Vous êtes sur la page 1sur 21

INTRODUCTION Osteoarthritis (OA) is a common cause of joint pain and disability.

The treatment of OA is directed towards reduction of symptoms and the prevention of


disability. There are no pharmacologic therapies that have been proven to prevent the
progression of joint damage due to OA. (See "Clinical manifestations of osteoarthritis".)
The management of OA includes a combination of nonpharmacologic approaches, such
as exercise and patient education; pharmacologic therapies, including oral, topical, and
intraarticular medications; and surgical interventions, including total joint arthroplasty. The
goal of finding disease-modifying agents for OA is being addressed through ongoing
research.
The initial pharmacologic therapy of OA will be reviewed here. The risk factors,
pathogenesis, clinical manifestations, and diagnosis of OA; the treatment of patients who
are resistant to initial pharmacologic therapy; and the nonpharmacologic, surgical, and
investigational pharmacologic therapies of OA are presented separately. (See "Risk
factors for and possible causes of osteoarthritis" and "Pathogenesis of
osteoarthritis" and "Clinical manifestations of osteoarthritis" and "Diagnosis and
classification of osteoarthritis" and "Treatment of osteoarthritis resistant to initial
pharmacologic therapy" and "Nonpharmacologic therapy of osteoarthritis" and "Surgical
therapy of osteoarthritis" and "Investigational approaches to the pharmacologic therapy of
osteoarthritis".)
OVERVIEW OF OA TREATMENT The goals of therapy for patients with osteoarthritis
(OA) are to control pain and swelling, minimize disability, improve the quality of life, and
educate the patient about their role in disease management. Pain and other symptoms of
OA can be confused with soft tissue processes such as bursitis at periarticular sites; in
addition, pain in a particular area may be referred from OA at other site or may be due to a
nonarticular process. Thus, an important first step in management is to be confident that
pain in a particular joint is most likely due to OA at that site. (See "Clinical manifestations
of osteoarthritis" and "Diagnosis and classification of osteoarthritis".)
Management should be individualized based upon the patient's expectations, their level of
function and activity, the joints involved, the severity of disease, occupational and
avocational needs and interests, and the nature of any coexisting medical problems.
Subjective complaints and objective findings may guide the clinician in designing
appropriate therapeutic goals together with the patient. The degree to which the treatment
targets have been achieved should be periodically reassessed; such assessment can
facilitate collaborative decision-making with the patient regarding whether and what
adjustments may be needed in the treatment program.
Nonpharmacologic treatment Nonpharmacologic interventions other than surgical
approaches, such as exercise programs, counseling regarding weight loss, and patient
education, are generally begun before medications. Effective nonpharmacologic
management may diminish the need, and hence the risks, of medications used for
symptom control. These strategies are discussed in detail separately.
(See "Nonpharmacologic therapy of osteoarthritis".)
Acupuncture and complementary and alternative medical therapies are discussed
elsewhere. (See "Acupuncture", section on 'Knee osteoarthritis' and "Complementary and
alternative remedies for rheumatic disorders".)
Initial pharmacotherapy Pharmacologic agents are used for the treatment of OA in
patients with symptomatic disease that has not responded adequately to initial
nonpharmacologic measures. Treatment is not required during periods when symptoms
are absent or too minimal to be bothersome to the patient, as available interventions have
not been shown to be disease-modifying. The major medications used in the
pharmacologic management of OA include analgesics, such as acetaminophen (APAP);
nonsteroidal antiinflammatory drugs (NSAIDs), which are also analgesic; and intraarticular
glucocorticoids. Other agents may be of benefit as alternatives or as adjuvant therapy if
these initial interventions are of insufficient benefit or are contraindicated. (See "Treatment
of osteoarthritis resistant to initial pharmacologic therapy".)
The choice of medication depends upon the severity of disease, presence or absence of
local inflammatory changes, and the efficacy of previously employed therapies. (See 'Initial
pharmacologic treatment' below.)
Our management strategy is generally consistent with the guidelines developed by
professional organizations, including the American College of Rheumatology [1,2], the
European League Against Rheumatism [3-5], and the Osteoarthritis Research Society
International [6,7]. A more detailed discussion of the specific therapeutic agents and the
evidence supporting their use is presented in the sections below.
The following briefly describes our approach to initial pharmacotherapy:
Initial treatment of noninflammatory OA with acetaminophen In patients with
OA lacking signs or symptoms of inflammation, we initiate pharmacologic therapy
with acetaminophen (paracetamol, APAP) on an as-needed basis. If this is
inadequate, we use APAP on a regular basis up to three to four times daily.
(See 'Initial pharmacologic treatment' below and 'Noninflammatory OA' below.)
NSAIDs if APAP is inadequate or inflammatory OA is present We use
NSAIDs in patients with inadequate symptom relief with APAP and those with
evidence of inflammatory OA, such as an inflamed interphalangeal joint or a swollen
knee with a joint effusion. NSAIDs may be used in addition to or in place of APAP
depending upon the degree of symptom relief. NSAIDs should be initiated in low
doses on an as-needed basis to minimize risk of adverse events, but may be
increased to regular daily antiinflammatory doses if required for symptom relief and
permitted by the patients comorbid medical conditions. We use the lowest dose
required to control the patients symptoms. (See 'Inadequate response to APAP or
inflammatory OA' below.)
Topical NSAIDs or capsaicin as alternative to oral NSAIDs or APAP We use
topical medications, such as a topical NSAID or capsaicin, as an alternative
treatment in patients who cannot tolerate or have contraindications to oral agents, or
who may be at increased risk of adverse effects with the use of oral NSAIDs, such as
older adults (eg, patients 75 and older). We also use topic agents as an adjunct to
other therapies. Topical agents may also be preferred by patients and clinicians who
wish to defer the need for or avoid an injection.
(See 'Oral agents inadequate or contraindicated' below and 'Intraarticular
glucocorticoids' below.)
Diagnostic reassessment for recurring joint swelling or inflammation
Patients with OA who experience recurring episodes of joint swelling or inflammation
despite appropriate treatment should be evaluated for evidence of crystal disease or
other inflammatory arthropathies with arthrocentesis and synovial fluid examination.
(See "Diagnosis and classification of osteoarthritis", section on 'Differential
diagnosis' and "Clinical manifestations and diagnosis of calcium pyrophosphate
crystal deposition disease".)
We do not use glucosamine or chondroitin compounds because of insufficient evidence of
clinically meaningful benefit. However, in patients who wish to take these agents, we
advise that use be limited to a six-month trial to determine if there is adequate symptom
relief to justify continued therapy. (See 'Glucosamine and chondroitin' below.)
Resistant to initial pharmacotherapy In patients who do not receive adequate
symptomatic benefit from the combination of nonpharmacologic interventions (other than
surgery) and initial pharmacologic therapies, or who have contraindications to such
therapy, several types of therapies may be of benefit or are frequently tried by patients.
These therapies, which are of varying effectiveness, are discussed in detail separately.
(See "Treatment of osteoarthritis resistant to initial pharmacologic therapy".)
Briefly, these therapies include:
Opioid analgesics
Intraarticular hyaluronans
Glucosamine and chondroitin compounds
Other agents, including colchicine
Indications for consultation Most patients with OA can be effectively managed by a
primary care physician; however, some patients with severe symptoms may require
referral to a subspecialist. Consultation with an expert in the diagnosis of joint diseases
and medical therapy of OA, such as a rheumatologist, may be helpful especially if the
diagnosis is uncertain and for assistance with needle aspiration or injection. A consultation
may also be useful for patients requiring narcotic analgesics, in whom the diagnosis
should be confirmed and for whom alternative treatments should be sought.
Patients with severe OA unrelieved by oral, topical, and intraarticular medications may
require surgery and should be referred for orthopedic consultation. (See "Surgical therapy
of osteoarthritis".)
INITIAL PHARMACOLOGIC TREATMENT The initial treatment in patients with
osteoarthritis (OA) who do not experience sufficient relief of pain with nonpharmacologic
interventions depends, in our experience, upon whether the patient has noninflammatory
or inflammatory OA and the severity of pain. (See 'Noninflammatory OA' below
and 'Inadequate response to APAP or inflammatory OA' below.)
Patients with noninflammatory OA generally have pain and disability-related complaints as
their only symptoms. Physical findings in affected joints include tenderness, bony
prominence, and crepitus. Patients with inflammatory OA complain of articular swelling,
morning stiffness lasting for more than 30 minutes, and night pain. Signs of inflammation
may include joint effusion on examination or radiography, warmth on palpation of the joint,
and synovitis on arthroscopic examination. (See "Clinical manifestations of osteoarthritis",
section on 'Noninflammatory versus inflammatory OA'.)
Noninflammatory OA In most patients with noninflammatory OA, we recommend
initiating drug treatment with a nonopioid analgesic such as acetaminophen (paracetamol,
APAP), especially in patients with mild to moderate pain that is intermittent and usually
related to activity. We prefer APAP in this setting because of the greater safety of this
approach, compared with the use of nonsteroidal antiinflammatory drugs (NSAIDs), most
of which are associated with increased cardiovascular, gastrointestinal, and other risks.
The risks associated with the use of NSAIDs are discussed in detail separately.
(See 'Initial pharmacotherapy' above and 'Adverse effects of oral NSAIDs' below
and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of selective COX-
2 inhibitors", section on 'Toxicities and possible toxicities' and "Nonselective NSAIDs:
Adverse cardiovascular effects".)
We start treatment with APAP on an as-needed basis, but in patients with persistent
symptoms advise regular use at doses of up to 3 g/day (eg, 1000 mg every six hours up to
threetimes/day or 650 mg every six hours up to four times/day). The degree of benefit from
a given dose or regimen can be assessed over the four to six hours after taking the
medication and generally does not require more than a day or two of therapy to gauge the
effect of treatment as activity varies.
The use of APAP in this setting is consistent with evidence supporting its modest benefit
compared with placebo and its relative safety [8], and is further supported by the
recommendations of professional guidelines [2,3]. The dose limit of 3 g/day is consistent
with labeling developed by the brand name manufacturer [9].
Treatment with acetaminophen appears to be slightly more effective than placebo in
relieving overall pain from OA, but less effective than NSAIDs. In a 2006 meta-analysis of
five randomized trials involving a total of 1835 patients, which compared acetaminophen
4000 mg daily with placebo, acetaminophen produced a statistically significant reduction in
pain of uncertain clinical significance, with absolute improvement of only 4 points on a 0 to
100 scale [8].
Safety and monitoring of acetaminophen Adverse effects of therapeutic doses of
APAP are generally mild; in a 2006 meta-analysis the safety profile of APAP was similar to
placebo [8]. Hepatotoxicity can occur but, at these doses, is primarily seen only in patients
who concurrently consume excessive amounts of alcohol. However, all patients should be
cautioned not to exceed the recommended dose and warned regarding the use of other
prescription and nonprescription products that include APAP to avoid unintentional
overdosing [10]. (See "Acetaminophen (paracetamol) poisoning in adults:
Pathophysiology, presentation, and diagnosis".)
One study has suggested that use of acetaminophen in doses of 2 g/day or greater might
be associated with an increased risk for gastrointestinal (GI) complications, including
bleeding and perforation, but these complications were not increased at lower
acetaminophen doses; additionally, the risk of GI complications was greater with the
combination of acetaminophen and an NSAID than with either alone [11]. Use of APAP
may increase the anticoagulant effect of vitamin K antagonists, such as warfarin.
(See "Unusual causes of peptic ulcer disease", section on 'Acetaminophen'.)
There is suggestive but not definitive evidence that chronic, especially
daily acetaminophen use has dose-dependent, long-term nephrotoxicity. The supportive
data are presented separately. (See "Analgesic-related chronic kidney disease", section
on 'Acetaminophen'.)
We ask patients who take APAP on a chronic daily basis, particularly those with any liver
disease or at increased risk of hepatotoxicity (eg, heavy drinkers of alcohol) to have
periodic laboratory testing to monitor for hepatotoxicity. Patients taking only occasional
APAP and who are without risk or evidence of liver disease generally do not require such
testing.
Inadequate response to APAP or inflammatory OA In patients with an inadequate
response to APAP, with inflammatory OA, or with severe pain (eg, consistently with use or
at rest) we recommend the use of an orally administered nonselective NSAID or a COX-2
selective NSAID (commonly termed a coxib), because of the greater efficacy of NSAIDs
compared with APAP for relief of pain from OA and their antiinflammatory properties,
which APAP lacks. (See "Clinical manifestations of osteoarthritis", section on
'Noninflammatory versus inflammatory OA' and 'Noninflammatory OA' above.)
Because of the risks associated with orally administered NSAIDs, particularly in the older
population with multiple comorbidities in whom OA is prevalent, we use the lowest dose
necessary and for the least time required for adequate symptom control when these
agents are employed.
Choice and use of oral NSAIDs The choice of a NSAID is based upon a variety of
factors including adverse effect profile, cost to the patient, type of OA, and patient
preference regarding frequency of administration. There is no convincing evidence that
any of the available NSAIDs is more effective than any other for OA of the knee or hip
[12,13]. The pharmacology and mechanism of action of NSAIDs are reviewed elsewhere.
(See "NSAIDs: Mechanism of action".)
We generally use the following approach when selecting from the available nonselective
NSAIDs and coxibs (table 1):
A short- to medium-acting NSAID (preferably naproxen, 220 to 375 mg once or
twice daily) is generally used initially on an episodic basis in patients with
noninflammatory OA, since the presence and intensity of symptoms usually vary with
time [14]. Because of the importance of continuous dosing for control of
inflammation, continuous NSAID therapy (eg, naproxen 375 to 500 mg twice daily)
should be used in patients with inflammatory OA. It usually takes about two to four
weeks to evaluate the efficacy of a given NSAID because of the delay in achieving
an antiinflammatory effect, which may require one to two weeks of therapy, and due
to the variability of symptoms from day to day or week to week [15]. In patients who
are not at increased cardiovascular risk another short- or medium-acting NSAID
(eg, ibuprofen 200 to 400 mg up to two or three times daily) may be used as an
alternative, particularly if naproxen is contraindicated, poorly tolerated, or ineffective.
The dose of the NSAID should be gradually increased if there is inadequate control
of symptoms with the initial dose, toward the maximum for that drug, and the drug
should be used on a continuous basis (table 1). The patient should be monitored
more closely as the dose is increased and should be educated to monitor for
symptoms indicative of side effects, including gastrointestinal symptoms and rash.
(See "Nonselective NSAIDs: Overview of adverse effects" and "Overview of selective
COX-2 inhibitors", section on 'Toxicities and possible toxicities'.)
If one NSAID is not effective after two to four weeks on a maximal dosage, then
another should be tried, as individuals can respond variably to different NSAIDs
(see "NSAIDs: Therapeutic use and variability of response in adults"). In patients who
benefit from but do not have adequate relief with any of three different NSAIDs, we
try additional therapies depending upon the involved joints and patient preference,
such as intraarticular injections, topical agents, or other interventions. NSAIDs should
be discontinued if they do not provide any significant relief beyond that obtained by
use of acetaminophen. (See 'Topical medications' below and "Treatment of
osteoarthritis resistant to initial pharmacologic therapy".)
Patients should be informed of the potential relative and absolute cardiovascular,
gastrointestinal, and other major risks of both nonselective NSAIDs and coxibs
(see 'Adverse effects of oral NSAIDs' below). Naproxen has a more favorable
cardiovascular risk profile than ibuprofen or diclofenac, especially when high doses
of medication are required and in patients at increased risk of cardiovascular
disease. The relative cardiovascular risks of different NSAIDs are discussed in detail
separately. (See "Nonselective NSAIDs: Adverse cardiovascular effects" and "COX-2
selective inhibitors: Adverse cardiovascular effects".)
Efficacy of oral NSAIDs The greater efficacy of nonselective NSAIDs and coxibs
compared with placebo and with APAP, in the treatment of OA (particularly with respect to
pain relief), has been shown in randomized trials of individual drugs and in meta-analyses
of randomized trials [8,16-18]. Additionally, the demonstration of superinduction of
prostaglandin E2 in human OA cartilage suggests that PGE2 may contribute to the local
inflammation and provides a further biologic rationale for the use of NSAIDs rather than
APAP, which is not antiinflammatory, in inflammatory OA [19,20]. The coxibs
(eg, celecoxib and etoricoxib) appear to be as effective as the traditional nonselective
NSAIDs.
As an example, the greater efficacy of nonselective NSAIDs and coxibs in OA of the hip or
knee, compared with APAP, was shown in a 2006 meta-analysis of data from 15
randomized controlled trials [8]. The following findings were noted:
NSAIDs (ibuprofen 2400 mg
daily, diclofenac, diclofenac/misoprostol, celecoxib, naproxen) showed a greater
reduction in overall pain (measured by multiple methods) compared with APAP in
data analyzed from eight studies involving 2358 patients (standardized mean
difference, SMD, -0.25, 95% CI -0.33 to -0.17). The degree of benefit compared
withacetaminophen in different studies and using different measures was somewhat
varied and was generally small to moderate.
There was no significant difference between acetaminophen and NSAIDs, however,
in the small beneficial effects observed on rest pain and pain with motion.
Adverse effects of oral NSAIDs The use of both nonselective NSAIDs and coxibs is
often limited by toxicity or by risks of these agents. Among the side effects and risks are
[15,21]:
Rash and hypersensitivity reactions
Abdominal pain and gastrointestinal bleeding
Impairment of renal, hepatic, and bone marrow function, and platelet aggregation
Increased risk of cardiovascular disease, including myocardial infarction and stroke,
increased blood pressure, worsening of heart failure, and arrhythmia
Interference with cardiopreventive antiplatelet effects of low-dose aspirin
Central nervous system dysfunction in the elderly
These adverse reactions are discussed in detail elsewhere. (See "Nonselective NSAIDs:
Overview of adverse effects" and "Overview of selective COX-2 inhibitors", section on
'Toxicities and possible toxicities' and "Nonselective NSAIDs: Adverse cardiovascular
effects" and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension".)
Gastrointestinal symptoms were more frequent with use of nonselective NSAIDs
compared with APAP (relative risk, RR, 1.47, 95% CI 1.08-2.00) in a meta-analysis of data
from multiple randomized trials [8]. The risk of adverse gastrointestinal events with coxibs
was not significantly different from the risk with acetaminophen.
There is immense variability in the responses of individual patients to the different agents
in terms of both efficacy and toxicity, although the basis for some of the variability is not
well understood [15]. In some settings a particular nonselective NSAID or coxib may be
preferred or should be avoided (table 1). (See "Nonselective NSAIDs: Overview of adverse
effects"and "Overview of selective COX-2 inhibitors" and "NSAIDs: Therapeutic use and
variability of response in adults".)
Use of NSAIDs with other drugs or comorbidities We avoid the use of either
nonselective NSAIDs or coxibs, or use them with particular caution, in certain groups of
patients:
In patients with a history of peptic ulcer disease or at elevated risk for
gastroduodenal disease, which includes older adults (greater than approximately 60
years of age), we combine a nonselective NSAID with a gastroprotective agent (eg, a
proton pump inhibitor or misoprostol) or use a coxib (eg, celecoxib). We avoid the
use of both nonselective NSAIDs and coxibs in patients with active peptic ulcer
disease. The relative gastrointestinal toxicity of different NSAIDs and prevention of
NSAID-induced gastroduodenal damage are discussed separately. (See "NSAIDs
(including aspirin): Primary prevention of gastroduodenal toxicity", section on
'Nonselective NSAIDs' and "NSAIDs (including aspirin): Secondary prevention of
gastroduodenal toxicity".)
In patients taking aspirin for cardiovascular prevention we avoid the use of coxibs.
Patients receiving both agents in this setting would still require an additional agent,
such as a proton pump inhibitor or misoprostol, for effective protection from
gastrointestinal injury [22]. Additionally, the beneficial effect of aspirin may be
attenuated by prior or ongoing administration of some nonselective NSAIDs, such
as ibuprofen or naproxen. Thus, regular NSAID use should be avoided, if possible, in
patients taking low-dose aspirin for cardiovascular protection. In patients on ASA
who require NSAIDs on an occasional short-term basis, aspirin should be taken at
least two hours before the NSAID. (See"Nonselective NSAIDs: Adverse
cardiovascular effects", section on 'Patients taking aspirin for
prevention' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal
toxicity".)
In patients on warfarin or other chronic anticoagulation therapies, we avoid the use
of nonselective NSAIDs because of their capacity to inhibit platelet function. NSAIDs
which do not affect platelet function, such as the coxibs, can be used cautiously in
this setting in patients at low cardiovascular risk, as can nonacetylated salicylates,
but patients should be fully informed of the risks of these and other alternatives.
(See "Nonselective NSAIDs: Overview of adverse effects", section on 'Antiplatelet
effects' and "Overview of selective COX-2 inhibitors", section on 'Lack of effect upon
platelets'.)
In patients with or at increased risk of cardiovascular disease, including myocardial
infarction, stroke, heart failure, unstable angina, or hypertension, the use of both
nonselective NSAIDs and coxibs may be restricted. Use in these settings is
described in detail elsewhere. (See "Nonselective NSAIDs: Adverse cardiovascular
effects" and "COX-2 selective inhibitors: Adverse cardiovascular
effects" and "NSAIDs and acetaminophen: Effects on blood pressure and
hypertension".)
In patients at risk of renal insufficiency, such as those with intrinsic renal disease,
heart failure, or cirrhosis, and those receiving diuretic therapy, there is increased risk
for developing reversible renal failure while using either nonselective NSAIDs or
coxibs. In these settings, the synthesis of vasodilator renal prostaglandins helps to
maintain renal perfusion; interfering with this protective response with an NSAID can
lead to renal ischemia and an elevation in the plasma creatinine concentration.
NSAIDs should be avoided in patients with stage 4 or 5 chronic KIDNEY DISEASE
(estimated glomerular filtration rate of <30 mL/min per 1.73 m
2
or treatment by
dialysis). (See "NSAIDs: Acute kidney injury (acute renal failure)".)
In patients with aspirin sensitivity syndrome, we avoid the use of nonselective
NSAIDs. Celecoxib may be less likely to provoke symptoms in aspirin sensitive
reactive airways disease. This issue is discussed in more detail elsewhere.
(See "Aspirin-exacerbated respiratory disease".)
We generally avoid the use of multiple NSAIDs in combination (including concurrent
therapy with both oral and topical NSAIDs) because of the potentially greater risk of
adverse events with higher total NSAID doses and with multiple medications and because
of the lack of evidence that the use of two or more NSAIDs concurrently is associated with
improved efficacy that justifies the increased risk of high total NSAID doses [14]. Similarly,
we generally avoid the combination of acetaminophen at doses of 2 g/day or greater
together with an NSAID because of the possibility that it might have a higher risk of
gastrointestinal complications and the lack of significantly greater efficacy than with an
NSAID alone. (See 'Safety and monitoring of acetaminophen' above.)
Drug interactions associated with the use of NSAIDs are described in more detail
elsewhere. (See "NSAIDs: Mechanism of action", section on 'Drug interactions'.)
NSAID laboratory monitoring In patients being treated chronically with daily NSAIDs,
particularly with use of antiinflammatory continuous dosing, we obtain a complete blood
count, blood urea nitrogen and creatinine, and aspartate aminotransferase at least once
yearly. In patients at increased risk of adverse effects, such as anemia, renal compromise,
and drug-related liver injury, more frequent testing may be required.
ORAL AGENTS INADEQUATE OR CONTRAINDICATED Options for patients who are
unresponsive to oral therapies, have relative or absolute contraindications to the use
ofacetaminophen (APAP) and nonsteroidal antiinflammatory drugs (NSAIDs), or who
report a preference for another type of treatment include topical agents (table 2), such as
topical NSAIDs or capsaicin, and intraarticular glucocorticoids. In patients with only a few
involved joints, the use of intraarticular glucocorticoids may be an effective alternative,
particularly when only one or two large joints are involved and symptoms are severe.
(See 'Topical medications' below and 'Intraarticular glucocorticoids' below.)
Topical medications We use topical medications (table 2), such as a topical NSAID
or capsaicin, as an alternative treatment in patients who cannot tolerate or have
contraindications to oral agents, or who may be at increased risk of adverse effects with
the use of oral NSAIDs, such as older adults (eg, patients 75 and older). We also use
topical agents as an adjunct to other therapies (see 'Topical NSAIDs' below
and 'Capsaicin' below). Additionally, topical agents may be preferred by patients and
clinicians who wish to defer the need for or avoid an injection. The available topical agents
have significant limitations; topical NSAIDs may sometimes provide only modest or
sometimes short-lived benefit, and capsaicin can be difficult to apply and cause local
irritation. There are no trials that directly compare topical therapies, and there has been
insufficient study to document the effectiveness or safety of topical medicinal plant
products [23].
Topical NSAIDs We suggest topical NSAIDs as an alternative to orally administered
NSAIDs in patients with mild to moderate pain who are unable to tolerate or should avoid
oral NSAIDs (eg, those 75 and older) (see 'Use of NSAIDs with other drugs or
comorbidities' above). They may also be used as an adjunct to other non-NSAID therapies
or in place of other treatments based upon patient preference. We prefer a trial of topical
NSAIDs in patients who poorly tolerate oral NSAIDs rather than using opioids, capsaicin,
or continued trials of multiple different oral NSAIDs because of the greater safety and
better tolerance of the topical agent, and thus also prefer topical NSAIDs over opioids in
patients unable to take oral NSAIDs. Formulations of several nonsteroidal antiinflammatory
drugs (NSAIDs) are available for topical use in a number of countries. Two preparations of
topical diclofenac are available for use in the United States; a 1 percent gel for treatment
of symptoms of osteoarthritis (OA) and a patch for treatment of musculoskeletal pain due
to minor trauma (strains, sprains, and contusions) [24,25].
The 1 percent diclofenac gel is applied four times daily to affected joints of the upper
(2 g/application) or lower extremities (4 g/application). The maximum total body dose of
the 1 percent gel should not exceed 32 g/day, which equals the total dose used to treat
both knees without application to other joints.
The benefits of topical NSAIDs may be sustained for at least two to three months with
ongoing therapy [26], although early analyses of trial data involving fewer trials and
patients had suggested that the benefits might be relatively short in duration (one or two
weeks) [27]. A 2012 systematic review and meta-analysis of 23 randomized trials involving
7688 patients compared the effects of topical NSAIDs with placebo or orally administered
NSAIDs for the treatment of chronic musculoskeletal pain, primarily OA [26]. The best data
were for treatment of osteoarthritis of the hand or knee with topical diclofenac. The
following findings were reported in this review:
In trials of two to three weeks duration, including four trials involving 569 patients,
significantly more patients using topical diclofenac compared with those receiving
placebo achieved clinical success, defined as at least a 50 percent reduction in
patient-reported pain or an equivalent measure (40 versus 20 percent, risk ratio, RR,
1.98, 95% CI 1.52-2.58). The number needed to treat (NNT) for successful treatment
was five.
In trials of 8 to 12 weeks duration, including six trials involving 2440 patients,
significantly more patients using topical diclofenac achieved clinical success (60
versus 50 percent, RR 1.19, 95% CI 1.11-1.28). The NNT was 10.
In the five trials involving 1735 patients that compared topical with oral
administration, using several different NSAIDs and topical formulations, the
proportion of patients who achieved clinical success did not differ between the topical
and oral NSAID groups (55 and 54 percent).
In five trials involving 1651 patients, local adverse effects, which were mostly mild
skin reactions, were more common in patients using topical compared with oral
NSAIDs (22 versus 6 percent, relative risk, RR, 3.7, 95% CI 2.8-5.1). However,
gastrointestinal (GI) adverse events with topical agents did not differ from placebo,
and they were less frequent compared with oral NSAIDs (17 versus 26 percent, RR
0.66, 95% CI 0.56-0.77). Topical NSAIDs were not associated with any increase in
serious adverse events.
Local skin reactions with the topical NSAIDs include rash, itch, or burning [27]. Such
reactions may be more common with topical solutions, typically using
a dimethylsulfoxide(DMSO) vehicle, although topical solutions might have greater efficacy
than topical gels [26]. In one trial, 27 percent of patients using
topical diclofenac/DMSO had dry skin and 12 percent had rash, while only 1 and 2 percent
of those receiving oral diclofenac and a low-concentration DMSO-containing vehicle had
these skin problems [28]. The use of DMSO for rheumatic disease is discussed elsewhere.
(See "Complementary and alternative remedies for rheumatic disorders".)
A diclofenac patch (diclofenac epolamine topical patch) is available in the US for
musculoskeletal pain due to minor trauma [25]; it may also be effective for pain relief in
patients with OA of the knee [29].
Capsaicin In patients with inadequate benefit from oral and topical NSAIDs we suggest
the topical application of capsaicin as an adjunct to these measures or as an alternative
therapy. We also use capsaicin in patients who are unable to tolerate oral and topical
NSAIDs or have contraindications to the use of NSAIDs. A thin film is applied three to four
times daily until benefit is achieved or for a one-month trial. If ineffective after one month
we advise discontinuation of therapy. In our experience, reduced frequency of dosing (eg,
twice daily) may be effective once benefit is achieved with more frequent dosing. Some
patients report benefit with only once- or twice-daily dosing initially, but this has not been
documented in randomized trials.
Capsaicin, the topically applied active principle of hot chili pepper, exerts its therapeutic
effect by enhancing the release of substance P from unmyelinated C nerve fibers [30].
Substance P is then rapidly depleted and signal transmission of pain from C fibers to
higher neurologic centers is reduced in the area of administration [30].
Capsaicin has shown mild to moderate efficacy in randomized trials in hand and knee OA
in comparison with placebo, lacks systemic effects, and has shown efficacy with continued
use in trials lasting up to four weeks [31-33]. As an example, benefit was demonstrated in
a trial involving 70 patients with OA and 31 with rheumatoid arthritis, in which patients
were randomly assigned to treatment with topical capsaicin (0.025 percent) or its vehicle
(placebo) applied four times per day to painful knees [31]. After four weeks, patients with
rheumatoid arthritis and OA demonstrated mean pain reduction of 57 and 33 percent,
respectively; these changes were statistically significant compared with those given
placebo. The most common side effects were local irritation (burning, stinging, and
erythema), which occurred in approximately 40 percent of patients. There is a lack of trial
data comparing capsaicin with other active agents, and trial quality was limited by the
difficulty of obtaining effective double-blind conditions due to the locally irritating effects of
the medication.
Capsaicin appears to be useful and relatively safe in patients with OA. However, it is
relatively expensive when applied four times per day. Additionally, some patients find the
local irritation intolerable or that capsaicin is difficult to apply without accidentally irritating
other areas. Patients should be cautioned regarding the dangers of contact by the drug
residue from the region being treated with mucous membranes, eyes, and genital areas.
The frequency of dosing may be decreased once pain relief has been accomplished with
four times a day regimens in some patients in our experience. Long-term data regarding
efficacy are not available, but in patients who benefit from this agent continued use is safe
in our experience. Twice-daily application of a higher strength preparation (0.075 percent)
may also be effective, but may cause more local irritation [34].
Intraarticular glucocorticoids We suggest the use of intraarticular glucocorticoids in
patients with:
Symptoms of moderate to severe pain affecting one or a few joints, which is not
adequately relieved by orally administered drugs, including acetaminophen and
nonselective NSAIDs or coxibs
Monoarticular or pauciarticular inflammatory osteoarthritis in whom NSAIDs are
contraindicated
The efficacy of intraarticular glucocorticoids in this setting is supported by randomized
trials and meta-analyses demonstrating their benefit compared with placebo and other
therapies [17,35,36], and further supported by treatment guidelines from multiple
professional organizations [1,3-7,14,37]. However, the benefits are maximal during the first
two weeks following the injection and subsequently wane; neither long-term benefit nor
harm has been demonstrated [17,35,36].
We repeat injections, if clinically indicated, at intervals up to every three months. However,
the benefits of repeated injections seen for up to one year may not be demonstrable after
two years of such therapy, despite continued injections every three months [35]. Common
synthetic glucocorticoid suspensions used for intraarticular injection
include triamcinoloneacetonide, triamcinolone hexacetonide, and
microcrystalline methylprednisolone. The amount of these agents generally used depends
upon joint size (see "Intraarticular and soft tissue injections: What agent(s) to inject and
how frequently?"):
10 mg for small joints (interphalangeal, metacarpophalangeal, and
metatarsophalangeal joints)
20 mg for medium-sized joints (wrists, elbows, ankles, and acromioclavicular joints)
40 mg for larger joints (shoulders, knees, hips).
The use of aseptic technique is essential to minimize the risk of infection. (See "Joint
aspiration or injection in adults: Technique and indications".)
In patients with evidence of a joint effusion, we aspirate synovial fluid that is present prior
to injecting glucocorticoids to exclude infection or crystal disease; analysis of the synovial
fluid should include the cell count and differential, a crystal search, and Gram stain and
culture if an infection is suspected. The joint should not be injected until there is
confidence that an infection is not present [38]. Clinical findings suggestive of possible joint
infection include fever, leukocytosis, or the rapid onset of a large effusion. (See "Synovial
fluid analysis".)
Efficacy of intraarticular glucocorticoids The knee is the best-studied joint, with
multiple trials demonstrating benefit of intraarticular glucocorticoids, usually compared with
placebo [17,35]. However, more limited evidence has suggested efficacy in other joints,
including the hip [39,40]. Clinically evident inflammation does not need to be present for
intraarticular glucocorticoids to result in symptom relief [41]. The following examples
illustrate the potential benefit of these agents:
In a 2006 meta-analysis of 28 trials involving 1973 patients, intraarticular
glucocorticoids were more effective at reducing pain than intraarticular placebo
injections at one week following knee injection and were more likely to lead to
improvement in patient global assessment [35]. Significantly more patients reported
reduced pain after receiving glucocorticoids at two to three weeks (RR 1.81, 95% CI
1.09-3.00, and RR 3.11, 95% CI 1.61-6.01), but not at 4 to 24 weeks; there was no
evidence of significant functional improvement following injection. All three trials
analyzed in which treatment preference was assessed found that a significantly
higher proportion of patients reported a preference for the injections with
intraarticular glucocorticoids compared with placebo (83 versus 17, 83 versus 46,
and 51 versus 24 percent).
A randomized trial of fluoroscopically guided glucocorticoid injection for OA of the
hip, involving 52 patients, demonstrated at least 20 percent improvement in pain at
two months postinjection in statistically significantly more patients receiving
intraarticular triamcinolone hexacetonide (40 mg) plus anesthetic than patients
receiving saline plus anesthetic (68 versus 24 percent) [39]. Benefits were
maintained after three months in many of the patients (58 versus 10 percent).
The efficacy of glucocorticoid injections at sites other than the knee or hip is less well
established. A prospective case series of injections of the carpometacarpal (CMC) joint in
25 patients showed significant improvement in pain at one month, but not at 3, 6, or 12
months following injection [42]. A randomized trial involving 40 patients with CMC joint
arthritis assigned to receive a single injection of triamcinolone hexacetonide (0.25 mL) or
saline failed to show greater benefit from the glucocorticoid injection, although both groups
had decreased pain [43]. We use CMC joint glucocorticoid injections in patients who have
not responded adequately to nonpharmacologic interventions based upon our clinical
experience, which is supported by the opinion of other experts and the limited trial data
available [5].
Adverse effects of intraarticular glucocorticoids Intraarticular glucocorticoid
injections are generally well tolerated in usual doses (eg, 20 to 80 mg for the knee) [36];
septic arthritis is rare. However, glucocorticoids formulated for intraarticular injection are in
crystalline suspension; the crystals rarely lead to a transient mild flare of synovitis. The
adverse effects of glucocorticoid injection are discussed in detail elsewhere. (See "Joint
aspiration or injection in adults: Complications".)
There was no evidence of deleterious effects on the anatomic structure of the knee in a
two-year trial of injections of either glucocorticoid (triamcinolone acetonide 40 mg) or
saline placebo every three months [44]. No joint infections and no acute "flares" of joint
pain were noted in either group in this study.
GLUCOSAMINE AND CHONDROITIN The use of glucosamine and chondroitin for
osteoarthritis (OA) has been controversial, and these widely used remedies are of
uncertain benefit; results of randomized trials have varied [45-60]. We do not advise
patients to use these medications, but there appear to be few if any risks associated with
their use. Thus, in patients who wish to try these drugs we do not object to their use, but
review the evidence of limited benefit, acknowledge the controversy and advise patients to
discontinue the drugs after six months if no significant benefit is present. Preparations from
various manufacturers are available without prescription in many countries.
Glucosamine has typically been studied at a dose of 500 mg three times daily, and
chondroitin at a dose of 400 mg three times daily. Glucosamine should not be
administered to patients who are allergic to shellfish.
The balance of evidence from high-quality trials has shown little to no evidence of clinically
meaningful benefit [45-47,61,62]. Trials that suggest benefit have been criticized on
various methodologic grounds. Significant adverse effects have generally not been
observed.
The following findings are among the most informative:
The most representative evidence of the limited efficacy of these compounds is a
2010 network meta-analysis of the large randomized trials in patients with OA of the
knee or hip that compared glucosamine, chondroitin, or their combination either
head-to-head or with placebo [47]. This analysis of 10 trials involving 3803 patients
found that use of neither the individual drugs nor their combination resulted in
clinically significant improvement; such improvement was defined based upon the
prespecified minimal clinically significant difference in pain intensity of 0.9 cm on a 10
cm visual analogue scale. No evidence of time-dependent effects was observed.
Neither glucosamine sulfate nor glucosamine hydrochloride exhibited clinically
relevant benefit.

The analysis also found that trials that were commercially funded had larger effect
sizes than those that were independent of industry. Radiographic changes (minimal
width of joint space) with the drugs were also very small, and did not reach statistical
significance. The frequency of adverse effects did not differ between the individual
drugs and placebo.
The combination of glucosamine and chondroitin sulfate was not significantly more
effective than placebo for pain relief or functional improvement in patients with OA of
the knee in the Glucosamine/chondroitin Arthritis Intervention Trial (GAIT trial), in
which 1583 patients with painful OA of the knee were randomly assigned to receive
either placebo, glucosamine HCL (500 mg three time daily), chondroitin sulfate (400
mg three time daily), glucosamine plus chondroitin sulfate (500 mg plus 400 mg three
times daily), orcelecoxib 200 mg/day [45,46].

After 24 weeks of treatment there was no significant difference in the proportion of
patients who had at least a 20 percent decrease in pain (a predetermined response)
when placebo, glucosamine, chondroitin sulfate, and combination groups were
compared [45]. The proportion of patients who responded to celecoxib was
significantly greater than placebo at this time point (70 versus 60 percent,
respectively). A possible benefit of the combination of glucosamine and chondroitin
sulfate compared with placebo was suggested in an exploratory subgroup analysis of
the 24-week data for patients with moderate to severe pain (20 percent pain
reduction in 79 versus 54 percent, respectively).

However, at two years, none of the treatments resulted in a statistically significant or
clinically important difference in pain or function compared with placebo. Adverse
events were similar among treatment groups and serious adverse effects were rare.
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 6
th
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 10
th
to 12
th
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 information: Osteoarthritis (The Basics)")
Beyond the Basics topics (see "Patient information: Osteoarthritis symptoms and
diagnosis (Beyond the Basics)" and "Patient information: Osteoarthritis treatment
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
We use pharmacologic agents for the treatment of osteoarthritis (OA) in patients
with symptomatic OA that has not responded adequately to initial nonpharmacologic
measures. (See 'Overview of OA treatment' above and 'Initial pharmacologic
treatment' above.)
In patients with noninflammatory OA, we recommend initiating drug treatment
with acetaminophen (paracetamol, APAP), rather than a nonsteroidal
antiinflammatory drug (NSAID), especially in patients with only mild to moderate pain
(Grade 1A). Patients should be cautioned not to exceed the recommended dose.
(See 'Initial pharmacologic treatment' above and 'Noninflammatory OA' above.)
In patients with an inadequate response to APAP, with inflammatory OA, or with
severe pain, we recommend the use of a nonselective NSAID or COX-2 selective
NSAID (coxib), rather than acetaminophen, in the lowest dose and for the shortest
time necessary for adequate relief or symptoms (Grade 1B). (See 'Initial
pharmacologic treatment' above and'Inadequate response to APAP or inflammatory
OA' above and 'Efficacy of oral NSAIDs' above.)
In patients being treated chronically with daily NSAIDs, particularly with use of
antiinflammatory continuous dosing, we obtain a complete blood count, blood urea
nitrogen and creatinine, and aspartate aminotransferase at least once yearly. In
patients at increased risk of adverse effects, such as anemia, renal compromise, and
drug-related liver injury, more frequent testing may be required. Patients at increased
risk of liver disease who are taking acetaminophen should be monitored for
hepatotoxicity with periodic liver function testing. (See 'Safety and monitoring of
acetaminophen' above and 'NSAID laboratory monitoring' above.)
In patients with mild to moderate pain who are unable to tolerate or have
contraindications to oral NSAIDs, we suggest a topical NSAID (eg, diclofenac gel)
(table 2) rather than an opioid or capsaicin (Grade 2C). In patients with poor
tolerance of oral NSAIDs, we also use topical NSAIDs rather than continued trials of
multiple different orally administered NSAIDs. Topical NSAIDs may also be used as
an alternative to oral NSAID therapy based upon patient preference. (See 'Topical
NSAIDs' above.)
In patients with inadequate benefit from oral and topical NSAIDs, we suggest the
topical application of capsaicin as an adjunct to these measures (table 2), or as an
alternative therapy, rather than use of an opioid (Grade 2C). We also use capsaicin
in patients who are unable to tolerate oral and topical NSAIDs or have
contraindications to the use of NSAIDs. (See 'Capsaicin' above.)
In patients with moderate to severe pain affecting one or a few joints, which is not
adequately relieved by orally administered drugs (including acetaminophen and
topical and oral nonselective NSAIDs or coxibs), and in patients with inflammatory
OA and a contraindication to NSAIDs, we suggest the use of intraarticular
glucocorticoids rather than opioid analgesics or other intraarticular agents (Grade
2B). (See 'Intraarticular glucocorticoids' above and 'Efficacy of intraarticular
glucocorticoids' above.)
The use of glucosamine and chondroitin for OA has been controversial, and results
of randomized trials have varied. We do not advise patients to use these
medications, but there appear to be few risks associated with their use. In patients
who use these medications we advise their discontinuation if significant relief is not
achieved after a six-month trial. (See 'Glucosamine and chondroitin' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000
update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines.
Arthritis Rheum 2000; 43:1905.
2. 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.
3. Jordan KM, Arden NK, Doherty M, et al. EULAR Recommendations 2003: an evidence
based approach to the management of knee osteoarthritis: Report of a Task Force of the
Standing Committee for International Clinical Studies Including Therapeutic Trials
(ESCISIT). Ann Rheum Dis 2003; 62:1145.
4. Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the
management of hip osteoarthritis: report of a task force of the EULAR Standing Committee
for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005;
64:669.
5. Zhang W, Doherty M, Leeb BF, et al. EULAR evidence based recommendations for the
management of hand osteoarthritis: report of a Task Force of the EULAR Standing
Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann
Rheum Dis 2007; 66:377.
6. 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.
7. 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.
8. Towheed TE, Maxwell L, Judd MG, et al. Acetaminophen for osteoarthritis. Cochrane
Database Syst Rev 2006; :CD004257.
9. New Initiatives to Help Encourage Appropriate Use of Acetaminophen. McNeil-PPC, Inc.
http://www.tylenol.com/news/newdosing (Accessed on October 24, 2013).
10. U.S. Food and Drug Administration News Release.
www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm (Accessed
on September 15, 2011).
11. Doherty M, Hawkey C, Goulder M, et al. A randomised controlled trial of ibuprofen,
paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived
people with knee pain. Ann Rheum Dis 2011; 70:1534.
12. Watson MC, Brookes ST, Kirwan JR, Faulkner A. Non-aspirin, non-steroidal anti-
inflammatory drugs for osteoarthritis of the knee. Cochrane Database Syst Rev 2000;
:CD000142.
13. Towheed T, Shea B, Wells G, Hochberg M. Analgesia and non-aspirin, non-steroidal anti-
inflammatory drugs for osteoarthritis of the hip. Cochrane Database Syst Rev 2000;
:CD000517.
14. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of
osteoarthritis. Part I. Osteoarthritis of the hip. American College of Rheumatology. Arthritis
Rheum 1995; 38:1535.
15. Batchlor EE, Paulus HE. Principles of drug therapy. In: Osteoarthritis: Diagnosis and
Medical/Surgical Management, Moskowitz RW, Howell DS, Goldberg VM, Mankin HJ
(Eds), WB Saunders Co., Philadelphia 1992. p.465.
16. Bjordal JM, Ljunggren AE, Klovning A, Slrdal L. Non-steroidal anti-inflammatory drugs,
including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of
randomised placebo controlled trials. BMJ 2004; 329:1317.
17. Bjordal JM, Klovning A, Ljunggren AE, Slrdal L. Short-term efficacy of
pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis of
randomised placebo-controlled trials. Eur J Pain 2007; 11:125.
18. Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of
osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004;
63:901.
19. Amin AR, Attur M, Patel RN, et al. Superinduction of cyclooxygenase-2 activity in human
osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest 1997; 99:1231.
20. Li X, Afif H, Cheng S, et al. Expression and regulation of microsomal prostaglandin E
synthase-1 in human osteoarthritic cartilage and chondrocytes. J Rheumatol 2005; 32:887.
21. Coles LS, Fries JF, Kraines RG, Roth SH. From experiment to experience: side effects of
nonsteroidal anti-inflammatory drugs. Am J Med 1983; 74:820.
22. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs
nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS
study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA
2000; 284:1247.
23. Cameron M, Chrubasik S. Topical herbal therapies for treating osteoarthritis. Cochrane
Database Syst Rev 2013; 5:CD010538.
24. Diclofenac gel for osteoarthritis. Med Lett Drugs Ther 2008; 50:31.
25. A diclofenac patch (Flector) for pain. Med Lett Drugs Ther 2008; 50:1.
26. Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults.
Cochrane Database Syst Rev 2012; 9:CD007400.
27. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical non-steroidal anti-inflammatory
drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ
2004; 329:324.
28. Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study of a topical diclofenac solution
(pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the
knee: a randomized controlled trial. J Rheumatol 2004; 31:2002.
29. Brhlmann P, Michel BA. Topical diclofenac patch in patients with knee osteoarthritis: a
randomized, double-blind, controlled clinical trial. Clin Exp Rheumatol 2003; 21:193.
30. Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and
therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis.
Drugs Aging 1995; 7:317.
31. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a
double-blind trial. Clin Ther 1991; 13:383.
32. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the
treatment of chronic pain. BMJ 2004; 328:991.
33. McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful
osteoarthritis of the hands. J Rheumatol 1992; 19:604.
34. Schnitzer TJ, Posner M, Lawrence ID. High strength capsaicin cream for osteoarthritis
pain: rapid onset of action and improved efficacy with twice daily dosing. J Clin Rheumatol
1995; 1:268.
35. Bellamy N, Campbell J, Robinson V, et al. Intraarticular corticosteroid for treatment of
osteoarthritis of the knee. Cochrane Database Syst Rev 2006; :CD005328.
36. Intra-articular injections for osteoarthritis of the knee. Med Lett Drugs Ther 2006; 48:25.
37. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of
osteoarthritis. Part II. Osteoarthritis of the knee. American College of Rheumatology.
Arthritis Rheum 1995; 38:1541.
38. Gatter RA, Andrews RP, Cooley DA, et al. American college of rheumatology guidelines
for performing office synovial fluid examinations. J Clin Rheumatol 1995; 1:194.
39. Lambert RG, Hutchings EJ, Grace MG, et al. Steroid injection for osteoarthritis of the hip: a
randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2007; 56:2278.
40. Kullenberg B, Runesson R, Tuvhag R, et al. Intraarticular corticosteroid injection: pain
relief in osteoarthritis of the hip? J Rheumatol 2004; 31:2265.
41. Jones A, Doherty M. Intra-articular corticosteroids are effective in osteoarthritis but there
are no clinical predictors of response. Ann Rheum Dis 1996; 55:829.
42. Joshi R. Intraarticular corticosteroid injection for first carpometacarpal osteoarthritis. J
Rheumatol 2005; 32:1305.
43. Meenagh GK, Patton J, Kynes C, Wright GD. A randomised controlled trial of intra-articular
corticosteroid injection of the carpometacarpal joint of the thumb in osteoarthritis. Ann
Rheum Dis 2004; 63:1260.
44. Raynauld JP, Buckland-Wright C, Ward R, et al. Safety and efficacy of long-term
intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind,
placebo-controlled trial. Arthritis Rheum 2003; 48:370.
45. 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.
46. Sawitzke AD, Shi H, Finco MF, et al. Clinical efficacy and safety of glucosamine,
chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of
the knee: 2-year results from GAIT. Ann Rheum Dis 2010; 69:1459.
47. Wandel S, Jni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in
patients with osteoarthritis of hip or knee: network meta-analysis. BMJ 2010; 341:c4675.
48. Setnikar I, Pacini MA, Revel L. Antiarthritic effects of glucosamine sulfate studied in animal
models. Arzneimittelforschung 1991; 41:542.
49. Biggee BA, Blinn CM, McAlindon TE, et al. Low levels of human serum glucosamine after
ingestion of glucosamine sulphate relative to capability for peripheral effectiveness. Ann
Rheum Dis 2006; 65:222.
50. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucosamine therapy for treating
osteoarthritis. Cochrane Database Syst Rev 2005; :CD002946.
51. Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis:
why do trial results differ? Arthritis Rheum 2007; 56:2267.
52. Reginster JY. The efficacy of glucosamine sulfate in osteoarthritis: financial and
nonfinancial conflict of interest. Arthritis Rheum 2007; 56:2105.
53. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on
osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;
357:251.
54. Mazzuca SA, Brandt KD, Lane KA, Katz BP. Knee pain reduces joint space width in
conventional standing anteroposterior radiographs of osteoarthritic knees. Arthritis Rheum
2002; 46:1223.
55. Pavelk K, Gatterov J, Olejarov M, et al. Glucosamine sulfate use and delay of
progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind
study. Arch Intern Med 2002; 162:2113.
56. Rozendaal RM, Koes BW, van Osch GJ, et al. Effect of glucosamine sulfate on hip
osteoarthritis: a randomized trial. Ann Intern Med 2008; 148:268.
57. Rozendaal RM, Uitterlinden EJ, van Osch GJ, et al. Effect of glucosamine sulphate on joint
space narrowing, pain and function in patients with hip osteoarthritis; subgroup analyses of
a randomized controlled trial. Osteoarthritis Cartilage 2009; 17:427.
58. Cibere J, Kopec JA, Thorne A, et al. Randomized, double-blind, placebo-controlled
glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum 2004; 51:738.
59. Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: chondroitin for osteoarthritis of
the knee or hip. Ann Intern Med 2007; 146:580.
60. Gabay C, Medinger-Sadowski C, Gascon D, et al. Symptomatic effects of chondroitin 4
and chondroitin 6 sulfate on hand osteoarthritis: a randomized, double-blind, placebo-
controlled clinical trial at a single center. Arthritis Rheum 2011; 63:3383.
61. 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.
62. Kwoh CK, Roemer FW, Hannon MJ, et al. Effect of oral glucosamine on joint structure in
individuals with chronic knee pain: a randomized, placebo-controlled clinical trial. Arthritis
Rheumatol 2014; 66:930.