extended-release opioids as a one-timeinjection. One such product is extended-release epiduralmorphine, commercially available as DepoDur, whichprovides 48 h of extended morphine release. In a study ofpatients treated with total knee arthroplasty who receivedextended-release epidural morphine through a single injec-tion and post-operative patient-controlled analgesia opioids,Hartrick et al noted decreased pain and opioid consumption,compared with the values for patients who received a shamepidural, although four patients over 64 years of age experi-enced serious respiratory depression.24 Currently, it is rec-ommended that extended-release epidural morphine beused cautiously in older patients and patients with sleepapnea. Meta-analyses of studies of epidural analgesia havedemonstrated improved pain control, especially during earlypost-operative periods.25 Significant side effects includepruritus (odds ratio ¼ 4.74), urinary retention (oddsratio ¼ 3.50), and hypotension (odds ratio ¼ 2.78). Theodds ratios for respiratory depression and nausea were notsignificant (the confidence interval included 1).

Fig. 6 Intra-operative photograph showing the locations fordeep intra-operative injection: posterior capsule (1); poster-omedial structures (2); periarticular synovium (3).

Pain management in TKR Review Article 329

Patient-controlled analgesia (PCA)

This method provides an intravenous pump attached to theintravenous site-allowing patient to administer his own painmedication after surgery. The machine has been used forover 20 years and has a safe record of use. The machinehas a control button that can be pushed 8e10 times perhour when pain is experienced.

The PCA has several advantages as well as disadvan-tages due to the nature of the medication being adminis-tered. Since the medicine is administered directly into theintravenous line, the medication works very quickly. Ifpatient is in pain, patient does not need to call the nurseto be given pain medication.

The main disadvantage of PCA is that the medicationused can be quite sedating for some patients, making itdifficult to participate in post-operative physical therapy.Other disadvantages are the side effects associated withnarcotics including nausea, vomiting, itching and urinaryretention (inability to urinate). The PCA cannot be used ifpatient has an allergy or sensitivity to these medications.Contrary to popular belief, patient cannot become addictedto morphine by using a PCA in a controlled environmentand for a limited period of time. The use of PCA is limitedto 72 h or less to prevent or decrease side effects. The effec-tiveness of analgesia attributed to the PCA pump is about75% so breakthrough pain medications are readily availablefor all patients on PCA.

Multimodal analgesia

As the name implies, multimodal pain managementinvolves the use of multiple agents that act at differentregions of the pain pathway. The rationale for this strategyis that it reduces the use of opioid agents and their adverseside effects. A combination approach allows better overallpain control. One aspect of multimodal pain managementinvolves pre-emptive administration of analgesics and/oranti-inflammatory agents. These agents are given prior tothe initiation of operative treatment and the release of localinflammatory pain mediators. Pre-emptive analgesia wasfirst described by Wall in 1985. Since then, there hasbeen extensive research related to administration of agentsbefore surgery in an effort to alleviate post-operativepain. Kehlet and Dahl introduced multimodal pain manage-ment in 1993 with encouragement and equivocation.26

Much of the pain pathway had been investigated, but strongclinical evidence supporting multimodal pain managementwas lacking. Since that report, evidence has mounted tosupport much of this pain management process. Currently,the American Society of Anesthesiologists Task Force onAcute Pain Management recommends a multimodal pain

regimen, specifically with the incorporation of non-steroidalanti-inflammatory drugs (NSAIDs) when medicallyappropriate.27

Over the past 10 years, multimodal pain managementprotocol after TKA has undergone several changes usingvarious agents to reduce post-operative pain, includingthe adoption of pre-emptive analgesia, the use of local peri-articular injections, and the introduction of a comprehensivepost-operative pain protocol.28,29

Local infiltration analgesia

In order to avoid the problems of regional analgesia oropioid, and to minimize the complications, recently, a localinfiltration analgesia (LIA) technique was developed byKerr and Kohan in Sydney, Australia (Röstlund and Kehlet2007, Kerr and Kohan 2008).30 The technique involves theinfiltration of a large volume dilute solution of a long-actinglocal anesthetic agent, often with adjuvants (e.g. epineph-rine, ketorolac, an opioid), throughout the wound at thetime of surgery (Figs. 6 and 7).

The technique, known as local infiltration analgesia(LIA), was developed specifically to avoid sedation andfacilitate rapid physiological recovery after lower limbarthroplasty in order to enable early mobilization anddischarge. The idea of administering analgesia directly tothe operative site with minimal systemic side effects is anattractive option. Surgical trauma during total knee replace-ment modifies the responsiveness of the nervous system intwo ways. It causes peripheral sensitization by reducing thethreshold for afferent nociceptive neurons, and it causescentral sensitization by increasing the excitability of spinal

Fig. 7 Intra-operative photograph showing the locations forsuperficial intra-operative injection.

330 Apollo Medicine 2012 December; Vol. 9, No. 4 Vaishya and Majeed

neurons. Together these changes contribute to post-opera-tive pain hypersensitivity, which increases the response tonoxious stimuli and decreases the pain threshold at thesite of the injured tissue as well as the surrounding unin-jured tissue. The pre-emptive use of analgesia has beenshown to prevent central sensitization and improve post-operative pain control. It may be that the window of oppor-tunity for pre-empting central pain activation is limited.

The existing literature provides evidence that the use oflocal anesthetic wound infiltration as part of a multimodalanesthetic regimen reduces short-term post-operative painand length of hospital stay and improves joint function afterknee joint replacement.31,32

NON-INVASIVE MANAGEMENT OF PAIN INTKR

Cryotherapy

There is emerging evidence that application of ice to thesite of an arthroplasty results in improved pain control.Ice is believed to work by reducing inflammation, metabo-lism, and nerve conduction velocity. It is possible thatcombining ice application with compression for edemaprevention could result in further vasoconstriction andinflammation reduction. Kullenberg et al prospectivelyrandomized patients treated with total knee arthroplastyto receive cryotherapy or epidural analgesia.33 Opioidconsumption and VAS data were equivalent in the twogroups, and the patients treated with cryotherapy had anearlier discharge from the hospital. Levy and Marmarrandomized eighty patients undergoing unilateral total

knee arthroplasty to be treated with cryotherapy or normalcompressive dressings and found that the cryotherapygroup required less morphine.34 Current evidence supportsthe use of cryotherapy, as this modality has little or no sideeffects.

Pharmaceutical agents

AcetaminophenAcetaminophen in moderate dosages has become ubiqui-tous as an antipyretic and analgesic agent. It lacks theside effects of NSAIDs and acts as a central analgesicagent. Acetaminophen is available in oral form, andrecently it has become available, outside the United States,as an intravenous agent. While hepatotoxicity is the primaryside effect, dosages associated with this complication thusfar have ranged on the order of 1e4 g/day. Available inEurope, intravenous acetaminophen has proven efficaciousfor post-operative pain control following major orthopedicsurgery. Compared with patients treated with a placebo,those who received intravenous acetaminophen reporteddecreased pain for the first 6 h following surgery andconsumed less morphine during the first 24 h post-opera-tively. In a similar study, Zhou et al administered 2 g ofintravenous paracetamol to patients with moderate or severepain.35 In the first 5 h after administration, the intravenousparacetamol resulted in decreased pain compared with thatprovided by a placebo and its efficacy was similar to that ofketorolac over the same time period. The addition of acet-aminophen to a multimodal pain regimen seems to haveutility, but a complete understanding requires additionalevidence.

NSAIDs and COX-2 inhibitorsIn comparison with acetaminophen, NSAIDs and theirrelated cyclooxygenase type-2 (COX-2) inhibitors havea larger evidence base. The traditional NSAIDs inhibitthe activity of both COX-1 and COX-2 enzymes. COX-2enzyme is seen more specifically in acute or chronicinflammatory tissue. Use of selective COX-2 inhibitorsdampens adverse effects on gastric mucosa and decreasesinhibition of prostaglandin production in the gastrointes-tinal tract. COX-2 drugs are 100e1000 times more selec-tive for COX-2 than for COX-1. Celecoxib was the firstCOX-2 drug to be approved for marketing by the FDA,over a decade ago. Despite inconsistent evidence ofincreases in cardiac morbidity with COX-2 usage, painrelief with improved gastric tolerance remains the founda-tion of the benefit of selective COX-2 inhibition. Inanet al reported on the use of lornoxicam (a COX-1 agent)for pain control in patients treated with total knee

Pain management in TKR Review Article 331

arthroplasty.36 These subjects received pre-operative andpost-operative lornoxicam as well as patient-controlledanalgesia with morphine post-operatively. Patients in thecontrol group received patient-controlled analgesia withmorphine only. During the first 48 h after the arthroplasty,opioid consumption was significantly lower in the patientsreceiving lornoxicam (p < 0.05). The patients in thecontrol group also exhibited a trend toward a higher rateof opioid-related side effects. Another study demonstratedthe efficacy of COX-2 in reducing both pain and opioidconsumption.37 Celecoxib was administered 1 h beforetotal knee arthroplasty and every 12 h thereafter. Patient-controlled analgesia with opioid medication was alsoprovided. The control cohort received patient-controlledanalgesia only. The patients receiving celecoxib reportedsignificantly decreased pain on a VAS at forty-eight(p ¼ 0.03) and seventy-two (p ¼ 0.02) hours followingthe total knee arthroplasty. Opioid consumption wasreduced by 40% in the celecoxib group. The active kneerange of motion was significantly greater (10e15�) duringthe first three post-operative days in the celecoxib group(p ¼ 0.03). Similar evidence presented by Buvanendranet al supports COX-2 usage. Compared with a placebo,rofecoxib administered pre-operatively and for 8 daysfollowing the index total knee arthroplasty resulted insignificantly decreased opioid consumption (p < 0.05),decreased VAS pain scores (p < 0.001), decreased sideeffects (p ¼ 0.047), and an increased knee range of motionover 1 month (p ¼ 0.01). Extrapolation of these results alsodemonstrated improved patient satisfaction and a shorterperiod of physical therapy to achieve an adequate rangeof motion. Analysis of side effects in these studies showsno statistically significant difference in bleeding or theneed for transfusion post-operatively. There is over-whelming evidence supporting the use of NSAIDs andCOX-2 inhibitors as an integral part of multimodal painmanagement in orthopedic patients. Concerns have beenraised regarding the effect of COX-2 inhibitors andNSAIDs on osseointegration and fracture healing. At thispoint, little Level-I or II evidence is available to supportor refute this concern. There is also a concern regardingbleeding and inhibition of platelet aggregation, whichalso is not supported by Level-I or Level-II evidence.However, the latter concern may be mitigated by pre-emp-tively discontinuing use of all NSAIDs 7e10 days prior tosurgery. In addition, COX-2 inhibitors with anti-inflamma-tory properties alone do not seem to be associated withthese potential side effects. While previous research hasindicted COX-2 inhibitors for increasing thromboembolicevents in patients undergoing coronary artery bypass graftsurgery, no increase in association with other surgicalprocedures has been established.

Gabapentin/pregabalin

Marketed as an anticonvulsant and used for neuropathicpain, gabapentin acts on the a2d subunit of the presynapticvoltage gated calcium channels. These channels areaccessed along the dorsal horn synapse in spinal neurons.The end result is a decrease in excitatory signal releasealong the afferent pathway. Peri-operative use of gabapen-tin and pregabalin has been investigated in prospectivetrials. In one study, patients were randomized to receiveor not receive pregabalin before and for 14 days after totalknee arthroplasty.38 The patients who had received thedrug had less neuropathic pain at 3 and 6 months, reducedopioid consumption while they were hospitalized, andimproved knee flexion over the first 30 days after the oper-ation. A higher risk of side effects (increased confusionand sedation during post-operative day 0 and 1) was re-ported in the pregabalin group. Using a peri-operativemodel, Clarke et al found similar results for patients under-going total knee arthroplasty.39 However, they evaluatedall permutations of pre-operative and post-operative gaba-pentin administration. Post-operative doses of gabapentindecreased opioid consumption during the first 2 days afterthe operation and significantly improved knee flexion ondays 2 and3. The sample size was limited to thirty-sixpatients, and the study did not demonstrate improved effi-cacy with the pre-operative use of gabapentin. In a relatedstudy examining patients undergoing total hip arthroplasty,Clarke et al found no difference between groups treatedwith and without gabapentin.40 However, this study alsohad limited power, and only one dose of gabapentin wasadministered pre-operatively and post-operatively. Thegabapentinoids studied outside the setting of total jointarthroplasty have demonstrated efficacy when used incombination with other agents or alone. More research isneeded to identify the true efficacy with respect to theduration and timing of administration to patients under-going orthopedic procedures. Common side effects ofthese agents are dizziness and somnolence.

Tramadol

Tramadol is a synthetic centrally acting opioid agonist andmonoamine uptake inhibitor (acting on noradrenaline andserotonin). These two synergistic pathways create a poten-tial for a unique adjuvant for pain control. However, effi-cacy has been found to be limited in prospective trials.Stubhaug et al provided 50 and 100-mg doses of tramadolin a placebo-controlled study of patients undergoing totaljoint arthroplasty.41 There was no difference in any paincontrol outcome variable between the placebo and tramadol

332 Apollo Medicine 2012 December; Vol. 9, No. 4 Vaishya and Majeed

groups. Stiller et al evaluated tramadol use in a multimodalrole as an adjuvant to patient-controlled analgesia withmorphine in patients treated with total knee arthroplasty.42

While pain relief was not significantly different betweenthose receiving tramadol with patient-controlled analgesiaand those using patient-controlled analgesia alone,morphine consumption was significantly decreased in thetramadol group (p < 0.05). Differences in the designs ofthese prospective studies make it difficult to ascertain therole of tramadol in multimodal pain management.

N-Methyl-D-aspartate non-competitive

antagonistsN-methyl-D-aspartate (NMDA) receptor antagonists poten-tiate the effect of opioids and prevent hyperalgesic compli-cations from uncontrolled pain. Agents used to modulatethe pain pathway in the central nervous system include ket-amine, magnesium, and dextromethorphan. In a study offorty patients randomized to receive magnesium sulfate orsaline solution parenterally during spinal anesthesia, withboth groups receiving patient-controlled analgesia withmorphine and ketorolac post-operatively, the magnesiumgroup had lower pain scores and utilized less opioid withoutany difference in side effects.43 In another study, evaluatingthe role of magnesium added to epidural fentanyl, patientsreceiving magnesium required significantly (p < 0.05) lessfentanyl without any increase in side effects.44 Ketamine isanother NMDA antagonist advocated for nociceptive relief.Remérand et al studied 154 patients treated with total jointarthroplasty; seventy-nine received intravenous ketaminepre-operatively and for 24 h post-operatively and theplacebo group received saline solution infusion.45 Allpatients were managed with a multimodal pain managementregimen concurrently. The results showed significantlydecreased morphine consumption (p ¼ 0.004) and signifi-cantly decreased pain in the patients receiving ketamine(p ¼ 0.036). There appears to be a promising role for ket-amine as a multimodal analgesic, although potential sideeffects include hallucinations, nausea, emesis, and visionchanges.

Transdermal patchesWhile transdermal fentanyl patches add to the total narcoticdosage, they also provide an alternative route for adminis-tration of pain control agents. Comparisons with patient-controlled morphine analgesia have demonstrated compa-rable efficacy and safety. Given the varying delivery andtime course of narcotic administration, the synergisticeffects of fentanyl patches with other routes of pain controlmay be beneficial. Minville et al reported on a small groupof patients who had had a 50-mg/h matrix fentanyl patch

applied 10 h prior to a total hip arthroplasty.46 No differ-ence in respiratory depression was noted between thatgroup and patients who had not received the patch. Theapplication of the patch decreased post-operative use ofpatient-controlled analgesia with morphine; however, trans-dermal patches may not curtail overall opioid consumptiondue to the administration of fentanyl in this study. Becauseof a concern regarding unpredictable delivery and potentialadverse effects, most centers do not consider transdermalpatches as a suitable modality for management of acutepost-operative pain.

DISCUSSION

Total knee replacement (TKR) is one of the most successfulsurgical procedures. Management of pain following TKR isan important aspect of this procedure. Satisfactory painmanagement after TKR has several important implications.Adequate pain control allows faster rehabilitation1 andreduces the risk of post-operative complications. Paincontrol is also the most important component of patientsatisfaction. Patients with well-controlled post-operativepain have an improved health-related quality of life andless time lost from work, and they are more satisfied withtheir treatment. Appropriate and adequate post-operativepain management is associated with shorter hospital stays,reduced rates of unanticipated hospital admissions andreadmissions due to pain, and an overall reduced cost ofcare. Opioids are very effective analgesics and constitutethe foundation of the management of moderate-to-severeacute post-operative pain despite their association withincreased respiratory, cardiac, urinary, gastrointestinal,and neurological complications. In addition, opiate-inducedrespiratory depression and the associated post-operativehypoxia is linked with myocardial ischemia, tachycardia,acute cognitive disturbances, delayed wound-healing, andan increased incidence of wound infection. Because ofconcerns about side effects, physicians often prescribedoses of opioids that are lower than what would have theoptimal effect.

A newer concept in pain management in TKR is multi-modal pain management. This concept was introduced in anattempt to control pain with less reliance on opioids. Multi-modal analgesia is a multidisciplinary approach to painmanagement with a goal to maximize the analgesic effectand minimize the side effects of the medications. It takesadvantage of the additive or synergistic effects of variousanalgesics, permitting the use of smaller doses witha concomitant reduction in side effects. Because many ofthe negative effects of analgesic therapy are related toparenteral opioid limiting its use is a major principle of

Table 4 Pain management in TKR.

Pain management in TKR Review Article 333

multimodal analgesia. Over the past decade, a greaterunderstanding of pain mechanisms has led to the conceptof pre-emptive analgesia. Pre-emptive analgesia involvesthe administration of analgesics prior to painful stimuli toprevent the establishment of central sensitization and thusthe amplification of post-operative pain. It starts beforesurgery and covers both the period of surgery and the initialpost-operative period. In order to understand multimodalpain management, a fundamental knowledge of how painis generated is required. Available evidence indicates thatmultimodal pain management has a useful role for patientsundergoing total joint arthroplasty. The rationale for multi-modal pain management is to provide pain relief for thepatient with less reliance on opioids.

There is ample evidence to suggest that traditionalNSAIDs and the associated COX-2 inhibitors are themost effective agents for decreasing opioid consumption.Fewer investigators have analyzed pain levels and theimpact on post-operative mobilization. Overall, NSAIDs,spinal analgesia, peripheral nerve blocks, and intra-artic-ular injections have resulted in improved VAS pain scores,with variable strengths of evidence. The most informationhas been reported for NSAID use. There is still a lack ofresearch on many adjunctive agents and potentialoutcomes. However, most agents have shown trendstoward improved activity in physical therapy and patientsatisfaction.

Thus, the primary goal of modern pain management is toreduce pain at both the central and the peripheral levels, incombination with pre-emptive analgesia using a multimodalprotocol (Table 4). This strategy should enhance restorationof function by allowing patients to participate in the rehabil-itation programs more easily, thereby improving the overallpost-operative outcome.

CONFLICTS OF INTEREST

All authors have none to declare.

REFERENCES

1. National Joint Registry. 7th Annual Report; 2010.2. Agency for Healthcare Research and Quality. HCUP: A Tool

for Identifying, Tracking, and Analyzing National HospitalStatistics. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb34.jsp.

3. Jain NB, Higgins LD, Ozumba D, et al. Trends in epidemi-ology of knee arthroplasty in the United States, 1990e2000.Arthritis Rheum. 2005;52:3928e3933.

4. TaskForceonTaxonomyPart III.PainTerms.ACurrent ListwithDefinitions and Notes on Usage. International Association for theStudy of Pain Web site, http://www.iasp-pain.org/Content/NavigationMenu/GeneralResource-Links/PainDefinitions/default.htm; Published 1994. Accessed 12.01.11.

5. Phillips DM. JCAHO pain management standards areunveiled. Joint Commission on Accreditation of HealthcareOrganizations. JAMA. 2000;284(4):428e429. http://dx.doi.org/10.1001/jama.284.4.428 [CrossRef].

6. Bonica JJ. Postoperative pain. In: Bonica JJ, ed. The Manage-ment of Pain. 2nd ed. Philadelphia: Lea and Febiger; 1990:461e480.

7. Wylde V, Rooker J, Halliday L, Blom A. Acute post-operativepain at rest after hip and knee arthroplasty: severity, sensoryqualities and impact on sleep. Orthop Traumatol Surg Res.in press.

8. Capdevila X, Bringuier S, Borgeat A. Infectious risk of contin-uous peripheral nerve blocks. Anesthesiology. 2009;110:182e188.

9. Biboulet P, Morau D, Aubas P, Bringuier-Branchereau S,Capdevila X. Postoperative analgesia after total-hip arthro-plasty: comparison of intravenous patientcontrolled analgesiawith morphine and single injection of femoral nerve or psoascompartment block. A prospective, randomized, double-blindstudy. Reg Anesth Pain Med. 2004;29:102e109.

10. Kardash K, Hickey D, Tessler MJ, Payne S, Zukor D,Velly AM. Obturator versus femoral nerve block for analgesiaafter total knee arthroplasty. Anesth Analg. 2007;105:853e858.

11. Ozen M, Inan N, Tümer F, Uyar A, Baltaci B. The effect of 3-in-1 femoral nerve block with ropivacaine 0.375% on postop-erative morphine consumption in elderly patients after totalknee replacement surgery. Agri. 2006;18:44e50.

12. Singelyn FJ, Deyaert M, Jorist D, Pendeville E,Gouverneur JM. Effects of intravenous patient-controlledanalgesia with morphine, continuous epidural analgesia, andcontinuous three-in-one block on postoperative pain andknee rehabilitation after unilateral total knee arthroplasty.Anesth Analg. 1998;87:88e92.

13. Ilfeld BM, Ball ST, Gearen PF, et al. Ambulatory continuousposterior lumbar plexus nerve blocks after hip arthroplasty:

334 Apollo Medicine 2012 December; Vol. 9, No. 4 Vaishya and Majeed

a dual-center, randomized, triple-masked, placebo-controlledtrial. Anesthesiology. 2008;109:491e501.

14. Richman JM, Liu SS, Courpas G, et al. Does continuousperipheral nerve block provide superior pain control toopioids? A meta-analysis. Anesth Analg. 2006;102:248e257.

15. Fowler SJ, Symons J, Sabato S, Myles PS. Epidural analgesiacompared with peripheral nerve blockade after major kneesurgery: a systematic review and metaanalysis of randomizedtrials. Br J Anaesth. 2008;100:154e164.

16. Barrington MJ, Watts SA, Gledhill SR, et al. Preliminaryresults of the Australasian Regional Anaesthesia Collabora-tion: a prospective audit of more than 7000 peripheral nerveand plexus blocks for neurologic and other complications.Reg Anesth Pain Med. 2009;34:534e541.

17. Postoperative analgesia and functional recovery after total-knee replacement: comparison of a continuous posteriorlumbar plexus (psoas compartment) block, a continuousfemoral nerve block, and the combination of a continuousfemoral and sciatic nerve block. Reg Anesth Pain Med.2005;30:434e445. CrossRefMedlineWeb of Science.

18. Continuous versus single injection lumbar plexus blocks:comparison of the effects on morphine use and early recoveryafter total knee arthroplasty. Reg Anesth Pain Med. 2005;30:541e547. CrossRefMedlineWeb of Science.

19. Postoperative analgesia following total knee replacement: anevaluation of the addition of an obturator nerve block tocombined femoral and sciatic nerve block. Acta AnaesthesiolScand. 2002;46:95. CrossRefMedlineWeb of Science.

20. Block BM, Liu SS, Rowlingson AJ, Cowan AR,Cowan JA Jr, Wu CL. Efficacy of postoperative epidural anal-gesia: a meta-analysis. JAMA. 2003;290:2455e2463.

21. Capdevila X, Barthelet Y, Biboulet P, Ryckwaert Y,Rubenovitch J, d’Athis F. Effects of perioperative anal-gesic technique on the surgical outcome and duration ofrehabilitation after major knee surgery. Anesthesiology.1999;91:8e15.

22. Casati A, Ostroff R, Casimiro C, et al. Chiropolis StudyGroup. 72-hour epidural infusion of 0.125% levobupivacainefollowing total knee replacement: a prospective, randomized,controlled, multicenter evaluation. Acta Biomed. 2008;79:28e35.

23. Förster JG, Rosenberg PH. Small dose of clonidine mixedwith low-dose ropivacaine and fentanyl for epidural analgesiaafter total knee arthroplasty. Br J Anaesth. 2004;93:670e677.

24. Hartrick CT, Martin G, Kantor G, Koncelik J, Manvelian G.Evaluation of a singledose, extended-release epiduralmorphine formulation for pain after knee arthroplasty.J Bone Jt Surg Am. 2006;88:273e281.

25. Choi PT, Bhandari M, Scott J, Douketis J. Epidural analgesiafor pain relief following hip or knee replacement. CochraneDatabase Syst Rev. 2003;3:CD003071.

26. Kehlet H, Dahl JB. The value of “multimodal” or “balancedanalgesia” in postoperative pain treatment. Anesth Analg.1993;77:1048e1056.

27. American Society of Anesthesiologists Task Force onAcute Pain Management. Practice guidelines for acutepain management in the perioperative setting: an updatedreport by the American Society of AnesthesiologistsTask Force on Acute Pain Management. Anesthesiology.2004;100:1573e1581.

28. Ranawat CS, Ranawat AS, Mehta A. Total knee arthroplastyrehabilitation protocol: what makes the difference?J Arthroplasty. 2003;18(3 suppl 1):27e30. http://dx.doi.org/10.1054/arth.2003.50080 [CrossRef].

29. Ranawat AS, Ranawat CS. Pain management and acceleratedrehabilitation for total hip and total knee arthroplasty.J Arthroplasty. 2007;22(7 suppl. 3):12e15. http://dx.doi.org/10.1016/j.arth.2007.05.040 [CrossRef].

30. Kerr DR, Kohan L. Local infiltration analgesia: a techniquefor the control of acute postoperative pain following kneeand hip surgery: a case study of 325 patients. Acta Orthop.2008;79:174e183.

31. Adam F, Chauvin M, Du Manoir B, Langlois M, Sessler DI,Fletcher D. Small-dose ketamine infusion improves postoper-ative analgesia and rehabilitation after total knee arthroplasty.Anesth Analg. 2005;100(2):475e480. http://dx.doi.org/10.1213/01.ANE.0000142117.82241.DC [PMC free article][PubMed] [Cross Ref].

32. Liu SS, Richman JM, Thirlby RC, Wu CL. Efficacy of contin-uous wound catheters delivering local anesthetic for postoper-ative analgesia: a quantitative and qualitative systematicreview of randomized controlled trials. J Am Coll Surg.2006;203(6):914e932. http://dx.doi.org/10.1016/j.jamcoll-surg.2006.08.007 [PubMed] [Cross Ref].

33. Kullenberg B, Ylipää S, Söderlund K, Resch S. Postoperativecryotherapy after total knee arthroplasty: a prospective studyof 86 patients. J Arthroplasty. 2006;21:1175e1179.

34. Levy AS, Marmar E. The role of cold compression dressingsin the postoperative treatment of total knee arthroplasty. ClinOrthop Relat Res. 1993;297:174e178.

35. Zhou TJ, Tang J, White PF. Propacetamol versus ketorolac fortreatment of acute postoperative pain after total hip or kneereplacement. Anesth Analg. 2001;92:1569e1575.

36. Inan N, Ozcan N, Takmaz SA, Ozcan A, Erdo�gan I, Baltaci B.Efficacy of lornoxicam in postoperative analgesia after totalknee replacement surgery. Agri. 2007;19:38e45.

37. Huang YM, Wang CM, Wang CT, Lin WP, Horng LC,Jiang CC. Perioperative celecoxib administration forpain management after total knee arthroplasty e a random-ized, controlled study. BMC Musculoskelet Disord.2008;9:77.

38. Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M,Tuman KJ. Perioperative oral pregabalin reduces chronic pain

Pain management in TKR Review Article 335

after total knee arthroplasty: a prospective, randomized,controlled trial. Anesth Analg. 2010;110:199e207.

39. Clarke H, Pereira S, Kennedy D, et al. Gabapentin decreasesmorphine consumption and improves functional recoveryfollowing total knee arthroplasty. Pain Res Manag. 2009;14:217e222.

40. Clarke H, Pereira S, Kennedy D, et al. Adding gabapentin toa multimodal regimen does not reduce acute pain, opioidconsumption or chronic pain after total hip arthroplasty.Acta Anaesthesiol Scand. 2009;53:1073e1083.

41. Stubhaug A, Grimstad J, Breivik H. Lack of analgesic effectof 50 and 100 mg oral tramadol after orthopaedic surgery:a randomized, double-blind, placebo and standard activedrug comparison. Pain. 1995;62:111e118.

42. Stiller CO, Lundblad H, Weidenhielm L, et al. The addi-tion of tramadol to morphine via patient-controlled anal-gesia does not lead to better post-operative pain relief

after total knee arthroplasty. Acta Anaesthesiol Scand.2007;51:322e330.

43. Hwang JY, Na HS, Jeon YT, Ro YJ, Kim CS, Do SH. I.V.infusion of magnesium sulphate during spinal anaesthesiaimproves postoperative analgesia. Br J Anaesth. 2010;104:89e93.

44. Bilir A, Gulec S, Erkan A, Ozcelik A. Epidural magnesiumreduces postoperative analgesic requirement. Br J Anaesth.2007;98:519e523.

45. Remérand F, Le Tendre C, Baud A, et al. The early anddelayed analgesic effects of ketamine after total hip arthro-plasty: a prospective, randomized, controlled, double-blindstudy. Anesth Analg. 2009;109:1963e1971.

46. Minville V, Lubrano V, Bounes V, et al. Postoperative anal-gesia after total hip arthroplasty: patient-controlled analgesiaversus transdermal fentanyl patch. J Clin Anesth. 2008;20:280e283.

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