Osteoarthritis Readings

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C H A P T E R 95 Osteoarthritis

LUCINDA M. BUYS AND MARY ELIZABETH ELLIOTT

KEY CONCEPTSApproximately 46 million Americans have osteoarthritis (OA).OA prevalence increases with age, with women more com-monly affected than men.

Contributors to OA are systemic (age, genetics, hormonal status,obesity, occupational or recreational activity) and/or local (injury,overloading of joints, muscle weakness, or joint deformity).

OA is primarily a disease of cartilage that reflects a failure of thechondrocyte to maintain proper balance between cartilage for-mation and destruction. This leads to loss of cartilage in the joint,local inflammation, pathologic changes in underlying bone, andfurther damage to cartilage triggered by the affected bone.

The most common symptom associated with OA is pain, whichleads to decreased function and motion. Pain relief is the pri-mary objective of medication therapy.

Manifestations of OA are local, affecting one or a few joints,usually the knees, hips, and hands. Osteophytes (bony prolif-eration of affected joints) are often found, in contrast to thesoft-tissue swelling of rheumatoid arthritis.

Nonpharmacologic therapy is the foundation of the pharma-ceutical care plan and should be initiated before or concurrent-ly with pharmacologic therapy.

Based upon efficacy, safety, and cost considerations, sched-uled acetaminophen, up to 4 g/day, should be tried initially forpain relief in OA. If this fails, a nonsteroidal antiinflammatorydrug (NSAID) may be tried, if there are no contraindications

Strategies to reduce NSAID-induced GI toxicity include the useof nonacetylated salicylates, COX-2 selective inhibitors, or the ad-dition of misoprostol or a proton pump inhibitor. COX-2 selectiveinhibitors vary in their ability to prevent GI toxicity, and concom-itant use of aspirin largely negates their gastroprotective effects.

COX-2 selective inhibitors can increase the risk of cardiovascu-lar events. This may be a class effect, but the extent of this risk varies among COX-2 selective inhibitors, and traditionalNSAIDs may also pose risks. This hazard, in addition to the GItoxicity possible with all NSAIDs, underscores the importanceof using NSAIDs only as needed and after assessing the indi-vidual patients risk.

NSAIDs are associated with GI, renal, cardiovascular, liver, andcentral nervous system toxicity. Monitoring with completeblood count, serum creatinine, and hepatic transaminase levelscan be valuable in detecting potential toxicity.

Other agents useful in treating OA include topical NSAIDs orcapsaicin, opioids, glucosamine and chondroitin in combina-tion, and intraarticular injections of corticosteroids or hyaluronicacid.

Osteoarthritis (OA) is extremely common and poses tremendouspersonal, societal, and economic costs. Although OA has beendefined in different ways, one definition created by a consensuspanel reads

OA diseases are a result of both mechanical and biologic eventsthat destabilize the normal coupling of degradation and syn-thesis of articular cartilage, chondrocytes, and extracellularmatrix, and subchondral bone. Although they may be initiatedby multiple factors, including genetic, developmental, meta-bolic, and traumatic, OA diseases involve all of the tissues of the diarthrodial joint. Ultimately, OA diseases are manifestedby morphologic, biochemical, molecular, and biomechanicalchanges of both cells and matrix which lead to a softening,

fibrillation, ulceration, loss of articular cartilage, sclerosis andeburnation of subchondral bone, osteophytes, and subchon-dral cysts, when clinically evident, OA diseases are character-ized by joint pain, tenderness, limitation of movement,crepitus, occasional effusion, and variable degrees of inflam-mation without systemic effects. 1

This chapter first amplifies and clarifies the issues included in theabove definition and summarizes the basics of OA diagnosis. It thenfocuses on pharmacologic and nonpharmacologic treatments cur-rently in use for OA, as well as investigational agents. Becausemillions of persons take medications for OA, the overall risks posedby medications deserve thorough consideration, particularly by clinicians who treat and/or advise their patients on drug therapy forOA. This chapter examines the risks and benefits of OA treatments,with emphasis on those individuals who have the highest risk foradverse events, so as to help clinicians maximize benefit and reducerisks to their patients with OA.

EPIDEMIOLOGY

OA is the most prevalent of the rheumatic diseases and is responsi-ble for enormous disability and loss of productivity. 24 As the U.S.population continues to age, the economic impact of the lostproductivity and the quality of life limitations from disability willbecome even more pronounced.

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PREVALENCE BY AGE, SEX, AND RACE

The prevalence of clinician-diagnosed arthritis is estimated at 46million in the United States and is projected to increase to nearly 67million by 2030, of which 25 million are expected to report arthritis-related activity limitations. 5 The prevalence of OA is higher in olderage groups than in younger groups. In those younger than age 45 years, about one-fifth have OA of the hands, whereas of those ages75 to 79 years, 85% have OA of the hands. OA of the knee occurs inless than 0.1% of those ages 25 to 34 years, but in 10% to 20% of those ages 65 to 74 years.

OA severity also increases with age. 24 In persons between 65 and74 years of age, 33% have moderate to severe knee OA, and 50% havemoderate to severe hip OA. Women are more often affected by OA,with older women being twice as likely as men to have OA of the kneeand hands. 3 Women are also more likely to have inflammatory OA of the proximal and distal interphalangeal joints of the hands, giving riseto the formation of Bouchard and Heberden nodes, respectively (Fig.951). Knee OA appears to be twice as prevalent in black as opposedto white women. Chinese, East Indian, and Native American peoplehave lower incidences of hip OA than do whites.

INCIDENCE

The overall incidence of hip or knee OA is approximately 200 per100,000 person-years. Approximately one-half million symptomaticnew cases of OA are estimated to occur annually in the United States.

ETIOLOGY

The etiology of OA is multifactorial. Many patients have morethan one risk factor for the development of OA. The most commonrisk factors for the development of OA include obesity, previousoccupation, participation in certain sports, history of joint trauma,and a genetic predisposition to OA. Patients with osteoarthritis areless likely to have osteoporosis because heavy individuals havehigher bone density as a result of weight-bearing, but an increasedrisk of OA as a consequence of excessive joint loading. 3

OBESITY

Increased body weight is strongly associated with hip, knee, andhand OA, and obesity is regarded as the number one preventable

risk factor for OA. 68 Obesity often precedes OA and contributes toits development, rather than occurring as a result of inactivity from joint pain. In a three-decade Framingham Study, the highest quin-tile of body mass was associated with a higher relative risk of kneeOA (relative risk of 1.5 to 1.9 for men and 2.1 to 3.2 for women).Another study of 1,108 men in their twenties showed that a highbody mass index was associated with later development of kneeOA.8 The risk of developing OA increases by approximately 10%with each additional kilogram of weight, and in obese personswithout OA, weight loss of even 5 kg decreases the risk of future

knee OA by half. In addition to being a risk factor for OA, obesity isalso a predictor for eventual prosthetic joint replacement.

OCCUPATION, SPORTS, AND TRAUMA

Those participating in activities involving repetitive motion orinjury are at increased risk for developing OA. 6,10 Workers exposedto repetitive stress of the hands or lower limbs (e.g., shipyardworkers, carpenters, and agricultural workers) are at higher risk forOA of the stressed joints.

OA is associated with participation in activities such as wrestling,boxing, baseball pitching, cycling, and football, although recre-ational participants may not have the increased risk seen in theprofessional athlete. Risk for OA also depends on the type andintensity of physical activity. The Framingham Study showed thatheavy physical activity increases knee OA risk, especially in theobese, whereas moderate or light activity does not. 11 Interestingly,long-distance runners are not at higher risk of developing OA. 12

Age at injury does matter, because older individuals who damageligaments tend to develop OA more rapidly than young people witha similar injury. However, trauma that occurs early in life issignificant: The incidence of knee OA by age 65 years was more thandoubled for men who sustained a knee injury in adolescencecompared to those who had not. 13

Quadriceps strength is also related to knee OA and disability.Quadriceps weakness, once thought to result from disuse atrophy inOA patients, may precede and contribute to the development of OA, possibly through decreased knee stability. 14

GENETIC FACTORS

OA is a multifactorial disease in which many genes are consideredto play a role. Genetics may play different roles in different types of arthritis. 4 Heberden nodes are 10 times more prevalent in womenthan in men, for example, with a twofold higher risk if the womansmother had them. Genetic links also have been shown with OA of the first metatarsophalangeal joint and with generalized OA. Twinstudies indicate that OA can be attributed substantially to geneticfactors (39% to 65%, 60%, and 70% for hand, hip, and spine OA,respectively). 15

Genome-wide linkage studies (associating OA with a specificregion out of the total human genome) also have been used to searchfor the genetic bases for OA. 16 These studies have been carried outfor persons with OA who were all from unrelated families. Thesestudies, carried out in the United Kingdom (481 pedigrees), Finland(27 pedigrees), Iceland (329 pedigrees), and the United States (296pedigrees) show that there are dozens of loci that may include OA-linked genes. Searches for candidate genes (known proteins that areplausibly connected to OA, such as structural proteins in cartilage, orproteins that regulate chondrocyte function, such as interleukins andother signaling molecules) within the identified loci has providedsome promising clues. Variants in the interleukin-1 family (ininterleukin-1, in an interleukin-1 receptor antagonist, and in theinterleukin-1 receptor), in the interleukin-4 receptor, and in thesecreted frizzled-related protein (involved in regulation of chondro-

FIGURE 95-1. Heberden nodes (distal interphalangeal joint) noted on allfingers and Bouchard nodes (proximal interphalangeal joint) noted on mostfingers. (From Johnson BE. Arthritis: Osteoarthritis, Gout and Rheumatoid

Arthritis. In: South-Paul JE, Matheny SC, Lewis EL, eds. Current Diagnosisand Treatment in Family Medicine. New York: McGraw-Hill; 2004, p. 266,

p. 267.)


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genesis) all showed very significant associations with OA. Since then,one major collaborative research group used the more powerfultechnique of genome-wide association studies. 16 This group identi-fied the gene which codes for asporin, an extracellular matrixprotein, as being significant in OA. This was true as well for the genecoding for calmodulin, an intracellular regulator that has a largenumber of physiologic roles, including expression of the gene fortype II collagen. In vitro functional studies accompanying thesegenetic studies provided additional evidence of the importance of these genetic findings in OA.

Rapid progress in identifying and understanding the contribu-tions of genetic variation to the development of OA is being made.Especially for relatively common alleles coding for proteins thatregulate cartilage function, there is exciting potential for new drugsthat affect these regulatory proteins so as to prevent, mitigate, ortreat OA.

PATHOPHYSIOLOGY

OA falls into two major etiologic classes. Primary (idiopathic) OA,the most common type, has no identifiable cause. Subclasses of primary OA are localized OA, involving one or two sites, and generalized OA,affecting three or more sites. Erosive osteoarthritis isused to describe the presence of erosion and marked proliferation inthe proximal and distal interphalangeal joints of the hands. Secon-dary OA is that associated with a known cause such as rheumatoidor another inflammatory arthritis, trauma, metabolic or endocrinedisorders, and congenital factors. 3,4,17,18

Although OA was previously considered a wear-and-tear disease,increased knowledge about articular cartilage physiology has led toa more dynamic understanding of OA. Some changes in the OA joint may reflect compensatory processes to maintain function inthe face of ongoing joint destruction. Not only biomechanicalforces, but also inflammatory, biochemical, and immunologic fac-tors are involved. 1719 To aid in understanding the pathophysiology of OA, a brief review of the biochemistry and function of normalcartilage and of the diarthrodial joint is provided.

NORMAL CARTILAGE

Function, Structure, and Composition of CartilageArticular cartilage is a unique substance, with viscoelastic propertiesthat provide lubrication with motion, shock absorbency duringrapid movements, and load support. In synovial joints, articularcartilage is found between the synovial cavity on one side, and anarrow layer of calcified tissue overlying subchondral bone, on theother side (Fig. 952). 20 The layer of cartilage is narrow, with medialfemoral articular cartilage being approximately 2 to 3 mm thick inhumans. Despite this, healthy articular cartilage in weight-bearing joints withstands millions of cycles of loading and unloading each

year. Another key feature of cartilage is that it is almost frictionless;for example, in comparison to articular cartilage, Teflon produces20 times as much friction (has a 20-fold higher coefficient of slidingfriction). 21 Articular cartilage is also far superior to artificial jointsin regard to friction. 9 Articular cartilage enables movement in the joint, distributes load across joint tissues to prevent damage, andstabilizes the joint. Cartilage is easily compressed, losing up to 40%of its original height when a load is applied. Compression increasesthe area of contact and disperses force more evenly to underlyingbone, tendons, ligaments, and muscles.

The robustness of articular cartilage, its extremely low coefficientof friction, its compressibility, and other exceptional features are afunction of its unique structure. Cartilage is comprised of a com-plex, hydrophilic, extracellular matrix. It is approximately 75% to85% water, 2% to 5% chondrocytes (the only cells in cartilage), andcontains collagen proteins, smaller amounts of several other pro-teins, proteoglycans, and long hyaluronic acid molecules. 20 Theproteoglycans combine with long hyaluronic acid molecules to formlarge complexes, which are located within a meshwork of collagenfibers. Five types of collagen are located in cartilage, approximately 95% being type II collagen.

The collagen network supports and holds together the extracellu-lar matrix in which proteoglycanhyaluronic complexes are heldand in which chondrocytes are embedded. Cross-linking of type II

collagen fibrils with other matrix proteins also provides tensilestrength to cartilage and maintains its volume and shape. It is dueto the hydrophilic and anionic nature of the proteoglycanhyaluro-nate complexes in the collagen network that cartilage possesses theviscoelastic properties required for resiliency and load bearing.

Collagens also contribute to the function of joint cartilage inother ways, with orientation of collagen fibers being critical: super-ficial fibers are parallel to the surface, reducing friction and allowingforces to be dissipated; basal layer collagen fibers are perpendicularto the surface to anchor cartilage to the calcified zone or subchon-dral bony end plate. 17

It is not clear exactly how biomechanical signals, such as stress,strain, or cyclic loading and unloading during walking, translateinto biochemical signals which affect chondrocyte metabolism and

cartilage turnover. Regulation of chondrocyte function and cartilagemetabolism is complex. 1719 Insulin-like growth factor, epidermalgrowth factor, fibroblast growth factor, and other agents enhancechondrocyte proliferation and proteoglycan synthesis. By contrast,interleukin-1 and tumor necrosis factor- promote enzymes thatdegrade matrix proteins and suppress proteoglycan and collagensynthesis in the extracellular matrix. In healthy adult cartilage, asopposed to OA or during development, anabolic and catabolicinfluences are in homeostatic balance, resulting in a low metabolicrate and very slow turnover of cartilage. 9,20,22,23

Finally, it is important to note that adult articular cartilage isavascular, with chondrocytes nourished by synovial fluid. Withmovement and cyclic loading and unloading of joints, nutrients

FIGURE 95-2. Characteristics of osteoarthritis in the diarthrodial joint.(Courtesy of Dr. D. Gotlieb.)

Regular normalsubchondral bone texture

Normal, thick, smootharticular cartilage

Smooth joint margin

Normal, single-celllayered synovium

Thin, even capsule

Irregular thickeningand remodeling ofsubchondral bone,with sclerosis and cysts

Thickening, distortion,and fibrosis of thecapsule

Fibrillation, loss ofvolume, and degradationof articular cartilage

Modest, patchy, chronicsynovitis

Osteophytosis andsoft tissue growth atjoint margin


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flow into the cartilage, whereas immobilization reduces nutrientsupply. This is one of the reasons that normal physical activity isbeneficial for joint health.

OSTEOARTHRITIC CARTILAGE

Important contributors to the development of OA are localmechanical influences, genetic factors, inflammation, and aberrantchondrocyte function leading to loss of articular cartilage. At amolecular level, OA pathophysiology involves the interplay of dozens, if not hundreds, of extracellular and intracellular moleculeswith roles including chondrocyte regulation, proteolytic degrada-tion of cartilage components, and interactions between articularcartilage, underlying subchondral bone, and the joint synovium.

OA most commonly begins with damage to articular cartilage,through trauma or other injury, excess joint loading from obesity orother reasons, or instability or injury of the joint that causesabnormal loading. 15 Although normal cartilage is in a state of slowturnover (see Normal Cartilage section), damage to cartilage dra-matically increases the metabolic activity of chondrocytes. Thisleads to increased synthesis of matrix constituents, with swelling of cartilage. This hypertrophic phase is thought to represent a repara-tive response to damage, stimulated by the peptide annexin, par-athyroid hormone-related protein, and other effectors. 9 Thishypertrophic response, however, does not restore the cartilage tonormal, but instead is the first step in a process ultimately leading tofurther loss of cartilage.

Following the hypertrophic phase, there is increased turnover(increased collagen synthesis and destruction), but with destructionoutpacing formation, with net loss of cartilage. Key players in thisdestruction are the matrix metalloproteinases (MMPs), specifically MMPs 1, 3, 13, and 28. 9 In normal cartilage, activities of theseenzymes are blocked by tissue inhibitors of metalloproteinases. InOA cartilage, however, there is increased expression and synthesis of MMPs, resulting in the MMPtissue inhibitors of metalloproteinasebalance tilting toward proteolysis. In addition, chondrocytes con-tribute to loss, secreting MMPs in response to inflammatory medi-ators present in OA (interleukin-1 and tumor necrosis factor- ).

Also, chondrocytes in OA cartilage undergo apoptosis, likely as aresult of induction of nitric oxide synthase and production of toxicmetabolites. 15,20 This leaves fewer chondrocytes to synthesize matrixcomponents. In addition, OA chondrocytes are hyporesponsive tothe anabolic stimulus transforming growth factor- .20 The netresult of all of these processes is that there is a progressive cycle of cartilage destruction and loss of chondrocytes.

In addition to changes taking place in OA cartilage, there is also arole in OA for the subchondral bone adjacent to articular cartilage.Subchondral bone undergoes pathologic changes that may precede,coincide with, or follow damage to the articular cartilage. Thisdamage to subchondral bone may play an essential role in allowingdamage to articular cartilage to progress. 9,18,24,25 In OA, subchondralbone releases vasoactive peptides and MMPs. Neovascularization

and subsequent increased permeability of the adjacent cartilage alsooccurs and contributes further to cartilage loss. 18,25

Substantial loss of cartilage causes joint space narrowing andleads to a painful, deformed joint. Furthermore, the remainingcartilage softens and develops fibrillations (vertical clefts into thecartilage), and there is splitting, further loss of cartilage, andexposure of underlying bone. 26 As cartilage is destroyed and theadjacent subchondral bone undergoes pathologic changes, cartilageis eroded completely, leaving denuded subchondral bone, whichbecomes dense, smooth, and glistening (eburnation). A more brit-tle, stiffer bone results, with decreased weight-bearing ability anddevelopment of sclerosis and microfractures. New bone formations,or osteophytes also appear at joint margins distant from cartilage

destruction, and are thought to arise from local and humoralfactors. There is direct evidence that osteophytes can help stabilizeosteoarthritic joints. 27

Accompanying the changes in cartilage and subchondral bone,local inflammatory changes and pathologic changes can occur in the joint capsule and synovium. Infiltration of the synovium with Tcells with T-helper type 1 phenotype occurs, as well as the appear-ance of immune complexes. 15 Contributors to this inflammationmay include crystals or cartilage shards in synovial fluid. Withincreased levels of interleukin-1, prostaglandin E 2, tumor necrosis

factor- , and nitric oxide observed in synovial fluid, these agentscould also play a role. 27 With inflammatory changes in the syn-ovium, effusions and synovial thickening occur.

The pain of OA is not related to the destruction of cartilage,but arises from the activation of nociceptive nerve endings withinthe joint by mechanical and chemical irritants. 3 OA pain may resultfrom distension of the synovial capsule by increased joint fluid,microfracture, periosteal irritation, or damage to ligaments, syn-ovium, or the meniscus.

CLINICAL PRESENTATION

CLINICAL PRESENTATION OF OSTEOARTHRITIS

General The patient may have mild symptoms for months to years

prior to seeking medical care; self-treatment is common formild symptoms.

Typical age at presentation is usually >50 years.Symptoms Nearly all patients have pain in the affected joints, with the

hands, knees, and hips being the most common locations. Pain is most commonly associated with motion, but pain in

late disease can occur with rest. Joint stiffness resolves with motion; recurs with rest.Signs Joint stiffness with or without joint enlargement. Crepitus, a crackling or grating sound heard with joint move-

ment that is caused by irregularity of joint surfaces may bepresent.

Limited range of motion that may be accompanied by jointinstability.

Late-stage disease is associated with joint deformity (Fig. 953).Laboratory Tests There are no specific laboratory tests useful in the diagnosis.Other Radiologic TestsPlain Radiographic Films Joint space narrowing, appearance of osteophytes in moderate

disease (Fig. 954). Abnormal alignment of joints and joint effusion in late disease.

DIAGNOSIS

The diagnosis of OA is made through history, physical examina-tion, characteristic radiographic findings, and laboratory testing. 3,24

The major diagnostic goals are (a) to discriminate between primary and secondary OA, and (b) to clarify the joints involved, severity of joint involvement, and response to prior therapies, providing a basisfor a treatment plan. The American College of Rheumatology haspublished traditional diagnostic criteria and also decision trees forOA diagnosis.24 As for all guidelines, the authors stress these are for


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assisting the clinician rather than replacing clinical judgment. Forexample, traditional criteria are as follows: (a) For hip OA, a patientmust have pain in the hip and at least two of the following three: anerythrocyte sedimentation rate


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The benefits of patient education have been documented in avariety of programs, including those using monthly telephonecontact between trained volunteers and individuals with OA. 2

Volunteers speak with patients about symptoms, function, drugs,and clinic visits, resulting in improved pain and functional status atlow cost. Likewise, OA patients participating in the program reportdecreases in joint pain and OA-related clinic visits, and improvedphysical activity and quality of life.

Diet

Excess weight increases the biomechanical load on weight-bearing joints and is the single best predictor of need for eventual jointreplacement. 4,8,33,36 Even a 5-kg weight loss can decrease the load ona weight-bearing joint. Weight loss is associated with decreasedsymptoms and disability, although results are variable. 36,37 At leastone randomized, controlled trial has demonstrated improvement in

FIGURE 95-5. Treatment algorithm for osteoarthritis. (COX, cyclooxygenase; GI, gastrointestinal; IA, intraarticular; NSAID,nonsteroidal antiinflammatory drug; OA, osteoarthritis; PPI, proton pump inhibitor.)

Continuetherapy

Continuetherapy

No

Analgesics Oral: acetaminophen Topical capsaicin

Consider glucosamine sulfate/ chondroitin sulfate

NSAIDSelect product based on: Cost (generics) Prior peptic ulcer disease

or gastrointestinalintolerance to NSAID

History of aspirin orNSAID allergy

History of cardiovasculardisease, congestiveheart failure, renal orhepatic dysfunction,hypertension

History of bleedingdisorders, alteredplatelet function

Concomitant medications

For these patients Age >65 years Comorbid medical

conditions Oral glucocorticoid use History of peptic ulcer

disease History of upper GI bleed Oral anticoagulant use

Select:COX-2 inhibitor

or

NSAID + PPIor

NSAID + misoprostolor

COX-2 inhibitor + PPI

Yes

Yes

No

Pain attributed to OAjoint involvement

Evaluate course andmanage

Bursitis Tendonitis Muscle pain

Nondrug therapyas needed and incombination withdrug therapy

Rest Physical therapy

range of motion,muscle strengthening

Dietary modifications Assistive devices Patient education

Adequate response?

NoYesAdequate response?

No

No

Yes

Yes

Adequate response?

Try another NSAID

Trial 12 wk for pain;24 wk if inflammation

persists

Consider narcotic analgesics,hyaluronate injections (IA),

and evaluate for surgery

Continuetherapy

Adequate response?


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pain and self-reported physical function using a combination of modest weight loss (5%) and exercise. 38 Although dietary interven-tion for overweight OA patients is reasonable, weight loss usually requires a motivated patient and a structured weight-loss program.

Physical and Occupational Therapy Physical therapywith heat or cold treatments and an exerciseprogramhelps to maintain and restore joint range of motion andto reduce pain and muscle spasms. Warm baths or warm watersoaks may decrease pain and stiffness. Heating pads should be usedwith caution, especially in the elderly. Patients should be warnednot to fall asleep on the heat source or to lie on it for more than brief periods to avoid burns.

Exercise programs and quadriceps strengthening can improvephysical functioning and can decrease disability, pain, and analgesicuse by OA patients. 2,38,39 Isometric exercise is preferred over isotonicexercise because the latter can aggravate affected joints. Exercisesshould be taught and then observed before the patient exercises athome, ideally three to four times daily. The patient should beinstructed to decrease the number of repetitions if severe paindevelops with exercise.

The decision about whether to encourage walking should bemade on an individual basis. With weak or deconditioned muscles,the load is transmitted excessively to the joints, so weight-bearingactivities can exacerbate symptoms. However, avoidance of activity by those with hip or knee OA leads to further deconditioning orweight gain. A program of patient education, muscle stretching andstrengthening, and supervised walking can improve physical func-tion and decrease pain in patients with knee OA. 2,38,39 Referral to thephysical and/or occupational therapist is especially helpful forpatients with functional disabilities. The therapist can assess musclestrength and joint stability, and recommend exercises and methodsof protecting the affected joint from excessive forces. The therapistcan also provide assistive and orthotic devices, such as canes,

walkers, braces, heel cups, splints, or insoles for use during exerciseor daily activities.

Surgery Surgery can be recommended for OA patients with functionaldisability and/or severe pain unresponsive to conservative therapy.Criteria for total joint replacement (arthroplasty) of the knee weredeveloped at an National Institutes of Health consensus confer-ence.40 Likewise, criteria for total hip replacement, as well as asummary of clinical outcomes resulting from this procedure havebeen published. 41 These hip and knee replacement recommenda-tions have been based on critical review of the literature as well ason expert opinion. For patients with advanced disease, a partial ortotal arthroplasty can relieve pain and improve motion, with thebest outcomes after hip or knee arthroplasty.

Other surgical options are also available. Arthrodesis (joint fusion)can reduce pain but will restrict motion, and may be appropriate forsmaller joints that are causing intractable pain. For patients with mildknee OA, an osteotomy (removal of bony tissue) may correct themisalignment of genu varum (bowlegged knees) or genu valgum(knock-knees). In addition, osteotomies of the pelvis or femur canameliorate joint misalignment in hip OA, subsequently slowing pro-gression of disease. Although knee arthroscopy or lavage have beenrecommended for short-term relief of pain, these procedures appearto be equivalent to sham surgery. 39 Experimental but potentially restorative approaches involve soft-tissue grafts, chondrocyte trans-plantation, gene therapy, and use of growth factors or artificialmatrices. 42 Cartilage-restoration approaches are investigational, andresults regarding pain control and joint function have been mixed.

PHARMACOLOGIC THERAPY Drug therapy in OA is targeted at relief of pain. OA is commonly seen in older individuals who have other medical conditions, and

TABLE 95-1 Summary of Recommendations for Osteoarthritis

RecommendationLevel of Evidence a

Grade of Recommendation b

1. Patientphysician communication Patients should be fully informed about evolving information regarding the benefits and risksof their treatment options.

3 C

2. Indications NSAIDs and coxibs are generally more effective and preferred by patients over acetamino-phen, although a trial of the latter is warranted for some patients. Topical NSAIDformulations may confer benefit in knee OA.

1 A

3. GI toxicity In patients with risk factors for PUB, a coxib is still the antiinflammatory drug of choice,depending on the patients cardiovascular risks. High-risk patients who must use nonselec-

tive NSAIDs should have a PPI.

1 A

4. Renal Before starting an NSAID or coxib, determine renal status and creatinine clearance in patientsolder than 65 years and in those with comorbid conditions that may affect renal function.

3 C

Advise patients that if they cannot eat or drink that day, they should withhold that days doseof NSAID/coxib.

4 D

5. Hypertension In patients receiving antihypertensive drugs, measure blood pressure within a few weeks afterinitiating NSAID/coxib therapy and monitor appropriately; drug doses may need adjustment.

1 A

6. Cardiovascular Patients taking rofecoxib have been shown to have an increased risk of CV events. Currentdata suggest that this increased CV risk may be an effect of the NSAID/coxib class. Physiciansand patients should weigh the benefits and risks of NSAID/coxib therapy.

1 A

7. Geriatric consideration NSAIDs/coxibs should be used with caution in elderly patients, who are at the greatest risk forserious GI, renal, and CV side effects.

3 C

8. Pharmacoeconomics Although the data are ambiguous, coxibs may be more cost-effective than traditional NSAID+ proprietary PPI in high-risk patients.

3 C

CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug; OA, osteoarthritis; PPI, proton pump inhibitor; PUB, perforations, ulcers, and bleeds.aLevels of evidence: 1A, meta-analysis of randomized, controlled trial; 1B, at least one randomized, controlled trial; 2A, at least one controlled study without randomization; 3, descriptive scomparative, correlation, or case-control studies; 4, expert committee reports or opinions and/or clinical experience of respected authorities. bGrades of recommendation: A, Category 1 evidence; B, Category 2 evidence or extrapolated recommendation from Category 1 evidence; C, Category 3 evidence or extrapolated recommenda1 or 2 evidence; D, Category 4 evidence or extrapolated recommendation from Category 2 or 3 evidence. From Tannenbaum H, Bombardier C, Davis P, Russell AS, Third Canadian Consensus Conference Group. An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Consensus Conference. J Rheumatol 2006;33:140157. Reprinted with permission from the Journal of Rheumatology and the author.


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OA treatment is often long-term. As such, a conservative approachto drug treatment, focusing on the needs of the individual patient,is warranted (see Fig. 955). For mild or moderate pain, topicalanalgesics or acetaminophen can be used. If these measures fail, orif there is inflammation, NSAIDs may be useful. Even when drugtherapy is initiated, appropriate nondrug therapies should be con-tinued and reinforced. Nondrug modalities are the cornerstone of OA management and may provide as much relief as drug therapy.

AcetaminophenPlace in Therapy The American College of Rheumatology

recommends acetaminophen as first-line drug therapy for pain man-agement in OA because of its relative safety, efficacy, and lower costcompared to NSAIDs. 2,34,43 Pain relief with acetaminophen has beenreported as similar to that obtained with aspirin, naproxen, ibupro-fen, and other NSAIDs, although many patients respond better toNSAIDs.2,43,44 In addition to guidelines from the American College of Rheumatology, recommendations for OA management have beenpublished by The European League Against Rheumatism, and areview of the evidence and suggestions for OA management havebeen formulated by rheumatology faculty in the Medical ResearchCouncil (UK) Environmental Epidemiology Unit. 2,45,46 These guide-lines stress the importance of acetaminophen as first-line drug ther-apy for OA.

Pharmacology and Mechanism of Action Acetaminophen isunderstood to act within the central nervous system by inhibitingsynthesis of prostaglandins, agents that enhance pain sensations.Acetaminophen prevents prostaglandin synthesis by blocking theaction of central cyclooxygenase. Acetaminophen is well absorbedafter oral administration, with a bioavailability of 60% to 98%. Itachieves peak concentrations within 1 to 2 hours, is inactivated inthe liver by conjugation with sulfate or glucuronide, and its metab-olites are renally excreted.

Efficacy Comparable relief of mild to moderate OA pain has beendemonstrated for acetaminophen at 2.6 to 4 g/day, aspirin 650 mgfour times daily, and NSAIDS, including ibuprofen at 1,200 or 2,400mg daily, and naproxen 750 mg daily. 2,43,47 Although studies haveshown comparable efficacy for acetaminophen and NSAIDs, severalothers have reported that patients experience better pain control withNSAIDs than with acetaminophen. 2,44,47 Patients with OA have beenshown to prefer NSAIDs compared to acetaminophen in clinicaltrials, but when queried using a questionnaire that included consider-ations of side effects, NSAIDs were less preferred by patients. 48

Adverse Effects Although acetaminophen is one of the safestanalgesics, its use carries some risks, primarily hepatotoxicity, andpossibly renal toxicity with long-term use. 2,7,43,49 With acetamino-phen overdose, serious hepatotoxicity, including fatalities, have beenwell documented. (See Chap. 10 for treatment of acetaminophenoverdose.) In a study of normal, healthy volunteers administeredacetaminophen 4 g/day (1 g every 6 hours), alone or with concomi-

tant opioid therapy, for 14 days, elevations of alanine aminotransfer-ase at levels above three times the upper limits of normal were foundin 31% to 44% of patients, depending on treatment group. 50 None of these participants had clinical symptoms of acute liver disease.Although the results of this study are not robust enough to alter thecurrent standard dosing recommendations, it serves as an importantreminder that the maximum dose of acetaminophen should be notbe exceeded in any patient population, and that chronic use of eventhe maximum 4 g/day can affect the liver. Acetaminophen should beused cautiously in patients with liver disease or in those who abusealcohol. Acute liver failure has been reported in patients taking lessthan 4 g/daily. 51 The most common risk factor for liver failure inthese patients was chronic alcohol intake. The FDA has recom-

mended that chronic alcohol users (three or more drinks daily)should be warned regarding an increased risk of liver damage or GIbleeding with acetaminophen. Other individuals do not appear to beat increased risk of GI bleeding.

The National Kidney Foundation strongly discourages the use of nonprescription combination analgesic products (e.g., acetamino-phen and NSAIDs) because this is associated with an increasedprevalence of renal failure. 49 Finally, patients should be warnedabout potential toxicity if they inadvertently ingest more than therecommended dose when using both nonprescription and prescrip-

tion products containing acetaminophen.Recent prospective cohort studies in women and in men havesuggested that regular long-term use of acetaminophen is associatedwith development of hypertension, although the risk appears lessfor men. 52,53 However, these studies were not designed to evaluatethe effects of analgesics on the risk of developing hypertension, butwere part of the Nurses Health Study and Physicians Health Study.Furthermore, patients taking analgesics for OA or other pain may have other risk factors for the development of hypertension, includ-ing advanced age, uncontrolled pain, use of other medications,obesity, and comorbid medical illness. Prospectively designed trialsare needed to determine if the risk of developing hypertension isdefinitively linked to analgesic use, including acetaminophen.

DrugDrug Interactions and DrugFood Interactions Druginteractions with acetaminophen can occur; for example, isoniazid canincrease the risk of hepatotoxicity. Chronic ingestion of maximal dosesof acetaminophen may intensify the anticoagulant effect in patientstaking warfarin; such individuals may need closer monitoring.Although food decreases the maximum serum concentration of aceta-minophen by approximately half, the overall efficacy is unchanged.

Dosing and Administration When used for chronic OA, aceta-minophen should be administered in a scheduled manner. It may betaken with or without food. Acetaminophen can be taken at 325 to650 mg every 4 to 6 hours, but total dose must not exceed 4 g daily (see Adverse Effects above). If acetaminophen is used in the settingof chronic alcohol intake or in those with underlying disease, theduration should be limited and the dose should not exceed 2 g daily.

Nonsteroidal Antiinflammatory DrugsPlace in Therapy The American College of Rheumatology rec-ommends consideration of NSAIDs for OA patients in whomacetaminophen is ineffective. NSAIDs have analgesic properties atlower doses and antiinflammatory effects at higher doses. NSAIDsall display comparable analgesic and antiinflammatory efficacy andare similarly beneficial in OA (Table 952). 54,55

Pharmacology and Mechanism of Action Blockade of pros-taglandin synthesis by inhibiting cyclooxygenase enzymes (COX-1and COX-2) is thought to account for the ability of NSAIDs torelieve pain and inflammation (Fig. 956). 47,5557 Because nonspe-cific NSAIDs and COX-2 selective inhibitors have similar efficacy,drug selection often depends on toxicity and cost. Increasing con-cern regarding safety of all NSAIDs, and particularly COX-2 selec-tive inhibitors, has made patient safety paramount in drug selection.The next section will review the differences between nonspecificNSAIDs and COX-2 selective inhibitors. 47,5557

Nonspecific NSAIDs and COX-2 Selective Inhibitors TheCOX-1 enzyme participates in housekeeping or routine physiologicfunctions such as generation of gastroprotective prostaglandins topromote gastric blood flow and bicarbonate generation (see Fig. 956).47,5557 COX-1 is expressed constitutively not only in gastricmucosa, but also in vascular endothelial cells, platelets, and renalcollecting tubules, so that COX-1generated prostaglandins and


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thromboxane also participate in hemostasis and renal blood flow. Incontrast, the COX-2 enzyme is not as widely expressed in most body tissues, but is rapidly induced by inflammatory mediators, localinjury, and cytokines, including interleukins, interferon, and tumornecrosis factor (see Fig. 956). 47,5557 Prostaglandins made by COX-2contribute to pain sensations in OA and other conditions. Prostaglan-dins made by the COX-2 enzyme, including prostacyclin (prostaglan-din I 2) are also implicated in some physiologic processes, includingrenal function, tissue repair, reproduction, and development.

Nonspecific NSAIDs block both COX-1 and COX-2 enzymes. Inview of the above roles of the COX enzymes, COX-1 blockade thatoccurs with nonspecific NSAIDs is potentially undesirable and canlead to GI ulcers and increased bleeding risk by inhibiting plateletaggregation. 47,5558 Specific blockade of COX-2 activity could thusreduce prostaglandins, inflammation, and pain, without blockingeffects of COX-1. This desirable quality led to development of specificCOX-2 selective agents (coxibs). These agents are efficacious inrelieving OA and other pain and some do have improved GI safety.

Celecoxib and rofecoxib were the first two COX-2 selective agentsmarketed and have been widely used for pain relief in OA and otherconditions.

It is now appreciated that the COX-2 enzyme may play an impor-tant physiologic role in normal hemostasis. The COX-2 enzyme,found in blood vessel endothelial cells, leads to production of prosta-glandin I 2 (prostacyclin), which has antithrombotic effects. TheCOX-1 found in platelets forms thromboxane A 2 a prothromboticmolecule. As far back as 1999, and continuing today, some research-ers postulate that blocking COX-2 alone could upset the hemostaticbalance, in favor of thromboxane A 2, with prothrombotic eventspossible.57,59 Although this explanation is plausible and is appealing inits simplicity, it has not been proven. Thus, whether the prothrom-botic imbalance explanation accounts for the increased cardiovascu-lar risk seen with COX-2 selective inhibitors is unknown. 57,59,60

Rofecoxib was withdrawn from the market in 2004 because of increased cardiovascular events, and celecoxib is less often used nowand carries a black box warning for cardiovascular and GI risks, as

TABLE 95-2 Medications Commonly Used in the Treatment of Osteoarthritis

Medication Dosage and Frequency Maximum Dosage (mg/day)Oral analgesicsAcetaminophen 325650 mg every 46 hours or 1 g three to four times/day 4,000Tramadol 50100 mg every 46 hours 400Acetaminophen/codeine 3001,000 mg/1560 mg every 4 hours as needed 4,000 mg/360 mga

Acetaminophen/oxycodone 325650 mg/2.510 mg every 6 hours as needed 4,000 mg/40 mga

Topical analgesicsCapsaicin 0.025% or 0.075% Apply to affected joint 34 times per day Nutritional supplements

Glucosamine HCl/chondroitin sulfate 500 mg/400 mg three times/day 1,500/1,200Nonsteroidal antiinflammatory drugs (NSAIDs)Carboxylic acidsAcetylated salicylatesAspirin, plain, buffered, or enteric-coated 325650 mg every 46 hours for pain; antiinflammatory doses start at 3,600 mg/day

in divided doses3,600 b

Nonacetylated salicylatesSalsalate 5001,000 mg two to three times a day 3,000 b

Diflunisal 5001,000 mg two times a day 1,500Choline salicylatec 5001,000 mg two to three times a day 3,000c

Choline magnesium salicylate 5001,000 mg two to three times a day 3,000c

Acetic acidsEtodolac 8001,200 mg/day in divided doses 1,200Diclofenac 100150 mg/day in divided doses 200Indomethacin 25 mg two to three times a day; 75 mg SR once daily 200; 150Ketorolacd 10 mg every 46 hours 40Nabumetonee 5001,000 mg one to two times a day 2,000

Propionic acidsFenoprofen 300600 mg three to four times a day 3,200Flurbiprofen 200300 mg/day in two to four divided doses 300Ibuprofen 1,2003,200 mg/day in three to four divided doses 3,200Ketoprofen 150300 mg/day in three to four divided doses 300Naproxen 250500 mg twice a day 1,500Naproxen sodium 275550 mg twice a day 1,375Oxaprozin 6001,200 mg daily 1,800

FenamatesMeclofenamate 200400 mg/day in three to four divided doses 400Mefenamic acid f 250 mg every 6 hours 1,000

OxicamsPiroxicam 1020 mg daily 20Meloxicam 7.5 mg daily 15

CoxibsCelecoxib 100 mg twice daily or 200 mg daily 200 (400 for RA)

RA, rheumatoid arthritis; SR, sustained release.a Maximum dosage in combination product limited by acetaminophen maximum of 4,000 mg/day. bMonitor serum salicylate levels over 33.6 g/day.c Only available as a liquid; 870 mg salicylate/5 mL.d Not approved for treatment of osteoarthritis for more than 5 days.e Nonorganic acid but metabolite is an acetic acid. f Not approved for treatment of osteoarthritis.


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do other NSAIDs at this time. Although new coxibs are in develop-ment and some are in use in Canada and Europe, celecoxib is theonly remaining coxib available in the United States.

Pharmacokinetics The various NSAIDs exhibit several pharma-cokinetic similarities, including high oral availability, high proteinbinding, and absorption as active drugs (except for sulindac andnabumetone, which require hepatic conversion for activity). Themost important difference in NSAIDs is a serum half-life rangingfrom 1 hour for tolmetin to 50 hours for piroxicam, impacting thefrequency of dosing and, potentially, compliance with therapy. 47

Elimination of NSAIDs largely depends on hepatic inactivation,with a small fraction of active drug being renally excreted. NSAIDspenetrate joint fluid, reaching approximately 60% of blood levels. 47

Efficacy Prescription-strength NSAIDs are often prescribed forOA patients after treatment with acetaminophen proves ineffectiveor for patients with inflammatory OA. 61 All NSAIDs and aspirin havesimilar analgesic and antiinflammatory effects, but these agents areonly modestly more effective than acetaminophen. 34,47,54,61,62 In eval-uating efficacy in OA studies, commonly used end points includepain on the visual analog scale (0 to 100), and the patients globalassessment of disease activity and functional status, assessed usingthe Western Ontario and McMaster Universities OsteoarthritisIndex questionnaire. 63 Because of differences among study designsand patient populations, comparisons between efficacies of treat-ments are best made within the same study.

A systematic review of studies of NSAIDs for OA found noevidence to support a definitive ranking of NSAID efficacy. 62 How-ever, individual patient response does differ among NSAIDs. Theprescriber often relies on personal experience in choosing an NSAID.To assess efficacy in the individual patient, a trial that is adequate intime (2 to 3 weeks) and dose is needed. If the first trial fails, anotherNSAID in the same or another chemical class can be tried until aneffective agent is found (see Table 952). 34,47,54,61,62 Patients mustunderstand this approach, appreciate the necessity of adherence tomedication therapy throughout this trial period, and actively partici-pate in assessment of drug efficacy. Combining two NSAIDs increasesadverse effects without providing additional benefit.

COX-2 selective inhibitors demonstrate similar analgesic benefitsto traditional NSAIDs and to each other. 64 Newer COX-2 selectiveinhibitors in development have also shown similar efficacy totraditional NSAIDs. Lumiracoxib 100 to 400 mg/day 6567 and etori-coxib 30 to 90 mg/day 6870 provided significant relief in OA com-pared to placebo and showed efficacy similar to other comparator

NSAIDs (ibuprofen 2,400 mg/day, naproxen 1,000 mg/day, ordiclofenac 150 mg/day). The newer COX-2 selective inhibitors havealso been compared to older COX-2 selective inhibitors: Etoricoxib30 mg/day and celecoxib 200 mg/day were similarly efficacious inOA and superior to placebo. 71 Lumiracoxib 100 to 200 mg/day wassimilarly efficacious as celecoxib 200 mg/day in treating OA. 65,66,72

Given that no proven efficacy differences exist among all tradi-tional and COX-2 selective NSAIDs in OA, it is especially importantthat potential toxicities of these agents be rigorously examined.These safety issues are reviewed below.

Adverse EffectsGastrointestinal Effects of Nonselective NSAIDs. The mostcommon adverse effects of NSAIDs involve the GI tract, contribut-ing to many treatment failures. 55 Minor complaintsnausea, dys-pepsia, anorexia, abdominal pain, flatulence, and diarrheaaffect10% to 60% of patients. To minimize these symptoms, NSAIDsshould be taken with food or milk, except for enteric-coatedproducts, which should not be taken with milk or antacids.

All NSAIDs have the potential to cause GI bleeding. 55 Un-ionizedNSAIDs enter gastric mucosal cells, release hydrogen ions, and areconcentrated (ion trapped) within cells, with cell death or dam-age. Gastric mucosal injury can also result from NSAID inhibitionof gastroprotective prostaglandins.

The most common sites of GI injury are the gastric and duodenalmucosae. 55 The incidence of gastric ulcers with NSAID use is approx-imately 11% to 13%, and that for duodenal ulcers is 7% to 10%.Serious GI complications are associated with NSAIDs, includingperforations, gastric outlet obstruction, and bleeding. These impor-tant GI complications occur in 1.5% to 4% of patients per year.NSAIDs are so widely used that these small percentages translate intosubstantial morbidity and mortality. 2,55 Moreover, the risk increasesto 9% per year for patients with the risk factors of advanced age,history of peptic ulcer or GI bleeding, or cardiovascular disease.Consequently, about 16,500 deaths are associated annually withNSAID use in rheumatoid arthritis or OA patients. A recent reviewthat included a total of 1.3 million patients taking traditional NSAIDSfor at least 2 months showed that 1 in 5 developed endoscopically evident ulcers, 1 in 70 had ulcer symptoms, 1 in 150 developed a GItract perforation, and 1 in 1,200 died. 34

A key part of the clinicians decision regarding starting NSAIDtherapy for an OA patient is the patients risk for GI toxicity.Increased GI risk is seen for those with a history of complicated ulcer(relative risk [RR] 13.5), use of multiple NSAIDs, including aspirin(RR = 9), use of high-dose NSAID (RR = 7), use of anticoagulant(RR = 6.4), age older than 70 years (RR = 5.6), and concomitant useof corticosteroids (RR = 2.2). 34

For patients taking NSAIDs, there is a poor correlation between GIulceration and GI symptoms. The American College of Rheumatol-ogy recommends a complete blood count yearly to detect a silentbleeding ulcer characterized by an asymptomatic decline in hemato-crit.73 Fecal occult blood is an unreliable predictor of complications.

Medications are available for the treatment or prevention of ulcers in high-risk patients. 2,74 Misoprostol protects against bothgastric and duodenal NSAID-induced ulcers, and more impor-tantly, their associated serious GI complications (perforations, gas-tric outlet obstruction, and bleeding). 74 Unfortunately, misoprostolfrequently causes diarrhea and abdominal cramps. Because of itsabortifacient properties, misoprostol is contraindicated in preg-nancy and in women of childbearing age who are not maintainingadequate contraception. It must be dispensed in its original con-tainer, which carries a warning for these individuals. Misoprostol isalso available in a combination product with diclofenac, whichbears the same restrictions as misoprostol alone.

Other agents have been evaluated in attempts to prevent NSAID-induced gastropathy. Proton pump inhibitors (PPIs) appear to be

FIGURE 95-6. Pathway of synthesis for prostaglandins and leukotrienes.COX-1 and COX-2 are cyclooxygenase 1 and 2 enzymes. The minus ()sign indicates inhibitory influence. Prostaglandins include PGE2 and PGI2,the latter also known as prostacyclin.

Membrane phospholipids

Arachidonic acid Lipoxygenase Leukotrienes

Phospholipase A2

Cyclooxygenase-2Inducible with inflammation;

constitutive

Cyclooxygenase-1Constitutive

(Homeostatic)

GastroprotectionPlatelet aggregation

Renal function

Pain, fever, renalfunction, tissue repair,

reproduction, development,other

ProstaglandinsThromboxanes

Prostaglandins

CorticosteroidsNSAIDs

COX-2inhibitors


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effective, although neither sucralfate or H 2 antagonists have beenshown to be protective. In a recent meta-analysis that included 156studies, misoprostol, COX-2 selective NSAIDs, and probably PPIs,were judged to significantly reduce the risk of symptomatic ulcers.Further work is required to strengthen the case for PPIs ability toreduce the risk of serious NSAID-induced GI complications. A newrandomized, controlled trial has lent weight to this idea by showingthat for persons who have experienced a prior GI bleed, thecombination of a PPI with celecoxib substantially decreased the riskof future bleeding ulcers compared to celecoxib alone. 75

At present, use of either a COX-2 selective inhibitor, or an NSAIDin combination with either a proton pump inhibitor or misoprostolis recommended for treatment of OA patients who are at high riskfor GI complications by OA authorities in the United States,Canada, and Europe. 24,34,45

Gastrointestinal Effects of COX-2 Selective Inhibitors. Cele-coxib, rofecoxib, and all COX-2 selective inhibitors studied to datehave demonstrated fewer endoscopically observed ulcers compared totraditional NSAIDs. Such ulcers are relatively common with NSAIDsand are often asymptomatic. Data regarding the rare but serious GIcomplications of perforation, obstruction, or bleeding are moredifficult to obtain as very large numbers of patients are required forsuch studies.

To evaluate the risk of serious GI complications with celecoxib,Celecoxib Long-term Arthritis Safety Study (CLASS) investigatorsused celecoxib (400 mg twice daily, or twice the highest FDA-approved dose) compared to diclofenac and ibuprofen at standarddose. Celecoxib use was reported to be associated with a reducedincidence for the combined end point of symptomatic ulcers andulcer complications (perforations, gastric outlet obstruction, orbleeding) after 6 months. 76 However, this difference was not seen at1 year and was not seen in patients taking aspirin. Furthermore,there was no reduction in the category of perforations, gastricoutlet obstruction, or bleeding itself, but only if symptomaticulcers were also included. Concerns have been raised by the FDA,which concluded that although there were trends favoring cele-coxib, this drug did not show clear statistical superiority overnonspecific NSAIDs for clinically significant upper GI events.

In celecoxibs favor, its use was associated with decreased outpa-tient physician claims for upper GI symptoms compared with otherprescription nonspecific NSAIDs. Celecoxib was also comparable toa combination of diclofenac and misoprostol in reducing the risk of recurrent GI bleeding in patients who had a prior GI bleed. 77

Celecoxib remains on the market and is an alternative to traditionalNSAIDs for those at high risk for GI toxicity.

GI safety for rofecoxib was evaluated in the Vioxx Gastrointesti-nal Outcomes Research (VIGOR) study, where patients were ran-domized to receive rofecoxib 50 mg daily or naproxen 500 mg twicedaily; use of concomitant aspirin was prohibited. Those randomizedto rofecoxib experienced a 50% lower risk of serious GI events. 78

These findings led to its approval by the FDA, but rofecoxib waswithdrawn from the worldwide market in 2004 because of increasedrisk of cardiovascular events, as discussed in Cardiovascular Inhibi-tors: Traditional NSAIDs section.

Lumiracoxib was evaluated in the Therapeutic Arthritis Researchand Gastrointestinal Event Trial (TARGET), in which more than18,000 patients were randomized to lumiracoxib 400 mg/day com-pared to naproxen 1,000 mg/day or ibuprofen 2,400 mg/day. 79 Withlumiracoxib, there was a significant reduction in the risk of serious GIevents (perforation, gastric outlet obstruction, bleeding) compared tonaproxen (hazard ratio 0.34 [0.22 to 0.52], P


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coxibs (celecoxib and rofecoxib both posing risk), that this risk existedfor rofecoxib at any dose, but to celecoxib when used at higher doses. 34

The cardiovascular safety of lumiracoxib was evaluated in theTherapeutic Arthritis Research and Gastrointestinal Event Trial(TARGET) study. 85 In this study of more than 18,000 patients,cardiovascular risk showed a nonsignificant increase relative to ibu-profen (but no increase relative to naproxen), and this increase wasonly seen in those not taking aspirin. One potential drawback to thisstudy is that cardiovascular events were low (59 for lumiracoxib, 50for ibuprofen). The cardiovascular safety of etoricoxib was evaluated

in the MEDAL study.86

In this study, more than 34,000 subjects wererandomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac(150 mg daily). Very similar rates for thrombotic cardiovascularevents occurred for the etoricoxib group and for the diclofenac group(event rates of 1.24 and 1.30 per 100 patient-years, respectively, witha hazard ratio of 0.95 [95% CI 0.81 to 1.11]) for etoricoxib comparedwith diclofenac. The number of events in each arm was more than300, which lends reassurance to the results. Despite these clear results,some investigators have indicated that diclofenac, having some COX-2 selectivity (almost as selective as celecoxib) should not be used as thecomparator drug. Ibuprofen or naproxen are nonselective and may be better comparator drugs for determining if a COX-2 selectiveinhibitor possesses risk relative to nonspecific NSAIDs. Although theTARGET study for lumiracoxib and the MEDAL study for etoricoxib

are somewhat reassuring, given the study limitations, further confir-mation of their cardiovascular safety would be welcome.In addition to controlled trials, analysis of cohort or case control

studies can also contribute to information about risk, but such studieshave confounders and do not necessarily produce consistent findings.Some studies have shown increased risk for coxibs and for nonspecificNSAIDs. Recently, in a systematic review of observational studies of COX-2 inhibitors and traditional NSAIDs, including an approximate1 million patients, risk for cardiovascular events were calculated incomparison to nonusers or those with remote use of NSAIDs. 87 Thesummary relative risk was 1.33 (95% CI 1.00 to 1.79) for rofecoxib 25mg/day, and 2.19 (95% CI 1.64 to 2.91) with more than 25 mg/day,with risk apparent within the first month of treatment. Celecoxibsummary relative risk was 1.06 (95% CI 0.91 to 1.23) (but without

enough information to dose stratify). Other summary relative riskswere also reassuring, with naproxen at 0.97 (95% CI 0.87 to 1.07),piroxicam at 1.06 (95% CI 0.70 to 1.59), and ibuprofen at 1.07 (95%CI 0.97 to 1.18). Diclofenac, however, showed an increased summary relative risk of 1.40 (CI 1.16 to 1.70), which is concerning. 87

Taken together, the above data, both from controlled trials andfrom observational studies, confirm the increased cardiovascular riskseen with rofecoxib. Celecoxib 200 mg/day or even 400 mg/day doesnot appear to increase risk, but cardiovascular risk is likely increasedwith doses above 400 mg/day. Although studies with lumiracoxib andetoricoxib are somewhat reassuring and do not point to substantially increased cardiovascular risk, further work is needed on this issue.The balance of the evidence also suggests that, for the traditionalNSAIDs which have been examined, with the exception of diclofenac,

there is no significant or substantial increase in risk.6

CLINICAL CONTROVERSY

Controversy has arisen regarding both the gastroprotective effectsof COX-2 selective inhibitors and the cardiovascular risk they may pose. Are all COX-2 selective inhibitors GI protective? Do they allpose cardiovascular risk? Is there a relationship between these twofeatures for different coxibs? Although both rofecoxib and cele-coxib are COX-2 selective inhibitors, rofecoxib demonstratedmore robust reduction in GI complications. However, rofecoxibposed greater cardiovascular risk than celecoxib.

These differences may depend on the degree of selectivity of specific COX-2 inhibitors for COX-2 versus COX-1 enzymes. COX-2selectivity is relative: Some traditional NSAIDs, such as diclofenac,possess some COX-2 selectivity, and even among the formally labeledCOX-2 inhibitors, COX-2 selectivity varies. Interestingly, rofecoxib ismore COX-2 selective than celecoxib. It is possible that rofecoxibsgreater selectivity is responsible both for better GI protection and forincreased cardiovascular risk. Such a connection is plausible, giventhe effects of COX-1 and COX-2 enzymes on the formation of thromboxane A 2 and prostacyclin. A highly selective COX-2 inhibitor

may tilt the balance in favor of thromboxane A 2, thus promotingplatelet aggregation (beneficial for preventing GI bleeds, but posing aprothrombotic risk to the cardiovascular system).

Several other COX-2 selective inhibitors are in development, andtwo key issues will be their degree of gastroprotection and what, if any, cardiovascular risk they pose. Further study will be needed todetermine if one or more of these agents will be safe for thecardiovascular system and also gastroprotective, or whether thedegree of gastroprotection is inextricably linked to the extent of cardiovascular risk for all COX-2 selective inhibitors.

Considerations for Patients at Risk for Both GI and Car-diovascular Events. For those without increased GI or cardio-vascular risk, a nonspecific NSAID is reasonable. For patients withelevated GI risk or cardiovascular risk who need treatment with anNSAID, careful consideration of risk and benefit is warranted. 34Recommendations for those with increased GI risk but not on aspirininclude consideration of a COX-2 selective inhibitor or a traditionalNSAID taken with a PPI. For those taking regular low-dose aspirin forcardiovascular risk (with or without increased GI risk), a traditionalNSAID taken with a PPI, or a COX-2 selective inhibitor taken with aPPI can be considered. Given the current concerns regarding cardio-vascular risk with COX-2 selective inhibitors or possibly any NSAIDs,and continuing concern about GI events, treatment with the lowestdose possible for the shortest duration possible is warranted.

Other Toxicities Associated with NSAIDs. NSAIDs may cause kidney diseases, including acute renal insufficiency, tubuloin-terstitial nephropathy, hyperkalemia, and renal papillary necrosis. 88

Clinical features of these NSAID-induced renal syndromes includeincreased serum creatinine and blood urea nitrogen, hyperkalemia,elevated blood pressure, peripheral edema, and weight gain. Mecha-nisms of NSAID injury include direct toxicity, and inhibition of localprostaglandins that promote vasodilation of renal blood vessels andpreserve renal blood flow. Patients at high risk are those with condi-tions associated with decreased renal blood flow or taking certainmedications. Examples are those with chronic renal insufficiency,congestive heart failure, severe hepatic disease, nephrotic syndrome,advanced age, or taking diuretics, angiotensin-converting enzymeinhibitors, cyclosporine, or aminoglycosides (Fig. 957).

Close monitoring is advisable for high-risk patients taking anNSAID, with monitoring of serum creatinine at baseline and within3 to 7 days of drug initiation. For those with impaired renal

function, the National Kidney Foundation recommends acetamin-ophen as the drug of choice. 49

Coxibs can also pose renal risks, and there is neither evidence norrationale why this class of drugs would be safer than nonspecificNSAIDs. In a meta-analysis of randomized trials of NSAIDs includ-ing more than 100,000 patients, rofecoxib was shown to significantly increase risk of renal toxicity in comparison to placebo, celecoxib,and nonspecific NSAIDs. 84 Although rofecoxib is now off the mar-ket, this study provides an important caution as new coxibs areapproved: renal safety of coxibs may differ substantially. Keeping inmind that many OA patients may not be as healthy as trial partici-pants, it is prudent to prescribe all coxibs and other NSAIDs withcaution in patients who are at increased risk for renal dysfunction. 89


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Coxibs and NSAIDs uncommonly cause drug-induced hepatitis;the two NSAIDs most frequently implicated are diclofenac andsulindac. Patient monitoring should include periodic liver enzymes(aspartate aminotransferase and alanine aminotransferase), withcessation of therapy if these values exceed two to three times thenormal range.

Other toxic effects of NSAIDs include hypersensitivity reactions,rash, and central nervous system complaints of drowsiness, dizzi-ness, headaches, depression, confusion, and tinnitus. 47 AlthoughNSAIDs are generally avoided in patients with asthma who areaspirin-intolerant, studies indicate that celecoxib is well tolerated inaspirin-sensitive asthma, providing a viable option for thesepatients. 90 Celecoxib is a sulfonamide and is thus contraindicatedfor those with sulfa allergies. However, some patients with sulfaallergies have shown no reaction to celecoxib, and in a meta-analysisincluding more than 11,000 patients, allergic reactions for thosewho did have sulfonamide allergies were similar in those takingcelecoxib compared to those taking other NSAIDs. 91

All nonspecific NSAIDs inhibit COX-1dependent thromboxaneproduction in platelets and thus increase bleeding risk. Importantly,aspirin inhibition is irreversible, and bleeding time requires 5 to 7days to normalize after cessation of therapy, as new platelets enterthe circulation. Other nonspecific NSAIDs inhibit thromboxaneformation reversibly, with normalization of platelet function 1 to 3days after the drug is stopped. The nonacetylated salicylate productsand nabumetone, which have partial COX-2 selectivity, may bepreferable to nonspecific NSAIDs. 47 COX-2 selective inhibitors donot block thromboxane synthesis and should pose even less bleed-ing risk. However, because warfarin and celecoxib are metabolizedby the cytochrome P450 isoenzyme CYP2C9, patients receivingwarfarin and COX-2 inhibitors should be followed closely.

Finally, NSAIDs should be used only with great caution and only if definitely necessary during pregnancy because of the risk to thefetus posed by the bleeding problems. In late pregnancy, all NSAIDsshould be avoided because they may enhance premature closure of the ductus arteriosus. NSAIDs have a pregnancy risk factor of C/D(third trimester). Aspirin is also listed as C/D (D in third trimester if used at full dose). Acetaminophen has a pregnancy risk factor of B.

DrugDrug and DrugFood Interactions Important druginteractions with NSAIDs can be pharmacokinetic or pharmacody-namic in origin and have been reviewed. 47,92 The most potentially serious interactions include the use of NSAIDs with lithium, war-farin, oral hypoglycemics, high-dose methotrexate, antihyperten-sives, angiotensin-converting enzyme inhibitors, -blockers, anddiuretics. Anticipation and careful monitoring often can preventserious events when these drugs are used together.

Another recent drug interaction has been noted for those takingsome NSAIDs and cardioprotective doses of aspirin. Ibuprofen, usedat doses of 400 mg or more, may block aspirins antiplatelet effect if itis taken prior to aspirin. Patients are advised to take a single dose of ibuprofen at least 30 minutes after taking aspirin, or they should taketheir aspirin at least 8 hours after taking ibuprofen. 93 It is possible thatother nonselective NSAIDs, such as naproxen, also may cause suchinteractions. Acetaminophen does not appear to interfere with theantiplatelet effect of aspirin.

Specific drug interactions are also seen with coxibs. Celecoxib

metabolism is primarily via CYP2C9.92

In clinical studies, increasedcelecoxib levels were seen with fluconazole administration. Cyto-chrome P450 inducers such as rifampin, carbamazepine, and phenytoin have the potential to reduce celecoxib levels. However, noclinically significant interactions have been documented with cele-coxib and methotrexate, glyburide, ketoconazole, phenytoin, ortolbutamide. Because celecoxib inhibits CYP2D6, it has the poten-tial to increase concentrations of a variety of agents, includingantidepressants. Celecoxib increases lithium levels, as do otherNSAIDs, thus caution is needed when using coxibs or NSAIDs withlithium.

Dosing and Administration Administration of NSAIDs mustbe tailored to the individual patient with OA. For the OA patientwho has failed an adequate trial of acetaminophen, trial with anNSAID is warranted, if no contraindications exist. Selection of anNSAID depends on the prescribers experience, medication cost,patient preference, allergies, toxicities, and adherence issues. Indi-vidual patient response differs among NSAIDs (see Table 952), soif an inadequate response is obtained with one NSAID, anotherNSAID may yet provide benefit. 2,47,54

Topical Therapies Topical products can be used alone or in combination with oralanalgesics or NSAIDs. Capsaicin, isolated from hot peppers, releasesand ultimately depletes substance P from afferent nociceptive nervefibers. Substance P has been implicated in the transmission of painin arthritis, and capsaicin cream has been shown in four placebo-

controlled studies to provide pain relief in OA when applied overaffected joints. 2,94 Data comparing topical capsaicin to other effec-tive pharmacologic treatments for OA is lacking.

Adverse events associated with capsaicin are primarily local, with1 in 3 patients experiencing burning, stinging, and/or erythema thatusually subsides with repeated application. Some patients may experience coughing associated with application. Capsaicin is anonprescription product available as a cream, gel, or lotion inconcentrations ranging from 0.025% to 0.075%.

To be effective, capsaicin must be used regularly, and it may takeup to 2 weeks to take effect. Although use is recommended fourtimes a day, a twice-daily application may enhance long-termadherence and still provide adequate pain relief. 94 Patients shouldbe warned not to get the cream in their eyes or mouth and to wash

their hands after application. When patients were queried using anelectronic questionnaire that considered possible toxicities of treat-ments, as well as route of administration and cost, capsaicin was themost preferred by patients, even when it was portrayed as being lesseffective than NSAIDs. 48

Topical diclofenac in a dimethyl sulfoxide (DMSO) carrier(Pennsaid) is a safe and effective treatment for pain associated withOA.95 Pennsaid is available in Canada and other European countriesand is currently under review at the FDA. The mechanism of actionof topical NSAIDs is thought to be primarily by local inhibition of COX-2 enzymes. This mode of delivery minimizes systemic expo-sure and may decrease the risk of the serious adverse eventsassociated with oral NSAIDs.

FIGURE 95-7. Mechanisms implicated in NSAID-induced renal injury.The minus () sign indicates inhibitory influence. (CHF, congestive heartfailure; NSAIDs, nonsteroidal antiinflammatory drugs.)

Sympathetic nervoussystem activity

Reduced renal function

Renal vasoconstriction

Compensatory vasodilatationby renal prostaglandins

High-risk patient : CHF, renal disease, elderly,diuretic use, volume depletion, cirrhosis

NSAIDs

Renin-angiotensin axis

Normalized renal function


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Although not well studied in a controlled setting, the use of topical rubefacients, containing methylsalicylate, trolamine salicyl-ate, and other salicylates, may have modest, short-term efficacy inthe treatment of acute pain associated with musculoskeletal condi-tions, including OA. 96 These agents act by providing topical coun-terirritation to the affected joint area, rather than by local inhibitionof COX-2 enzymes. Chronic OA pain may respond less favorably than acute pain. Clinically significant adverse events are local skinreactions that occur rarely. There are no reports of systemic toxicity associated with topical rubefacients.

Glucosamine and ChondroitinInterest in chondroitin and glucosamine was spurred initially by anecdotal reports of benefit in animals and humans, and by theability of these substances to stimulate proteoglycan synthesis fromarticular cartilage in vitro. The excellent safety profile of these agentsmakes them especially appealing for use in those at high risk foradverse events, such as elderly patients, and in those with multiplemorbidities. Recently, enthusiasm for these agents has waned some-what as additional efficacy data has become available. 9799

A meta-analysis of glucosamine and chondroitin had indicatedthat both agents had efficacy in reducing pain and improvingmobility, and that glucosamine reduced joint space narrowing. 98 Useof glucosamine or chondroitin sulfate was associated with slower lossof cartilage than placebo in knees of OA patients. 100 Further supportfor the objective benefits of these compounds was seen in a followupsurvey carried out 5 years after completion of a 3-year study compar-ing glucosamine and placebo. This survey showed that rates of lowerlimb joint replacement were twofold higher in subjects given pla-cebo, compared with subjects given glucosamine. In addition, subjects treated with glucosamine had lower rates of pain, joint spacenarrowing, and limitations of physical function. 99

In contrast to earlier reports, a recent large, well-controlledNational Institutes of Health-sponsored study demonstrated nosignificant clinical response to glucosamine therapy alone, chon-droitin therapy alone, or combination glucosaminechondroitintherapy when compared to placebo across all patients. 97 In sub-group analyses, however, patients with moderate to severe knee painshowed a response to combination glucosaminechondroitin ther-apy superior to placebo. This finding did not reach the predeter-mined threshold for pain reduction. The safety of the glucosamineand chondroitin therapy was similar to that of placebo.

The exact role of glucosamine, chondroitin, or a combination of the two products is still unclear. Because of the relative safety of theseagents, a trial of glucosaminechondroitin may be reasonable inpatients considering alternatives to traditional OA treatments. Dos-ing should be at least 1,500 mg/day of glucosamine and 1,200 mg/day of chondroitin. The glucosamine component should be the sulfatesalt rather than the hydrochloride salt, as nearly all positive efficacy studies used the better-absorbed sulfate salt. Glucosamine-relatedadverse events are generally mild and include gastrointestinal symp-toms (gas, bloating, cramps). If made from shellfish, however,glucosamine should not be used in patients with shellfish allergies.The initial concerns regarding glucosamine-induced hyperglycemiahad likely been overstated as later safety data in both healthy subjectsand those with type 2 diabetes mellitus did not show significantelevations in blood glucose. Chondroitin is extremely well toleratedwith the most common adverse effect being nausea. Depending onthe source of chondroitin (cattle, pig, or shark), this compoundcould also pose risk to persons who are allergic to shark.

Because glucosamine and chondroitin are marketed in the UnitedStates as dietary supplements, neither the products nor their purity is adequately regulated by the FDA. The potential consequencesrelated to the lack of regulatory oversight for these products canaffect both efficacy and safety. Products containing less-than-

labeled doses can compromise efficacy, while those containingingredients not included on the labeling can compromise safety. Avariety of brand name and generic products are available.

CorticosteroidsIntraarticular glucocorticoid injections can provide excellent painrelief, particularly when a joint effusion is present. 2,101 Aspiration of the effusion and injection of glucocorticoid are carried out asepti-cally, with examination of the aspirate recommended to excludecrystalline arthritis or infection. (This risk is low, howeverapprox-imately 1 in 50,000 procedures.) After injection, the patient shouldminimize activity and stress on the joint for several days. Initial painrelief may be seen within 24 to 72 hours after injection, with peakpain relief about 1 week after injection and lasting up to 4 to 8 weeks.

Several randomized, placebo-controlled, double-blind studieshave shown that intraarticular corticosteroids are superior to pla-cebo in alleviating knee pain and stiffness caused by OA. 101 Thebranched esters of triamcinolone and methylprednisolone are pre-ferred by practitioners because of the reduced solubility that allowsthe agents to remain in the joint space longer. There is no evidenceof a clinically superior corticosteroid for intraarticular use, withequipotent doses of methylprednisolone acetate and triamcinolonehexacetonide having similar efficacy. 102 Average doses for injectionof large joints in adults are 10 to 20 mg of triamcinolone hexace-tonide or 20 to 40 mg of methylprednisolone acetate. The therapy isgenerally limited to three or four injections per year because of thepotential systemic effects of steroids, and because the need for morefrequent injections indicates little response to the therapy.

Adverse events associated with intraarticular injection of cortico-steroids can be local or systemic in nature. Systemic adverse eventsare the same as with any other systemic corticosteroid and caninclude hyperglycemia, edema, elevated blood pressure, dyspepsia,and, rarely, adrenal suppression with continuous, repeated injec-tions. Local adverse effects can include infection in the affected joint,osteonecrosis, tendon rupture, and skin atrophy at the injection site.It has long been thought that intraarticular corticosteroids canhasten cartilage loss, but the potential risk of cartilage destructionwith steroid injections has not been substantiated. The rate of cartilage loss tends to be similar between treated and control groups.

Systemic corticosteroid therapy is not recommended in OA,given the lack of proven benefit and the well-known adverse effectswith long-term use.

Hyaluronate InjectionsAgents containing hyaluronic acid (HA; sodium hyaluronate) areavailable for intraarticular injection for treatment of knee OA. 103,104

High-molecular-weight HA is an important constituent of synovialfluid. Endogenous HA may also have antiinflammatory effects.Because the concentration and molecular size of synovial HAdecrease in OA, administration of exogenous HA products has beenstudied, with the theory that this could reconstitute synovial fluidand reduce symptoms. In fact, HA injections temporarily and mod-estly increase viscosity. Although HA injections were reported todecrease pain, most studies were short-term and poorly controlled,and placebo injections also reduced OA pain dramatically. A study of patients who received two series of injections of HA demonstratedefficacy for 27 weeks after the first series of injections. 103

HA products are injected once weekly for either 3 or 5 weeks,depending on the specific agent administered. There are four commer-cially available preparations, Hyalgan (20 mg sodium hylaronate/2mL), Supartz (25 mg sodium hylaronate/2.5 mL), (16 mg hylanpolymers/2 mL), and Orthovisc (30 mg hyaluronan/2 mL). Hyalganand Supartz are administered weekly for five injections, whereasSynvisc and Orthovisc are administered weekly for three injections.


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One study has demonstrated that a series of three injections of Hyalganwas as effective as a longer series of six injections. 103 Injections are welltolerated, although acute joint swelling and local skin reactions,including rash, ecchymoses, and pruritus have been reported.

HA injections may be beneficial for patients with knee OAunresponsive to other therapies. These agents are expensive becausethe treatment includes both drug costs and administration costs. Asa result, HA injections are often used after less-expensive therapieshave demonstrated a lack of efficacy.

Opioid AnalgesicsLow-dose opioid analgesics can be useful in patients who experienceno relief with acetaminophen, NSAIDs, intraarticular injections, ortopical therapy. These agents are particularly useful in patients whocannot take NSAIDs because of renal failure, and for patients in whomall other treatment options have failed and who are at high surgicalrisk, precluding joint arthroplasty. Low-dose opioids are the initialintervention, usually given in combination with acetaminophen.

Sustained-release compounds usually offer better pain controlthroughout the day, and are used when simple opioids are ineffective.A recent randomized, double-blind, placebo-controlled study showedthat extended-release oxycodone (20 to 120 mg twice daily) wassuperior to placebo in reducing pain and improving both functionand quality of life, although a high number of patients (36%) did notcomplete the study as a consequence of adverse events. 105 Nearly all(93%) patients in the oxycodone group experienced a typical opioid-related (nausea, somnolence, constipation, and dizziness) adverseevent in this 90-day study. Although this is not an unexpected finding,it serves as a reminder to use opioids cautiously in elderly patientswho may be more susceptible to adverse effects.

If pain is intolerable and limits activities of daily living, and thepatient has sufficiently good cardiopulmonary health to undergomajor surgery, joint replacement may be preferable to continuedreliance on opioids.

TramadolTramadol, with or without acetaminophen has modest analgesic

effects in patients with OA when compared to placebo.106

Tramadol isalso modestly effective as add-on therapy in patients taking concomi-tant NSAIDs or COX-2 selective inhibitors. 107 As with opioid analge-sics, tramadol may be helpful for patients who cannot take NSAIDs orCOX-2 selective inhibitors. Tramadol should be initiated at a lowerdose (100 mg per day) and may be titrated as needed for pain controlto a dose of 200 mg per day. Tramadol is available in a combinationtablet with acetaminophen and as a sustained-release tablet.

Opioid-like adverse effects such as nausea, vomiting, dizziness,constipation, headache, and somnolence are common with trama-dol. These occur in 60% to 70% of treated patients, and 40%discontinue tramadol because of an adverse effect. 106 Although thefrequency of adverse effects is high, the severity of adverse effects isless than with NSAIDs, as tramadol use is not associated with life-

threatening gastrointestinal bleeding or with renal failure.

Novel Therapies and Disease-Modifying DrugsDisease-modifying drugs are targeted not at pain relief but atpreventing, retarding, or reversing damage to articular cartilage.Thus far, OA is a progressive disease that can only be treatedsymptomatically. Because of this, clinicians were very interested inthe possible ability of chondroitin and/or glucosamine to slow jointdamage, although those findings require further study (see Glu-cosamine and Chondroitin above).

New approaches to slow progression of OA are being investigated,but most products have been tested in animal models, and limitedhuman data are available. One approach involves pharmacologic

agents that could mimic tissue inhibitors of metalloproteinases andthus potentially decrease cartilage destruction. Some studies haveexplored the use of tetracycline or doxycycline, which appear toinhibit metalloproteinases. 108 In knee OA, doxycycline has been seento delay loss of articular cartilage (joint space narrowing) in humanswhen compared with placebo. 109 Other agents that act as inhibitorsof metalloproteinase gene expression, are also under considerationin developing drugs to inhibit joint damage in OA. 21

Another agent being studied is diacerein, an interleukin-1 inhib-itor. In a meta-analysis including a total of 2,069 OA patients, this

agent decreased pain to a modest but statistically significant extentcompared to placebo. In long-term studies, diacerein appeared toshow a significant slowing of progression of joint space narrowing atthe hip, but not at the knee. 110

Aside from agents that may prevent disease progression, attempts tofind new agents or methods to treat symptoms of OA are being made.There is recent interest in the potential of cyclooxygenase-inhibitingnitric oxide-donor compounds to relieve OA pain while sparing GIadverse effects. There are two lipid-based nontraditional therapies thathave received some attention for treatment of symptoms related toOA; avocado/soy unsaponifiables and fish oil (particularly n-3 PUFA).Several short-term studies hav

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