INTRODUCTION Evidence-based approaches to the treatment of knee

osteoarthritis (OA) include nonpharmacologic, pharmacologic, and surgical

modalities targeted at relieving pain, improving joint function, and modifying risk
factors for disease progression. Treatments to modify the course of the disease
have not reached a threshold of efficacy to gain regulatory approval, despite
numerous efforts.

There are multiple mechanisms that can contribute to the pain experience, and a
holistic assessment of the patient is a paramount component of knee OA
treatment. In addition, clinical decision-making is often influenced by specific
patient and disease characteristics. This topic will provide an overview of the
management of knee OA, with a focus on the management of mild knee OA.
Separate topic reviews on OA as well as knee pain include the following:

●(See "Pathogenesis of osteoarthritis".)
●(See "Epidemiology and risk factors for osteoarthritis".)
●(See "Clinical manifestations and diagnosis of osteoarthritis".)
●(See "Overview of the management of osteoarthritis".)
●(See "Management of moderate to severe knee osteoarthritis".)
●(See "Comorbidities that impact management of osteoarthritis".)
●(See "Approach to the adult with unspecified knee pain".)
●(See "Approach to the adult with knee pain likely of musculoskeletal origin".)

DEFINITIONS These definitions are based on the severity of the impact

of the disease on the person rather than on radiographic severity in line with a
person-centered approach to management and the fact that symptoms and
radiographic findings are not necessarily well correlated and that imaging is not
usually required for diagnosis [1]. (See "Overview of the management of
osteoarthritis", section on 'Mechanisms of pain'.)
●Mild knee osteoarthritis – Patients with mild knee osteoarthritis (OA) have
low levels of or intermittent knee pain with relatively well-preserved joint
function and quality of life.
●Moderate/severe knee osteoarthritis – Patients with moderate to severe
OA have persistent pain which significantly impairs functionality, activity
participation, and quality of life. (See "Management of moderate to severe
knee osteoarthritis".)

GENERAL PRINCIPLES All patients with osteoarthritis (OA) should be

thoroughly assessed with regard to their knowledge about the disease and
treatment alternatives, previous experiences with treatment, and expectations of
current treatment. The presence of misconceptions, such as that exercise will
worsen OA or that OA will inevitably get worse, may attenuate the results of
treatment if not properly identified and countered. Patient education about OA and
its treatment options can occur during the clinical encounter and can be
complemented by provision of written materials and referral to national or
rheumatology association websites. Creating realistic and positive expectations for
treatment efficacy may enhance adherence, especially to therapies that require
lifestyle changes, and has been shown to positively influence treatment outcomes
[2,3]. The management principles for OA, including education, self-management,
and goal-setting, are discussed in detail separately. (See "Overview of the
management of osteoarthritis", section on 'General principles'.)

The management of patients with knee OA should include a holistic assessment.

Monitoring of the patient's response to therapy should also be done on a regular
basis. A detailed discussion on monitoring and assessment of OA patients can be
found elsewhere. (See "Overview of the management of osteoarthritis", section on
'Monitoring and assessment'.)

APPROACH BASED ON CLINICAL PRESENTATION Patients

with knee osteoarthritis (OA) may fall into different categories that must be
considered when making treatment decisions.

Our management approach is generally consistent with guidelines developed by

professional organizations [4-9].

Mild knee osteoarthritis — Nonpharmacologic therapies alone, focusing on

education, exercise, and weight management, or in combination with topical
therapies or analgesics on an as-needed basis are likely to provide adequate
control of symptoms in this group of patients (algorithm 1).

Moderate/severe knee osteoarthritis — Nonpharmacologic interventions are the

first-line therapy for this group of patients, and aquatic exercises are usually better
tolerated than land-based exercises in patients with severe pain (algorithm 2).
Special consideration should be given to extraarticular factors potentially
contributing to pain, such as mood disturbances, pain catastrophizing, sleep
problems, and chronic widespread pain (see "Overview of the management of
osteoarthritis", section on 'Factors affecting response to therapy'). Other treatment
alternatives may be required, including oral nonsteroidal antiinflammatory drugs
(NSAIDs), intraarticular steroids, duloxetine, and surgery.

Knee osteoarthritis with one or more joints involved — OA can be localized in

the knee only or occur concomitantly with OA in multiple joints. The best approach
for managing patients with multijoint, symptomatic OA is to prioritize therapies that
address the pain at the individual level and not at the joint level. Local interventions
such as intraarticular steroid injections, topical NSAIDs or capsaicin, and knee
braces may help with knee pain but are likely to be insufficient to provide adequate
improvement in the patient's OA symptoms as a whole.

Patients with comorbidities — Knee OA is often comorbid with other conditions

such as cardiovascular disease, diabetes, hypertension, obesity, depression, and
peptic ulcer disease. In addition, knee OA is highly prevalent in the older adult
population, although it is important to note that its diagnosis usually occurs earlier
in life (median age 55 years) and around two-thirds of the patients are younger
than 65 years [10,11]. Therapies should be chosen to minimize the potential for
adverse events while optimizing function and quality of life. (See "Comorbidities
that impact management of osteoarthritis".)

MILD KNEE OSTEOARTHRITIS Nonpharmacologic interventions are

the backbone of knee osteoarthritis (OA) management, irrespective of OA severity,

and can be used in combination with pharmacologic therapy (algorithm 1). The
duration of therapy depends upon the individual patient's needs; however, lifelong
treatment with nonpharmacologic therapies is generally recommended in order to
relieve symptoms and prevent further joint damage.

Initial nonpharmacologic measures — Nonpharmacologic interventions in the

management of patients with mild OA includes exercise and, when pertinent,
weight loss.

Exercise — In all patients with knee OA, we recommend ongoing exercise for pain
relief and joint protection. Exercise, alongside weight loss when indicated, is a core
component of knee OA management [2,3,5,12,13]. All patients with knee OA
should be counseled on exercise irrespective of age, radiographic disease severity,
pain intensity, functional levels, and comorbidities. A Cochrane review of 54 trials,
among which 19 were considered as "low risk of bias," concluded that there is
moderate- to high-quality evidence suggesting that land-based exercise improves
knee pain and function with moderate effect size immediately after treatment [12].
This magnitude of effect is comparable to that reported for oral nonsteroidal
antiinflammatory drugs (NSAIDs) [5]. However, the benefits of exercise were not
sustained in the long term, which is largely related to the decreasing adherence
rates to the exercise program over time [13]. Strategies to improve adherence
should be adopted, such as patient education about OA and the benefits of
exercise and long-term monitoring. (See "Overview of the management of
osteoarthritis", section on 'General principles' and "Overview of the management of
osteoarthritis", section on 'Monitoring and assessment'.)

At present, there is no strong evidence on the best prescription of exercise

modalities and dosage (ie, intensity, duration, and frequency) [14]. In clinical
practice, exercise prescription is frequently personalized according to individual
findings. We refer our patients for physical therapy to optimize the effectiveness of
the exercise program [15]. We prefer a combination of low-impact aerobic fitness
training (eg, walking, cycling, rowing, and deep-water running) and lower-limb
strengthening exercises, which addresses the full spectrum of impairments in most
patients with knee OA. Nevertheless, exercise choice should be also based on
patient's mobility, specific impairments (eg, strength, range of motion, aerobic
fitness, and balance), and preferences [14]. Exercises involving high impact on the
joints such as running or jumping are usually discouraged in order to avoid further
joint damage, especially in cases of more advanced OA, although research
evidence demonstrating an association between running and progression of knee
OA is scarce [16]. For those patients who already run or jog for exercise and
develop mild symptoms of OA but wish to continue running, we advocate a load
management approach with attention paid to factors such as rest days, running
surface, distance and speed, and footwear, as well as building up muscle strength.
Stretching or flexibility exercises, particularly of the hamstrings to avoid or minimize
flexion contracture of the knee, can also be part of the exercise program to
increase knee range of motion [14,15].

Aquatic exercise also has clinically relevant effects on knee pain, function, and
stiffness, but the effects are small when compared with non-treatment controls [17].
This exercise modality is particularly useful for patients with severe pain and/or
poor physical function due to its better tolerance and lower potential to cause
adverse events.

We also consider Tai Chi as a treatment option for the rehabilitation of patients with
knee OA, according to patients' preferences. Despite the limited number of large
trials investigating the long-term effects of Tai Chi, it has been shown to be as
effective as a standard exercise program after 12 weeks in terms of knee pain,
physical function, and reduction in analgesic use, in addition to having greater
improvement in depression [18,19]. Moreover, Tai Chi improves balance and is
associated with a reduced falls risk in older patients with knee OA [20].

Weight loss — Because of the substantial load placed on the knees during

weightbearing activities, maintaining an ideal body weight is critical to preserve
joint structures and improve symptoms. In addition to the mechanical
consequences of obesity and overweight to the joint, adipokines released by the
adipose tissue such as leptin and adiponectin are directly involved in the
inflammatory component of OA and cartilage damage [21,22]. (See "Pathogenesis
of osteoarthritis" and "Comorbidities that impact management of osteoarthritis",
section on 'Obesity'.)

We encourage health care professionals to consult available local community

programs or refer patients to a dietitian to ensure that overweight and obese
patients are offered optimal support to lose weight [23]. (See "Obesity in adults:
Overview of management".)

Our approach of a combination of a calorie-restricted diet and physical activity to

achieve weight loss is supported by several studies [24]. As an example, the IDEA
trial randomized 454 overweight and obese adults with knee OA into one of three
groups: diet plus exercise, diet alone, or exercise alone [25]. Participants in the diet
plus exercise group had the highest percentage of weight lost (11.4 percent of
body weight) and improvement in pain after 18 months, achieving a decrease in
pain scores of approximately 50 percent, with 38 percent of patients reporting no or
little pain at the end of the trial.

Moreover, a dose-response relationship between the extent of percentage change

in body weight and improvement in joint symptoms has been demonstrated, with
more robust effects achieved when at least a 10 percent reduction in body weight
is attained [26]. A reasonable initial target is a 5 to 10 percent weight reduction
within a six-month period [27], and initial goals should be reassessed periodically
and individually for each patient.

Caloric restriction, particularly in order adults, may contribute to loss of lean mass
and lead to muscle weakness and should, therefore, be combined with
strengthening exercises to prevent these adverse effects. Other interventions such
as anti-obesity drugs (eg, orlistat) and surgical approaches (eg, gastric bypass) are
less well studied in the context of OA. (See "Obesity in adults: Overview of
management".)

Inadequate response to nonpharmacologic measures — Pharmacologic

therapy can be started in combination with or after a trial of nonpharmacologic
interventions, if satisfactory pain relief is not achieved with these measures alone.
Topical therapies (table 1) for the treatment of mild knee OA are particularly
appealing due to the frequent presence of comorbid conditions in this patient
population and the relatively common side effects of other systemic treatment
options. Despite the chronic nature of OA, research evidence on the long-term
efficacy (≥1 year) of pharmacologic therapies is limited [28]. Nonetheless, in our
experience, topical NSAIDs, used either as needed or on a daily basis, may
provide long-term benefits when combined with nonpharmacologic measures.
Topical capsaicin, however, is less tolerated by patients due to the relatively high
frequency of local side effects, including a local burning sensation. We do not
use topical salicylates in our patients with OA.

Topical NSAIDs — We suggest topical nonsteroidal antiinflammatory drugs

(NSAIDs) rather than oral NSAIDs for patients with mild OA localized to the knee or
with concomitant hand involvement, given the superficial location of the joints in
these cases. A Cochrane review found that about 60 percent of patients achieved
at least 50 percent improvement in pain with topical NSAIDs, which was
comparable to the effect obtained with oral formulations and slightly better than
that observed with topical placebo [29]. The risk of gastrointestinal, renal, and
cardiovascular toxicity is much lower with topical NSAIDs as compared with its oral
formulation due to the reduced systemic absorption (5- to 17-fold lower for
topical diclofenac compared with oral) [30,31]. The tolerability profile is also better
with topical NSAIDs, with mild skin rashes being the most commonly reported side
effect. The drugs studied with the most frequency were diclofenac gel or solution
and ketoprofen, applied over the affected knee two to four times daily, for the
duration necessary to control symptoms. We most commonly use diclofenac gel,
but the choice of topical agent may vary according to local availability and cost.
Topical capsaicin — For patients with mild OA localized to the knee or a few
other joints in whom other treatments are ineffective or contraindicated, we suggest
topical capsaicin. Capsaicin is a substance derived from hot chili peppers with the
potential to alleviate pain through the down-regulation of the TRPV1 receptor
activity on nociceptive sensory neurons and the depletion of substance P.
Continued use of capsaicin results in desensitization of nociceptive fibers and
inhibition of pain stimulus transmission. However, the causative role of substance
P depletion on pain reduction associated with capsaicin use has come into
question [32].

There are relatively few randomized controlled trials investigating

topical capsaicin treatment for knee OA pain, most with a short follow-up (up to 12
weeks) and overall good methodological quality [33]. In most studies, topical
capsaicin was superior to placebo, with an overall 33 percent pain reduction after
four weeks in one study, which was significantly greater than placebo [34]. In a 12-
week randomized, multicenter trial, 113 patients received either capsaicin 0.025%
cream four times daily or placebo [35]. Capsaicin provided greater pain relief after
4 to 12 weeks and a greater number of patients on capsaicin (81 percent)
compared with placebo (54 percent) were improved based on physician's global
evaluation.

Local burning sensation is the most common side effect of topical capsaicin and

may occur in over half of patients. However, it is usually mild to moderate and
improves with continued application. In addition, topical capsaicin should not come
in contact with mucous membranes, abraded skin, eyes, or genital areas. Systemic
adverse effects of capsaicin are not significantly higher compared with placebo.
We prefer topical NSAIDs over capsaicin in our practice due to better tolerability
and stronger evidence for efficacy.

MODERATE/SEVERE KNEE OSTEOARTHRITIS The

management of moderate to severe knee osteoarthritis (OA) is discussed in detail

separately. (See "Management of moderate to severe knee osteoarthritis".)

THERAPIES LACKING EFFICACY OR OF UNCERTAIN

BENEFIT There are several approaches that have been used to treat

patients with knee osteoarthritis (OA) that we generally do not routinely use or
recommend due to lack of sufficient evidence base for widespread dissemination
such as nerve blocks, nerve ablation, stem cell injections, and joint distraction. In
addition, there are other therapies in which the benefit remains uncertain. It would
be reasonable, however, to try some of the therapies discussed below as
adjunctive measures for patients who do not respond to the approach described
above after consideration of potential harm, cost, and patient preference.

Insoles — Due to the evidence indicating against the use of lateral wedge insole in
medial compartment knee OA, we do not recommend their use. However, we
consider medially wedged insoles for patients with lateral tibiofemoral OA and
valgus deformity based on evidence from one study of significant improvements in
pain for these patients [36]. Nevertheless, there are fewer studies investigating
medial compared with lateral wedge insoles [37].

Lateral wedge insoles have been shown to modestly reduce the external knee
adduction moment and thereby reduce medial knee joint loading. However,
compared with control inserts (neutral soles), lateral wedge insoles provided no
clinically significant improvement in pain in patients with medial knee OA, as
examined in meta-analyses including trials with both neutral and no insole control
[37,38]. Moreover, a randomized trial including 200 participants with mild to
moderate medial knee OA found no differences between full-length lateral wedged
insole and flat insole in medial tibial and femoral cartilage volume loss and change
in size of bone marrow lesions on magnetic resonance imaging (MRI) over 12
months [39]. Another randomized trial that involved prescreening to select those
patients more likely to respond to insoles (ie, those who showed a ≥2 percent
reduction in the knee adduction moment with insoles and without patellofemoral
OA) found that lateral wedge insoles reduced pain more than control insoles [40].
However, the effect of treatment was small and likely to be of clinical significance in
only a minority of patients.

Glucosamine and chondroitin — In our clinical practice, we do not recommend

these supplements routinely to all patients; however, we do not discourage their
use for patients who are keen to take them, especially if symptomatic benefit is
achieved with their use (except for glucosamine hydrochloride, which we
recommend against). There have been conflicting results from randomized trials
evaluating the efficacy of glucosamine and chondroitin in knee OA [41]. Results
from reviews with larger, methodologically sound studies found negligible effects of
glucosamine hydrochloride on knee pain, while higher doses or higher-grade
formulations of glucosamine sulfate (1500 mg/day) or chondroitin (800 mg/day)
showed more favorable results and may have a statistically significant but small
effect on symptoms compared with placebo [42-45]. As an example, in an industry-
sponsored randomized trial including 604 patients with symptomatic knee OA who
were followed for six months, pharmaceutical-grade chondroitin sulfate was found
to be statistically superior to placebo and similar to celecoxib in reducing pain and
improving function [45]. Either chondroitin (800 mg), celecoxib (200 mg), or
placebo was given once daily in the evening. One important limitation of the study
is the uncertain clinical relevance of the statistical significance for the primary
outcomes, which were based on a degree of change from baseline on a visual
analog scale (VAS) for pain (0 to 100 mm) and the Lequesne index (a composite
score of pain and function). Also, the number of patients who achieved the minimal
clinically important improvement of 20 mm on the VAS for pain was not different
among the three groups. Other meta-analyses also suggested that glucosamine
sulfate (1500 mg/day) and chondroitin (800 mg/day) may have small effects in
delaying structural progression of OA with long-term use (two to three years)
[46,47].

A strong placebo effect has been demonstrated in the studies involving these
dietary supplements. This is well illustrated by the landmark
Glucosamine/Chondroitin Intervention Trial (GAIT), in which around 60 percent of
participants experienced at least 20 percent pain reduction irrespective of whether
they received placebo, glucosamine hydrochloride, chondroitin, or the combination
of both [48] (see "Overview of the management of osteoarthritis", section on
'Factors affecting response to therapy' and "Overview of the management of
osteoarthritis", section on 'Role of placebo effect'). In another multicenter
randomized noninferiority trial, 164 patients with moderate to severe knee OA were
treated with either chondroitin sulfate plus glucosamine or placebo [49]. At six
months' follow-up, the mean reduction in the global pain score was significantly
greater in the placebo group (33 percent) compared with the chondroitin sulfate
plus glucosamine group (19 percent). Limitations of the study include the small size
and potentially inadequate dosing of chondroitin and glucosamine. Whether some
patient subgroups may benefit more from glucosamine than others has also been
investigated, but no difference from placebo was found in any of the prespecified
subgroups according to baseline pain severity, body mass index (BMI), gender,
presence of inflammatory signs, or radiographic severity [50]. However, it is of note
that the risk of any adverse event with these supplements is low and comparable to
placebo. Due to these contradictory and still uncertain data, glucosamine and
chondroitin are not strongly recommended by major OA guidelines [4,6,51,52].

Other nutritional supplements — There is limited evidence supporting the use of

other nutritional supplements for knee OA. In clinical practice, we often trial
supplements such as fish oil, curcumin (active ingredient of turmeric),
and/or Boswellia serrata for knee OA patients for symptomatic relief. Of note, as
curcumin is poorly absorbed by the gastrointestinal tract, curcumin supplements
formulated to enhance absorption and bioavailability are usually preferred (eg,
combinations of curcumin with piperine or bioperine, a constituent of black pepper).

A systematic review and meta-analysis of nutritional supplements for OA of the

knee, hand, or hip including 69 studies (20 different supplements) found large and
clinically important effects for seven supplements (L-carnitine, Pycnogenol,
curcumin, Boswellia serrata extract, Curcuma longa extract, passion fruit peel
extract, and collagen hydrolysate) compared with placebo in reducing pain in the
short-term (≤3 months) [53]. Most of these supplements were investigated in only a
limited number of small trials, and the quality of evidence for this finding was
variable (very low to moderate). Six other supplements (undenatured type II
collagen, avocado soybean unsaponifiables, methylsulfonylmethane, diacerein,
glucosamine, and chondroitin) were statistically better than placebo, but it was
unclear if the effects were clinically important. Among the trials reporting long-term
outcomes (>6 months, n = 17), no supplement was found to have clinically
important effects on pain. The meta-analysis found no increased risk of side effects
of supplements compared with placebo, except for diacerein, although safety
profile was investigated in only a limited number of trials. It is also important to note
that most trials (64 percent) were industry funded and were considered at high or
unclear risk of bias (46 and 44 percent, respectively).

In another study, vitamin D supplementation had no benefit over placebo on pain

and change in tibial cartilage volume over two years in a large clinical trial [54]. A
study assessing the efficacy of low- versus high-dose fish oil (0.45 and 4.5 g
omega 3 fatty acids, respectively) on clinical outcomes found greater
improvements in pain and function in the group receiving low-dose fish oil at two
years [55]. Adverse events were common in both groups, particularly
gastrointestinal events (around 60 percent in each group) such as gastrointestinal
upset and reflux. Fish oil has also been studied in rheumatoid arthritis with positive
results, probably through the antiinflammatory effects of the eicosapentaenoic and
docosahexaenoic acids. However, its clinical benefit in OA is still unclear.

Limited evidence has also suggested that phytoflavonoids, a class of natural

compounds with antiinflammatory properties, may have beneficial effects on knee
OA symptoms [56-58]. Flavocoxid, a specific type of phytoflavonoid, has been
associated with reports of serious adverse events related to liver injury and
hypersensitivity pneumonitis, and its use is not recommended. (See "Hepatotoxicity
due to herbal medications and dietary supplements", section on 'Flavocoxid'.)

Opioids — Due to the relatively high incidence of side effects such as drowsiness,

dizziness, and nausea, and the potential to cause harm with long-term use, we
avoid using opioids whenever possible, especially in the older adult population. In
our clinical practice, we use opioids only in patients with severe pain awaiting joint
replacement (ie, short-term use). We use it in the lowest dose and duration
necessary to control symptoms and monitor common side effects. (See "Use of
opioids in the management of chronic non-cancer pain".)

Several studies of patients with knee OA have found the efficacy of opioids with
respect to pain reduction to be similar to that of NSAIDs. A meta-analysis revealed
an overall small effect size (standardized mean difference [SMD] -0.28, 95% CI
-0.35 to -0.20) of non-tramadol opioids on pain reduction, which corresponds to a
difference of 0.7 cm on VAS (0 to 10 cm) between opioids and placebo [59].
Improvement in knee function was also small, and there was no influence of
daily morphine equivalence dose on the benefits on function. Patients receiving
opioids were more likely to drop out due to adverse events and more likely to
experience side effects (6.5 versus 1.7 percent and 22 versus 15 percent,
respectively) [59]. A network meta-analysis also did not demonstrate a difference in
efficacy between potent opioids (hydromorphone and oxycodone), a less-potent
opioid (tramadol), and NSAIDs in trials of at least eight weeks' duration [60]. In
addition, a randomized trial including 240 patients with chronic back pain or hip or
knee OA pain did not demonstrate a difference in pain-related function after 12
months of treatment with non-opioid versus opioid medications [61].

In addition to the known potential risks and harms of opioid use, there are some
data to suggest an association between tramadol use and increased mortality
among patients with OA. In a propensity score-matched study using data from
88,902 patients with OA, patients prescribed tramadol had a higher rate of mortality
over the one-year follow-up period compared with commonly prescribed NSAIDs
such as naproxen (hazard ratio 1.71 [95% CI 1.41-2.07]) [62]. These findings,
however, may be susceptible to confounding by indication as the tramadol users
had a higher comorbidity burden than patients receiving NSAIDs prior to propensity
score matching.

Hyaluronans — The use of any intraarticular hyaluronic acid (HA) formulation is

not widely recommended and not routinely used in our practice due to the lack of
robust evidence demonstrating clinically relevant benefits over intraarticular
placebo [4,6,9,51]. There has been a longstanding debate and conflicting data
across trials and meta-analyses regarding the benefit of viscosupplementation (ie,
intraarticular HA) for the treatment of symptomatic knee OA. The evidence from
large, double-blinded, and high-quality trials indicates that intraarticular HA has a
small, clinically irrelevant benefit over intraarticular placebo [63-65]. Moreover,
intraarticular HA is associated with high costs and potential side effects such as
pain flare-ups and joint infection, although the latter is a rare complication.

Platelet-rich plasma — Due to the lack of solid evidence for the recommendation

of platelet-rich plasma (PRP) injection in patients with knee OA, we do not
recommend its use. Nevertheless, evidence supporting its efficacy on OA
symptoms has been growing rapidly. Injection of intraarticular PRP resulted in
significant improvement in knee pain and function over intraarticular placebo and
intraarticular HA up to 12 months post-injection [66]. However, evidence is still
limited due to overall high risk of bias in previous trials and great variability
between studies regarding the number of injections (generally one to four), interval
between injections, preparation of the PRP, and volume injected [66]. There is also
uncertainty regarding whether individuals with less severe OA may benefit more
from this intervention compared with individuals with more advanced structural
damage (ie, Kellgren-Lawrence grade [KLG] ≥3). Additional information on the use
of PRP for OA can be found elsewhere. (See "Investigational approaches to the
management of osteoarthritis", section on 'Platelet-rich plasma'.)

Acetaminophen — Due to safety concerns pertaining

to acetaminophen (paracetamol) use and an increased awareness of its negligible
and non-clinically significant effects on pain [4,67-70], we do not initiate treatment
with acetaminophen for knee OA in our clinical practice. Data from a meta-analysis
including 10 trials (3541 patients) revealed that there is high-quality evidence that
paracetamol has only small, non-clinically meaningful benefits for pain in the short
term [69]. This finding was further strengthened by a network meta-analysis
comparing different analgesics for the treatment of OA pain, which demonstrated
that paracetamol was not superior when compared with placebo irrespective of the
dose (4 mm difference on a 0 to 100 mm VAS) [67]. The risk of harm of
acetaminophen is usually higher with increasing dose but may also occur at doses
within the therapeutic range, including gastrointestinal bleeding, liver toxicity, renal
failure, and cardiovascular disease [70]. This is especially concerning due to the
risk of unintentional overdose, as paracetamol is frequently combined with other
common over-the-counter medications used to treat pain and cold symptoms.

Transcutaneous electrical nerve stimulation — Data on the efficacy of

transcutaneous electrical nerve stimulation (TENS) in OA are conflicting [71]. Its
mechanism of action is based on the gate-control theory, in which modulation of
the nociceptive stimulus to the brain occurs through its presynaptic inhibition in the
spinal cord dorsal horn. A Cochrane review found that the evidence regarding the
efficacy for TENS was inconclusive based on the poor methodological quality of
most studies, small sample sizes, and moderate to high heterogeneity between
trials [71]. Another trial including 203 patients found no additional pain or function
benefits from TENS, interferential currents, or shortwave diathermy compared with
sham interventions in patients participating in an education and exercise training
program [72]. In addition, there is evidence indicating a significant placebo
component of the effect of TENS [72,73].

Acupuncture — The use of acupuncture in the management of OA is discussed

elsewhere. (See "Acupuncture", section on 'Knee osteoarthritis'.)

Local heat and cold — Local application of heat using a heat pack or hot-water
bottle as a self-management strategy may have beneficial short-term effects on
pain in patients with knee OA [74-76]. In a small cohort study of patients with knee
OA, local heat application in addition to routine management was associated with
more improvements in pain and disability compared with routine management
alone [76]. However, there are no robust clinical trials evaluating its effectiveness.
Similarly, while not well studied, some patients may find icing of the joint useful
temporarily to deal with a flare in pain or increase in swelling, for example, after an
activity that has exacerbated symptoms.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient

education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5 th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-
depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)
 ●Basics topics (see "Patient education: Osteoarthritis (The
Basics)" and "Patient education: Arthritis and exercise (The Basics)")
●Beyond the Basics topics (see "Patient education: Osteoarthritis symptoms
and diagnosis (Beyond the Basics)" and "Patient education: Osteoarthritis
treatment (Beyond the Basics)" and "Patient education: Arthritis and exercise
(Beyond the Basics)")

SOCIETY GUIDELINE LINKS Links to society and government-

sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Osteoarthritis".)

SUMMARY AND RECOMMENDATIONS

●All patients with knee osteoarthritis (OA) should be thoroughly assessed with
regard to their knowledge about the disease and treatment alternatives,
previous experiences with treatment, and expectations of current treatment.
Patient education about OA and its treatment options can occur during the
clinical encounter and can be complemented by provision of written materials.
Monitoring of the patient's response to therapy should also be done on a
regular basis. (See 'General principles' above.)
●Patients with knee OA may fall into different categories, based on patient
presentation rather than imaging, that must be considered when making
treatment decisions (see 'Approach based on clinical presentation' above):
•Mild knee OA – Patients with mild knee OA have low levels of or
intermittent knee pain with relatively well-preserved joint function and
quality of life. Nonpharmacologic therapies alone or in combination with
topical therapies or analgesics on an as-needed basis are likely to provide
adequate control of symptoms (algorithm 1). (See 'Mild knee
osteoarthritis' above.)
•Moderate/severe knee OA – Patients with moderate to severe OA have
persistent pain which significantly impairs functionality, activity
participation, and quality of life. Nonpharmacologic interventions are also
first-line therapy, but other treatment alternatives are usually required,
including oral nonsteroidal antiinflammatory drugs (NSAIDs), intraarticular
steroids, duloxetine, and possibly surgery (algorithm 2).
(See 'Moderate/severe knee osteoarthritis' above.)
•Knee OA with one or more joints involved – The best approach for
management patients with multijoint, symptomatic OA is to prioritize
therapies that address the pain at the individual level and not the joint
level. (See 'Knee osteoarthritis with one or more joints involved' above.)
•Patient with comorbidities – Knee OA is often comorbid with other
conditions (eg, cardiovascular disease, diabetes); therapies should be
chosen to minimize the potential for adverse events while optimizing
function and quality of life. (See 'Patients with comorbidities' above.)
 ●For all patients with knee OA, we recommend ongoing exercise for pain relief
and joint protection (Grade 2B). There is no strong evidence on the best
prescription of exercise modalities and dosage (ie, intensity, duration, and
frequency). We prefer a combination of low-impact aerobic fitness training (eg,
walking, cycling, rowing, and deep-water running) and lower-limb
strengthening exercises. (See 'Exercise' above.)
●For patients with knee OA who are overweight, we suggest a calorie-
restricted diet and exercise program to preserve joint structures and improve
symptoms (Grade 2B). We encourage health care professionals to consult the
available local community programs or refer patients to a dietitian to ensure
that overweight and obese patients are offered optimal support to lose weight.
(See 'Weight loss' above.)
●For patients with mild OA localized to the knee or with concomitant hand
involvement, we suggest initial treatment with a topical NSAID rather than an
oral NSAID (Grade 2C). The risk of gastrointestinal, renal, and cardiovascular
toxicity is much lower with topical NSAIDs as compared with its oral
formulation due to the reduced systemic absorption. The tolerability profile is
also better with topical NSAIDs, with mild skin rashes being the most
commonly reported side effect. (See 'Topical NSAIDs' above.)
●For patients with mild OA localized to the knee or a few other joints in whom
other treatments are ineffective or contraindicated, we suggest
topical capsaicin (Grade 2C). (See 'Topical capsaicin' above.)
●There are several approaches that have been used to treat patients with knee
OA that we generally do not routinely use due to lack of data demonstrating
efficacy. These include therapies for which the benefit remains uncertain; thus,
some may be reasonable to try as adjunctive measures for patients who do
not respond to the approach described above. These include:
•Insoles and footwear (see 'Insoles' above)
•Glucosamine and chondroitin (see 'Glucosamine and chondroitin' above)
•Other nutritional supplements (see 'Other nutritional supplements' above)
•Opioids (see 'Opioids' above)
•Hyaluronans (see 'Hyaluronans' above)
•Platelet-rich plasma (PRP) (see 'Platelet-rich plasma' above)
•Acetaminophen (see 'Acetaminophen' above)
•Transcutaneous electrical nerve stimulation (TENS)
(see 'Transcutaneous electrical nerve stimulation' above)
•Acupuncture (see 'Acupuncture' above)
•Local heat (see 'Local heat and cold' above)
Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES
1. Bedson J, Croft PR. The discordance between clinical and radiographic
knee osteoarthritis: A systematic search and summary of the literature. BMC
Musculoskelet Disord 2008; 9:116.
2. Hammer NM, Bieler T, Beyer N, Midtgaard J. The impact of self-efficacy on
physical activity maintenance in patients with hip osteoarthritis - a mixed methods
study. Disabil Rehabil 2016; 38:1691.
3. Damush TM, Perkins SM, Mikesky AE, et al. Motivational factors influencing
older adults diagnosed with knee osteoarthritis to join and maintain an exercise
program. J Aging Phys Act 2005; 13:45.
4. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the
non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;
22:363.
5. Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the
management of hip and knee osteoarthritis: part III: Changes in evidence following
systematic cumulative update of research published through January 2009.
Osteoarthritis Cartilage 2010; 18:476.
6. Hochberg MC, Altman RD, April KT, et al. American College of
Rheumatology 2012 recommendations for the use of nonpharmacologic and
pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care
Res (Hoboken) 2012; 64:465.
7. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the
management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert
consensus guidelines. Osteoarthritis Cartilage 2008; 16:137.
8. Fernandes L, Hagen KB, Bijlsma JW, et al. EULAR recommendations for
the non-pharmacological core management of hip and knee osteoarthritis. Ann
Rheum Dis 2013; 72:1125.
9. National Clinical Guideline Centre (UK). Osteoarthritis: Care and
Management in Adults, National Institute for Health and Care Excellence (UK),
London 2014.
10. Losina E, Weinstein AM, Reichmann WM, et al. Lifetime risk and age at
diagnosis of symptomatic knee osteoarthritis in the US. Arthritis Care Res
(Hoboken) 2013; 65:703.
11. Hunter DJ. Osteoarthritis. Best Pract Res Clin Rheumatol 2011; 25:801.
12. Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the
knee: a Cochrane systematic review. Br J Sports Med 2015; 49:1554.
13. Pisters MF, Veenhof C, van Meeteren NL, et al. Long-term effectiveness of
exercise therapy in patients with osteoarthritis of the hip or knee: a systematic
review. Arthritis Rheum 2007; 57:1245.
14. Hunter DJ, Harvey W, Gross KD, et al. A randomized trial of patellofemoral
bracing for treatment of patellofemoral osteoarthritis. Osteoarthritis Cartilage 2011;
19:792.
15. Nelson AE, Allen KD, Golightly YM, et al. A systematic review of
recommendations and guidelines for the management of osteoarthritis: The chronic
osteoarthritis management initiative of the U.S. bone and joint initiative. Semin
Arthritis Rheum 2014; 43:701.
16. Timmins KA, Leech RD, Batt ME, Edwards KL. Running and Knee
Osteoarthritis: A Systematic Review and Meta-analysis. Am J Sports Med 2017;
45:1447.
17. Bartels EM, Juhl CB, Christensen R, et al. Aquatic exercise for the treatment
of knee and hip osteoarthritis. Cochrane Database Syst Rev 2016; 3:CD005523.
18. Yan JH, Gu WJ, Sun J, et al. Efficacy of Tai Chi on pain, stiffness and
function in patients with osteoarthritis: a meta-analysis. PLoS One 2013; 8:e61672.
19. Wang C, Schmid CH, Iversen MD, et al. Comparative Effectiveness of Tai
Chi Versus Physical Therapy for Knee Osteoarthritis: A Randomized Trial. Ann
Intern Med 2016; 165:77.
20. Mat S, Tan MP, Kamaruzzaman SB, Ng CT. Physical therapies for
improving balance and reducing falls risk in osteoarthritis of the knee: a systematic
review. Age Ageing 2015; 44:16.
21. Gómez R, Conde J, Scotece M, et al. What's new in our understanding of
the role of adipokines in rheumatic diseases? Nat Rev Rheumatol 2011; 7:528.
22. de Boer TN, van Spil WE, Huisman AM, et al. Serum adipokines in
osteoarthritis; comparison with controls and relationship with local parameters of
synovial inflammation and cartilage damage. Osteoarthritis Cartilage 2012; 20:846.
23. http://oa.hwfl.com.au/ (Accessed on September 26, 2016).
24. Wluka AE, Lombard CB, Cicuttini FM. Tackling obesity in knee
osteoarthritis. Nat Rev Rheumatol 2013; 9:225.
25. Messier SP, Mihalko SL, Legault C, et al. Effects of intensive diet and
exercise on knee joint loads, inflammation, and clinical outcomes among
overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical
trial. JAMA 2013; 310:1263.
26. Riddle DL, Stratford PW. Body weight changes and corresponding changes
in pain and function in persons with symptomatic knee osteoarthritis: a cohort
study. Arthritis Care Res (Hoboken) 2013; 65:15.
27. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in
obese patients diagnosed with knee osteoarthritis: a systematic review and meta-
analysis. Ann Rheum Dis 2007; 66:433.
28. Gregori D, Giacovelli G, Minto C, et al. Association of Pharmacological
Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A
Systematic Review and Meta-analysis. JAMA 2018; 320:2564.
29. Derry S, Conaghan P, Da Silva JA, et al. Topical NSAIDs for chronic
musculoskeletal pain in adults. Cochrane Database Syst Rev 2016; 4:CD007400.
30. Roth SH, Fuller P. Diclofenac topical solution compared with oral diclofenac:
a pooled safety analysis. J Pain Res 2011; 4:159.
31. Kienzler JL, Gold M, Nollevaux F. Systemic bioavailability of topical
diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J
Clin Pharmacol 2010; 50:50.
32. Anand P, Bley K. Topical capsaicin for pain management: therapeutic
potential and mechanisms of action of the new high-concentration capsaicin 8%
patch. Br J Anaesth 2011; 107:490.
33. De Silva V, El-Metwally A, Ernst E, et al. Evidence for the efficacy of
complementary and alternative medicines in the management of osteoarthritis: a
systematic review. Rheumatology (Oxford) 2011; 50:911.
34. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical
capsaicin: a double-blind trial. Clin Ther 1991; 13:383.
35. Altman RD, Aven A, Holmburg CE, et al. Capsaicin cream 0.025% as
Monotherapy for Osteoarthritis: A double-blind study. Semin Arthritis Rheum 1994;
23 (Suppl 3):25.
36. Rodrigues PT, Ferreira AF, Pereira RM, et al. Effectiveness of medial-
wedge insole treatment for valgus knee osteoarthritis. Arthritis Rheum 2008;
59:603.
37. Duivenvoorden T, Brouwer RW, van Raaij TM, et al. Braces and orthoses
for treating osteoarthritis of the knee. Cochrane Database Syst Rev 2015;
:CD004020.
38. Parkes MJ, Maricar N, Lunt M, et al. Lateral wedge insoles as a
conservative treatment for pain in patients with medial knee osteoarthritis: a meta-
analysis. JAMA 2013; 310:722.
39. Bennell KL, Bowles KA, Payne C, et al. Lateral wedge insoles for medial
knee osteoarthritis: 12 month randomised controlled trial. BMJ 2011; 342:d2912.
40. Felson DT, Parkes M, Carter S, et al. The Efficacy of a Lateral Wedge
Insole for Painful Medial Knee Osteoarthritis After Prescreening: A Randomized
Clinical Trial. Arthritis Rheumatol 2019; 71:908.
41. Eriksen P, Bartels EM, Altman RD, et al. Risk of bias and brand explain the
observed inconsistency in trials on glucosamine for symptomatic relief of
osteoarthritis: a meta-analysis of placebo-controlled trials. Arthritis Care Res
(Hoboken) 2014; 66:1844.
42. Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: chondroitin for
osteoarthritis of the knee or hip. Ann Intern Med 2007; 146:580.
43. Singh JA, Noorbaloochi S, MacDonald R, Maxwell LJ. Chondroitin for
osteoarthritis. Cochrane Database Syst Rev 2015; 1:CD005614.
44. Wu D, Huang Y, Gu Y, Fan W. Efficacies of different preparations of
glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised,
double-blind, placebo-controlled trials. Int J Clin Pract 2013; 67:585.
45. Reginster JY, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade
Chondroitin sulfate is as effective as celecoxib and superior to placebo in
symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus
Placebo Trial (CONCEPT). Ann Rheum Dis 2017; 76:1537.
46. Lee YH, Woo JH, Choi SJ, et al. Effect of glucosamine or chondroitin sulfate
on the osteoarthritis progression: a meta-analysis. Rheumatol Int 2010; 30:357.
47. Hochberg MC. Structure-modifying effects of chondroitin sulfate in knee
osteoarthritis: an updated meta-analysis of randomized placebo-controlled trials of
2-year duration. Osteoarthritis Cartilage 2010; 18 Suppl 1:S28.
48. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and
the two in combination for painful knee osteoarthritis. N Engl J Med 2006; 354:795.
49. Roman-Blas JA, Castañeda S, Sánchez-Pernaute O, et al. Combined
Treatment With Chondroitin Sulfate and Glucosamine Sulfate Shows No
Superiority Over Placebo for Reduction of Joint Pain and Functional Impairment in
Patients With Knee Osteoarthritis: A Six-Month Multicenter, Randomized, Double-
Blind, Placebo-Controlled Clinical Trial. Arthritis Rheumatol 2017; 69:77.
50. Runhaar J, Rozendaal RM, van Middelkoop M, et al. Subgroup analyses of
the effectiveness of oral glucosamine for knee and hip osteoarthritis: a systematic
 review and individual patient data meta-analysis from the OA trial bank. Ann
Rheum Dis 2017; 76:1862.
51. Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of
the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg 2013;
21:577.
52. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-
surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis
Cartilage 2019.
53. Liu X, Machado GC, Eyles JP, et al. Dietary supplements for treating
osteoarthritis: a systematic review and meta-analysis. Br J Sports Med 2018;
52:167.
54. Jin X, Jones G, Cicuttini F, et al. Effect of Vitamin D Supplementation on
Tibial Cartilage Volume and Knee Pain Among Patients With Symptomatic Knee
Osteoarthritis: A Randomized Clinical Trial. JAMA 2016; 315:1005.
55. Hill CL, March LM, Aitken D, et al. Fish oil in knee osteoarthritis: a
randomised clinical trial of low dose versus high dose. Ann Rheum Dis 2016;
75:23.
56. Lopez HL. Nutritional interventions to prevent and treat osteoarthritis. Part II:
focus on micronutrients and supportive nutraceuticals. PM R 2012; 4:S155.
57. Levy RM, Khokhlov A, Kopenkin S, et al. Efficacy and safety of flavocoxid, a
novel therapeutic, compared with naproxen: a randomized multicenter controlled
trial in subjects with osteoarthritis of the knee. Adv Ther 2010; 27:731.
58. Levy RM, Saikovsky R, Shmidt E, et al. Flavocoxid is as effective as
naproxen for managing the signs and symptoms of osteoarthritis of the knee in
humans: a short-term randomized, double-blind pilot study. Nutr Res 2009; 29:298.
59. da Costa BR, Nüesch E, Kasteler R, et al. Oral or transdermal opioids for
osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2014; :CD003115.
60. Smith SR, Deshpande BR, Collins JE, et al. Comparative pain reduction of
oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis:
systematic analytic review. Osteoarthritis Cartilage 2016; 24:962.
61. Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid
Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or
Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA 2018;
319:872.
62. Zeng C, Dubreuil M, LaRochelle MR, et al. Association of Tramadol With All-
Cause Mortality Among Patients With Osteoarthritis. JAMA 2019; 321:969.
63. Jevsevar D, Donnelly P, Brown GA, Cummins DS. Viscosupplementation for
Osteoarthritis of the Knee: A Systematic Review of the Evidence. J Bone Joint
Surg Am 2015; 97:2047.
64. Rutjes AW, Jüni P, da Costa BR, et al. Viscosupplementation for
osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med
2012; 157:180.
65. Hunter DJ. Viscosupplementation for osteoarthritis of the knee. N Engl J
Med 2015; 372:1040.
66. Meheux CJ, McCulloch PC, Lintner DM, et al. Efficacy of Intra-articular
Platelet-Rich Plasma Injections in Knee Osteoarthritis: A Systematic Review.
Arthroscopy 2016; 32:495.
67. da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of non-steroidal
anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a
network meta-analysis. Lancet 2016; 387:2093.
68. Barrios JA, Butler RJ, Crenshaw JR, et al. Mechanical effectiveness of
lateral foot wedging in medial knee osteoarthritis after 1 year of wear. J Orthop Res
2013; 31:659.
69. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of
paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis
of randomised placebo controlled trials. BMJ 2015; 350:h1225.
70. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as
we thought? A systematic literature review of observational studies. Ann Rheum
Dis 2016; 75:552.
71. Rutjes AW, Nüesch E, Sterchi R, et al. Transcutaneous electrostimulation
for osteoarthritis of the knee. Cochrane Database Syst Rev 2009; :CD002823.
72. Atamaz FC, Durmaz B, Baydar M, et al. Comparison of the efficacy of
transcutaneous electrical nerve stimulation, interferential currents, and shortwave
diathermy in knee osteoarthritis: a double-blind, randomized, controlled,
multicenter study. Arch Phys Med Rehabil 2012; 93:748.
73. Vance CG, Rakel BA, Blodgett NP, et al. Effects of transcutaneous electrical
nerve stimulation on pain, pain sensitivity, and function in people with knee
osteoarthritis: a randomized controlled trial. Phys Ther 2012; 92:898.
74. Denegar CR, Dougherty DR, Friedman JE, et al. Preferences for heat, cold,
or contrast in patients with knee osteoarthritis affect treatment response. Clin Interv
Aging 2010; 5:199.
75. Mazzuca SA, Page MC, Meldrum RD, et al. Pilot study of the effects of a
heat-retaining knee sleeve on joint pain, stiffness, and function in patients with
knee osteoarthritis. Arthritis Rheum 2004; 51:716.
76. Yildirim N, Filiz Ulusoy M, Bodur H. The effect of heat application on pain,
stiffness, physical function and quality of life in patients with knee osteoarthritis. J
Clin Nurs 2010; 19:1113.