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Roy Davis Altman, MD
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Practical Considerations for the Pharmacologic Management of Osteoarthritis

Roy Davis Altman, MD


Pharmacologic treatment options for osteoarthritis (OA) are diverse both in terms of mechanisms of action and delivery formulations; however, no single agent has been demonstrated to consistently offer both a high level of tolerability and a sustained degree of efficacy across a broad OA patient population. Ultimately, a multimodal approach to OA treatment is the best option, offering a greater likelihood of tolerability by avoiding sustained exposure to higher risk agents while improving efficacy by combining agents with more than one mechanism of action. Such an approach should take into consideration the compatibility of different pharmacologic therapies while also taking advantage of nonpharmacologic treatments. Oral nonsteroidal anti-inflammatory drugs (NSAIDs), which are both easily accessible to patients and generally effective for pain relief, are the most popular pharmacologic therapies used in OA; unfortunately, these agents are associated with gastrointestinal and other cardiovascular risks. Combining these agents with other treatments possessing differing side-effect profiles and mechanisms of action will likely reduce the safety and tolerability risk. The recent availability in the United States of a topical NSAID gel with less systemic exposure than oral NSAIDs may offer clinicians an additional means of achieving effective analgesia in OA of superficial joints while minimizing the risk of adverse events.

(Am J Manag Care. 2009;15:S236-S243)


Osteoarthritis (OA) is a joint disease characterized by the gradual loss of articular cartilage accompanied by bony remodeling, atrophy of periarticular muscles, and capsular stretching.1,2 Synovitis will occur in some OA patients, and is often accompanied by ligament laxity and, ultimately, bone marrow lesions.2 There is an enormous variability between patients with regard to patterns of disease progression: many patients will experience remission or a relatively stable disease status while a minority will experience rapid joint deterioration and high levels of pain and loss of quality of life.2 The most commonly affected joints are those of the hands, knees, spine, and hips.3

The primary goals of OA treatment are reducing pain and stiffness while avoiding drug toxicity, improving function and quality of life, and limiting disease progression to the greatest extent possible.4-6 Therapeutic options available for the treatment of OA include numerous nonpharmacologic (Table) and pharmacologic treatment modalities and the major clinical guidelines for managing OA encourage a combination of both therapeutic approaches.4-6 A proposed algorithm for the treatment of OA is reflected in the Figure.

Nonpharmacologic treatment approaches are quite diverse and include educational initiatives, physical exercises, and changes in lifestyle that should ideally be tailored to the specific needs of the patient.5 One of the most frequently recommended educational initiatives is the Arthritis Foundation Self-Management Program, which is widely regarded as a valuable and low-cost means of improving function and limiting pain.6-8 Physical exercises commonly applied to OA management include range-of-motion exercises, aerobic exercise, muscle strengthening (eg, quadriceps strengthening for knee OA), and physical therapy.4,6-8 Lifestyle changes most commonly consist of weight-loss programs (among overweight patients), as well as the use of devices, such as appropriate footwear, lateral wedged insoles, and canes for individuals with knee or hip OA.4,6-8

This article examines the range of pharmacologic options for the management of OA which, as with nonpharmacologic options, are quite diverse. Available data on oral and topical treatments, including prescription agents and several over-the-counter options, are also reviewed.

Oral Agents for OA

Acetaminophen has anti-inflammatory activity yet acts as an inhibitor of cyclooxygenase (COX)-1 and -2 in the central nervous system.9 Its use for the relief of mild-to-moderate OA pain is recommended by numerous OA clinical guidelines (typically <4 g/day), including those published by the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and Osteoarthritis Research Society International (OARSI).4-6 Whereas the ACR guidelines note that acetaminophen is among the safest oral analgesics, it does confer a degree of risk for hepatic toxicity, although rarely at doses of 4 g/day or less.6 It is therefore recommended that acetaminophen be avoided in patients with existing liver disease and those with chronic alcohol abuse. Caution should also be exercised in the use of high-dose acetaminophen because of its capacity to prolong the half-life of warfarin sodium and thereby induce excess anticoagulant effects.6 Because of the potential for hepatotoxicity, the US Food and Drug Administration (FDA) has issued a warning on the use of acetaminophen. Patients need to be aware that many analgesics and "cold remedies" contain acetaminophen. Use of several of these agents at the same time as taking full doses of acetaminophen is potentially hepatotoxic.

A 2006 Cochrane review of acetaminophen in the treatment of OA found that although acetaminophen was significantly superior to placebo for pain relief, the clinical significance of the improvement was dubious.10 It is also worth noting that the superiority of acetaminophen versus placebo was based on a set of measures including pain response, pain on motion, physician global assessment, modified Health Assessment Questionnaire (HAQ), and patient global assessment; however, significant improvement was not seen for acetaminophen when measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne index.10 No significant differences were observed for safety issues among patients receiving acetaminophen compared with those receiving placebo.

The same Cochrane review analyzed study data comparing acetaminophen to nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, arthrotec, celecoxib, naproxen, diclofenac, and rofecoxib. For pain reduction, NSAIDs demonstrated superiority to acetaminophen in the areas of rest pain, overall pain, and pain measured by both WOMAC and HAQ, but not pain measured by the Lequesne index.10 In the area of physical function, NSAIDs also demonstrated superiority to acetaminophen on the WOMAC function scale, but not on the HAQ or Lequesne function index nor in the 50-foot walk time test.10 In terms of safety, patients taking "traditional" NSAIDs-that is, ibuprofen, diclofenac, and naproxen-were twice as likely as those taking acetaminophen to withdraw from studies based on adverse gastrointestinal (GI) events. There was, however, no overall difference in serious adverse events, including serious GI events-such as perforations, peptic ulcers, and GI bleeding-although such events are likely to be very rare in the short-term studies that comprised the subject matter of this Cochrane review.4,5,10


Oral NSAIDs may be broadly divided between those that are selective for COX-2 inhibition and those that are nonselective, indicating a degree of inhibition of both COX-1 and COX-2.11 NSAIDs, which function both centrally and peripherally, are primarily effective in limiting pain by their capacity to reduce inflammation and nociceptor pain through COX-2 inhibition.12 Anxiety surrounding the propensity for oral nonselective NSAIDs to cause serious GI events has led major guidelines to recommend that nonselective NSAIDs be prescribed along with gastroprotective agents such as a proton pump inhibitor or misoprostol when being given to patients with elevated GI risk.4,6 Oral NSAIDs have also been seen to possess renal risk as well as a risk of potential central nervous system adverse events and allergic reactions.13 The OARSI guidelines specifically recommend use of these agents at the lowest dose possible and to avoid long-term use when possible.4 It should also be noted that risk of adverse events increases when NSAIDs are combined.7

The desire to avoid GI side effects associated with nonselective NSAIDs was a key motivation for the development of NSAIDs that were selective for COX-2, and it is this considerably reduced GI risk that has made the COX-2 inhibitors a treatment choice commonly recommended by OA clinical guidelines.4-6,14 However, extensive use of COX-2 inhibitors, after their initial introduction, revealed them to confer potentially substantial cardiovascular (CV) risk.15 Indeed, 2 widely distributed COX-2 inhibitors, rofecoxib and valdecoxib, were withdrawn from the market as a result of elevated CV risk.13

In terms of analgesic efficacy, COX-2 inhibitors appear to be roughly equivalent to nonselective NSAIDs based on a systematic review of randomized controlled trials.13 The review also found a greater rate of CV events for COX-2 inhibitors compared with nonselective NSAIDs, although it should be noted that data regarding CV risk for nonselective NSAIDs are very limited.13 Among COX-2 inhibitors, the greatest quantity of evidence for CV risk was seen with COX-2 agents having the greatest degree of patient exposure.13 At present, all NSAIDs, other than aspirin, both selective and nonselective, carry the same black box warning for CV risk.

Opioids and Related Analgesics

The opioid class of drugs constitutes a diverse grouping with various degrees of efficacy and adverse-event risks. Most opioids, morphine being the primary example, function mainly through mu receptor inhibition.16 Opioids appear to be more effective with neurogenic rather than nociceptive pain.17 The use of opioids in treating OA pain is typically limited, a caution borne of anxieties about side effects and the risk of dependency, but they are recommended when other pain treatments have proved ineffective.4-6 Clinical treatment guidelines state a preference for weaker opioids, such as codeine (often in combination with acetaminophen) or the synthetic opioid tramadol. To date, no long-term trials of opioids for the treatment of OA have been conducted.4 Shorter term data, however, suggest that opioids are effective for OA pain although they are associated with side effects that result in a high rate of discontinuation.18

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