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DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition

Chapter 110: Osteoarthritis

Lucinda M. Buys; Sara A. Wiedenfeld

CHAPTER SUMMARY FROM THE PHARMACOTHERAPY HANDBOOK

For the Chapter in the Schwinghammer Handbook, please go to Chapter 2, Osteoarthritis.

KEY CONCEPTS

KEY CONCEPTS

Osteoarthritis (OA) is a common disease. OA prevalence increases with age and number of other chronic conditions, with women more
commonly 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 the chondrocyte to maintain proper balance between cartilage formation and
destruction. This leads to loss of cartilage in the joint, local inflammation, pathologic changes in underlying bone, and further damage to
cartilage triggered by the affected bone.

The most common symptom associated with OA is pain, which leads to decreased function and motion. Pain relief is the primary objective
of medication therapy.

Manifestations of OA are local, affecting one or a few joints; the knees are most commonly affected, as well as the hips and hands.

Nonpharmacologic therapy is the foundation of the treatment plan for all patients with OA. Nonpharmacologic therapy should be initiated
before or concurrently with pharmacologic therapy.

Based upon efficacy, safety, and cost considerations, scheduled acetaminophen, up to 4 g/day, should be tried initially for pain relief in
knee and hip OA. If this fails, nonsteroidal anti­inflammatory drugs (NSAIDs; topical or oral) are recommended, if there are no
contraindications.

Topical NSAIDs, in lieu of oral NSAIDs, are recommended for patients older than 75 years of age to decrease the risks of systemic toxicity.

Strategies to reduce NSAID­induced gastrointestinal (GI) toxicity include the use of nonacetylated salicylates, COX­2 selective inhibitors, or
the addition of misoprostol or a proton pump inhibitor.

Other agents useful in treating knee OA include intra­articular injections of corticosteroids, duloxetine, or tramadol.

BEYOND THE BOOK

BEYOND THE BOOK

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This activity Osteoarthritis, Lucinda
designed to build skillsM.
inBuys; Sara A.
developing Wiedenfeld
a safe­and­effective patient­specific PLAN as part of the patient care process. Page 1 / 41
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Create a table of drug treatment options for a patient with knee, hip, and hand osteoarthritis and a history of a myocardial infarction.
 Other agents useful in treating knee OA include intra­articular injections of corticosteroids, duloxetine, or tramadol.
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BEYOND THE BOOK

BEYOND THE BOOK

This activity is designed to build skills in developing a safe­and­effective patient­specific PLAN as part of the patient care process.

Create a table of drug treatment options for a patient with knee, hip, and hand osteoarthritis and a history of a myocardial infarction.

INTRODUCTION

Osteoarthritis (OA) is the most common joint disease and one of the leading causes of disability in the United States.1 Knee OA alone is as important a
contributor to disability as cardiovascular (CV) disease and more important than other comorbidities. OA is a common co­occurrence with other
chronic health conditions that adversely affect quality of life.1

The progressive destruction of articular cartilage has long been appreciated in OA, but OA involves the entire diarthrodial joint, including articular
cartilage, synovium, capsule, and subchondral bone, with surrounding ligaments and muscles also playing important roles. Changes in structure and
function of these tissues produce clinical OA, characterized by joint pain and tenderness, with decreased range of motion, weakness, joint instability,
and disability.

This chapter will review the epidemiology, etiology, pathophysiology, and clinical presentation of OA. It then will focus on nonpharmacologic and
pharmacologic treatments for OA. Because millions of persons take medications for OA, the overall risks posed by these medications require careful
consideration, particularly by clinicians who treat or advise patients on drug therapy for OA. This chapter examines the risks and benefits of OA
treatments, with emphasis on those individuals who have the highest risk for adverse events, to help clinicians maximize benefits and minimize risks to
their patients with OA.

EPIDEMIOLOGY

During 2013 to 2015, an estimated 54.4 million adults in the United States reported doctor­diagnosed arthritis (osteoarthritis, rheumatoid arthritis,
gout, lupus, or fibromyalgia), with 23.7 million reporting arthritis­attributable activity limitation (AAAL).1 The prevalence of AAAL among adults with
arthritis increased by almost 20% over time (2002­2015).1 Arthritis is projected to affect 78.4 million adults by 2040.2 OA imposes a tremendous cost
burden with combined arthritis­attributable medical expenditures and earnings losses totaling approximately $303 billion dollars in 2013.3 The US
Medical Expenditure Panel Survey found that arthritis­attributable medical expenditures were $139.8 billion, representing 11% of the total medical
expenditures in 2013.3 Among all adults in the US population, adults with arthritis had the highest overall average cost per person ($9,233), followed by
adults with at least one nonarthritis chronic condition ($6,272) and those with no chronic conditions ($1,369).3 Total hospital costs associated with the
specific diagnosis of osteoarthritis were $16.5 billion attributed to 1 million hospital stays in 2013.4 Arthritis­attributable lost earnings were $163.7
billion with almost half of lost earnings due to lower adjusted per­person earnings for those with arthritis.3

Prevalence by Age, Sex, and Race

Prevalence estimates for OA vary depending on the age group of interest, gender, ethnic group, and the specific joint involved. Estimates also depend
on the specific means by which OA is assessed and documented. Clinical OA is based on physical exam and patient history, whereas radiographic OA is
determined by x­ray or other imaging, and symptomatic OA is based on patient history and physical exam plus x­ray. OA is more prevalent with
increasing age. In the United States, the prevalence of self­reported doctor­diagnosed arthritis in the 2013 to 2015 National Health Interview Survey
(NHIS) is 22.7% for all persons over age 18, but 49.6% for persons age 65 and older.1 Prevalence for AAAL among persons with doctor­diagnosed
arthritis is 43.5% for all persons over age 18 and 44% for persons age 65 and older.1 Radiologically confirmed hip OA shows clear trends through all age
groups, affecting 1.6% of those between ages 30 and 39, up to a prevalence of 14% in those over 85 years of age.5 Radiographic hand OA is found in 5%
of those aged 40, but in 65% of those older than 80 years of age.6

Prevalence of physician­diagnosed arthritis is 26.3% in White populations, and ranges from 11.1% for Asian populations to 21.8% for Black
populations.1 African American men are approximately 35% more likely to have radiographic knee OA and twice as likely to have more severe knee OA
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than White men. 7 No significant differences were found between the prevalence of knee OA in Black women and White women, but Black women were
Chapter 110: Osteoarthritis, Lucinda M. Buys; Sara A. Wiedenfeld Page 2 / 41
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7 Among adults• with
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arthritis, the prevalence of severe joint pain is significantly
higher in women (29.7%), non­Hispanic Blacks (45.6%), those with less than a high school education (40.2%), and those unable to work (51.9%).8
arthritis is 43.5% for all persons over age 18 and 44% for persons age 65 and older.1 Radiologically confirmed hip OA shows clear trends through all age
University
groups, affecting 1.6% of those between ages 30 and 39, up to a prevalence of 14% in those over 85 years of age.5 Radiographic hand of
OAthe West in
is found Indies
5%
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of those aged 40, but in 65% of those older than 80 years of age.6

Prevalence of physician­diagnosed arthritis is 26.3% in White populations, and ranges from 11.1% for Asian populations to 21.8% for Black
populations.1 African American men are approximately 35% more likely to have radiographic knee OA and twice as likely to have more severe knee OA
than White men.7 No significant differences were found between the prevalence of knee OA in Black women and White women, but Black women were
50% more likely than White women to have more severe involvement.7 Among adults with arthritis, the prevalence of severe joint pain is significantly
higher in women (29.7%), non­Hispanic Blacks (45.6%), those with less than a high school education (40.2%), and those unable to work (51.9%).8
Women are also more likely to have inflammatory OA of the proximal and distal interphalangeal joints of the hands, giving rise to the formation of
Bouchard and Heberden nodes, respectively (Fig. 110­1).

FIGURE 110­1

Heberden nodes (distal interphalangeal joint) noted on all fingers and Bouchard nodes (proximal interphalangeal joint) noted on most fingers.
(Reproduced, with permission, from Johnson BE. Arthritis: Osteoarthritis, gout, and rheumatoid arthritis. In: South­Paul JE, Matheny SC, Lewis EL, eds.
CURRENT Diagnosis and Treatment in Family Medicine. 4th ed. New York, NY: McGraw Hill; 2015.)

Incidence

As the incidence of a disease describes the number of newly diagnosed cases each year, OA poses a challenging situation for determining disease
incidence. These reasons include: (1) not all patients with OA seek medical treatment; (2) OA is common within the population; (3) many effective
treatments are available over the counter, promoting self­treatment; (4) not all radiographically diagnosed OA is symptomatic and patients may not be
formally diagnosed with OA; and (5) many patients have multiple affected joints, making it difficult to track the overall occurrence of OA in these
individuals.

ETIOLOGY

The etiology of OA is multifactorial and complex, with development of OA depending on interplay between person­level risk factors and joint­level
risk factors.9 Many patients have more than one risk factor for the development of OA. The most common risk factors for the development of OA
include age, obesity, sex, occupation, participation in certain sports, history of joint injury or surgery, and genetic predisposition.

Obesity

Obesity is the most important preventable risk factor for OA. This linkage is strongest for knee OA, although hip OA and even hand and wrist OA may be
linked with obesity. The etiology of this association of OA in non­weight­bearing joints is thought to be the adverse metabolic and inflammatory effects
produced by obesity.10 As the epidemic of obesity spreads in the United States and in other developed countries, so will the burdens imposed by OA.
For every five unit increase in BMI, the risk of knee OA increases 35%.9 Obesity often precedes OA and contributes to its development, rather than
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occurring as a result of inactivity from joint pain. In an 11­year study of approximately 30,000 Norwegian men and women, obesity significantly
Chapter 110: Osteoarthritis, Lucinda M. Buys; Sara A. Wiedenfeld Page 3 / 41
increased
©2025 the riskHill.
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whereas women who were obese at baseline had a 4.4­fold increased risk in developing knee OA compared to the nonobese women. Also, there was
an increased risk for severe knee OA in obese subjects.11
Obesity
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Obesity is the most important preventable risk factor for OA. This linkage is strongest for knee OA, although hip OA and even hand
Access andby:
Provided wrist OA may be
linked with obesity. The etiology of this association of OA in non­weight­bearing joints is thought to be the adverse metabolic and inflammatory effects
produced by obesity.10 As the epidemic of obesity spreads in the United States and in other developed countries, so will the burdens imposed by OA.
For every five unit increase in BMI, the risk of knee OA increases 35%.9 Obesity often precedes OA and contributes to its development, rather than
occurring as a result of inactivity from joint pain. In an 11­year study of approximately 30,000 Norwegian men and women, obesity significantly
increased the risk of developing OA.11 Men who were obese at baseline had a 2.8­fold increase in developing knee OA compared to the nonobese men,
whereas women who were obese at baseline had a 4.4­fold increased risk in developing knee OA compared to the nonobese women. Also, there was
an increased risk for severe knee OA in obese subjects.11

Occupation, Sports, and Trauma

OA risk is increased for people in occupations involving excessive mechanical stress. Work that involves prolonged standing, kneeling, squatting,
lifting, or moving of heavy objects increases risk of OA. Such occupations include construction, mining, healthcare assistance, factory work, carpentry,
and farming.9 Repetitive motion also contributes to hand OA, with the dominant hand usually affected. Risk for OA depends on the type and intensity
of physical activity and whether injury incurred in the activity. Increased risk of OA is associated with participation in activities such as wrestling, soccer,
weight lifting, football, and hockey, although recreational participants do not have the increased risk seen in the professional athlete.12 Studies that
have included running, including long distances, have produced decidedly mixed results.12 In the study of 30,000 Norwegians, exercise intensity was
not associated with any increased risk in the obese subjects compared to those of normal weight.11

Traumatic knee injury, either during sports or in accidents, significantly increases the risk of knee OA over a 10­year period.12 These injuries include
anterior cruciate ligament tears, meniscal tears, and direct cartilage injuries.9 Meniscal damage increases the risk of knee OA because of the loss of
proper load bearing and shock absorption, and increased focal load on cartilage and on subchondral bone. Quadriceps muscle weakness is also
recognized to increase the risk for knee OA, as these muscles are important in maintaining joint stability.10 As proper alignment of the joint structures
is critical to proper function of the joint, knee malalignment increases risk of developing OA. In the person who already has OA, knee malalignment is
strongly associated with faster progression of OA.10

Genetic Factors

OA is a complex disease with a strong genetic component. The genetic contribution to OA has been supported by many studies and it is estimated that
30% of the risk of OA is genetically determined.13 There is not a single genetic variant responsible for OA, but likely thousands of loci associated with
the complex nature of the disease. Identification of these genetic loci may promote development of agents to prevent OA or to slow or halt its
progression. Heberden nodes are 10 times more prevalent in women than in men, for example, with a twofold higher risk if the woman’s mother had
them. Genetic links have been shown with OA of the first metatarsophalangeal joint and with generalized OA. Twin studies indicate that OA can be
attributed substantially to genetic factors.14

One approach OA researchers have used is the candidate gene approach which is hypothesis based and focuses on genes with known function which
could be plausibly linked with the OA. This approach requires a priori knowledge of disease etiology and only very small regions of the genome can be
studied at a time. Studies of 199 candidate genes found that only two variants (COL11A1 and VEGF genes) reached significance.13 These results confirm
that using existing joint biology knowledge to identify genetic variants is unlikely to facilitate the understanding of the genetic risks of OA.

Genome­wide association studies (GWAS) use a hypothesis­free methodology that involves scanning hundreds of thousands or millions of genetic
markers, in the form of single­nucleotide polymorphisms (SNPs). Using GWAS studies, at least 21 independent susceptibility loci to OA have been
found.13 A meta­analysis of GWAS with 6,709 knee OA cases and 44,439 controls revealed that the Chrom7Q22 locus was highly significantly associated
with knee OA. The locus also included six genes which code for proteins that are known to be expressed in joint tissues.15

It is quite likely that the genetic risk of developing OA, like many other diseases, is determined by a combination of genetic differences. This
underscores the point that understanding of the genetics and pathology of OA is in its early stages.

PATHOPHYSIOLOGY
OA falls into two major etiologic classes. Primary (idiopathic) OA, the more common type, has no identifiable cause. Secondary OA is that associated
with a known cause such as inflammation, trauma, metabolic or endocrine disorders, and congenital factors.16
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The old view
Chapter 110:ofOsteoarthritis,
OA as a “wear­and­tear”
Lucinda [Link] degenerative
Buys; disease, largely focused on joint cartilage, has long been superseded by an appreciation
Sara A. Wiedenfeld Page 4of the
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tissues. Some changes in the OA joint may reflect compensatory
processes to maintain function in the face of ongoing joint destruction. Not only biomechanical forces but also inflammatory, biochemical, and
immunologic factors are involved. An appreciation of the biology and function of normal cartilage can aid in understanding osteoarthritic cartilage and
PATHOPHYSIOLOGY University of the West Indies
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OA falls into two major etiologic classes. Primary (idiopathic) OA, the more common type, has no identifiable cause. Secondary OA is that associated
with a known cause such as inflammation, trauma, metabolic or endocrine disorders, and congenital factors.16

The old view of OA as a “wear­and­tear” or degenerative disease, largely focused on joint cartilage, has long been superseded by an appreciation of the
dynamic nature of OA and that it represents a failure of the joint and surrounding tissues.10 Some changes in the OA joint may reflect compensatory
processes to maintain function in the face of ongoing joint destruction. Not only biomechanical forces but also inflammatory, biochemical, and
immunologic factors are involved. An appreciation of the biology and function of normal cartilage can aid in understanding osteoarthritic cartilage and
is summarized below.

Normal Cartilage

Function, Structure, and Composition of Cartilage

Articular cartilage possesses viscoelastic properties that provide lubrication with motion, shock absorbency during rapid movements, and load
support. In synovial joints, articular cartilage is found between the synovial cavity on one side and a narrow layer of calcified tissue overlying
subchondral bone on the other side (Fig. 110­2).16,17 The layer of cartilage is narrow, with human medial femoral articular cartilage being
approximately 2 to 3 mm thick. Despite this, healthy articular cartilage in weight­bearing joints withstands millions of cycles of loading and unloading
each year. Cartilage is easily compressed, losing up to 40% of its original height when a load is applied. Compression increases the area of contact and
disperses force more evenly to underlying bone, tendons, ligaments, and muscles. In addition, cartilage is almost frictionless, and together with its
compressibility, this enables smooth movement in the joint, distributes load across joint tissues to prevent damage, and stabilizes the joint.

FIGURE 110­2

Characteristics of osteoarthritis in the diarthrodial joint. (Reprinted, with permission, from Loeser RF. Age­related changes in the musculoskeletal
system and the development of osteoarthritis. Clin Geriatr Med. 2010;26(3):371­386.)

Strength, a low coefficient of friction, and compressibility of cartilage derive from its unique structure. Cartilage is a complex, hydrophilic, extracellular
matrix (ECM). It is approximately 70% water, 10% collagen, 8% proteoglycans, chondrocytes, other proteins, and long hyaluronic acid molecules.18 The
two major structural components in articular cartilage are type II collagen and aggrecans.16 Type II collagen has a tightly woven triple helical structure,
which provides the tensile strength of cartilage. Aggrecan is a proteoglycan linked with hyaluronic acid, providing the long aggrecan molecules a high
negative charge. These are squeezed together by surrounding fibrils of type II collagen. The strong electrostatic repulsion of proteoglycans held in
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ability is withstand further compression. Within the cartilage ECM, chondrocytes, the only cells in cartilage, are
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Normal cartilage turnover helps repair and restore cartilage in response to demands of joint loading and during physical activity. In adults, cartilage
chondrocyte metabolism is slow and is regulated by growth factors, including bone morphogenetic protein 2, insulin­like growth factor­1, and
Strength, a low coefficient of friction, and compressibility of cartilage derive from its unique structure. Cartilage is a complex, hydrophilic,
University of theextracellular
West Indies
matrix (ECM). It is approximately 70% water, 10% collagen, 8% proteoglycans, chondrocytes, other proteins, and long hyaluronic acid molecules.
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18 The

two major structural components in articular cartilage are type II collagen and aggrecans.16 Type II collagen has a tightly woven triple helical structure,
which provides the tensile strength of cartilage. Aggrecan is a proteoglycan linked with hyaluronic acid, providing the long aggrecan molecules a high
negative charge. These are squeezed together by surrounding fibrils of type II collagen. The strong electrostatic repulsion of proteoglycans held in
close proximity gives cartilage the ability to withstand further compression. Within the cartilage ECM, chondrocytes, the only cells in cartilage, are
responsible for laying down all the components of cartilage.

Normal cartilage turnover helps repair and restore cartilage in response to demands of joint loading and during physical activity. In adults, cartilage
chondrocyte metabolism is slow and is regulated by growth factors, including bone morphogenetic protein 2, insulin­like growth factor­1, and
transforming growth factor, and by catabolism and proteolysis stimulated by matrix metalloproteinases (MMPs), tumor necrosis factor­α (TNF­α),
interleukin­1, and other cytokines. Tissue inhibitors of metalloproteinase (TIMP) also contribute to the balance by restraining the catabolic actions of
MMPs. If cartilage is injured, chondrocytes react by removing the damaged areas and increasing synthesis of matrix constituents to repair and restore
cartilage.17

Other components supporting healthy joints are the joint protective mechanisms, such as muscles bridging the joint, sensory receptors in feedback
loops to regulate muscle and tendon function, supporting ligaments, and subchondral bone that has shock­absorbent properties.

Finally, note that adult articular cartilage is avascular, with chondrocytes nourished by synovial fluid. With movement and cyclic loading and unloading
of joints, nutrients flow into the cartilage, whereas immobilization reduces nutrient supply. This is one of the reasons that normal physical activity is
beneficial for joint health.

Osteoarthritic Cartilage

Important contributors to the development of OA are local mechanical influences, genetic factors, inflammation, and aberrant chondrocyte
function leading to loss of articular cartilage.16,19 At a molecular level, OA pathophysiology involves the interplay of dozens, if not hundreds, of
extracellular and intracellular molecules with roles including chondrocyte regulation, phenotypic changes, proteolytic degradation of cartilage
components, and interactions between articular cartilage, underlying subchondral bone, and the joint synovium.10,19

OA most commonly begins with damage to articular cartilage, through trauma or other injury, excess joint loading from obesity or other reasons, or
instability or injury of the joint that causes abnormal loading. In response to cartilage damage, chondrocyte activity increases in an attempt to remove
and repair the damage. Depending on the degree of damage, the balance between breakdown and resynthesis of cartilage can be lost, and a vicious
cycle of increasing breakdown can lead to further cartilage loss and apoptosis of chondrocytes.10,19 Studies have revealed several aspects of the
complex nature of OA.

There is increased appreciation of the role of tissues beyond cartilage, within the joint and surrounding subchondral bone.19 Subchondral bone
undergoes pathologic changes that may precede, coincide with, or follow damage to the articular cartilage. In OA, subchondral bone releases
vasoactive peptides and MMPs, and damage to subchondral bone may trigger further damage to articular cartilage.18 Neovascularization and
subsequent increased permeability of the adjacent cartilage contribute further to cartilage loss.

Joint space narrowing results from loss of cartilage, which can lead to a painful, deformed joint (Fig. 110­3). Remaining cartilage softens and develops
fibrillations (vertical clefts into the cartilage), followed by splitting off of more cartilage and exposure of underlying bone.18 During this time, adjacent
subchondral bone undergoes further pathologic changes, cartilage is eroded completely, leaving denuded subchondral bone, which becomes dense,
smooth, and glistening (eburnation). A more brittle, stiffer bone results, with decreased weight­bearing ability and development 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 humoral factors. There is direct evidence that osteophytes can help stabilize osteoarthritic joints.16

FIGURE 110­3

Plain x­ray films of the knee demonstrating joint space narrowing. (Reproduced, with permission, from Johnson BE. Arthritis: Osteoarthritis, gout and
rheumatoid arthritis. In: South­Paul JE, Matheny SC, Lewis EL, eds. CURRENT Diagnosis & Treatment in Family Medicine. 4th ed. New York, NY: McGraw
Hill; 2015.)

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FIGURE 110­3

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Plain x­ray films of the knee demonstrating joint space narrowing. (Reproduced, with permission, from Johnson BE. Arthritis: Osteoarthritis, gout and
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rheumatoid arthritis. In: South­Paul JE, Matheny SC, Lewis EL, eds. CURRENT Diagnosis & Treatment in Family Medicine. 4th ed. New York, NY: McGraw
Hill; 2015.)

In the joint capsule and synovium, inflammatory changes and pathologic changes can occur.19 Contributors to inflammation may include crystals or
cartilage shards in synovial fluid. Other possible factors are interleukin­1, prostaglandin E2, TNF­α, and nitric oxide that are found in synovial fluid.
With inflammatory changes in the synovium, 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 within the joint by
mechanical and chemical irritants.10,16 OA pain may result from distension of the synovial capsule by increased joint fluid, microfracture, periosteal
irritation, or damage to ligaments, synovium, or the meniscus. Consequently, x­ray changes in OA correlate poorly with pain severity.

CLINICAL PRESENTATION
Diagnosis

The diagnosis of OA is made through history, physical examination, characteristic radiographic findings, and laboratory testing.20 The major
diagnostic goals are (1) to discriminate between primary and secondary OA and (2) to clarify the joints involved, severity of joint involvement, and
response to prior therapies, providing a basis for a treatment plan. The American College of Rheumatology has published traditional diagnostic
criteria and “decision trees” for OA diagnosis.20 As with all guidelines, the authors stress these are for assisting the clinician rather than replacing
clinical judgment. For example, traditional criteria are as follows: (1) For hip OA, a patient must have pain in the hip and at least two of the following
three: an erythrocyte sedimentation rate <20 mm/hr (5.6 µm/s), femoral or acetabular osteophytes on radiography, or joint space narrowing on
radiography. This provides a sensitivity of 89% and a specificity of 91%. For a clinical diagnosis of knee OA, a patient must have pain at the knee and
osteophytes on radiography plus one of the following: age older than 50 years, morning stiffness no more than 30 minutes, crepitus on motion, bony
enlargement, bony tenderness, or no palpable warmth. This provides a sensitivity of 95% and a specificity of 69%. The addition of laboratory or
radiographic data further improves accuracy of diagnosis. Criteria for hand OA have also been published.21

Prognosis

The prognosis for patients with primary OA is variable and depends on the joint involved. If a weight­bearing joint or the spine is involved,
considerable morbidity and disability are possible. In the case of secondary OA, the prognosis depends on the underlying cause. Treatment of OA may
relieve pain or improve function but does not reverse preexisting damage to the joint.

CLINICAL PRESENTATION: OSTEOARTHRITIS

Age

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Gender

Age <45 years more common in men

relieve pain or improve function but does not reverse preexisting damage to the joint.
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CLINICAL PRESENTATION: OSTEOARTHRITIS

Age

Usually occurs in older adults (≥65 years of age)

Gender

Age <45 years more common in men

Age >45 years more common in women

Symptoms

Pain

Deep, aching character

Pain on motion

Stiffness in affected joints

Resolves with motion, recurs with rest (“gelling phenomenon”)

Usually duration <30 minutes

Often related to weather

Limited joint motion

May result in limitations of activities of daily living

Instability of weight­bearing joints

Signs, history, and physical examination

Monoarticular or oligoarticular, asymmetrical involvement

Hands

Distal interphalangeal joints

Herberden nodes (osteophytes or bony enlargements) (Fig. 110­1)

Proximal interphalangeal joints

Bouchard’s nodes (osteophytes)

First metacarpal joint

Osteophytes give characteristic square appearance to hands

Knee

Pain related to climbing stairs

Transient joint effusion

Genu varum (“bow­legged”)

Hips

Groin pain during weight­bearing exercises

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after activity Page 8 / 41
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Limited joint movement
 Transient joint effusion
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Hips

Groin pain during weight­bearing exercises

Stiffness, especially after activity

Limited joint movement

Spine

Lumbar involvement is most common at L3 and L4

Paresthesia

Loss of reflexes

Feet

Typically involves the first metatarsophalangeal joint

Shoulder, elbow, acromioclavicular, sternoclavicular, temporomandibular joints may also be affected

Observation on joint examination

Bony proliferation or occasional synovitis

Local tenderness

Crepitus

Limited motion with passive/active movement

Deformity

Radiologic evaluation

Early mild OA

Radiographic changes are often absent

Progressive OA

Joint space narrowing (Fig. 110­3)

Subchondral bone sclerosis

Marginal osteophytes

Late OA

Abnormal alignment of joints

Effusions

PATIENT CARE PROCESS

Patient Care Process for the Management of Osteoarthritis*

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Patient Care Process for the Management of Osteoarthritis*

Collect

Patient characteristics (eg, age, weight, height, race, sex, pregnant)

Patient history (past medical, family, social—trauma, diet, exercise, alcohol use)

Symptom information: type and location of pain, duration, effect of motion and rest, range of motion and limitations on activities, joint
instability

Current and past medications, including nonprescription agents and dietary supplements, and medications’ relief of symptoms

Objective data

Physical examination, appearance of joints

Radiologic evaluation—changes in joints, subchondral bone sclerosis, effusions

Body mass index (presence of overweight or obesity)

Assess

Distribution and severity of joint involvement

Impact of symptoms on patients’ movements, health­related quality of life, amount of disability

Plan

Patient education about disease, prognosis, treatment options, application and use of topical products

Nonpharmacologic therapy (see Table 110­1)—weight loss (if overweight or obese), exercise, surgery (for severe pain or functional disability)

Drug therapy regimen including specific analgesics, dose, route, frequency, and duration; specify the continuation and discontinuation of
existing therapies (see Figs. 110­4 and 110­5 and Tables 110­2 and 110­3)

Monitoring parameters including efficacy (eg, symptom relief) and safety (medication­specific adverse effects) (see Table 110­3)
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M. Buys;and weight—where
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Referrals to other providers when appropriate (eg, physician, orthopedic surgeon, physical therapist, dietician)

*
 Nonpharmacologic therapy (see Table 110­1)—weight loss (if overweight or obese), exercise, surgery (for severe painUniversity
or functional disability)
of the West Indies
Access Provided by:
Drug therapy regimen including specific analgesics, dose, route, frequency, and duration; specify the continuation and discontinuation of
existing therapies (see Figs. 110­4 and 110­5 and Tables 110­2 and 110­3)

Monitoring parameters including efficacy (eg, symptom relief) and safety (medication­specific adverse effects) (see Table 110­3)

Self­monitoring of symptoms, exercise, and weight—where and how to record results

Referrals to other providers when appropriate (eg, physician, orthopedic surgeon, physical therapist, dietician)

Implement*

Provide patient education regarding all elements of treatment plan

Use motivational interviewing and coaching strategies to maximize adherence

Schedule follow­up

Follow­up: Monitor and Evaluate

Assess symptom relief, effectiveness of weight loss and exercise programs

Presence of adverse effects (see Table 110­3), including CV and renal effects of NSAIDs and hepatic effects of acetaminophen

Closely monitor proper use of opioids, including dependence, addiction, tolerance, hyperalgesia, and diversion (see text); joint replacement
may be preferred to chronic opioids

Patient adherence to treatment plan using multiple sources of information

* Collaborate with patient, caregivers, and other healthcare professionals.

FIGURE 110­4

Treatment recommendations for knee and hip osteoarthritis. (CV, cardiovascular; GI, gastrointestinal; NSAID, nonsteroidal anti­inflammatory drug.)
a Selection of a medication should consider patient­specific characteristics. bThe patient must be counseled regarding all acetaminophen­containing

products. cWhen used for chronic management of OA, consider addition of a proton­pump inhibitor.

FIGURE 110­5

Treatment recommendations for hand osteoarthritis. (NSAID, nonsteroidal anti­inflammatory drug.) aSelection of a medication should consider
patient­specific characteristics. bWhen used for chronic management of OA, consider addition of a proton­pump inhibitor. cShould not combine
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 University of the West Indies
FIGURE 110­5 Access Provided by:

Treatment recommendations for hand osteoarthritis. (NSAID, nonsteroidal anti­inflammatory drug.) aSelection of a medication should consider
patient­specific characteristics. bWhen used for chronic management of OA, consider addition of a proton­pump inhibitor. cShould not combine
topical NSAIDs and oral NSAIDs.

TABLE 110­1
Nonpharmacologic Interventions in the Treatment of OA

Intervention Strength of Recommendation

Exercise Strong

Weight loss (if overweight) Strong

Patient education Strong

Use of assistive device (ie, cane) Moderate

Use of shoe insoles Moderate

Application of heat Moderate

Use of fitted knee braces Minimal

Lateral patellar taping Minimal

Passive exercise alone Minimal

Data from References 24, 25.

Robustness of recommendation: Strong—fully supported by evidence­based guidelines; Moderate—supported by evidence­based guidelines; Minimal—little
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Dosing of Medications for Osteoarthritis
 University of the West Indies
Access Provided by:

TABLE 110­1
Nonpharmacologic Interventions in the Treatment of OA

Intervention Strength of Recommendation

Exercise Strong

Weight loss (if overweight) Strong

Patient education Strong

Use of assistive device (ie, cane) Moderate

Use of shoe insoles Moderate

Application of heat Moderate

Use of fitted knee braces Minimal

Lateral patellar taping Minimal

Passive exercise alone Minimal

Data from References 24, 25.

Robustness of recommendation: Strong—fully supported by evidence­based guidelines; Moderate—supported by evidence­based guidelines; Minimal—little
support by evidence­based guidelines.

TABLE 110­2
Dosing of Medications for Osteoarthritis

Drug Brand Name Starting Usual Range Special Other

Dose Population Dose

Oral analgesics

Acetaminophen Tylenol 325­500 325­650 mg every 4­6 Chronic alcohol Contained in

mg hours or 1 g three to intake, hepatic many
three four times/day disease combination
times a analgesics
day

Tramadol Ultram 25 mg in Titrate dose in 25­mg Creatinine May need to

Tramadol ER Ultram ER the increments to reach a clearance <30 taper dose upon
morning maintenance dose of mL/min (0.5 discontinuation
100 mg 50­100 mg three mL/s)— to prevent
daily times a day maximum dose withdrawal
Titrate to 200­300 mg is 200 mg daily symptoms
daily Do not use if
creatinine
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©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility mL/min (0.5
mL/s)
 morning maintenance dose of mL/min (0.5 discontinuation
100 mg 50­100 mg three mL/s)— University of the West Indies
to prevent
daily times a day maximum dose Access Provided by:
withdrawal
Titrate to 200­300 mg is 200 mg daily symptoms
daily Do not use if
creatinine
clearance <30
mL/min (0.5
mL/s)

Hydrocodone/acetaminophen Lortab, 5 2.5­10 mg/325­650 mg Titrate dose Maximum dose

Vicodin, mg/325 three to five times slowly in older limited by total
Norco mg daily adults (age >65 daily dose of
three years) acetaminophen
times
daily

Oxycodone/acetaminophen Percocet 5 2.5­10 mg/325­650 mg Titrate dose Maximum dose

mg/325 three to five times slowly in older limited by total
mg daily adults (age >65 daily dose of
three years) acetaminophen
times
daily

Topical analgesics

Capsaicin 0.025% or 0.15% Capzasin­ Apply to affected —

HP joint three to four
times per day

Diclofenac 1% gel Voltaren Apply 2 or 4 g per site

as prescribed, four
times daily

Diclofenac 1.3% patch Flector Apply one patch

twice daily to the site
to be treated, as
directed

Diclofenac 2% solution Pennsaid Apply 40 mg (two

pump actuations)
twice daily

Intra­articular corticosteroids

Triamcinolone Kenalog 5­15 10­40 mg/large­joint If multiple Often

mg/joint (knee, hip, shoulder) joints injected, administered
maximum total concomitantly
dose is usually with a local
80 mg anesthetic

Methylprednisolone acetate
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Sara A. Wiedenfeld (knee, hip, shoulder) medium joints Page 14 / 41
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 mg/joint (knee, hip, shoulder) joints injected, administered
maximum total University concomitantly
of the West Indies
dose is usually Access Provided
with aby:local
80 mg anesthetic

Methylprednisolone acetate Depo­ 10­20 20­80 mg/large­joint 10­40 mg for

Medrol mg/joint (knee, hip, shoulder) medium joints
(elbows, wrists)

Nonsteroidal anti­inflammatory drugs (NSAIDs)

Aspirin, plain, buffered, or Bayer, 325 mg 325­650 mg four Doses of 3,600

enteric­coated Ecotrin, three times a day mg/day are
Bufferin times a needed for anti­
day inflammatory
activity

Celecoxib Celebrex 100 mg 100 mg twice daily or

daily 200 mg daily

Diclofenac XR Voltaren­ 100 mg 100­200 mg daily

Diclofenac IR XR daily 50­75 mg twice a day
Cataflam 50 mg
twice a
day

Diflunisal Dolobid 250 mg 500­750 mg twice a

twice a day
day

Etodolac Lodine 300 mg 400­500 mg twice a

twice a day
day

Fenoprofen Nalfon 400 mg 400­600 mg three to

three four times a day
times a
day

Flurbiprofen Ansaid 100 mg 200­300 mg/day two

twice a to four divided doses
day

Ibuprofen Motrin, 200 mg 1,200­3,200 mg/day in Available OTC

Advil three three to four divided and Rx
times a doses
day

Indomethacin Indocin 25 mg Titrate dose by 25­50

Indomethacin SR Indocin twice a mg/day until pain
SR day controlled or
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SR once mg three
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• Accessibility
daily Can titrate to 75 mg
SR twice daily if
 day
University of the West Indies
Access Provided by:

Indomethacin Indocin 25 mg Titrate dose by 25­50

Indomethacin SR Indocin twice a mg/day until pain
SR day controlled or
75 mg maximum dose of 50
SR once mg three times a day
daily Can titrate to 75 mg
SR twice daily if
needed

Ketoprofen Orudis 50 mg 50­75 mg three to

three four times a day
times a
day

Meclofenamate Meclomen 50 mg 50­100 mg three to

three four times a day
times a
day

Mefenamic acid Ponstel 250 mg 250 mg four times a FDA approval for
three day 1 week of
times a therapy
day

Meloxicam Mobic 7.5 mg 15 mg daily

daily

Nabumetone Relafen 500 mg 500­1,000 mg one to

daily two times a day

Naproxen Naprosyn 250 mg 500 mg twice a day

twice a
day

Naproxen sodium Anaprox, 220 mg 220–550 mg twice a Available OTC

Naproxen sodium DR Aleve twice a day and Rx
Naprelan day 375­750 mg twice a
day

Oxaprozin Daypro 600 mg 600­1,200 mg daily

daily

Piroxicam Feldene 10 mg 20 mg daily

daily

Salsalate Disalcid 500 mg 500­1,000 mg two to

twice a three times a day

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TABLE 110­3
 Piroxicam Feldene 10 mg 20 mg daily
daily University of the West Indies
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Salsalate Disalcid 500 mg 500­1,000 mg two to

twice a three times a day
day

TABLE 110­3
Monitoring of Medications Used in Osteoarthritis Treatment

Drug Adverse Drug Reactions Monitoring Parameters Comments

Oral
analgesics

Acetaminophen Hepatotoxicity Total daily dose limits Use caution with multiple acetaminophen­containing products
—total 4 g limit (or less in patients with hepatic dysfunction)

Tramadol Nausea, vomiting, No routine labs recommended Drug­drug interaction with other serotonergic medications
somnolence

Opioids Sedation, constipation, No routine labs recommended Risks of addiction, dependence, and drug diversion
nausea, dry mouth, hormonal
changes

NSAIDs Dyspepsia, CV events, GI BUN/Creatinine, Hgb/Hct, blood Risks higher in those older than 75 years of age
bleeding, renal impairment pressure

Topical
analgesics

Capsaicin Skin irritation and burning Inspection of areas of application Wash hands thoroughly after application

NSAIDs Skin itching, rash, irritated Inspection of areas of application. Wash hands thoroughly after application. Avoid oral NSAID or
dyspepsia, CV events, GI As needed: BUN/Creatinine, aspirin other than cardioprotective dose. Ensure patient applies
bleeding, renal impairment Hgb/Hct, blood pressure gel, solution, or patch correctly

Injectable
drugs

Intra­articular Hypertension, hyperglycemia Glucose, blood pressure HPA axis suppression if used too frequently
corticosteroids

Intra­articular Local joint swelling, stiffness, No routine labs recommended Less effective than intra­articular corticosteroids; expensive
hyaluronates pain

TREATMENT
Desired Outcome

Management of the patient with OA begins with a diagnosis based on a careful history, physical examination, radiographic findings, and an assessment
of the extent of joint involvement. Treatment should be tailored to each individual. Goals are (1) to educate the patient, family members, and
caregivers; (2) to relieve pain and stiffness; (3) to maintain or improve joint mobility; (4) to limit functional impairment; and (5) to maintain or improve
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quality of110: Osteoarthritis, Lucinda
About half of the USM. Buys; Sara
population hasA. chronic health condition, with 25% having two or more conditions.26 With nearly
Wiedenfeld
one Page
25%17of/ the
41
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US adults with at least one chronic health condition having arthritis, it is essential that comprehensive patient­centered medication management is
provided to these patients to maximize treatment goals for OA and other chronic conditions, while minimizing medication­related adverse outcomes.
 University of the West Indies
Desired Outcome
Access Provided by:

Management of the patient with OA begins with a diagnosis based on a careful history, physical examination, radiographic findings, and an assessment
of the extent of joint involvement. Treatment should be tailored to each individual. Goals are (1) to educate the patient, family members, and
caregivers; (2) to relieve pain and stiffness; (3) to maintain or improve joint mobility; (4) to limit functional impairment; and (5) to maintain or improve
quality of life.24,25 About half of the US population has one chronic health condition, with 25% having two or more conditions.26 With nearly 25% of the
US adults with at least one chronic health condition having arthritis, it is essential that comprehensive patient­centered medication management is
provided to these patients to maximize treatment goals for OA and other chronic conditions, while minimizing medication­related adverse outcomes.

General Approach to Treatment

Treatment for each OA patient depends on the distribution and severity of joint involvement, comorbid disease states, concomitant medications, and
allergies. Management for all individuals with OA should begin with both oral and written patient education, a customized activity and exercise
program, and weight loss, if the patient is overweight or obese.24,25 A multidisciplinary intervention for knee OA initiated by pharmacists has been
shown to improve adherence to OA guideline recommendations, decrease pain scores, and improve functional assessment scores.27 These types of
multidisciplinary disease state management programs that implement strategies to provide comprehensive care should be offered to all OA patients to
maximize outcomes.

The primary objective of medication is to alleviate pain.24,25 Scheduled acetaminophen, up to 4 g/day, should be tried initially (knee, hip), if
contraindications are not present. Application of topical NSAIDs over specific joints (knee, hands) and topical capsaicin (hands) are recommended as
initial therapy. Nonsteroidal anti­inflammatory drugs (NSAIDs) or possibly a cyclooxygenase­2 (COX­2)–selective inhibitor (celecoxib) can be prescribed
after careful risk assessment if additional pain control is needed. Intra­articular corticosteroid injections (knee or hip) can relieve pain and are offered
concomitantly with oral analgesics or after failed trials of first­line medications, depending on the practitioner’s preference. With centrally acting
serotonin reuptake inhibition and analgesic properties, tramadol can also be considered if acetaminophen or topical treatment is ineffective or not
tolerated.

Consideration may also be given to duloxetine or, rarely, hyaluronic acid injections when additional pain control is needed for knee OA. When
symptoms are persistent or there is significant loss of function, joint replacement can be appropriate if the patient is a surgical candidate.

There is general agreement that glucosamine and/or chondroitin and topical medications lack uniform efficacy in the treatment of hip and knee OA
pain and are not preferred treatment options.

Nonpharmacologic Therapy

Nonpharmacologic therapy is an integral part of the treatment plan for all patients with OA.24,25,28 Nonpharmacologic therapy is the only available
treatment that has been shown to delay the progression of OA.2,29 Delaying the progression of OA through active participation in nonpharmacologic
therapy is critical to prevent future functional impairment. Patient­specific characteristics such as (1) number and location of affected joints, (2) degree
of functional impairment, (3) body mass index, (4) motivation, and (5) overall health status determine which nonpharmacologic therapies should be
offered. Nonpharmacologic therapy should be ongoing treatment for all patients, even those who require pharmacologic therapy for pain control
(Table 110­1).2,28,29

Patient Education

The first step in OA treatment is patient education about the disease process, the extent of OA, the prognosis, and treatment options. Education is
paramount, in that OA is often seen as a wear­and­tear disease, an inevitable consequence of aging for which nothing helps. Even worse, patients may
resort to the use of alternative but unproven medications or treatments. Organizations such as the Arthritis Foundation provide a wealth of
educational information for patients regarding OA, OA medications, and local clinics and agencies offering physical and economic assistance. Exercise,
weight loss, and nutritional information are also available. Most educational information is readily available online for patient use. Several mobile
applications are available to provide education, track symptoms and exercise, and encourage better self­management of OA.

The benefits of patient education have been documented in a variety of programs.22,28 These programs are provided across a wide spectrum of
delivery methods: from trained volunteers using telephone calls to group sessions for patient support to one­on­one educational sessions with
physical therapists or nurse educators. While nearly all of these delivery methods are effective, cost of delivery is highly variable. Long­term cost­
effectiveness is important for sustainability of these patient education programs.

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indicate a strong association between increasing BMI and surgical
replacement of the hip and knee joints.30 Weight loss of amounts as small as 4% body weight can lessen OA pain in the knee.31 Greater amounts of
2,29
The benefits of patient education have been documented in a variety of programs.22,28 These programs are provided across a wide spectrum of
University of the West Indies
delivery methods: from trained volunteers using telephone calls to group sessions for patient support to one­on­one educational sessions with
Access Provided by:
physical therapists or nurse educators. While nearly all of these delivery methods are effective, cost of delivery is highly variable. Long­term cost­
effectiveness is important for sustainability of these patient education programs.

Weight Loss

The association between OA and obesity has been well established. Studies also indicate a strong association between increasing BMI and surgical
replacement of the hip and knee joints.30 Weight loss of amounts as small as 4% body weight can lessen OA pain in the knee.31 Greater amounts of
weight loss, especially when associated with regular exercise improve joint function and substantially lessen pain.2,29 Modest weight loss (5%) has
been shown to provide some relief in obese patients with OA but the goal should be an initial decrease in body weight of at least 10% to provide
significant reductions in pain.30 The Intensive Diet and Exercise for Arthritis trial (IDEA) found that after 18 months, overweight and obese adults with
knee OA who participated in the diet and exercise treatment group had less inflammation, less pain, better function, and better quality of life.32 Weight
loss requires a motivated patient, but all patients with OA who also have obesity and overweight should be encouraged and supported in their efforts
to optimize their body size. Effective behavior change strategies should be employed to promote weight loss in patients with OA.29

Exercise

Exercise programs can improve joint function and can decrease disability, pain, and analgesic use by OA patients.2,33 Low­impact aerobic exercise
including both land­ and water­based methods are preferred.34 Exercises can be taught and then observed before the patient exercises at home. The
frequency, types of exercise, and setting of exercise are still uncertain, but patients who exercise have decreased pain and increased physical
function.35 The patient should be instructed to decrease the number of repetitions if severe pain develops with exercise.

Some regular exercise should be encouraged for all patients with OA.25 With weak or deconditioned muscles, the load is transmitted excessively to the
joints; weight­bearing activities can exacerbate symptoms. Many patients fear that exercise will promote further joint damage and avoid exercise as a
means to protect the joint. However, avoidance of regular exercise by those with hip or knee OA leads to further deconditioning and/or weight gain.
Further weight gain and deconditioning leads to more pain and impaired joint function, promoting a downward spiral of disability. Exercise therapy in
addition to patient education has been shown to decrease or postpone the need for hip replacement surgery in patients with hip OA.36

Referral to the physical and/or occupational therapist is especially helpful for developing a customized exercise plan for patients with functional
disabilities. The therapist can assess muscle strength and joint stability and recommend exercises and assistive and orthotic devices, such as canes,
walkers, braces, heel cups, splints, or insoles for use during exercise or daily activities. Heat or cold treatments help to maintain and restore joint range
of motion and to reduce pain and muscle spasms. Warm baths or warm water soaks may decrease pain and stiffness. Heating pads should be used
with caution, especially in the elderly. Patients should be warned not to fall asleep on the heat source or to lie on it for more than brief periods to avoid
burns.

Surgery

Surgery can be recommended for OA patients with functional disability and/or severe pain unresponsive to medical therapy.37 Total joint replacement
surgeries are quite common and expected to increase. Over 1 million total hip and knee replacement procedures are performed each year in the
United States. Seven million individuals are living with an artificial knee or hip, including 620,000 people who have both.23 Although total knee
arthroplasty can decrease pain and improve function for many patients, about 20% experience little or no improvement in pain, disability, and/or
quality of life.38 Patients who are obese are less likely to have improvement in symptoms from knee arthroplasty. Patients also experience less pain and
decreased length of hospitalization after surgery if they participate in a supervised exercise program for the first two months that begins on the day of
surgery.39

Total joint arthroplasty is responsible for a large portion of the direct medical costs associated with OA in the United States. The cost­effectiveness of
total knee arthroplasty has been evaluated for a Medicare­age population.40 Calculations were based on Medicare claims data and costs and outcomes
data. Cost projections were calculated for lifetime costs as well as quality­adjusted life expectancy (QALE) for different risk populations and across low­
volume to high­volume hospitals. Although total knee arthroplasty was found to be cost­effective across hospital settings and patient risk categories,
the procedure was found to be most cost­effective when performed in high­volume centers. The cost­effectiveness of knee arthroplasty was evaluated
against nonsurgical management. Knee arthroplasty was cost­effective at both low and high levels of improvement in pain and function in patients
with severe knee OA.41 Direct medical costs associated with joint replacement will continue to increase at a rate higher than predicted rates due to
increasing willingness of patients to undergo joint replacement surgery.3
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Pharmacologic Therapy
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Drug therapy in OA is targeted at relief of pain. OA is commonly seen in older individuals who have other medical conditions, and OA treatment is often
24,25,28
data. Cost projections were calculated for lifetime costs as well as quality­adjusted life expectancy (QALE) for different risk populations and across low­
volume to high­volume hospitals. Although total knee arthroplasty was found to be cost­effective across hospital settings and patientofrisk
University thecategories,
West Indies
the procedure was found to be most cost­effective when performed in high­volume centers. The cost­effectiveness of kneeAccess
arthroplasty
Provided by:was evaluated

against nonsurgical management. Knee arthroplasty was cost­effective at both low and high levels of improvement in pain and function in patients
with severe knee OA.41 Direct medical costs associated with joint replacement will continue to increase at a rate higher than predicted rates due to
increasing willingness of patients to undergo joint replacement surgery.3

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 OA treatment is often
long term. As such, a conservative and patient­centered approach to drug treatment is warranted (see Figs. 110­4 and 110­5).24,25,28 Even when
pharmacologic therapy is initiated, appropriate nondrug therapies should be continued and reinforced. Specific drug therapy recommendations
depend on which joint(s) are affected, response to previous trials of medication, and patient comorbidities.

Knee and Hip OA

First­Line Treatments

Acetaminophen

The American College of Rheumatology, as well as others, recommend acetaminophen as a first­line treatment for knee and hip OA.24,25,42
Acetaminophen has been extensively studied in the treatment of knee and hip OA and is more effective than placebo in controlling OA pain.43
Compared with oral NSAIDs, acetaminophen may be modestly less effective, but have lower risk of serious GI and CV adverse events and as a
consequence is preferred to oral NSAIDs as first­line treatment.28,42

Oral NSAIDs

The American College of Rheumatology and other key groups recommend nonspecific or COX­2 selective NSAIDs, depending on patient risk factors, as
a first­line option for knee and hip OA if the patient fails acetaminophen.25,26,41 Nonselective and COX­2 selective NSAIDs pose higher risks for GI, renal,
and CV adverse events compared to acetaminophen. COX­2 inhibitors carry less risk for both minor and serious GI adverse events in comparison to
nonselective NSAIDs (with the exception of diclofenac).42

Topical NSAIDs—Knee Only

The American College of Rheumatology and other authorities recommend topical NSAIDs as a first­line option for knee OA if the patient fails
acetaminophen and is preferred to oral NSAIDs for those older than age 75 years.24,25,42 Topical NSAIDs provide pain relief for OA similar to that
obtained with oral NSAIDs but with fewer GI adverse events. Topical NSAIDs offer a favorable safety profile and aren’t associated with systemic adverse
effects. The most common adverse effect of topical NSAIDs is a localized skin reaction.44

Intra­articular Corticosteroids

Intra­articular corticosteroid injections are recommended as alternative first­line treatment for both knee and hip OA when pain control with
acetaminophen or NSAIDs is suboptimal.24,25 Injections can also be administered with concomitant oral analgesic therapy as needed for additional
pain control. Intra­articular corticosteroids are generally safe and well tolerated, but should not be administered more frequently than once every 3
months due to risks of systemic adverse effects.

Tramadol

Tramadol is recommended as an alternative first­line treatment of knee and hip pain due to OA in patients who have failed treatment with scheduled
full­dose acetaminophen and topical NSAIDs, who are not appropriate candidates for oral NSAIDs, and who are not able to receive intra­articular
corticosteroids.25 Tramadol can also be safely added to partially effective acetaminophen or oral NSAID therapy. Less data are available to support the
use of tramadol as monotherapy for OA pain.

Second­Line Treatments

Opioid Analgesics

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opioid
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analgesics as the primary second­line medication for both knee and hip OA.25 Opioids
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may be considered in patients who have not had an adequate response to both nonpharmacologic and first­line pharmacologic therapies. Patients
who are at high surgical risk, precluding joint arthroplasty, are also candidates for opioid therapy. When compared to nonopioid medications in a 12­
corticosteroids.25 Tramadol can also be safely added to partially effective acetaminophen or oral NSAID therapy. Less data are available to support the
University of the West Indies
use of tramadol as monotherapy for OA pain.
Access Provided by:

Second­Line Treatments

Opioid Analgesics

The American College of Rheumatology recommends opioid analgesics as the primary second­line medication for both knee and hip OA.25 Opioids
may be considered in patients who have not had an adequate response to both nonpharmacologic and first­line pharmacologic therapies. Patients
who are at high surgical risk, precluding joint arthroplasty, are also candidates for opioid therapy. When compared to nonopioid medications in a 12­
month randomized trial, opioids were not found to be superior in improving pain­related function.45 Adverse effects, including serious events, limit
the routine use of opioids in the treatment of OA pain.

Duloxetine—Knee Only

Duloxetine can be used as adjunctive treatment in patients with knee OA who have had a partial response to first­line analgesics.24,25 It may be a
preferred second­line medication in patients with both neuropathic and musculoskeletal OA pain. Duloxetine has demonstrated efficacy primarily as
add­on therapy when there has been less than optimal response to acetaminophen or oral NSAIDs.46,47 Reduction in pain occurs at about 4 weeks after
initiation.48 Adverse events associated with duloxetine in the treatment of knee OA are most commonly GI, with nausea, vomiting, and constipation
being the most common. The recommended dose is 60 mg once daily. However, some patients may benefit from higher doses, up to a maximum dose
of 120 mg daily.48 Adverse events have been reported in OA trials that most commonly used doses of 60 mg/day. A higher dose is associated with an
increased risk of adverse reactions.

Intra­articular Hyaluronic Acid

The American College of Rheumatology, NICE, and others do not routinely recommend the use of intra­articular hyaluronic acid injections for knee OA
pain.24,25,28 HA injections do not provide clinically meaningful improvement in pain and/or function scores, although some studies may report
statistical differences in scores. These agents may be associated with serious adverse events such as increased pain, joint swelling, and stiffness.
Limited efficacy and risks of serious events limit the routine use of these agents.

Hand OA

First­Line Treatments

NSAIDs

The American College of Rheumatology and NICE recommend topical NSAIDs as a first­line option for hand OA.28 Application of diclofenac gel
compared to placebo topical product for hand OA provided significant relief.21 No difference was found between the efficacy of oral and topical
NSAIDs. Local adverse effects were seen more with topical versus oral NSAIDs but GI adverse effects were more common with oral NSAIDs.49,50 Efficacy
with topical NSAIDs was reported quickly, within 1 to 2 weeks.21

Oral NSAIDs are recommended as an alternative first­line treatment for hand OA by the American College of Rheumatology and as second­line therapy
in the NICE guidelines.25,28 For the person who cannot tolerate local skin reactions or who received inadequate relief from topical NSAIDs, oral NSAIDs
can offer relief, but the patient then faces increased risk for GI, renal, and CV adverse events.

Topical Capsaicin

Capsaicin cream is recommended as an alternative first­line treatment for hand OA.25 Clinical trial data supporting the use of capsaicin for the
treatment of hand OA is limited to small studies, but demonstrates about 50% reduction in pain scores.21 Adverse effects associated with capsaicin are
primarily skin irritation and burning; therefore, it is a reasonable therapeutic alternative for patients who are not able to take oral NSAIDs.

Tramadol

Tramadol is recommended by the American College of Rheumatology as an alternative first­line treatment for OA of the hand.25 No studies in hand OA
with tramadol have been performed.21 In clinical practice, tramadol is a therapeutic option for patients who do not respond to topical therapy and are
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acetaminophen, topical therapy, or oral NSAIDs. Page 21 / 41
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Drug Class Information
primarily skin irritation and burning; therefore, it is a reasonable therapeutic alternative for patients who are not able to take oral NSAIDs.
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Tramadol Access Provided by:

Tramadol is recommended by the American College of Rheumatology as an alternative first­line treatment for OA of the hand.25 No studies in hand OA
with tramadol have been performed.21 In clinical practice, tramadol is a therapeutic option for patients who do not respond to topical therapy and are
not candidates for oral NSAID treatment due to high GI, CV, or renal risks. Tramadol may also be used in combination with partially effective
acetaminophen, topical therapy, or oral NSAIDs.

Drug Class Information

Highlights of drug information is presented here. This section is not intended to be all inclusive but aims to provide pertinent drug information to
facilitate the safe­and­effective use of these medications in patients with OA.

First­Line Treatments

Acetaminophen

Pharmacology and Mechanism of Action

Acetaminophen is understood to act within the central nervous system (CNS) by inhibiting synthesis of prostaglandins, agents that enhance pain
sensations. Acetaminophen prevents prostaglandin synthesis by blocking the action of central cyclooxygenase (COX). Acetaminophen is well absorbed
after oral administration, with bioavailability of 60% to 98%. It achieves peak concentrations within 1 to 2 hours. It is inactivated in the liver by
conjugation with sulfate or glucuronide, and its metabolites are renally excreted.

Adverse Effects

Although acetaminophen is one of the safest analgesics for younger individuals without comorbidities, it carries greater risk in frail older adults.51
Serious hepatotoxicity, including fatalities, have been well documented with acetaminophen overdose (see Chapter e8, “Clinical Toxicology,” for
treatment of acetaminophen overdose).52 Unintentional overdoses of acetaminophen are due to a variety of circumstances including narrow
therapeutic window at the maximum dose (4 g/day), interpatient differences in sensitivity to liver injury from acetaminophen, a wide array of
nonprescription and prescription products that contain acetaminophen, which may be hard for patients to identify on the label, and consumers’ lack
of knowledge about the association of acetaminophen and serious liver injury.

Acetaminophen­related hepatotoxicity is dose­dependent. Even at therapeutic doses, acetaminophen may cause transient liver enzyme elevations and
potentially hepatotoxicity.53,54 The most common risk factor for liver failure in patients who take acetaminophen is chronic alcohol intake.55 The FDA
has recommended that chronic alcohol users (three or more drinks daily) avoid acetaminophen intake as it increases the risk of liver damage or GI
bleeding. Other individuals are not at increased risk of GI bleeding.

Drug­Drug Interactions and Drug­Food Interactions

Drug interactions with acetaminophen can occur; for example, isoniazid can increase the risk of hepatotoxicity. Chronic ingestion of maximal doses of
acetaminophen may intensify the anticoagulant effect for patients taking warfarin; such individuals may need closer monitoring. Although food
decreases the maximum serum concentration of acetaminophen by approximately half, the overall efficacy is unchanged.

Dosing and Administration

When used for chronic OA, acetaminophen should be administered in a scheduled manner. It may be taken with or without food. Acetaminophen can
be taken at 325 to 650 mg every 4 to 6 hours, but the total dose must not exceed 4 grams daily (see “Adverse Effects” section above). FDA labeling
requirements warn patients about potential liver toxicity if they inadvertently ingest more than the recommended dose when using multiple products
containing acetaminophen. Additionally, prescription analgesics containing acetaminophen are limited to 325 mg/tablet to further decrease the
opportunity for inadvertent overdose. Acetaminophen should be avoided in the setting of chronic alcohol intake or in those with underlying liver
disease.

Oral Nonsteroidal Anti­inflammatory Drugs

Pharmacology and Mechanism of Action

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NSAIDs
Chapterreduce pain, inflammation,
110: Osteoarthritis, and
Lucinda [Link] bySara
Buys; preventing synthesis of tissue prostaglandins and related prostanoids, which play a role in
A. Wiedenfeld triggering
Page 22 / 41
these symptoms. All NSAIDs bind (reversibly) to the cyclooxygenase 2 (COX­2) enzyme, blocking
©2025 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility its action and thus prostanoid production. Blockade of
prostaglandin synthesis by inhibiting COX enzymes (mainly COX­2) is thought to account for NSAIDs ability to relieve pain and inflammation (Fig. 110­
6).56 Nonselective NSAIDs were developed prior to extensive knowledge of COX enzymes, but in fact they block both COX­2 and COX­1. COX­1 has
disease.
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Oral Nonsteroidal Anti­inflammatory Drugs

Pharmacology and Mechanism of Action

NSAIDs reduce pain, inflammation, and fever by preventing synthesis of tissue prostaglandins and related prostanoids, which play a role in triggering
these symptoms. All NSAIDs bind (reversibly) to the cyclooxygenase 2 (COX­2) enzyme, blocking its action and thus prostanoid production. Blockade of
prostaglandin synthesis by inhibiting COX enzymes (mainly COX­2) is thought to account for NSAIDs ability to relieve pain and inflammation (Fig. 110­
6).56 Nonselective NSAIDs were developed prior to extensive knowledge of COX enzymes, but in fact they block both COX­2 and COX­1. COX­1 has
required “housekeeping” functions such as gastroprotection. COX­2 inhibitors selectively block COX­2 but not COX­1 activity.

FIGURE 110­6

Pathway of synthesis for prostaglandins and leukotrienes. COX­1 and COX­2 are cyclooxygenase­1 and cyclooxygenase­2 enzymes, respectively. The
minus (–) sign indicates inhibitory influence. Prostaglandins include PGE2 and PGI2; the latter is also known as prostacyclin.

The various NSAIDs exhibit several pharmacokinetic similarities, including high oral availability, high protein binding, and absorption as active drugs
(except for sulindac and nabumetone, which require hepatic conversion for activity). There is a broad range of serum half­lives for different NSAIDs,
which influence dosing frequency, and potentially, compliance with therapy.57 Elimination of NSAIDs largely depends on hepatic inactivation, with a
small fraction of active drug being renally excreted. NSAIDs penetrate joint fluid, reaching approximately 60% of blood levels.

Adverse Effects Gastrointestinal Effects of Nonselective NSAIDs

The most common adverse effects of NSAIDs involve the GI tract. NSAIDs can cause minor symptoms such as nausea and dyspepsia as well as more
serious effects such as ulcers and bleeding.58­60 All NSAIDs increase ulcer risk, but the serious GI complications associated with NSAIDs include
perforations, gastric outlet obstruction, and bleeding. These important GI complications occur in 1.5% to 4% of patients per year. NSAIDs are so widely
used that these small percentages translate into substantial morbidity and mortality. Moreover, the risk increases substantially for patients with risk
factors including a longer duration of NSAID usage, higher dosage, age older than 60 years, past history of peptic ulcer disease of any cause, history of
alcohol use, concomitant use of glucocorticoids, and/or anticoagulants.56 A patient treated with NSAIDs has a three to five times higher risk of
developing GI complications than a patient not treated with these medications.61

Options are available to reduce the GI risk of traditional NSAIDs. (1) Take the lowest dose possible and take only when needed. (2) Take the
prostaglandin analog, misoprostol four times daily that reduces the rate of ulcers and serious GI complications. Many patients cannot tolerate the GI
adverse events of misoprostol, especially diarrhea. (3) Take a proton pump inhibitor (PPI) or a full­dose H2 blocker daily. The PPI and the H2 blocker do
reduce minor GI complaints and reduce the risk of ulcers but are not rigorously proven to decrease the serious complications, possibly because of lack
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Another choice that is available to reduce risk of GI events with an NSAID is to take a COX­2 selective inhibitor (“coxib”).58,60 Celecoxib is the only coxib
available in the United States. Because this drug does not block the “housekeeping” gene, it may not have the same GI risks, but it is not without GI
developing GI complications than a patient not treated with these medications.61
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Options are available to reduce the GI risk of traditional NSAIDs. (1) Take the lowest dose possible and take only when needed. (2) Take
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prostaglandin analog, misoprostol four times daily that reduces the rate of ulcers and serious GI complications. Many patients cannot tolerate the GI
adverse events of misoprostol, especially diarrhea. (3) Take a proton pump inhibitor (PPI) or a full­dose H2 blocker daily. The PPI and the H2 blocker do
reduce minor GI complaints and reduce the risk of ulcers but are not rigorously proven to decrease the serious complications, possibly because of lack
of power to detect rare events.61

Another choice that is available to reduce risk of GI events with an NSAID is to take a COX­2 selective inhibitor (“coxib”).58,60 Celecoxib is the only coxib
available in the United States. Because this drug does not block the “housekeeping” gene, it may not have the same GI risks, but it is not without GI
risk.55 A meta­analysis showed that COX­2 selective inhibitors were associated with significantly fewer gastroduodenal ulcers and clinically important
ulcer complications. Celecoxib has been shown to be as safe to the upper GI tract as a nonselective NSAID plus a PPI.62 Another concern is the risk
associated with NSAID use in patients taking aspirin for cardioprotection. The GI risk is lower in patients taking a coxib medication and low­dose
aspirin than a nonselective NSAID. However, in patients with high GI risk the combination may still be harmful and gastroprotection is appropriate.62

Dosing and Administration

Administration of NSAIDs must be tailored to the individual patient with OA. Selection of an NSAID depends on the prescriber’s experience, medication
cost, patient preference, allergies, toxicities, and adherence issues. Individual patient response differs among NSAIDs, so if an inadequate response is
obtained with one NSAID, another NSAID may yet provide benefit.25,28

Cardiovascular Risk of COX­2 Inhibitors and Traditional NSAIDs

Both nonselective and selective NSAIDs are associated with an increased risk for hypertension, stroke, myocardial infarction (MI), and death. NSAIDs
should be avoided in patients with known active ischemic heart disease, cerebrovascular disease, and moderate­to­severe heart failure.56 The
mechanism for the CV effects of NSAIDs is not entirely clear.61 NSAIDs are associated with hypertension, increased preload, volume expansion, and
reduced sodium excretion.63 A large meta­analysis showed some differences among NSAIDs in terms of vascular risk. The risks of diclofenac and
ibuprofen were similar to that of coxibs but naproxen was not associated with an increased risk of major vascular events. Overall, coxibs were found to
increase vascular risk by approximately one­third.64 Several randomized controlled trials have compared NSAIDs to evaluate CV safety and found
celecoxib to be noninferior to other NSAIDs in terms of CV events. However, the celecoxib dose in these trials was lower than the doses previously
reported to be associated with increased CV risk. In these trials, more patients also discontinued celecoxib due to lack of efficacy compared to other
NSAIDs.64,65

In February 2014, an advisory committee to the FDA met to discuss the data relating the CV risk and NSAIDs. After their review it was decided to
strengthen the warning label for nonaspirin NSAIDs, warning patients on the risk of heart attack and stroke. The updated labeling warns that CV events
can happen at any point during NSAID therapy and the risk may increase with longer treatment and higher doses. The FDA concluded that there was
insufficient evidence that the risk of any NSAID was higher or lower than another. An increased risk for CV events is present even in patients with no
underlying CV disease. The data reviewed also showed patients taking an NSAID following a first MI were more likely to die in the first year following the
MI.66 Strategies to reduce CV risk with NSAIDs are not well documented. Naproxen may present less CV risk than coxibs and diclofenac at higher doses
and therefore seems prudent to consider this when choosing a specific NSAID.61,62,66

Other Toxicities Associated with NSAIDs

NSAIDs may cause kidney diseases, including acute renal insufficiency, sodium retention, acute interstitial nephritis, renal papillary necrosis, and
accelerated chronic kidney disease. In a trial evaluating NSAID safety, serious renal events occurred at a significantly lower rate in the celecoxib group
compared to the ibuprofen group but when celecoxib was compared to naproxen the difference in renal events was not significant.67 Sodium retention
has been reported to occur in up to 25% of NSAID­treated patients. This effect may be clinically important to cause exacerbations of congestive heart
failure.63 Clinical features of these NSAID­induced renal syndromes include increased serum creatinine and blood urea nitrogen, hyperkalemia,
elevated blood pressure, peripheral edema, and weight gain. Patients at high risk are those with conditions associated with decreased renal blood flow
or taking certain medications. Examples are those with chronic renal insufficiency, congestive heart failure, severe hepatic disease, and nephrotic
syndrome, those of advanced age, or those taking diuretics, angiotensin­converting enzyme inhibitors, cyclosporine, or aminoglycosides (Fig. 110­7).

FIGURE 110­7

Mechanisms implicated in NSAID­induced renal injury. The minus (–) sign indicates inhibitory influence. (CHF, congestive heart failure; NSAIDs,
nonsteroidal anti­inflammatory drugs.)
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syndrome, those of advanced age, or those taking diuretics, angiotensin­converting enzyme inhibitors, cyclosporine, or aminoglycosides (Fig. 110­7).
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FIGURE 110­7

Mechanisms implicated in NSAID­induced renal injury. The minus (–) sign indicates inhibitory influence. (CHF, congestive heart failure; NSAIDs,
nonsteroidal anti­inflammatory drugs.)

Close monitoring is advisable for high­risk patients taking an NSAID, with monitoring of serum creatinine at baseline and within 3 to 7 days of drug
initiation. For those with impaired renal function, the National Kidney Foundation recommends acetaminophen over NSAIDs, although
acetaminophen may pose risks, as discussed above.

Coxibs and NSAIDs uncommonly cause drug­induced hepatitis; the two NSAIDs most frequently implicated are diclofenac and sulindac. Patient
monitoring should include periodic liver enzymes (aspartate aminotransferase and alanine aminotransferase), with cessation of therapy if these
values exceed two to three times the upper limit of normal. Hepatotoxicity associated with NSAIDs is responsible for about 10% of medication­induced
liver injury.68

Other toxic effects of NSAIDs include hypersensitivity reactions, rash, and CNS complaints of drowsiness, dizziness, headaches, depression, confusion,
and tinnitus.57 NSAIDs should be avoided for patients with asthma who are aspirin­intolerant.

All nonspecific NSAIDs inhibit COX­1–dependent thromboxane production in platelets and thus increase bleeding risk. Unlike aspirin, celecoxib and
nonspecific NSAIDs inhibit thromboxane formation reversibly, with normalization of platelet function 1 to 3 days after the drug is stopped. Warfarin
and celecoxib are metabolized by the cytochrome P450 isoenzyme CYP2C9; thus, patients receiving warfarin and COX­2 inhibitors should be followed
closely.

Finally, if misoprostol is taken for GI protection, great care is indicated. Because of its abortifacient properties, misoprostol is contraindicated in
pregnancy and in women of childbearing age who are not maintaining adequate contraception. It must be dispensed in its original container, which
carries a warning for these individuals. Misoprostol is also available in a combination product with diclofenac, which bears the same restrictions as
misoprostol alone.

Drug­Drug Interactions

Avoidance of concomitant use, or anticipation and careful monitoring, can often prevent serious events when potentially interacting drugs are being
considered. The most potentially serious interactions include the use of NSAIDs with lithium, warfarin, other agents that increase bleeding risk, oral
hypoglycemics, methotrexate, antihypertensives, angiotensin­converting enzyme inhibitors, β­blockers, and diuretics.57 In addition, there are
probable drug interactions with tacrolimus for ibuprofen, naproxen, diclofenac, and possibly other NSAIDs.

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Specific drug interactions P Your
are also is celecoxib.69 Celecoxib metabolism is primarily via CYP2C9.69 Cytochrome P450 inducers such as rifampin,
seenIPwith
Chapter 110: Osteoarthritis, Lucinda M. Buys; Sara
carbamazepine, and phenytoin have the potential A. Wiedenfeld
to reduce
Page 25 / 41
celecoxib levels. Concomitant administration of celecoxib with fluconazole can increase
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plasma concentrations of celecoxib, due to fluconazole inhibition of the CYP2C9 isoenzyme. Because warfarin and celecoxib are both metabolized by
CYP2C9, patients receiving warfarin and COX­2 inhibitors should be followed closely. Because celecoxib inhibits CYP2D6, it has the potential to increase
Avoidance of concomitant use, or anticipation and careful monitoring, can often prevent serious events when potentially interacting drugs are being
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considered. The most potentially serious interactions include the use of NSAIDs with lithium, warfarin, other agents that increase bleeding risk, oral
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hypoglycemics, methotrexate, antihypertensives, angiotensin­converting enzyme inhibitors, β­blockers, and diuretics.57 In addition, there are
probable drug interactions with tacrolimus for ibuprofen, naproxen, diclofenac, and possibly other NSAIDs.

Specific drug interactions are also seen with celecoxib.69 Celecoxib metabolism is primarily via CYP2C9.69 Cytochrome P450 inducers such as rifampin,
carbamazepine, and phenytoin have the potential to reduce celecoxib levels. Concomitant administration of celecoxib with fluconazole can increase
plasma concentrations of celecoxib, due to fluconazole inhibition of the CYP2C9 isoenzyme. Because warfarin and celecoxib are both metabolized by
CYP2C9, patients receiving warfarin and COX­2 inhibitors should be followed closely. Because celecoxib inhibits CYP2D6, it has the potential to increase
concentrations of a variety of agents, including antidepressants. Celecoxib is a sulfonamide and is thus noted to be contraindicated for those with sulfa
allergies.69

Another drug interaction has been noted for those taking some NSAIDs and cardioprotective doses of aspirin. Ibuprofen, used at doses of 400 mg or
more, may block aspirin’s antiplatelet effect if it is taken prior to aspirin. Patients taking ibuprofen have been advised to take a single dose of ibuprofen
at least 30 minutes after taking aspirin, or to take their aspirin at least 8 hours after taking ibuprofen. It is possible that other nonselective NSAIDs, such
as naproxen, also may cause such interactions. The ACR recommends that patients taking aspirin who need an oral NSAID for OA choose an NSAID
other than ibuprofen or COX­2 selective inhibitors.25 Acetaminophen does not interfere with the antiplatelet effect of aspirin.

Topical NSAIDs

Pharmacology and Mechanism of Action

The mechanism of action of topical NSAIDs is considered to be through inhibition of the COX­2 enzyme in tissues near the site of application. Studies
show significant placebo effects which could result from rubbing the product into the skin, which may have a counterirritant effect. Topical NSAIDs are
significantly more efficacious compared to placebo vehicle in reducing pain due to musculoskeletal conditions, including osteoarthritis. Most trials
have shown topical diclofenac to be as effective as oral NSAIDs, including both oral diclofenac and other comparators.42,50,70 Diclofenac 1% gel as well
as the newer diclofenac solution and diclofenac patches are approved in the United States for osteoarthritis.

Adverse Effects
Compared to oral NSAIDs, topical NSAIDs are associated with many fewer GI adverse events and fewer adverse events overall, except for local
application site reactions. In comparison to placebo or oral NSAIDs, topical NSAID use is associated with more local adverse events, most often mild
skin reactions such as itching or rash, but with few serious adverse effects. Meta­analyses and reviews have found similar tolerability between topical
NSAIDs and placebo. Topical NSAIDs have not shown a significant link between their use and increased risk of CV events.44 From 1% to 15% of topical
NSAIDs enter the systemic circulation, but usually less than 5% contribute to its greater safety profile.70,71

Drug­Drug Interactions
Interactions listed for topical diclofenac are the same as those listed above for oral NSAIDs. The most potentially serious interactions include the use of
NSAIDs with lithium, warfarin, and other agents that increase bleeding risk, oral hypoglycemics, methotrexate, antihypertensives, angiotensin­
converting enzyme inhibitors, β­blockers, and diuretics. Other topical agents have not been studied with the product and there could be changes in
tolerability and absorption of diclofenac. For all of these interactions, as there is only a small percentage of diclofenac absorbed, the risks are likely
significantly less than that with oral drug, but the patient and provider should monitor appropriately for these interactions with any of these drugs the
patient is taking. Patients should avoid oral NSAIDs while using topical products to minimize additive adverse effects. Care should be taken to avoid
contact with the eyes or open wounds and to wash hands after application (except when treating hand OA).

Dosing and Administration

Diclofenac 1% gel (Voltaren®) can be used for hand or knee OA or other joints amenable to topical application (eg, not the hip or shoulder) and is
available as an OTC product. It is applied four times daily using the dose measuring cards provided by the manufacturer. Four grams of gel is
recommended for application to the affected area in the lower limb (eg, foot, ankle, knee) four times daily. For use on the upper extremities (eg, hand,
wrist, elbow), the dose is 2 g four times daily. Diclofenac solution (Pennsaid®), only approved for knee OA, is available as a 2% solution. The 2%
diclofenac solution is available in a meter­dose pump. It is applied as two actuations or 40 mg twice daily to the affected knee(s). The entire dose
should be pumped into the palm of the hand then applied evenly to the knee. The diclofenac patch (180­mg diclofenac epolamine) is applied twice
daily. If the patch doesn’t stick well, the patient can tape edges with first­aid tape. Patient counseling is important to carefully explain how to apply the
topical products. Other counseling points include hand washing after use, avoidance of touching the eyes, nose, or mouth directly after use, and how
long to wait before dressing, putting on gloves, showering, and so forth.

Pharmacoeconomic Impact of NSAIDs

The highest costs associated with the pharmacotherapy of OA are hospitalization for treatment of NSAID­related complications, particularly serious GI
adverse events.
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P Your IP is therapy or the use of COX­2–selective inhibitors for low­risk patients has not been cost­effective because
of the number
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110: Osteoarthritis, to prevent seriousSara
M. Buys; events is large, but most PPIs are generic, multisource products, making concomitant treatment
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PPIs effective. Pharmacoeconomic considerations for OA involve the selection of therapy for the initial treatment of patients with OA. Use of the
nonprescription analgesic acetaminophen as initial therapy has greatly reduced medication costs in comparison with the use of NSAIDs, many of which
daily. If the patch doesn’t stick well, the patient can tape edges with first­aid tape. Patient counseling is important to carefully explain how to apply the
topical products. Other counseling points include hand washing after use, avoidance of touching the eyes, nose, or mouthUniversitydirectly after use,West
of the and how
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Pharmacoeconomic Impact of NSAIDs

The highest costs associated with the pharmacotherapy of OA are hospitalization for treatment of NSAID­related complications, particularly serious GI
adverse events. Historically, gastroprotective therapy or the use of COX­2–selective inhibitors for low­risk patients has not been cost­effective because
of the number needed to treat to prevent serious events is large, but most PPIs are generic, multisource products, making concomitant treatment with
PPIs effective.72 Pharmacoeconomic considerations for OA involve the selection of therapy for the initial treatment of patients with OA. Use of the
nonprescription analgesic acetaminophen as initial therapy has greatly reduced medication costs in comparison with the use of NSAIDs, many of which
are by prescription only. Oral NSAID costs vary considerably, depending on the medication, daily dose, and regimen selected. As oral NSAIDs as a class
are therapeutically similar, the use of a less­expensive agent such as nonprescription ibuprofen or naproxen or a multisource generic product may
minimize the cost. More expensive NSAIDs can be prescribed if neither of these offers benefit after a 2­week trial at sufficient doses. Prescription­only
topical NSAIDs are significantly more costly than oral agents. Over­the­counter diclofenac products are likely to have a similar cost compared to many
generic prescription oral NSAIDs. Costs related to the serious complications associated with oral NSAID therapy are likely to outweigh the costs
associated with topical diclofenac in any form, making prescription status products cost­effective.

Intra­articular Corticosteroids

Pharmacology and Mechanism of Action

The anti­inflammatory properties of corticosteroids as a class are the primary mechanism of pain relief in the treatment of OA. These properties
decrease the formation and release of prostaglandins, kinins, liposomal enzymes, and histamine. These actions decrease erythema, swelling, heat,
and tenderness of the inflamed joints.25,73 Aspiration of the effusion and injection of glucocorticoid are carried out aseptically, with examination of the
aspirate recommended to exclude crystalline arthritis or infection. Several randomized, placebo­controlled, double­blind studies have shown that
intra­articular corticosteroids are superior to placebo in alleviating knee pain and stiffness caused by OA but with a relatively short duration.73 The
most commonly used corticosteroids for intra­articular use are triamcinolone acetonide and methylprednisolone acetate. The branched esters of
triamcinolone and methylprednisolone are preferred by practitioners because of the reduced solubility that allows the agents to remain in the joint
space longer.74,75

Adverse Events
Adverse events associated with intra­articular injection of corticosteroids can be local or systemic in nature. Systemic adverse events are the same as
with any other systemic corticosteroid and can include hyperglycemia, edema, elevated blood pressure, flushing, dyspepsia, and hypercortisolism.
There is an acute 2­ to 3­day rise in blood glucose in patients with diabetes following a single corticosteroid injection. The risk of systemic side effects
can be lessened by limiting the dose of the corticosteroid since doses greater than 40 mg for triamcinolone or methylprednisolone have not been
shown to provide any additional benefit.74 Local adverse effects can include infection in the affected joint, osteonecrosis, tendon rupture, and skin
atrophy at the injection site. Systemic corticosteroid therapy is not recommended in OA, given the lack of proven benefit and the well­known adverse
effects with long­term use.

Dosing and Administration

Average doses for injection of large joints in adults are 40 mg of triamcinolone and methylprednisolone acetate. Local anesthetics such as lidocaine or
bupivacaine are commonly combined with corticosteroids to provide rapid pain relief.74 This therapy is generally limited to three or four injections per
year due to the potential systemic effects of corticosteroids and because the need for more frequent injections indicates little response to the therapy.

After injection, the patient should minimize activity and stress on the joint for several days. Initial pain relief may be seen within 24 to 72 hours after
injection, with peak pain relief about 7 to 10 days after injection and lasting up to 4 to 8 weeks.

Capsaicin

Pharmacology and Mechanism of Action

Capsaicin, isolated from hot peppers, releases and ultimately depletes substance P from afferent nociceptive nerve fibers. Substance P has been
implicated in the transmission of pain in arthritis, and capsaicin cream has demonstrated to have moderate efficacy compared to placebo in clinical
trials.51 Due to the larger surface area and distance from the site of application to the joint, it is not expected that application of capsaicin would
provide efficacy in the treatment of hip OA.

Adverse Effects
Adverse events associated with capsaicin are primarily local, including burning, stinging, and/or erythema that usually subsides with repeated
application. Systemic effects are rare.51 The FDA has issued a public drug safety communication notifying consumers that rare cases of severe burns
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To be effective, capsaicin must be used regularly, and it may take up to 2 weeks to take effect. Use is recommended four times a day.51 Patients should
trials.51 Due to the larger surface area and distance from the site of application to the joint, it is not expected that application of capsaicin would
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Adverse Effects
Adverse events associated with capsaicin are primarily local, including burning, stinging, and/or erythema that usually subsides with repeated
application. Systemic effects are rare.51 The FDA has issued a public drug safety communication notifying consumers that rare cases of severe burns
have been reported.76 Some patients may experience coughing associated with application.

Dosing and Administration

To be effective, capsaicin must be used regularly, and it may take up to 2 weeks to take effect. Use is recommended four times a day.51 Patients should
be counseled not to get the cream in their eyes or mouth. Patients should also notify their healthcare provider immediately if they experience pain,
swelling, or blistering skin at the site of application.

Capsaicin is a nonprescription product available as a cream, gel, solution lotion, or patch in concentrations ranging from 0.025% to 0.15%.

Tramadol

Pharmacology and Mechanism of Action

Tramadol, an analgesic with affinity for the µ­opioid receptor, as well as weak inhibition of the reuptake of norepinephrine and serotonin
neurotransmitter, has shown moderate pain improvement for patients with OA when compared with placebo.77,78 Tramadol is also modestly effective
as add­on therapy for patients taking concomitant acetaminophen, NSAIDs, or COX­2–selective inhibitors. Tramadol may be helpful for patients who
cannot take NSAIDs or COX­2–selective inhibitors.

Adverse Events
Opioid­like adverse effects such as nausea, vomiting, dizziness, constipation, headache, and somnolence are common with tramadol. These occur in
45% to 84% of treated patients.79 Although the frequency of adverse effects is high, the severity of these effects is less than for NSAIDs, as tramadol use
is not associated with life­threatening GI bleeding, CV events, or renal failure. The most notable serious adverse event associated with tramadol use is
seizures. Withdrawal symptoms can occur if tramadol is stopped abruptly. Older adults are significantly more likely to experience adverse events.79
Tramadol was initially not classified as a controlled substance but was rescheduled as a class IV controlled substance due to its potential for
dependence, addiction, and diversion.

Drug­Drug Interaction
Medications that lower the seizure threshold should be used with caution in patients taking tramadol. These include tricyclic antidepressants, first­
generation antipsychotic medications, and cyclobenzaprine, as well as others. There is also an increased risk of serotonin syndrome (see Chapter 88,
“Depressive Disorders,” for description) when tramadol is used concomitantly with other serotonergic medications, including duloxetine.

Dosing and Administration

Tramadol should be initiated at a lower dose (100 mg/day) and may be titrated as needed for pain control to a dose of 200 mg/day, with a maximum
dose of 400 mg/day. Tramadol is available in a combination tablet with acetaminophen and as an extended­release tablet or capsule.

Second­Line Treatments

Opioid Analgesics
Opioid analgesics may be useful for patients who experience limited pain relief with acetaminophen, oral NSAIDs, intra­articular injections, or topical
therapy or who cannot tolerate the side effect profile of these agents.55 For patients with underlying conditions that limit the use of first­line
analgesics, opioid analgesics can effectively relieve acute OA pain. A common clinical scenario includes the patient who cannot take oral NSAIDs
because of renal failure or CV disease. Patients in whom all other treatment options have failed and who are at high surgical risk, precluding joint
arthroplasty, are also candidates for opioid therapy. It is important to carefully use opioids to promote safety. The CDC recommends only prescribing
opioids if the benefits from pain control and function outweigh the risk. The best practices for prescribing opioid include using the lowest effective
dose and the smallest quantity needed; providing patients with information on how to use, store, and dispose of opioid medications; and avoiding
combinations of opioids and sedating medications unless there is a specific indication to do so. Opioid use should be assessed at least every 3 months,
evaluating patient progression toward functional treatment goals, risks of harm, and adverse effects.80

Adverse effects are common in opioid­treated patients with OA. More than 75% of patients in clinical trials experience at least one typical opioid­
related (ie, nausea, somnolence, constipation, dry mouth, and dizziness) adverse effect. Although this is not an unexpected finding, it serves as a
reminder to use opioids cautiously in elderly patients who may be more susceptible to adverse effects.

Opioid dependence, addiction, tolerance, hyperalgesia, and issues surrounding drug diversion are more serious adverse effects associated with long­
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Chapter Prescription Lucinda
110: Osteoarthritis, opioid misuse/abuse/addiction is a major public health concern with the CDC reporting around 46 deaths every
M. Buys; Sara A. Wiedenfeld Pageday
28from
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including addiction, overdose, and death.

If pain is poorly controlled and limits activities of daily living, and the patient has sufficiently good cardiopulmonary health to undergo major surgery,
evaluating patient progression toward functional treatment goals, risks of harm, and adverse effects.
University of the West Indies
Adverse effects are common in opioid­treated patients with OA. More than 75% of patients in clinical trials experience at least one typical opioid­
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related (ie, nausea, somnolence, constipation, dry mouth, and dizziness) adverse effect. Although this is not an unexpected finding, it serves as a
reminder to use opioids cautiously in elderly patients who may be more susceptible to adverse effects.

Opioid dependence, addiction, tolerance, hyperalgesia, and issues surrounding drug diversion are more serious adverse effects associated with long­
term treatment. Prescription opioid misuse/abuse/addiction is a major public health concern with the CDC reporting around 46 deaths every day from
prescription opioid overdose.81 Patients should be educated on the risks of taking opioids, including addiction, overdose, and death.

If pain is poorly controlled and limits activities of daily living, and the patient has sufficiently good cardiopulmonary health to undergo major surgery,
joint replacement may be preferable to continued reliance on opioids.

Duloxetine

Duloxetine is a centrally acting dual­reuptake inhibitor of both serotonin and norepinephrine, although norepinephrine reuptake inhibition does not
occur until doses reach 60 mg/day. While the most common pain target in OA is peripheral nociceptive pain, there is some evidence that chronic
nociceptive pain leads to central pain sensitization thereby lowering the pain threshold.47 Duloxetine provides pain relief through the blocking of
central pain transmitters, including serotonin and norepinephrine.

Adverse effects commonly associated with duloxetine therapy include nausea, dry mouth, constipation, and anorexia. Expected neurologic adverse
effects include fatigue, somnolence, and dizziness. Rare, but serious adverse events associated with duloxetine include Stevens­Johnson syndrome
and liver failure. Patients should be notified to contact their healthcare provider immediately if they develop a rash while taking duloxetine.

Particular care should be taken to avoid the use of duloxetine with other serotonergic medications including tramadol. As tramadol is a first­line
treatment recommendation for OA, the likelihood of encountering this combination is high. Concomitant use of duloxetine with other medications
that increase serotonin concentrations increases the risk of serotonin syndrome.

Hyaluronic Acid Injections

Hyaluronate is a naturally occurring component of cartilage and synovial fluid. Exogenous intra­articular hyaluronate is available as a treatment for the
symptoms of knee OA. The goal of intra­articular HA is to provide and maintain intra­articular lubrication. HA may also have anti­inflammatory,
analgesic, and chondroprotective effects on the articular cartilage and joint synovium.82 Evidence has not shown intra­articular HA to have a clinically
significant benefit involving pain relief and functional improvement and therefore does not support the routine use of HA.83 Most HA products are
injected once weekly for either 3 or 5 weeks, depending on the specific agent administered. Patients are generally advised to repeat the injection
schedule by six months if they are satisfied with the previous course.73 Strenuous or prolonged weight­bearing activities should be avoided for 48
hours after treatment. Routinely, most of the improvement is expected from 5 to 13 weeks after injection with some effect still occurring at 24 weeks.82
Injections are generally well tolerated, although acute joint swelling, effusion, and stiffness can occur. Local skin reactions, including rash, ecchymosis,
and pruritus, have also been reported. Local adverse effects are more frequent in products from animal origin. Rarely, systemic adverse events
including hypersensitivity reactions have occurred. Joint infections are rare but have been reported.

At this time, the effect of HA injections on knee OA is modest at best.82 These agents are expensive because the treatment includes both drug costs and
administration costs. Patient expectations and cost effectiveness must be considered before choosing HA injection.73

Glucosamine and Chondroitin

Interest in chondroitin and glucosamine was spurred initially by anecdotal reports of benefit in animals and humans and by the ability of these
substances to stimulate proteoglycan synthesis from articular cartilage in vitro. Over the past decade, enthusiasm for these agents has waned as
additional efficacy data has become available to the point that the American College of Rheumatology conditionally recommends against the use of
glucosamine and chondroitin.25 Glucosamine, alone or in combination, has not been shown to provide uniform improvements in pain control or
functional status in patients with OA of the knee or hip.84

Numerous trials have examined the safety and efficacy of glucosamine and chondroitin; however, the duration of these studies has been relatively
short. The efficacy of glucosamine and chondroitin was evaluated after 2 years and was found not to be statistically superior to placebo.85 The
combination of glucosamine and chondroitin was well tolerated. There has previously been some concern that glucosamine may worsen diabetes or
asthma; however, with 2­year follow­up this was not substantiated.85 When the combination of glucosamine and chondroitin was compared to
celecoxib in patients with knee OA, it was noninferior in the reduction of pain at 6 months. The combination was well tolerated and the authors suggest
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glucosamine
Chapter 110:and chondroitinLucinda
Osteoarthritis, as a potential safeSara
M. Buys; alternative for patients with CV or GI conditions.86
A. Wiedenfeld Page 29 / 41
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Because glucosamine and chondroitin are marketed in the United States as dietary supplements, neither the products nor their purity is adequately
regulated by the FDA. The potential consequences related to the lack of regulatory oversight for these products can affect both efficacy and safety.
Numerous trials have examined the safety and efficacy of glucosamine and chondroitin; however, the duration of these studies has been
University relatively
of the West Indies
short. The efficacy of glucosamine and chondroitin was evaluated after 2 years and was found not to be statistically superior to placebo.
Access
85
Provided by: The

combination of glucosamine and chondroitin was well tolerated. There has previously been some concern that glucosamine may worsen diabetes or
asthma; however, with 2­year follow­up this was not substantiated.85 When the combination of glucosamine and chondroitin was compared to
celecoxib in patients with knee OA, it was noninferior in the reduction of pain at 6 months. The combination was well tolerated and the authors suggest
glucosamine and chondroitin as a potential safe alternative for patients with CV or GI conditions.86

Because glucosamine and chondroitin are marketed in the United States as dietary supplements, neither the products nor their purity is adequately
regulated by the FDA. The potential consequences related to the lack of regulatory oversight for these products can affect both efficacy and safety.
Products containing less than labeled doses can compromise efficacy, while those containing ingredients not included on the labeling can
compromise safety. A variety of brand name and generic products are available in various doses and formulations.

EVALUATION OF THERAPEUTIC OUTCOMES

For persons with OA, treatment decisions and pharmacotherapy monitoring are patient specific. The patient’s situation and individual needs should
be considered when devising a treatment plan. Is the patient bothered primarily by pain, by limitations in activity, or with concerns about side effects
from medications? Does the patient understand what OA is and why certain treatments are useful?

When the patient is first being assessed for the possibility of OA, the diagnosis is often straightforward, including history and physical exam, plain films
of the affected joint(s), and lab tests. The older patient with unilateral knee pain, limited range of motion, no palpable warmth, crepitus, and without
prolonged morning stiffness and other suspicious findings is highly likely to have knee OA. It is still reasonable to obtain x­rays that may help follow
disease over time (although joint space narrowing often does not correlate with the extent of pain or difficulty walking). Basic labs to help decide what
pharmacologic therapy is possible (eg, no NSAIDs with poor renal function), assessment of pain using a visual analog scale, range of motion for
affected joints. Additional tests of OA severity may include measurement of grip strength, 50 ft (~15 m) walking time, patient and physician global
assessment of OA severity, and assessment of ability to perform activities of daily living. Once the patient is assessed and diagnosed, patient and family
education is essential. Nondrug therapy may include a referral for physical and/or occupational therapy services, where the therapists can help to
maintain and improve range of motion. Referral for nutritional counseling and weight loss may also be necessary if the patient is overweight or obese.
These interventions may decrease pain and facilitate improved activity for OA patients.

Although all patients must be provided with nonpharmacologic therapies, results from these interventions usually require weeks to months. In the
meantime, the patient needs pain relief. First­line therapy continues to be acetaminophen. Adverse events with acetaminophen are uncommon,
although it is important that the patient understand the maximum daily dose limits and all possible sources of acetaminophen­containing products.
Although some do well on acetaminophen, many do not achieve sufficient pain relief. A step up to oral NSAIDs or second­line therapy might be
necessary but poses significant risks beyond acetaminophen. A switch to NSAIDs requires careful consideration of the patient’s age and comorbidities,
renal function, history of GI problems, hypertension, and CV health. Periodic monitoring would include open­ended questions followed by direct
questions relating to the commonest adverse effects associated with the respective medication. For an oral NSAID, symptoms of abdominal pain,
heartburn, nausea, or change in stool color provide valuable clues to the presence of GI complications, although serious GI complications can occur
without warning. Patients should be monitored for the development of hypertension, weight gain, edema, skin rash, and CNS adverse effects such as
headaches and drowsiness. Baseline serum creatinine, complete blood count, and serum transaminases are repeated at 6­ to 12­month intervals to
identify GI, renal, and hepatic toxicities.

Topical NSAIDs have demonstrated efficacy in OA of the hand and knee and are as effective as oral NSAIDs. Although they carry the same CV, renal, and
GI warnings, their area under the concentration–time curve (AUC) for a typical dose is only a few percent of the AUC from an equivalent dose of oral
NSAID. Topical NSAIDs’ most common side effects are local, with irritated skin, rash, or itching, usually mild, and with many fewer adverse effects of CV,
GI, or renal nature. These agents are a welcome addition to the limited treatment modalities for the common, costly, painful, and often disabling
disease of OA. It is important that the patient apply the topical products appropriately to achieve maximum benefit and avoid adverse events.

For patients receiving intra­articular corticosteroids, pain relief should begin with 2 to 3 days and last 4 to 8 weeks. Patients should be advised about
possible injection site reactions, as well as possible systemic effects, especially for those with hypertension or diabetes, as there is a potential for
increased blood pressure or blood glucose. For patients receiving opioids or tramadol, relief from pain should occur rapidly. Frail or elderly patients
should be monitored carefully and cautioned about sedation, dysphoria, nausea, risk of falls, and constipation. Special additional monitoring should
include strategies to assess development of opioid tolerance, addiction, misuse, and diversion.

CONCLUSION
OA is a common,
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P Your IP is that affects diarthrodial joints and is characterized by progressive deterioration of articular cartilage,
subchondral
Chapter 110:sclerosis, and osteophyte
Osteoarthritis, Lucinda [Link].
Buys; SaraClinical manifestations include gradual onset of joint pain, stiffness, and limitation of Page
A. Wiedenfeld motion.
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An individualized approach based on education, rest,
exercise, weight loss as needed, and analgesic medication can succeed in meeting these goals. Recommended drug treatment starts with
acetaminophen ≤4 grams/day and topical analgesics as needed. If acetaminophen is ineffective, oral NSAIDs may be used in appropriately selected
should be monitored carefully and cautioned about sedation, dysphoria, nausea, risk of falls, and constipation. Special additional monitoring should
include strategies to assess development of opioid tolerance, addiction, misuse, and diversion. University of the West Indies
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CONCLUSION
OA is a common, slowly progressive disorder that affects diarthrodial joints and is characterized by progressive deterioration of articular cartilage,
subchondral sclerosis, and osteophyte production. Clinical manifestations include gradual onset of joint pain, stiffness, and limitation of motion. The
primary treatment goals are to reduce pain, maintain function, and prevent further destruction. An individualized approach based on education, rest,
exercise, weight loss as needed, and analgesic medication can succeed in meeting these goals. Recommended drug treatment starts with
acetaminophen ≤4 grams/day and topical analgesics as needed. If acetaminophen is ineffective, oral NSAIDs may be used in appropriately selected
patients, often providing satisfactory relief of pain and stiffness. Individuals at increased risk for toxicity from NSAIDs, especially for GI, CV, or renal
events, deserve special attention. Celecoxib may have safety advantages in some OA patients, but its safety relative to other NSAIDs and its role in OA
remains poorly defined. Adjunctive therapy with tramadol, intra­articular corticosteroids, and duloxetine may be helpful in patients with poorly
controlled pain. Experimental therapy aimed at preventing the progression of OA requires further clinical investigation before entering widespread
clinical use.

ABBREVIATIONS

AAAL arthritis­attributable activities limitations

AUC area under the concentration–time curve

BMI body mass index

CNS central nervous system

COX cyclooxygenase

CV cardiovascular

ECM extracellular matrix

FDA Food and Drug Administration

GI gastrointestinal

GWAS genome­wide linkage studies

HA hyaluronic acid

IDEA Intensive Diet and Exercise for Arthritis

IR immediate release

MI myocardial infarction

MMP matrix metalloproteinase

NICE National Institute for Health and Clinical Excellence

NSAID nonsteroidal anti­inflammatory drug

OA osteoarthritis

OARSI Osteoarthritis Research International

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pump is
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quality­adjusted Terms of Use • Privacy Policy • Notice • Accessibility
expectancy

SNPs single­nucleotide polymorphisms

controlled pain. Experimental therapy aimed at preventing the progression of OA requires further clinical investigation before entering widespread
University of the West Indies
clinical use.
Access Provided by:

ABBREVIATIONS

AAAL arthritis­attributable activities limitations

AUC area under the concentration–time curve

BMI body mass index

CNS central nervous system

COX cyclooxygenase

CV cardiovascular

ECM extracellular matrix

FDA Food and Drug Administration

GI gastrointestinal

GWAS genome­wide linkage studies

HA hyaluronic acid

IDEA Intensive Diet and Exercise for Arthritis

IR immediate release

MI myocardial infarction

MMP matrix metalloproteinase

NICE National Institute for Health and Clinical Excellence

NSAID nonsteroidal anti­inflammatory drug

OA osteoarthritis

OARSI Osteoarthritis Research International

PPI proton pump inhibitor

QALE quality­adjusted life expectancy

SNPs single­nucleotide polymorphisms

SR sustained release

TIMP tissue inhibitors of metalloproteinase

TNF­α tumor necrosis factor­α

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53. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: A randomized
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54. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen­induced acute liver failure: Results of a United States multicenter, prospective study.
Hepatology. 2005;42(6):1364–1372. [PubMed: 16317692]

55. O’Neil CK, Hanlon JT, Marcum ZA. Adverse effects of analgesics commonly used by older adults with osteoarthritis: Focus on non­opioid and
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56. Meara AS, Simon LS. Advice from professional societies: Appropriate use of NSAIDs. Pain Med. 2013;14(suppl 1):S3–S10. [PubMed: 24373108]

57. McEvoy GK. AHFS Drug Information. Bethesda, MD: American Society of Health­System Pharmacists, Inc.; 2012ISBN 978­1­58528­247­0.

58. Lanas A. Nonsteroidal anti­inflammatory drugs and cyclooxygenase inhibition in the gastrointestinal tract: A trip from peptic ulcer to colon cancer.
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59. Moore N, Scheiman JM. Gastrointestinal safety and tolerability of oral non­aspirin over­the­counter analgesics. Postgrad Med. 2018;130(2):188–
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60. Rostom A, Moayyedi P, Hunt R; Canadian Association of Gastroenterology Consensus Group. Canadian consensus guidelines on long­term
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61. Patricio JP, Barbosa JP, Ramos RM, Antunes NF, de Melo PC. Relative cardiovascular and gastrointestinal safety of non­selective non­steroidal
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62. Scarpignato C, Lanas A, Blandizzi C, et al. Safe prescribing of non­steroidal anti­inflammatory drugs in patients with osteoarthritis—An expert
consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 2015;13:55. doi: 10.1186/s12916­015­0285­8.

63. Crofford LJ. Use of NSAIDs in treating patients with arthritis. Arthritis Res Ther. 2013;15(suppl 3):S2. [PubMed: 24267197]

64. Coxib and traditional NSAID Trialists’ (CNT) Collaboration; Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non­
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65. Antman EM. Evaluating the cardiovascular safety of nonsteroidal anti­inflammatory drugs. Circulation. 2017;135(21):2062–2072. [PubMed:
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67. Nissen SE. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2017;376(14):1390. [PubMed: 28379793]

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69. Celebrex® [package insert]. Available at: [Link] Accessed June 2016. Pfizer, Inc. NY; May 2016.

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73. Ayhan E, Kesmezacar H, Akgun I. Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. World J
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75. Pyne D, Ioannou Y, Mootoo R, Bhanji A. Intra­articular steroids in knee osteoarthritis: A comparative study of triamcinolone hexacetonide and
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76. FDA Drug Safety Communication, September 13, 2012. Available at [Link] Accessed September 10,
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77. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: A systematic review and metaanalysis. J Rheumatol. 2007;34(3):543–555.
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78. Howes F, Buchbinder R, Winzenberg TB. Opioids for osteoarthritis? weighing benefits and risks: A cochrane musculoskeletal group review. J Fam
Pract. 2011;60(4):206–212. [PubMed: 21472151]

79. Langley PC, Patkar AD, Boswell KA, Benson CJ, Schein JR. Adverse event profile of tramadol in recent clinical studies of chronic osteoarthritis
pain. Curr Med Res Opin. 2010;26(1):239–251. [PubMed: 19929615]

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81. Centers for Disease Control and Prevention (CDC). 2018 annual surveillance report of drug­related risks and outcomes—United States; surveillance
special report. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Accessed August 8, 2018 from
[Link]

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83. Jevsevar D, Donnelly P, Brown GA, Cummins DS. Viscosupplementation for osteoarthritis of the knee: A systematic review of the evidence. J Bone
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84. Wandel S, Juni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: Network meta­
analysis. BMJ. 2010;341:c4675. [PubMed: 20847017]

85. Sawitzke AD, Shi H, Finco MF, et al. The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: A report from
the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 2008;58(10):3183–3191. [PubMed: 18821708]

86. Hochberg MC, Martel­Pelletier J, Monfort J. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: A multicentre,
randomised, double­blind, non­inferiority trial versus celecoxib. Ann Rheum Dis. 2015;75(1):37–44.

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SELF­ASSESSMENT QUESTIONS
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1. Risk factors for the development of osteoarthritis (OA) include:
the glucosamine/chondroitin arthritis intervention trial. Arthritis Rheum. 2008;58(10):3183–3191. [PubMed: 18821708]
University of the West Indies
86. Hochberg MC, Martel­Pelletier J, Monfort J. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: A multicentre,
Access Provided by:
randomised, double­blind, non­inferiority trial versus celecoxib. Ann Rheum Dis. 2015;75(1):37–44.

SELF­ASSESSMENT QUESTIONS
1. Risk factors for the development of osteoarthritis (OA) include:

A. Smoking

B. Participation in running

C. Being underweight

D. Advanced age

E. B and D

2. Patient education for OA, such as programs in which volunteers regularly contact patients:

A. Has not yet been demonstrated to provide benefit to OA patients

B. Is too expensive to recommend for general use by OA patients

C. Should emphasize the “wear and tear” nature of OA as part of the educational message

D. Has been shown to improve pain and functional status of OA patients

E. All of the above

3. Matrix metalloproteinases (MMPs):

A. Are naturally occurring chemokines that work primarily by recruiting neutrophils and macrophages to the inflamed synovium

B. Help trigger degradation of articular cartilage by cleaving peptide bonds in proteoglycans

C. Are stimulated by tissue inhibitors of metalloproteinases (TIMPS)

D. Must be activated before they can ease the pain of OA

E. B and C

4. Which of the following are required for an accurate and appropriate diagnosis of OA?

A. Patient history and physical examination

B. Patient history, physical examination, and radiologic evaluation

C. Physical examination and magnetic resonance imaging

D. Patient history, physical examination, and positive response to pharmacologic treatment

E. Any of the above is accurate and appropriate

5. Acetaminophen:

A. Is recommended as an appropriate initial treatment in OA

B. Should be given on a scheduled basis for optimal pain control

C. Can be associated with hepatotoxicity at doses below 4 g/day

D. Provides
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E. All
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6. Traditional, nonselective nonsteroidal anti­inflammatory drugs (NSAIDs):

 A. Is recommended as an appropriate initial treatment in OA
University of the West Indies
B. Should be given on a scheduled basis for optimal pain control Access Provided by:

C. Can be associated with hepatotoxicity at doses below 4 g/day

D. Provides mild analgesia

E. All of the above

6. Traditional, nonselective nonsteroidal anti­inflammatory drugs (NSAIDs):

A. Block access of arachidonic acid to both COX­1 and COX­2 enzymes

B. Promote platelet aggregation through blockade of COX­2 activity

C. Promote prostaglandin and bicarbonate production in gastric mucosa through blockade of COX­2 activity

D. Counteract renal vasoconstriction by promoting formation of renal prostaglandins

E. Are anti­inflammatory at low doses and analgesic at higher doses

7. NSAIDs:

A. Are associated with thousands of serious or life­threatening GI adverse events every year

B. Provide superior relief of OA pain in some individuals

C. Will usually produce symptoms of dyspepsia or abdominal discomfort as a prelude to serious GI adverse events

D. When used in anti­inflammatory doses, should be consistently monitored by serum levels

E. A and B

8. NSAIDs:

A. Are recommended as an alternative to acetaminophen for controlling inflammation associated with OA

B. Provide pain relief by the inhibition of prostaglandins

C. Provide cardioprotective effects similar to aspirin

D. Increase renal blood flow, causing sodium and potassium excretion

E. B and C

9. Celecoxib, a COX­2 selective inhibitor:

A. Blocks the COX­ 2 enzyme with little or no inhibition of COX­1

B. Is more effective at relieving pain than nonselective NSAIDs

C. Is much safer to use in patients with cardiovascular disease

D. Carries a manufacturer’s warning against use in sulfa allergic patients

E. A and D

10. Intra­articular corticosteroids:

A. Have no role in OA, as this disease does not have any inflammatory component

B. Are recommended as maintenance therapy for patients who cannot tolerate NSAIDs and who have severe OA

C. Can be administered up to 12 times per year for the treatment of severe OA pain
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E. Should not be used for the treatment of hip OA

11. Hyaluronic acid injectable material:

 A. Have no role in OA, as this disease does not have any inflammatory component University of the West Indies
Access Provided by:
B. Are recommended as maintenance therapy for patients who cannot tolerate NSAIDs and who have severe OA

C. Can be administered up to 12 times per year for the treatment of severe OA pain

D. Are associated with hyperglycemia in patients without diabetes mellitus

E. Should not be used for the treatment of hip OA

11. Hyaluronic acid injectable material:

A. Is made using recombinant technology

B. Provides a long­term increase in viscosity of synovial fluid

C. Is a low cost pharmacologic therapy

D. Is highly effective when compared to placebo vehicle injections

E. Is less effective than intra­articular corticosteroids

12. Recommended treatment options for hip and knee OA patients who have failed acetaminophen include:

A. Nonselective NSAIDs used at analgesic doses, if the patient is not at high risk for GI bleeding

B. Nonselective NSAIDs with an H2 antagonist to prevent GI bleeding in the high­risk patient

C. COX­2 selective inhibitors with sucralfate in the high­risk patient

D. COX­2 selective inhibitors with misoprostol in the high­risk patient

E. None of the above

13. Knee replacement surgery should be considered in the patient with OA:

A. If the patient prefers not to try oral medications such as acetaminophen

B. If there is significant disability and interference with daily functioning

C. If the patient refuses treatment with low­dose NSAIDs

D. If the patient is at high risk for NSAID­related GI bleeding

E. If the patient does not respond to topical therapy with NSAIDs

14. Topical capsaicin therapy for the treatment of OA pain:

A. Produces systemic adverse effects

B. Provides therapeutic results within 48 hours

C. Is most effective when used on an as­needed basis

D. Must be used three times daily for best results

E. Is most appropriate for the treatment of hand OA

15. Which of the following patients is best suited to opioid analgesic therapy for their OA symptoms that have failed scheduled acetaminophen dosing?

A. History of alcoholism

B. History of small bowel obstruction

C. History of traumatic fall on home stairs

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E. History of poor adherence to medications
15. Which of the following patients is best suited to opioid analgesic therapy for their OA symptoms that have failed scheduled acetaminophen dosing?
University of the West Indies
A. History of alcoholism Access Provided by:

B. History of small bowel obstruction

C. History of traumatic fall on home stairs

D. History of myocardial infarction

E. History of poor adherence to medications

SELF­ASSESSMENT QUESTION­ANSWERS
1. D . Participation in sports and advancing age are both independent risk factors for the development of OA. Refer to “Etiology” section.

2. D . A variety of patient education programs have been shown to improve pain and function in OA patients, including volunteer programs. Refer to
“Nonpharmacologic Therapy” section.

3. B . MMPs are an important catalyst to normal cartilage turnover and repair. Refer to “Normal Cartilage” (”Function, Structure, and Composition of
Cartilage”) section.

4. B . A patient history to elicit symptoms, a physical exam to examine the affected joint, and basic x­ray examination to review for signs of joint space
narrowing and other signs of osteoarthritis are the elements needed to diagnose osteoarthritis. Refer to “Diagnosis” section.

5. E. Acetaminophen is guideline­recommended, first­line therapy for all types of OA. Due to short duration of action, scheduled dosing is optimal.
The most important toxicity is hepatoxicity. Refer to “Drug Class Information” (“Acetaminophen”) section.

6. A . The mechanism of action of NSAIDs is the blockade of both COX­1 and COX­2. Refer to “Drug Class Information” (“Oral Nonsteroidal Anti­
inflammatory Drugs [Pharmacology and Mechanism of Action]”) section.

7. E. Due to the mechanism of action, risks of GI adverse events are inherent to NSAID use. Some patients are at higher risk of serious GI adverse
events than others. Due to interpatient variability in response to analgesics, some patients have superior relief with NSAID use. Refer to “Drug Class
Information” (“Oral Nonsteroidal Anti­inflammatory Drugs [Adverse Effects]“) section.

8. B . Prostaglandins can generate pain signals. NSAIDs inhibit prostaglandins. Refer to “Drug Class Information” (“Oral Nonsteroidal Anti­
inflammatory Drugs [Pharmacology and Mechanism of Action]”) section.

9. E. Celecoxib is a COX­2 selective NSAID and as such has little to no inhibition of COX­1 enzyme. It also has a sulfonamide chemical structure, leading
to a warning against use in sulfa allergic patients. Refer to “Drug Class Information” (“Oral Nonsteroidal Anti­inflammatory Drugs [Pharmacology
and Mechanism of Action and Drug­Drug Interactions]”) sections.

10. D . Intra­articular corticosteroids are associated with the same toxicities as systemic corticosteroids, including hyperglycemia in patients with and
without preexisting diabetes mellitus. Refer to “Intra­articular Corticosteroids” (“Adverse Events”) section.

11. E. Hyaluronic acid injections are less effective than other therapies; in some studies, no more effective than placebo. Refer to “Drug Class
Information” (“Hyaluronic Acid Injections”) section.

12. A . After acetaminophen failure, the next step in therapy is nonselective NSAIDs alone in a patient not at high risk for GI bleeding. H2 antagonists are
not effective at preventing GI bleeding in high­risk patients and COX­2 selective inhibitors do not offer a therapeutic advantage in a low­risk patient.
Refer to “Drug Class Information” (“Oral Anti­inflammatory Drugs [Adverse Effects (Gastrointestinal Effects of Nonselective NSAIDs)]”) section.

13. B . Surgery is the best therapeutic option to improve significant disability and interference with activities of daily living. Refer to “Nonpharmacologic
Therapy” (“Surgery”) section.

14. E. Topical capsaicin is guideline­recommended alternative first­line therapy for hand OA. Refer to “Hand OA, First­Line Treatments and Drug Class
Information” (“First­Line Treatments [Capsaicin]”) section.

15. D . All NSAIDs are contraindicated in a patient with a history of a myocardial infarction. Refer to adverse effects under “Drug Class Information”
(“Second­Line Treatments [Opioid Analgesics]”) section.

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