Background

Osteoarthritis, the most common form of arthritis, is associated with substantial disability and reduced quality of life. Twenty-seven million adults in the United States are thought to have clinical osteoarthritis.¹ In large surveys, 5 percent to 17 percent of U.S. adults had symptomatic osteoarthritis of the knee, and 9 percent had symptomatic osteoarthritis of the hip.¹ Osteoarthritis is more common with increasing age. Osteoarthritis accounts for more disability in walking, stair climbing, and other tasks requiring use of the lower extremities than any other disease, particularly in the elderly.² The total costs for arthritis, including osteoarthritis, may be greater than 2 percent of the gross domestic product,³ with more than half of these costs related to work loss.²

In addition to nonpharmacologic interventions (such as physical therapy, weight reduction, and exercise), numerous medications and over-the-counter supplements are available to treat pain and potentially improve functional status in patients with osteoarthritis.⁴ Each class of medication or supplement is associated with a unique balance of risks and benefits. In addition, efficacy and safety may also vary for individual drugs within a class. Oral medications commonly used to treat osteoarthritis include nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. Many are available at lower over-the-counter and higher prescription doses. A dose comparison table of available NSAIDs is available in Appendix A. Commonly used supplements sold over the counter and not regulated as pharmaceuticals by the U.S. Food and Drug Administration (FDA) include glucosamine and chondroitin. Topical agents used by patients with osteoarthritis include rubefacients (including salicylates and capsaicin) and NSAIDs. Opioid medications are also used for patients with chronic osteoarthritis pain, especially if it is refractory to other therapies, but recommendations suggest cautious use due to risks of addiction, tolerance, diversion, and other adverse events.^5–7

NSAIDs exert analgesic, anti-inflammatory, and antipyretic effects by blocking cyclooxygenases (COX), enzymes that are needed to produce prostaglandins. Understanding of the pharmacology of NSAIDs continues to evolve, but it is thought that most NSAIDs block the COX-1 and COX-2 isoenzymes. COX-2 is found throughout the body, including joint and muscle, where it contributes to pain and inflammation. Because they block COX-2, NSAIDs reduce pain compared to placebo in patients with arthritis,⁸ low back pain,⁹ minor injuries, and soft-tissue rheumatism.

NSAIDs are also associated with important adverse effects. NSAIDs cause gastrointestinal (GI) bleeding because they also block the COX-1 enzyme, which mediates mucosal defense of the gastrointestinal tract, including protection from acid and platelet aggregation. The number of serious GI bleeds in the United States due to use of nonaspirin NSAIDs is not known with certainty. One study estimated 32,000 hospitalizations and 3,200 deaths annually in the 1990s, though other studies have reported higher estimates.¹⁰ A risk analysis¹¹ based on a retrospective case-control survey of emergency admissions for upper GI disease in two United Kingdom general hospitals provided estimates of the frequency of serious GI complications from NSAIDs.¹² In people taking NSAIDs, the 1-year risk of serious GI bleeding ranges from 1 in 2,100 in adults under age 45 to 1 in 110 for adults over age 75, and the risk of death ranges from 1 in 12,353 to 1 in 647 (Table 1). In addition to age, prednisone use, disability level, and previous NSAID-induced GI bleed are risk factors for GI bleeding.

Table 1

One-year risk of gastrointestinal bleeding due to NSAID.

NSAIDs differ in their selectivity for COX-2—how much they affect COX-2 relative to COX-1. Theoretically, an NSAID that blocks COX-2 but not COX-1 might reduce pain and inflammation in joints but not affect the gastrointestinal mucosa or cause platelet inhibition. Appendix B summarizes the NSAIDs and their selectivity based on assay studies (done in the laboratory instead of in living patients). The table gives an idea of how widely NSAIDs vary in their selectivity, but should be interpreted with caution. Different assay methods give different results, and assay method may not reliably predict what will happen when the drug is given to patients. Clinical studies, rather than these assay studies, are the best way to determine whether patients actually benefit from using more selective NSAIDs.

In addition to their propensity to cause GI bleeding, NSAIDs are also associated with adverse effects on blood pressure, renal function, and fluid retention. Mechanisms may involve attenuation of prostaglandin-mediated vasodilation, promotion of sodium and water retention, increased vascular resistance, and increased renal endothelin-1 synthesis.^14–16 An association between COX-2 selective NSAIDs and increased rates of myocardial infarction was first observed in the large, pivotal Vioxx Gastrointestinal Outcomes Research (VIGOR) trial comparing high-dose rofecoxib (50 mg) to naproxen 1,000 mg.¹⁷ Reasons for the increase in thromboembolic cardiovascular (CV) event risk are not completely understood. Initially, it was thought that the degree of COX-2 selectivity could predispose to CV events by suppressing endothelial-derived prostaglandin I2 formation, in the setting of unaffected platelet production of prothrombotic COX-1 mediated thromboxane A2.¹⁸ However, subsequent in vitro studies have not definitively confirmed this hypothesis. Blood pressure elevations associated with COX-2 selective NSAIDs may play a role in increasing CV risk,¹⁹ and CV events in VIGOR were also later found to be associated with a higher incidence of arrhythmias. On September 30, 2004, rofecoxib was withdrawn from the market after a long-term polyp prevention trial found an increased risk of myocardial infarction compared with placebo.²⁰ On December 9, 2004, the FDA issued a black-box warning for the selective COX-2 inhibitor valdecoxib for life-threatening skin reactions and increased CV risk. This drug was subsequently also withdrawn voluntarily by the manufacturer,²¹ leaving celecoxib the only COX-2 selective NSAID available in the United States.

Aspirin, or acetylsalicylic acid, has long been known to have analgesic, antipyretic, and anti-inflammatory effects.²² It is thought to be the most consumed medicinal drug in the world. Like the non-aspirin NSAIDs, aspirin’s effects are due to blockade of cyclooxygenases. However, an important distinction between aspirin and non-aspirin NSAIDs is that aspirin also induces irreversible functional defects in platelets (although non-aspirin NSAIDs also have effects on platelet aggregation, they are short lived). Because of these antiplatelet effects, low-dose aspirin is also used prophylactically to reduce the risk of thrombotic events.²³ However, even at doses of 325 mg daily or lower, the potential CV benefits must be balanced against dose-dependent risk of aspirin-induced adverse GI events. In addition, it is not known with certainty how frequently aspirin is used at the higher doses more effective for analgesia, where tolerability may be an issue. Salsalate, a nonacetylated salicylate, is a prodrug of salicylic acid, the active metabolite of aspirin. It is considered a relatively weak inhibitor of cyclooxygenases.²⁴

Acetaminophen (also known as paracetamol) is an antipyretic and analgesic medication that is not thought to have significant anti-inflammatory properties. Although its mechanism of inducing analgesia is still not completely understood, it is thought to work in part by indirectly decreasing production of prostaglandins through inhibitory effects involving COX-2.^{14, 25} Acetaminophen is frequently recommended as a first-line agent for osteoarthritis and other pain conditions because of its perceived favorable safety profile—particularly with regard to ulcer risk.⁶

Chondroitin sulfate and glucosamine sulfate are natural compounds found in cartilage. Both are marketed to patients who have osteoarthritis. The precise mechanisms of action are unknown, but may involve promotion of maintenance and repair of cartilage. Glucosamine, for example, has been shown to increase proteoglycan synthesis.²⁶ In the European Union countries, glucosamine is available as a prescription drug manufactured by the Rotta Pharmaceutical Company. In the United States, by contrast, glucosamine and chondroitin are considered dietary supplements and are not regulated as pharmaceuticals. Adequate standardization of glucosamine and chondroitin preparations is a significant concern. It has been shown that the actual content often varies substantially from what is stated on the label.²⁷ Such inconsistencies may have implications on estimates of efficacy and safety for different commercial preparations.

Topical administration of NSAIDs could theoretically result in local analgesic and anti-inflammatory effects by direct absorption through the skin, with reduced systemic adverse events compared with oral administration.²⁸ Research indicates that topical administration is associated with substantially higher concentrations of NSAIDs in soft tissue (particularly meniscus and cartilage) and lower peak plasma concentrations compared with oral administration.²⁹ For a topical NSAID to be effective, it has to reach the inflamed tissue in sufficient concentrations to produce analgesic and anti-inflammatory activity. The solubility of specific NSAIDs varies considerably, and is also affected by the carrier or formulation used.²⁸ Superior in vivo permeability characteristics, however, do not necessarily predict clinical effectiveness. At the time of the original comparative effectiveness review (CER), the FDA had approved no topical NSAID formulations, though compounding of oral NSAIDs into topical preparations was permitted. Since then, the FDA has approved several topical formulations of diclofenac.

In contrast to topical NSAIDs, whose mechanism of action involves inhibition of cyclooxygenase, topical rubefacients are thought to relieve pain through counter-irritation.^{29, 30} Although the mechanism of action of topical preparations containing salicylate esters is unclear, they are now usually classified as rubefacients rather than topical NSAIDs because they may not work via inhibition of cyclooxygenase.^{29, 31} Capsaicin, which may be classified as a rubefacient, is derived from the hot chili pepper (Capsicum species). It is applied topically and thought to work by stimulating the release of substance P and other neuropeptides from sensory nerve endings.³² Although this release can initially lead to burning and pain, analgesia occurs after repeated and continued application, as substance P becomes depleted. Although a wide variety of other rubefacients are available, only topical salicylates and capsaicin were included in this review.

The Agency for Healthcare Research and Quality (AHRQ) funded a CER of analgesics for osteoarthritis that was published in 2006,³³ based on searches conducted through 2006. Since that time, additional research has become available to better understand the comparative efficacy and safety of oral and topical medications for osteoarthritis, and a study³⁴ commissioned by AHRQ on the need to update CERs assigned high priority to the previous report on analgesics for osteoarthritis, based on an assessment of the number of potentially outdated conclusions and ongoing issues related to safety.

Scope and Key Questions

The purpose of this report was to update a previous comparative effectiveness review funded by AHRQ³³ on the comparative efficacy and safety of nonopioid oral medications (selective and nonselective non-aspirin NSAIDs, aspirin, salsalate, and acetaminophen), over-the-counter supplements (chondroitin and glucosamine), and topical agents (NSAIDs and rubefacients, including capsaicin) for osteoarthritis. The analytic framework and Key Questions guiding this report are described below.

Key Question 4

What are the comparative benefits and harms of treating osteoarthritis with oral medications compared with topical preparations, or of different topical medications compared with one another?

For the update of this comparative effectiveness review, changes have been made to clarify the Key Questions, but these changes do not alter the meaning of each Key Question. Additional coexisting diseases and concomitant medications were included.

Table 2 describes the characteristics and current indications for the drugs evaluated in this review.

Table 2

Indications and dosing for drugs included in the report.