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Kristine Phillips

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Case Presentation

A 53-year-old woman with right knee pain presents to her local primary care physician for evaluation and treatment. The knee pain has occurred almost daily for 6 months and is localized to the medial aspect of the knee. She rates her current pain as 4 on a scale of 0 to 10, with 10 being the worst level of pain. She has taken daily over-the-counter maximum strength acetaminophen for over 4 weeks and, subsequently, daily maximum strength naproxen for a 6-week period, but this has not relieved her symptoms. Her pain fluctuates daily, ranging from 3 to 6, and is worse when she is going down stairs. She has some associated symptoms, including worsening fatigue and occasional sleep disturbance. She reports no symptoms of chronic anxiety or depression but admits that stress is associated with worsening symptoms. Physical exam is notable for a body mass index of 32 and bony prominence of the right knee. Bilateral standing radiographs indicate mild to moderate degenerative joint disease of the right knee, with cartilage loss on the medial aspect of the knee, moderate sclerosis, and osteophyte formation.

Osteoarthritis (OA) is the most prevalent form of arthritis, affecting more than 21 million adults in the United States. During the development of OA, degradation of the cartilage matrix occurs initially. It is typically slowly progressive, with cartilage degeneration and the resulting loss of joint space proceeding at a pace that is not continuous. Once the collagen network has been degraded, it does not return to its original state. Periarticular bone changes can occur, with resulting osteophyte formation. There also appears to be an inflammatory component to some forms of OA, with resulting stiffness, swelling, and synovitis. The pain experienced by an individual does not necessarily correspond to the degree of cartilage loss or OA findings obtained via imaging modalities, although in a single individual worsening pain might correlate inversely with joint space width. Risk factors for OA include age, trauma (i.e., anterior cruciate ligment tear), biomechanical overloading (i.e., obesity), and genetic cartilage defects.

OA as a disease not only is associated with significant pain but also contributes to disability in adults. The disability associated with OA has a significant impact on the quality of life of patients with OA. Based on demographic trends, the impact on U.S. patients is expected to worsen in the near future. The combination of an aging population and increasing obesity has resulted in rapid growth in the number of patients undergoing knee replacement surgery for the treatment of pain associated with OA, a trend that will only increase in the upcoming decades.1,2 Total knee replacement can improve function and yields significant pain relief for the many patients who undergo the procedure.3,4 However, there are significant numbers of patients who have mild to moderate OA for whom non-surgical nociceptive treatments might be more appropriate. In addition, the modest association between radiographic joint damage and pain in OA suggests that there might be other components of pain such as inflammation or abnormal central pain processing. A proportion of patients have ongoing pain postoperatively, again suggesting that factors other than peripheral, nociceptive pain mechanisms are involved.57 As is the case with many chronic pain diseases, OA patient populations likely have distinct subgroups based on neurobiologic, psychological, and cognitive features.8,9

There are no known treatments that have been shown to reverse the progression of OA, although some treatments might slow the rate of progression. In addition to pain relief, the preservation of function is an important consideration. Pain related to underlying OA can result in decreased quality of life and progressive disability.10 Current studies are aimed at developing an approach to pain and disability management in OA that takes into account the total joint as an organ, with a focus on patient symptoms that will have a significant impact on the human and medical costs associated with chronic arthritis pain.


Musculoskeletal pain is the most common reason for medical appointments in the United States, amounting to millions of visits and billions of dollars each year in healthcare costs and lost productivity. All groups of persons, regardless of age, gender, ethnicity, or cultural background, experience unrelieved pain at some point, but women are significantly more likely to develop chronic pain disorders. Despite significant strides in understanding acute pain and developing effective treatments, the development and treatment of chronic musculoskeletal pain is not fully understood.

OA is one potential contributing factor to chronic musculoskeletal pain. Most patients presenting with chronic joint pain will have a radiograph of the affected joint to evaluate for OA, bony masses, or internal derangement. Standard views of the joint are usually the best starting point; in addition, radiographs of the opposite, unaffected joint might be helpful in evaluating anatomy and degree of cartilage loss. Bilateral standing views of the knees can be very helpful in assessing the extent of degenerative joint disease and the relative degree of cartilage loss. Although radiographs provide important information about alignment and cartilage, magnetic resonance imaging is suitable for better evaluation of not only cartilage but also soft tissue contrast and complex geometry. Several ongoing longitudinal studies will eventually provide important information regarding cartilage morphology and the timing of surgical treatment.11

Every experienced clinician realizes that pain is highly variable among individuals. In chronic OA pain, there is often dissociation between pain perception and underlying pathology. The degree of pain might not correspond to the radiographic findings at the time of evaluation, and this should be kept in mind when evaluating an individual patient. Significant pain that is disproportionate to objective findings is challenging to treat and frustrating for patients and clinicians alike.


Treatments for OA are aimed primarily at alleviating patients’ symptoms and improving physical function. The case outlined above is fairly typical for initial self-management of OA symptoms. This patient has several options and might have an approach individualized for her care that includes weight loss, increased physical activity, or medially directed non-pharmacologic therapies in addition to optimizing her pharmacologic treatment.

There have been many advances in understanding pain that localizes to a specific joint, but the disease is heterogeneous, and what works for one patient might not address the needs of a different patient. More work is needed to address some of the critical questions related to prevention, treatment, and monitoring of knee OA pain that is personalized for an individual with symptoms. Most treatments for OA have thus far been developed for peripheral nociceptive factors. Pain in OA has been historically attributed in part to joint damage, and nearly all therapies have been aimed at treating the pain derived from this peripheral structural problem, including exercise, topical analgesics, oral non-steroidal anti-inflammatory drugs (NSAIDS) and opioids, local injections, and eventually joint replacement. Although there are numerous interventions for OA nociceptive pain, there is no known cure for the cartilage and bone changes, and many patients experience progression of significant symptoms over the course of many years.

Recent data from an international study conducted by a task force of Osteoarthritis Research Society International and Outcome Measures in Rheumatology suggest that decisions regarding total joint arthroplasty cannot be predicted on the basis of the severity of the patients’ pain or physical limitations.12 Total knee replacement certainly can improve function and yields significant pain relief for many patients who undergo the procedure.13,14 However, there is evidence that some patients might have a significant component of centrally mediated pain that might be improved following joint replacement.15

General Approach

The American College of Rheumatology (ACR) completed a recent update of the recommendations for therapies for OA.16 The guidelines for management of hip and knee OA were originally published in 2000, and additional recommendations were provided in 2005. The updated recommendations published in 2012 were developed using the Grades of Recommendation Assessment, Development and Evaluation approach,17 which represents an advance in methodology over previously employed measures.18 These recommendations were made based on a systematic approach to the best available evidence of safety and benefit.

A summary of the recommendations of the ACR for hip and knee OA are outlined in Tables 10.110.3. Recommendations were classified as “conditional” or “strong.” Using a 5-point Likert scale, expert panelists were asked to make a recommendation for each modality in the setting of a clinical scenario. The scale provided to panelists included the following choices: strong recommendation to use, weak (or conditional) recommendation to use, no recommendation, weak (or conditional) recommendation not to use, and strong recommendation not to use. The strength of a recommendation is meant to serve as a proxy for the quality of the evidence supporting the use of the intervention, as well as the extent to which one can be confident in desirable effects. Non-pharmacologic interventions included in the strong recommendations are listed in Table 10.1.

Table 10.1 American College of Rheumatology Guidelines 2012: Strong Recommendations for Non-Pharmacologic Management of Knee or Hip OA

Participation in cardiovascular (aerobic) and/or resistance land-based exercise

Participate in aquatic exercise

Weight loss for persons who are overweight

Table 10.2 american college of rheumatology guidelines 2012: conditional recommendations for non-pharmacologic management of knee or hip oa

Participate in self-management programs

Manual therapy and supervised exercise

Psychosocial interventions

Instruction on the use of thermal agents

Use of walking aids as needed

For knee OA:

Use patellar taping that is medially directed

Wear medially wedged insoles for lateral compartment OA

Wear laterally wedged subtalar strapped insoles for medial compartment OA

Tai Chi programs

For moderate to severe knee OA:

Consideration of Chinese acupuncture

Transcutaneous electrical stimulation

Table 10.3 american college of rheumatology guidelines 2012: conditional recommendations for pharmacologic management of knee or hip oa



Topical NSAIDs for knee OA


Intra-articular corticosteroid injections

Patients with OA might benefit from weight loss, even in small amounts. Cardiovascular exercise should be encouraged if not otherwise contraindicated. There is no preference for aquatic versus land based exercises, and any exercise regimen may be optimized for patient preference and compliance. Avoidance of excessive weight gain and caution with load-bearing exercise should also be counseled. Non-pharmacologic conditional recommendations are listed in Table 10.2.

Assistive devices such as canes, supports, and braces might take some of the stress off of the affected joint. The use of medially directed patellar taping may be considered, in addition to instruction and participation in Tai Chi programs. Patients with medial compartment OA may consider wearing laterally wedged subtalar strapped insoles, and patients with lateral compartment OA may consider wearing medially wedged insoles. In addition to these recommendations, patients might be able to treat pain flares with the application of cold for no longer than 15 min of contact time; this may be repeated as needed. For other patients with significant stiffness, the application of moderate heat might be of benefit. Good nutrition and avoidance of trauma to the joint are also essential. The treatment of associated aggravating factors such as secondary bursitis also should be considered if warranted. Recent studies have shown alterations in pain processing that indicate a component of central nervous system mediation of pain (e.g., the presence of hyperalgesia) among people with knee and hip OA. It remains unclear how pain processing affects coping strategies to manage pain and perform activities. As with any chronic pain state, reducing stress or addressing relaxation strategies might prove beneficial.


Pharmacologic treatments are outlined in Table 10.3.

Acetaminophen (or paracetamol outside of the United States) is available without a prescription and is recommended for patients as a first-line pharmacologic therapy. Acetaminophen is relatively well tolerated when taken on a regular basis. Doses of 500 mg to 750 mg taken two to three times daily might provide significant relief. Caution should be used in patients with known liver disease. Patients should be counseled not to exceed 3000 mg of acetaminophen per day per updated recommendations, and they should note the content of mixed cold and flu remedies, as they might contain acetaminophen. Topical analgesic treatments contain salicylate and are available over the counter, and they might provide temporary relief. Patients who are allergic to aspirin or patients who take blood thinners should not use salicylate-based topical treatments until they have discussed potential side effects with their doctor. Capsaicin, made from chili pepper seeds, is another topical agent. Anecdotal reports suggest that capsaicin works best on joints that are close to the skin (i.e., fingers).

Anti-inflammatory Medications

NSAIDs target cyclooxygenase-1 and cyclooxygenase-2 (COX-2) and can provide relief from acute pain in patients with OA. However, they can cause or worsen gastritis, gastrointestinal hemorrhage or ulcers, renal insufficiency, congestive heart failure, hypertension, and cardiovascular disease. Also, many patients with arthritis have comorbidities; the use of NSAIDs is limited by their potential for interaction with other medications, in addition to their impact on underlying disease. Per ACR guidelines, topical NSAIDs, rather than oral NSAIDs, are recommended for consideration in persons older than 75 years of age.

COX-2-specific agents are approved in the United States by the U.S. Food and Drug Administration (FDA) and in Europe for use in arthritis patients. The gastrointestinal safety profile is more favorable for these agents, and they do not interfere with platelet activity, so they may be used in patients on warfarin. They should be used with caution in patients with renal or cardiovascular disease. The favorable gastrointestinal safety profile of COX-2 inhibitors is attenuated with the co-administration of aspirin.

Nonacetylated Salicylates

Nonacetylated salicylate compounds include choline magnesium trisalicylate. Doses of 500 to 750 mg two or three times daily are effective therapy for many patients and have been used by rheumatologists for the treatment of arthritis symptoms for many years. These medications have fewer adverse gastrointestinal side effects than regular aspirin compounds or NSAIDs.


Chronic systemic steroids should not be used for the management of OA. Local intra-articular injection of corticosteroids might provide significant relief of pain and stiffness, and despite the evidence in randomized trials, anecdotal reports suggest that some patients have long-lasting pain relief from a single injection.

The injection of corticosteroids into any joint should be performed in a sterile manner by physicians experienced with this technique; potential risks include infection, bleeding, bruising, lipodystrophy, and osteonecrosis. These complications are rare with careful technique in experienced hands. Patients might experience improvement of symptoms immediately after injection, and improvements might be greatest in those with joint effusion from whom synovial fluid is withdrawn prior to injection. Any synovial fluid present should be aspirated, if possible, with an aseptic technique before injection. The fluid should be sent for Gram stain, culture, cell count, and differential, and experienced personnel should perform an examination for crystals. Limited studies of some forms of intra-articular injections have shown no effect on the progression of radiographic disease.


Viscosupplements such as injectable hyaluronate are approved by the FDA and might provide modest relief. These were not included in the recommendations set out by the ACR.

Alternative Treatments

Many patients with OA use alternative therapies to try to relieve their symptoms. Many non-prescription supplements have not shown significant results in limited studies. Glucosamine and chondroitin sulfate are by far the most studied agents in this category, but their mechanism of action is unknown. Glucosamine and chondroitin sulfate at a dose of 1200 to 1500 mg daily appears to be safe in most patients with OA, and some studies suggest that their efficacy is similar to that of NSAIDs and acetaminophen. The ACR guidelines conditionally recommended against the use of glucosamine and chondroitin sulfate for patients with knee OA, citing significant heterogeneity in effect size in published trials.

Acupuncture, although used by many patients, has not been shown to be of consistent benefit in trials. Risks include reports of hepatitis transmission and pneumothorax.

Traditional Chinese acupuncture was recommended for consideration only in the setting of chronic pain and moderate to severe OA for which there is a relative or absolute contraindication to surgery.

Instruction in the use of transcutaneous electrical stimulation was similarly conditionally recommended only if the patient has moderate to severe pain and is a candidate for knee arthroplasty but is unwilling or unable to undergo the procedure.

Narcotic Analgesics

Narcotic analgesics should not be routinely used for patients with chronic OA, although they may serve a short-term role as a bridge to surgical intervention for patients with advanced joint disease. They may also be reserved for patients with severe joint disease and intolerable suffering who are not candidates for other therapeutic interventions. Lower potency medications, such as combination tramadol/acetaminophen or acetaminophen with codeine, should be tried first. Usual precautions should be taken when prescribing these, such as counseling patients about their correct use, sedative effects, and addictive potential. Additional caution should be used with older patients or patients with more co-morbidities. In the case of presumed tolerance or minimal efficacy with low-dose opioids, referral to a pain specialist or rheumatologist is warranted, as higher doses of opioids will seldom provide long-term benefit.

Centrally Acting Agents

“Central pain” is used to describe any central nervous system dysfunction or pathology that might be contributing to the development or maintenance of chronic pain. Central mechanisms that enhance the perception or modulation of pain differentially have also been referred to as central augmentation or amplification. This type of pain mechanism was originally thought to be confined to individuals with idiopathic or functional pain syndromes, such as fibromyalgia, headache, irritable bowel syndrome, temporomandibular joint disorder, and interstitial cystitis. These pain syndromes have been shown to be familial/genetic (e.g., the risk of developing fibromyalgia is eight times higher in first-degree relatives of patients with fibromyalgia). This type of pain often co-aggregates with other centrally mediated symptoms such as fatigue, memory difficulties, and mood disturbances.19 Recent twin studies support a genetic basis of pain, as well as this cluster of co-aggregating symptoms.

Central factors might play a role in pain related to OA. Emerging research suggests that many patients with OA demonstrate signs of generalized hyperalgesia and faulty central pain modulatory processing similar to those seen with other idiopathic pain disorders.20 Further work to establish the optimal means of quantifying and predicting pain is needed, particularly in patients with diffuse pain syndromes and OA. The recent FDA approval of a dual reuptake antidepressant (duloxetine) for musculoskeletal pain such as OA highlights the considerable amount of data that supports this approach.21

OA may also be viewed in some cases as a mixed pain state, with some individuals possessing more prominent features of central pain. In some patients, central factors might be superimposed upon the more traditional peripheral factors, leading to the need for a broader and more flexible approach to diagnosis and treatment. Patients with OA demonstrate signs of generalized hyperalgesia and faulty central pain modulatory processing similar to those seen with other idiopathic pain disorders.20

Because OA is a potentially mixed pain state, there are tremendous opportunities to move toward individualized analgesia by identifying individuals with OA who have a primary central component of pain that would likely preferentially respond to therapies known to be effective in central pain states such as centrally acting analgesics (e.g., dual reuptake inhibitors, gabapentinoids) and non-pharmacological therapies (exercise or cognitive behavioral therapy). Duloxetine is now approved for musculoskeletal pain, including OA.21 Additional centrally acting agents that might be of benefit include gabapentin, pregabalin, or other dual reuptake inhibitors such as milnacipran. Low doses of amitriptyline or nortriptyline might prove beneficial, particularly for nighttime pain. Additional studies in this area are needed to guide treatment options in this area.

Surgical Intervention

Arthroscopy is under review by the ACR and is not recommended in European League Against Rheumatism guidelines.22 It may still be used on a case-by-case basis for specific indications. Osteotomy is another surgical treatment for OA that is aimed at delaying disease progression, but additional studies with long-term follow-up are needed.

Arthroplasty is now used to treat many patients with severe OA, especially in those for whom more-conservative measures have failed. The life of a joint replacement is typically 10 to 20 years, although some patients do well for much longer. The reported failure rate following hip arthroplasty (due to pain) is quite high at approximately 10 percent, and it is even higher (approximately 15 percent to 20 percent) for knee replacement surgery.23,24 This severe pain persists at least 3 to 4 years after surgery in some patients and is not thought to have a peripheral neuropathic component.24 Replacement after the original joint arthroplasty surgery might be more complex and can have higher failure and infection rates than initial total joint replacement.


OA is the most common form of arthritis in the United States, and chronic pain related to underlying OA increases with advancing age. Many patients can achieve relief of their symptoms of chronic joint pain with appropriate care; however, further research is needed in order to improve the long-term outcomes of this disease. Advances in joint replacement surgery have made this an excellent treatment for many patients with more-severe disease. Additional studies are needed to further characterize disease-specific molecular pathways that may serve as potential targets for intervention.


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