Module 7
Osteoarthritis Assignment
a. Epidemiology
During 2013 to 2015, an estimated 54.4 million adults in the United States
reported doctor-diagnosed arthritis (osteoarthritis, rheumatoid arthritis, gout, lupus or
fibromyalgia) with 23.7 million reporting arthritis-attributable activity limitation
(AAAL).1 The prevalence of AAAL among adults with arthritis increased by almost
20% over time (2002-2015).1 Arthritis is projected to affect 78.4 million adults by
2040.2 OA imposes a tremendous cost burden with combined arthritis-attributable
medical expenditures and earnings losses totaling approximately $303 billion dollars
in 2013.3 The US Medical Expenditure Panel Survey found that arthritis-attributable
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).
The financial burden associated with osteoarthritis is substantial, reflecting
both direct medical costs and significant economic impacts related to productivity
losses. In 2013, total hospital costs specifically attributed to the diagnosis of
osteoarthritis reached an astounding $16.5 billion. This considerable expenditure is
linked to approximately 1 million hospital stays, underscoring the high prevalence and
severe impact of osteoarthritis on the healthcare system. These costs encompass a
wide range of medical services, including inpatient care, surgical procedures such as
joint replacements, medications, diagnostic tests, and post-surgical rehabilitation. The
management of osteoarthritis in a hospital setting often involves complex,
multidisciplinary approaches aimed at alleviating pain, improving joint function, and
enhancing the overall quality of life for patients.
Beyond the direct costs incurred by hospitalizations, osteoarthritis imposes a
significant economic burden due to arthritis-attributable lost earnings. In 2013, the
total lost earnings attributable to arthritis amounted to a staggering $163.7 billion.
This figure reflects the widespread impact of arthritis on the workforce, as individuals
with osteoarthritis often experience substantial reductions in their ability to work. The
condition can lead to decreased physical functioning, chronic pain, and fatigue, all of
which contribute to lower productivity and increased absenteeism. Moreover, the need
for frequent medical appointments and potential surgical interventions can result in
extended periods away from work.
A notable portion of these lost earnings, nearly half, is due to lower adjusted
per-person earnings for individuals living with arthritis. This reduction in earnings can
be attributed to several factors. First, individuals with osteoarthritis may be forced to
reduce their working hours or take on less demanding roles that offer lower
compensation, in an effort to manage their symptoms and avoid exacerbating their
condition. Additionally, the physical limitations imposed by osteoarthritis can hinder
career progression, as individuals may be unable to meet the demands of higher-level
positions that require greater physical exertion or prolonged activity.
The economic impact of osteoarthritis extends beyond the individuals directly
affected, influencing employers and the broader economy. Employers face increased
costs associated with healthcare benefits, disability claims, and the need to hire
temporary or replacement workers to cover for employees with arthritis-related work
limitations. Furthermore, the reduced earning potential and productivity of individuals
with osteoarthritis can lead to decreased consumer spending, affecting economic
growth and stability.
Addressing the economic burden of osteoarthritis requires a multifaceted
approach that includes effective management strategies, workplace accommodations,
and public health initiatives aimed at prevention and early intervention. Ensuring
access to comprehensive healthcare services, including physical therapy, pain
management, and surgical options when necessary, is crucial in helping individuals
maintain their functional abilities and quality of life. Additionally, promoting
workplace policies that support flexible scheduling, ergonomic modifications, and
reasonable accommodations can help individuals with osteoarthritis remain
productive members of the workforce.
Public health initiatives focused on prevention and early intervention are also
essential in mitigating the long-term impact of osteoarthritis. Encouraging regular
physical activity, weight management, and early diagnosis can help reduce the
severity of symptoms and slow the progression of the disease. Educational programs
aimed at raising awareness about the risk factors and management of osteoarthritis
can empower individuals to take proactive steps in maintaining their joint health.
In conclusion, the financial implications of osteoarthritis are profound, with
total hospital costs reaching $16.5 billion for 1 million hospital stays in 2013 and
arthritis-attributable lost earnings amounting to $163.7 billion. The significant
reduction in per-person earnings for those with arthritis highlights the widespread
economic impact of this condition. By adopting comprehensive management
strategies, supporting workplace accommodations, and implementing effective public
health initiatives, it is possible to alleviate the economic burden of osteoarthritis and
improve the lives of those affected by this debilitating condition.
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 x-ray or
other imaging, and symptomatic OA is based on patient history and physical exam
plus x-ray. OA is more prevalent with increasing age. In the United States, the
prevalence of self-reported doctor-diagnosed 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 doctor-
diagnosed 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.
Prevalence of physician-diagnosed 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%), non-Hispanic 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.
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 very
common within the population, (3) many effective treatments are available over the
counter, promoting self-treatment, (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.
b. Etiology
The etiology of OA is multifactorial and complex, with development of OA
depending on interplay between person-level risk factors and joint-level 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 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 nonweight bearing 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 11-
year 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 2.8-
fold increase in developing knee OA compared to the nonobese men, whereas women
who were obese at baseline had a 4.4-fold increased risk in developing knee OA
compared to the nonobese women. Also, there was an increased risk for severe knee
OA in obese subjects.
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.
Traumatic knee injury, either during sports or in accidents, significantly
increases the risk of knee OA over a 10-year 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, 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.
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.
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. Recent
studies of 199 candidate genes found that only 2 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. Genome-wide association studies (GWAS) use an hypothesisfree
methodology that involves scanning hundreds of thousands or millions of genetic
markers, in the form of single nucleotide polymorphisms (SNP’s). Using GWAS
studies at least 21 independent susceptibility loci to OA have been found. A meta-
analysis of GWA studies with 6,709 knee OA cases and 44,439 controls revealed that
the Chrom7Q22 locus was very 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.
It is quite likely that the genetic risk of developing osteoarthritis (OA), similar
to many other complex diseases, is determined by a combination of genetic
differences rather than a single gene mutation. This multifactorial genetic influence
suggests that multiple genetic variants, each contributing a small effect, collectively
increase an individual's susceptibility to OA. These genetic variations can influence
various biological pathways involved in joint health, including cartilage formation
and repair, inflammation, and metabolic processes.
The complexity of genetic contributions to OA underscores the point that our
understanding of the genetics and pathology of OA is still in its early stages. Despite
significant advances in genetic research and the identification of several risk loci
associated with OA, the precise mechanisms by which these genetic factors contribute
to the development and progression of the disease remain largely unclear. Many of the
identified genetic variants are located in non-coding regions of the genome, which
suggests they may affect gene regulation rather than protein-coding sequences, adding
another layer of complexity to deciphering their roles.
Moreover, the interplay between genetic predisposition and environmental
factors such as physical activity, injury, obesity, and diet further complicates the
landscape of OA risk. These environmental factors can interact with genetic
predispositions in ways that either exacerbate or mitigate the risk of developing OA.
For instance, individuals with a genetic predisposition to weaker cartilage may be
more susceptible to OA if they also engage in high-impact sports or have a history of
joint injuries.
Recent advances in genomic technologies, such as genome-wide association
studies (GWAS) and next-generation sequencing, have facilitated the discovery of
numerous genetic variants associated with OA. However, the effect sizes of these
variants are generally small, indicating that each variant only modestly increases the
risk of OA. This necessitates the identification of a large number of genetic variants to
fully understand the genetic architecture of OA.
In addition to identifying genetic variants, understanding the functional
consequences of these variants is crucial. Functional genomics approaches, including
transcriptomics, proteomics, and epigenomics, are essential to elucidate how these
genetic differences influence the biological pathways involved in OA. For example,
integrating data from these various omics approaches can help identify key regulatory
networks and molecular mechanisms that are disrupted in OA.
Furthermore, studying the genetic basis of OA in diverse populations is
important, as genetic risk factors may vary between different ethnic groups. Most
genetic studies of OA have been conducted in European populations, potentially
limiting the generalizability of the findings. Expanding genetic research to include
more diverse populations will provide a more comprehensive understanding of the
genetic risk factors for OA and may uncover population-specific genetic variants that
contribute to the disease.
The early stages of understanding the genetics and pathology of OA also
highlight the need for interdisciplinary research approaches. Collaboration between
geneticists, molecular biologists, epidemiologists, and clinicians is essential to
translate genetic discoveries into meaningful clinical applications. This includes
developing genetic risk prediction models, identifying potential therapeutic targets,
and personalizing treatment strategies based on an individual’s genetic profile.
Moreover, public health initiatives and patient education are vital components
in managing the risk of OA. Raising awareness about the genetic and environmental
risk factors for OA can empower individuals to take proactive steps in reducing their
risk. For instance, promoting joint-friendly physical activities, maintaining a healthy
weight, and preventing joint injuries are practical measures that can mitigate the
impact of genetic predispositions to OA.
In conclusion, the genetic risk of developing osteoarthritis is likely determined
by a complex interplay of multiple genetic differences. Our understanding of the
genetics and pathology of OA is still in its nascent stages, requiring further research to
unravel the intricate genetic and environmental factors that contribute to this common
and debilitating condition. By advancing our knowledge through comprehensive and
interdisciplinary research efforts, we can pave the way for improved prevention,
diagnosis, and treatment of osteoarthritis, ultimately enhancing the quality of life for
those affected by the disease.
c. Pathophysiology
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.
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 weight-
bearing 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.
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 close proximity gives cartilage the ability to withstand
further compression. Within the cartilage ECM are the chondrocytes, the only cells in
cartilage, 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, insulin-like growth factor-1, and transforming growth factor, and by
catabolism and proteolysis stimulated by matrix metalloproteinases (MMPs), tumor
necrosis factor-α (TNF-α), interleukin-1, 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
Another component 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
shock-absorbent properties. Finally, it is important to note that adult articular cartilage
is avascular, with chondrocytes nourished by synovial fluid.
The health and functionality of joint cartilage are heavily dependent on the
dynamic processes that occur with regular movement and the cyclic loading and
unloading of joints. These mechanical activities are crucial for facilitating the flow of
nutrients into the cartilage, a process that is vital for maintaining its structural
integrity and overall health. Cartilage is an avascular tissue, meaning it does not have
its own blood supply. Instead, it relies on the diffusion of nutrients from the
surrounding synovial fluid to sustain its cells, known as chondrocytes.
During physical activities, such as walking, running, or any other form of
exercise that involves joint movement, cyclic loading and unloading occur. This
mechanical loading compresses the cartilage and then releases it, creating a pumping
effect that enhances the exchange of nutrients and waste products between the
synovial fluid and the cartilage matrix. This process ensures that chondrocytes receive
the essential nutrients and oxygen required for their metabolic activities and for
maintaining the extracellular matrix, which is composed of collagen fibers and
proteoglycans.
The extracellular matrix of cartilage provides the tissue with its unique
properties, including resilience and the ability to withstand compressive forces.
Proteoglycans, in particular, attract water molecules, which help to keep the cartilage
hydrated and pliable. Regular movement promotes the retention of these water
molecules within the cartilage, thereby preserving its shock-absorbing capabilities and
reducing the risk of degeneration.
In contrast, immobilization or a sedentary lifestyle significantly reduces the
mechanical stimulation necessary for optimal nutrient diffusion. When joints are
immobilized, whether due to injury, surgery, or lack of physical activity, the pumping
effect is diminished, leading to decreased nutrient supply and accumulation of
metabolic waste products within the cartilage. Over time, this reduction in nutrient
flow can contribute to the degradation of cartilage, weakening its structure and
potentially accelerating the onset and progression of osteoarthritis.
Moreover, immobilization can lead to other detrimental effects on joint health.
The lack of movement can cause the synovial fluid to become more viscous, further
hindering the diffusion of nutrients. This can create a cycle of deterioration where the
cartilage becomes increasingly deprived of the necessary sustenance to repair and
regenerate itself. Additionally, the surrounding muscles and ligaments can weaken due
to disuse, contributing to joint instability and increasing the risk of injury and further
degeneration.
Engaging in regular physical activity has been shown to have numerous
benefits for joint health beyond the mechanical nourishment of cartilage. Exercise
helps to strengthen the muscles around the joints, providing better support and
stability. Strong muscles can absorb some of the stress that would otherwise be placed
directly on the joints, reducing the mechanical load on the cartilage and other joint
structures. This protective effect can help to prevent joint injuries and slow the
progression of degenerative joint diseases.
Furthermore, physical activity stimulates the production of synovial fluid,
enhancing its lubrication properties and improving joint flexibility and range of
motion. This lubrication reduces friction between the articulating surfaces of the joint,
minimizing wear and tear on the cartilage. Regular exercise also promotes overall
cardiovascular health, which can improve blood flow and nutrient delivery to the
joints indirectly by maintaining healthy tissues surrounding the joint.
Specific types of exercises, such as low-impact aerobic activities, strength
training, and flexibility exercises, are particularly beneficial for maintaining joint
health. Low-impact activities, such as swimming, cycling, and walking, provide the
necessary mechanical loading without placing excessive stress on the joints. Strength
training exercises help to build muscle mass and improve joint stability, while
flexibility exercises, such as stretching and yoga, enhance the range of motion and
prevent stiffness.
In conclusion, the movement and cyclic loading and unloading of joints play a
critical role in the health and functionality of cartilage by facilitating the flow of
nutrients and the removal of waste products. This process underscores the importance
of regular physical activity for joint health. Immobilization, on the other hand,
reduces nutrient supply and can lead to cartilage degradation and joint deterioration.
Therefore, incorporating regular physical activity into daily routines is essential for
maintaining healthy joints, preventing degenerative joint diseases, and promoting
overall musculoskeletal health. This holistic approach to joint care not only supports
the mechanical nourishment of cartilage but also enhances muscle strength, joint
stability, and flexibility, contributing to a higher quality of life and greater physical
independence.
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 Recent studies have
revealed several respects of the very complex nature of OA. There is increased
appreciation of the role of tissues beyond cartilage, within the joint and surrounding
it, 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
occur and contributes further to cartilage loss.
Joint space narrowing results from loss of cartilage, which can lead to a
painful, deformed joint. 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 weight-bearing 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 In the joint capsule and synovium, inflammatory changes and
pathologic changes can occur. Contributors to inflammation may include crystals or
cartilage shards in synovial fluid. Other possible factors are interleukin-1,
prostaglandin E2 , TNF-α, and nitric oxide that are found in synovial fluid. With
inflammatory changes in the synovium, effusions and synovial thickening occur.
The pain experienced by individuals suffering from osteoarthritis (OA) is a
complex phenomenon that is not directly related to the destruction of cartilage itself.
Instead, it arises from the activation of nociceptive nerve endings within the joint.
These nerve endings are highly sensitive and can be triggered by a variety of
mechanical and chemical irritants present in the joint environment. For example, as
the joint undergoes structural changes due to the progression of OA, these irritants can
include fragments of cartilage or bone, inflammatory cytokines, and other
biochemical mediators released by the synovium and other joint tissues.
Mechanical irritants play a significant role in the pain associated with OA.
One common source of mechanical irritation is the distension of the synovial capsule,
which can occur when there is an accumulation of excess joint fluid. This increased
fluid volume, known as effusion, causes the synovial capsule to stretch, activating the
nociceptive nerve endings and resulting in pain. Additionally, microfractures within
the subchondral bone, which lies just beneath the cartilage, can lead to significant
discomfort. These tiny fractures are often a response to the altered mechanical loading
and weakened bone structure that accompany OA.
Periosteal irritation is another contributor to OA pain. The periosteum is a
dense layer of vascular connective tissue enveloping the bones except at the surfaces
of the joints. Irritation of this tissue, which contains a rich supply of nerve endings,
can cause considerable pain. This irritation may be due to the formation of
osteophytes, or bone spurs, which are common in OA and can press against
surrounding tissues.
Moreover, damage to other structures within the joint, such as ligaments, the
synovium, and the meniscus, also contributes to the pain experienced by OA patients.
Ligament injuries can lead to instability and abnormal joint movements, further
exacerbating the mechanical stress on the joint and irritating nociceptive nerve
endings. The synovium, which lines the joint capsule and produces synovial fluid, can
become inflamed (a condition known as synovitis), releasing pro-inflammatory
cytokines and enzymes that sensitize nerve endings and increase pain perception. The
meniscus, a crescent-shaped cartilage structure that helps distribute load and stabilize
the knee, can suffer tears or degeneration in OA, adding to the pain and functional
impairment.
Interestingly, the severity of pain experienced by individuals with OA often
correlates poorly with the extent of structural changes visible on x-rays. X-rays are
commonly used to diagnose and monitor the progression of OA by showing changes
such as joint space narrowing, the presence of osteophytes, and subchondral sclerosis.
However, these radiographic findings do not always align with the patient's reported
pain levels. This discrepancy can be attributed to the fact that pain in OA is influenced
by a variety of factors, including the aforementioned mechanical and chemical
irritants, as well as individual differences in pain perception and the presence of
central sensitization, where the nervous system becomes more sensitive to pain
stimuli.
Therefore, managing OA pain requires a multifaceted approach that goes
beyond addressing cartilage loss. Effective pain management strategies may include
pharmacological treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs),
which reduce inflammation and pain, and analgesics to provide symptomatic relief.
Intra-articular injections of corticosteroids or hyaluronic acid can also be beneficial
for reducing inflammation and improving joint function.
Non-pharmacological interventions play a crucial role as well. Physical
therapy, aimed at strengthening the muscles around the joint and improving range of
motion, can help reduce pain and improve function. Weight management is essential
for reducing the mechanical load on weight-bearing joints, thereby decreasing pain
and slowing disease progression. Assistive devices, such as braces or orthotics, can
provide additional support and stability to affected joints.
In addition, emerging treatments such as regenerative medicine approaches,
including platelet-rich plasma (PRP) and stem cell therapy, are being investigated for
their potential to repair damaged tissues and modulate the inflammatory environment
within the joint. These innovative therapies offer hope for more effective long-term
management of OA pain.
In conclusion, the pain of osteoarthritis arises from the activation of
nociceptive nerve endings by a complex interplay of mechanical and chemical
irritants within the joint. This pain can result from various factors, including
distension of the synovial capsule, microfractures, periosteal irritation, and damage to
ligaments, the synovium, or the meniscus. Consequently, radiographic changes seen in
x-rays often correlate poorly with the severity of pain reported by patients.
Understanding these mechanisms is crucial for developing comprehensive pain
management strategies that address the multifactorial nature of OA pain and improve
the quality of life for those affected by this debilitating condition.
d. Clinical Presentation
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 improves accuracy of diagnosis. Criteria for hand OA
have also been published.
The prognosis for patients with primary OA is variable and depends on the
joint involved. If a weight-bearing 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.
Nonpharmacologic therapy is an integral part of the treatment plan for all
patients with OA.22,23,26 Nonpharmacologic therapy is the only available treatment
that has been shown to delay the progression of OA.2,27 Delaying the progression of
OA through active participation in nonpharmacologic therapy is critical to prevent
future functional impairment. Patient specific 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.
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 wear-and-tear 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, information about 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 self-management of OA. The benefits of patient
education have been documented in a variety of programs.26,28 These programs are
provided across a wide spectrum of delivery methods: from trained volunteers using
telephone calls to group sessions for patient support to one-on-one educational
sessions with physical therapists or nurse educators. While nearly all of these delivery
methods are effective, cost of delivery is highly variable. Long-term cost-
effectiveness is very important for sustainability of these patient education programs.
Exercise programs can improve joint function and can decrease disability,
pain, and analgesic use by OA patients.2,33 Low-impact aerobic exercise including
both land- and water-based 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.23 With weak or deconditioned
muscles, the load is transmitted excessively to the joints; weight-bearing 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.
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 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
replacements procedures are performed each year in the United States. It is estimated
that there are 7 million individuals living with an artificial knee or hip including
620,000 people who have both.29 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.
The American College of Rheumatology, as well as others, recommend
acetaminophen as a first-line treatment for knee and hip OA.22,23,42 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
gastrointestinal and cardiovascular adverse events and as a consequence is preferred
over oral NSAIDs as first-line treatment. The American College of Rheumatology and
other key groups recommend nonspecific or COX-2 selective NSAIDs, depending on
patient risk factors, as a first-line option for knee and hip OA if the patient fails
acetaminophen.23,24,41 Nonselective and COX-2 selective NSAIDs pose higher
risks for gastrointestinal, renal, and cardiovascular adverse events compared to
acetaminophen. COX-2 inhibitors carry less risk for both minor and serious
gastrointestinal adverse events in comparison to nonselective NSAIDs (with the
exception of diclofenac).
The American College of Rheumatology and other authorities recommend
topical NSAIDs as a first-line option for knee OA if the patient fails acetaminophen
and is preferred over oral NSAIDs for those older than age 75 years.22,23,42
Randomized trials have demonstrated that topical NSAIDs provide pain relief for OA
similar to that obtained with oral NSAIDs but 7 8 with fewer gastrointestinal 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.
Intra-articular corticosteroid injections are recommended as alternative first-
line treatment for both knee and hip OA when pain control with acetaminophen or
NSAIDs is suboptimal.22,23 Injections can also be administered with concomitant
oral analgesic therapy as needed for additional pain control. Intra-articular
corticosteroids are generally safe and well tolerated, but should not be administered
more frequently than once every three months due to risks of systemic adverse effects.
l Tramadol is recommended as an alternative first-line treatment of knee and hip pain
due to OA in patients who have failed treatment with scheduled full-dose
acetaminophen and topical NSAIDs, who are not appropriate candidates for oral
NSAIDs and are not able to receive intra-articular corticosteroids.23 Tramadol can
also safely be added to partially effective acetaminophen or oral NSAID therapy. Less
data are available to support the use of tramadol as monotherapy for OA pain.
The American College of Rheumatology recommends opioid analgesics as the
primary second-line medication for both knee and hip OA.23 Opioids may be
considered in patients who have not had an adequate response to both
nonpharmacologic and first-line 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 pain related function.45 Adverse effects,
including serious events, limit the routine use of opioids in the treatment of OA pain.
y Duloxetine can be used as adjunctive treatment in patients with knee OA
who have had a partial response to first-line analgesics.22,23 It may be a preferred
second-line medication in patients with both neuropathic and musculoskeletal OA
pain. Duloxetine has demonstrated efficacy primarily as add-on 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
gastrointestinal 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 not 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.
The American College of Rheumatology, NICE, and others do not routinely
recommend the use of intra-articular hyaluronic acid injections for knee OA
pain.22,23,26 HA injections do not appear to 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.
The American College of Rheumatology and NICE recommend topical
NSAIDs as a first-line option for hand OA.26 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 verses oral NSAIDs but gastrointestinal 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 first-line treatment for hand OA by the American College of
Rheumatology and as second-line therapy in the NICE guidelines.23,26 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 cardiovascular adverse events.
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 a 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.
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. 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
knowledge about the association of acetaminophen and serious liver injury.
Acetaminophen related hepatotoxicity is dose-dependent. 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 do not appear to
be at increased risk of GI bleeding.
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.
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 g daily (see
Adverse Effects 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.
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 (COX-2) enzyme,
blocking its action and thus prostanoid production. Blockade of prostaglandin
synthesis by inhibiting COX enzymes (mainly COX-2) is thought to account for
NSAIDs ability to relieve pain and inflammation. Nonselective NSAIDs were
developed prior to extensive knowledge of COX enzymes, but in fact they block both
COX-2 and COX-1. COX-1 has required “housekeeping” functions such as
gastroprotection. COX-2 inhibitors selectively block COX-2 but not COX-1 activity.
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 half-lives 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.
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. 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. A patient
treated with NSAIDs has a three to five times higher risk of developing
gastrointestinal complications than a patient not treated with these medications.
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 full dose 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 COX-2 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 important to note it is not without GI risk.55 A meta-analysis showed that
COX-2 selective inhibitors were associated with significantly fewer gastro-duodenal
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. It
appears the GI risk is lower in patients taking a coxib medication and low-dose aspirin
than a nonselective NSAID. However, in patients with high GI risk the combination
may still be harmful and gastroprotection is appropriate.
s Both nonselective and selective NSAIDs are associated with an increased
risk for hypertension, stroke myocardial infarction and death. NSAIDs should be
avoided in patients with known active ischemic heart disease, cerebrovascular disease
and moderate-to severe heart failure.56 It is not entirely clear the mechanism for the
cardiovascular effects of NSAIDs.61 NSAIDs are associated with hypertension,
increased preload, volume expansion and reduced sodium excretion.63 A large meta-
analysis showed some differences among NSAIDs in terms of vascular risk. The risk
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 one-third.64 Several recent randomized
controlled trials have compared NSAIDs to evaluate cardiovascular safety and found
celecoxib to be noninferior to other NSAIDs in terms of cardiovascular events.
However the celecoxib dose in these trials was lower than the doses previously
reported to be associated with increased cardiovascular risk. In these trials, more
patients also discontinued celecoxib due to lack of efficacy compared to other
NSAIDs.
In February 2014, an advisory committee to the FDA met to discuss the data
relating the cardiovascular 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 cardiovascular 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
cardiovascular events is present even in patients with no underlying cardiovascular
disease. The data reviewed also showed patients taking a NSAID following a first MI
were more likely to die in the first year following the MI.66 Strategies to reduce
cardiovascular risk with NSAIDs are not well documented. Naproxen may present
less cardiovascular risk than coxibs and diclofenac at higher doses and therefore
seems prudent to consider this when choosing a specific NSAID.
s 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 NSAID-treated patients. This effect may be clinically important to cause
exacerbations of congestive heart failure.63 Clinical features of these NSAID-induced
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, angiotensin-converting enzyme inhibitors,
cyclosporine, or aminoglycosides.
Close monitoring is advisable for high-risk 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 drug-induced 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. A review of hepatotoxicity associated with NSAIDs use
found them to be responsible for about 10% of medication induced liver injury.
Other toxic effects of NSAIDs include hypersensitivity reactions, rash, and
CNS complaints of drowsiness, dizziness, headaches, depression, confusion, and
tinnitus.57 It is also recommended that NSAIDs be avoided for patients with asthma
who are aspirin-intolerant. All nonspecific NSAIDs inhibit COX-1–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 one to three days after the drug is stopped. Warfarin
and celecoxib are metabolized by the cytochrome P450 isoenzyme CYP2C9, thus
patients receiving warfarin and COX-2 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.
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, angiotensin-converting enzyme inhibitors, β-blockers, 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 COX-2 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.
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. Currently, the ACR recommends that patients taking aspirin who need an
oral NSAID for OA choose an NSAID other than ibuprofen or COX-2 selective
inhibitors.23 Acetaminophen does not appear to interfere with the antiplatelet effect of
aspirin.
The mechanism of action of topical NSAIDs is considered to be through
inhibition of the COX-2 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 currently approved in the United States for osteoarthritis.
Compared to oral NSAIDs, topical NSAIDs are associated with many fewer
gastrointestinal 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 very few serious adverse effects. Meta-analyses 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
cardiovascular events.44 It is estimated that from 1% to 15% of topical NSAID enters
the systemic circulation, usually less than 5% that contributes to its greater safety
profile.
Interactions listed for topical diclofenac are the same as for oral NSAIDs,
which are 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, β-blockers, and diuretics. Other topical agents have not
been studied with the product and there could be changes in tolerability and
absorption of the diclofenac. For all of these interactions, as there is only a small
percentage of diclofenac absorbed, the risks are likely significantly less than with oral
drug, but the patient and provider would be wise to 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 potential for 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).
Diclofenac 1% gel (Voltaren®) can be used for hand or knee OA or other
joints amenable to topical application (eg, not the hip). 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 four times daily,
and for upper extremities, the dose is 2 g four times daily. Diclofenac solution
(Pennsaid®), only approved for knee OA, is available in 1.5% and 2% solution. Forty
drops of the 1.5% solution are to be applied four times a day to each affected knee.
The solution should be applied to the back, front, and sides of the knee. For each dose,
the patient places 10 drops at a time directly onto the painful knee (or first into the
hands and then immediately spreads onto the knee) and rubs the solution in. The
patient then repeats this process three more times until 40 drops worth have been
applied to the painful knee for that particular dose. The 2% diclofenac solution is
available in a meter-dose pump. Two actuations or 40 mg are applied 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 (180 mg diclofenac epolamine) is
applied twice daily. If the patch doesn’t stick well, the patient can tape edges with
first-aid tape. Patient counseling is important to carefully explain how to apply the
topical products and how long to wait before dressing, putting on gloves, showering,
and so forth.
The highest costs associated with the pharmacotherapy of OA are
hospitalization for treatment of NSAID-related complications, particularly serious GI
adverse events. Historically, gastroprotective therapy or the use of COX-2–selective
inhibitors for low-risk patients has not been costeffective because of the large number
needed to treat to prevent serious events, but most PPI’s are generic, multisource
products, making concomitant treatment with PPI’s 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 less-expensive 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 2-week trial at sufficient doses. Topical NSAIDs are significantly
more costly than oral agents, although may still be cost-effective in patients at
highrisk for costly complications associated with oral NSAID therapy.
Adverse events associated with intra-articular 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. Evidence shows an acute two to
three day 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 well-known adverse
effects with long-term use.
Opioid analgesics may be useful for patients who experience limited pain
relief with acetaminophen, oral NSAIDs, intra-articular 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 first-line 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 cardiovascular 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 practice for opioid prescribing 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 three months, evaluating patient progression toward
functional treatment goals, risks of harm, and adverse effects.
Duloxetine is a centrally acting dual-reuptake 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 Stevens-Johnson 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 first-line 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.
Hyaluronate is a naturally occurring component of cartilage and synovial
fluid. Exogenous intra-articular hyaluronate is available as a treatment for the
symptoms of knee OA. The goal of intra-articular HA is to provide and maintain
intra-articular lubrication. HA may also have anti-inflammatory, analgesic and
chondroprotective effects on the articular cartilage and joint synovium.82 Evidence
has not shown intra-articular 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 three or five weeks,
depending on the specific agent administered. Patients are generally advised to repeat
the injection schedule by 6 months if they are satisfied with the previous course.73
Strenuous or prolonged weight-bearing activities should be avoided for 48 hours after
treatment. Routinely, the most 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 as well as
local skin reactions, including rash, ecchymoses and pruritus have 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.
