Choosing the specific course of pharmacologic management for a patient with OA can be overwhelming given the number of options currently available. Acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitor NSAIDs, opioid analgesics, and various topical therapies have been shown to be efficacious in the management of OA pain.^4-6,8 Oral NSAIDs are commonly prescribed because of their established anti-inflammatory effects, clinical efficacy, and lack of addictive potential compared with opioids.^4-7 However, growing awareness of the gastrointestinal and cardiovascular adverse effects of oral NSAIDs and selective COX-2 inhibitors has raised the question of where these agents belong in the overall OA treatment paradigm, especially for patients with established cardiovascular disease or an elevated risk of gastrointestinal adverse events.^10-14 

The dose-related gastrointestinal adverse events associated with oral nonselective NSAIDs occur as a result of the inhibition of the COX-1 enzyme, which is responsible for normal gastroprotective processes.¹⁵ Common gastrointestinal adverse events observed with these agents include dyspepsia (3% to 26%), abdominal pain (3% to 22%), and nausea (2% to 13%).¹⁶ However, more serious adverse events can occur, including upper gastrointestinal bleeding, ulcerations, and death.¹⁷ Oral nonselective NSAIDs have been shown to increase the risk of gastrointestinal complications in individuals already at high risk, including those older than 70 years, those with certain comorbid medical conditions (such as a history of peptic ulcer disease, gastrointestinal bleeding, or active Helicobacter pylori infection), and those who take certain concurrent medications (such as corticosteroids and antiplatelet agents).^17,18 

Oral nonselective NSAIDs are known to cause an increase in blood pressure, but until recently their impact on cardiovascular outcomes was not known. It is now well established that both oral nonselective and COX-2 selective NSAIDs increase the incidence of myocardial infarction, stroke, and death.^12,13,19 This risk can be compounded by the multitude of risk factors for cardiovascular disease, including cigarette smoking, increased age, and comorbid conditions (eg, diabetes mellitus, hyperlipidemia, hypertension).²⁰ The American Heart Association's guidelines on NSAID use suggest that the cardiovascular risks are associated only with chronic use or with higher doses of drugs in this class.¹⁹ More recent evidence, however, suggests that the increase in risk is more rapid: a study of patients taking oral NSAIDs demonstrated that the risk of myocardial infarction increases after the first dose of certain oral nonselective NSAIDs and after 30 days for COX-2 selective NSAIDs.¹³ 

With the increased gastrointestinal and cardiovascular risks associated with oral nonselective NSAIDs, there is a need to establish a first-line therapy plan that maintains the established efficacy profile of these drugs while producing a lower incidence of systemic adverse events. Topical NSAIDs may provide a solution to this challenge for osteopathic physicians. 

Topical NSAIDs have an established role in the pharmacologic management of OA in Europe and were first approved in the United States in 2007.^1,5,6,21-23 Globally, topical preparations are available for diclofenac, eltenac, felbinac, ibuprofen, ketoprofen, and piroxicam.²⁴ Topical NSAIDs approved in the United States, however, are limited to 3 diclofenac formulations: diclofenac epolamine topical patch 1.3% (Flector Patch, King Pharmaceuticals Inc), diclofenac sodium topical gel 1% (Voltaren Gel, Endo Pharmaceuticals Inc), and diclofenac sodium topical solution 1.5% w/w (Pennsaid, Mallinckrodt Inc).^21-23 Of these, both diclofenac sodium topical gel 1% and diclofenac sodium topical solution 1.5% w/w are approved by the US Food and Drug Administration for the management of OA.^21,22 

The recommended use of topical NSAIDs varies among OA management guidelines.^4-7,9 Citing the safety and general effectiveness of topical NSAIDs, international organizations, including the European League Against Rheumatism (EULAR), the Osteoarthritis Research Society International (OARSI), and the National Institute for Health and Clinical Excellence (NICE), have incorporated topical NSAIDs into their OA management guidelines.^1,5,6 The OARSI recommendations state that NSAIDs be used adjunctively or as alternatives to oral analgesic or anti-inflammatory agents in knee OA,⁵ and EULAR recommends their use both in knee OA and preferentially over systemic treatments for hand OA, especially when pain is mild to moderate and affects only a few joints.^6,25 Regarding adjunctive use, it should be noted that current evidence shows that combining a topical NSAID with an oral NSAID confers no additional therapeutic benefit over either agent used alone, but it does increase the number of adverse events.²⁶ 

The NICE guidelines go further than both the EULAR and OARSI guidelines by recommending that topical NSAIDs be considered first-line therapy (ie, before oral NSAIDs, COX-2 inhibitors, or opioids) in all patients with localized OA (such as in the knee), regardless of gastrointestinal or cardiovascular risk. Acetaminophen is given the same recommendation. Under the NICE guidelines, all other pharmacologic options, including oral nonselective NSAIDs, COX-2 selective NSAIDs, and opioids, are considered adjunctive treatments if either a topical NSAID or acetaminophen is insufficient in providing pain relief.⁴ 

Guidelines based in the United States include those issued by the American Academy of Orthopaedic Surgeons, the American College of Rheumatology, and the American Geriatrics Society.^4,7,9 As in the European guidelines, all of these organizations generally agree that topical NSAIDs are safe and may be effective in the management of OA.^4,7,9 However, only the American Academy of Orthopaedic Surgeons⁴ specifically identifies topical NSAIDs as a first-line pharmacologic option in those at increased gastrointestinal risk. These include patients who are using corticosteroids or anticoagulants, are aged 60 years or older, have comorbid medical conditions, or have a history of peptic ulcer disease or gastrointestinal bleeding.⁴ American College of Rheumatology guidelines conditionally recommend topical NSAIDs for the initial management of hand or knee OA and recommend the use of topical rather than oral NSAIDs for patients aged 75 years or older who have hand or knee OA.⁹ 

Of the topical NSAIDs approved in the United States, both diclofenac gel and diclofenac solution have demonstrated efficacy in the management of OA of the knee. In this indication, diclofenac gel has been shown to be more effective than placebo in the management of OA of the knee;^27-29 topical diclofenac solution has demonstrated efficacy similar to that of oral diclofenac.^26,30 

Current guidelines for the management of OA recognize that the consideration of disease progression, level of functional impairment, and coexisting conditions that increase risk of adverse events is vital to the treatment of all patients with OA.^4-7,9 As shown in the Figure, this approach is aligned with the focus of osteopathic medicine on individualizing therapy to the specific patient and avoiding unnecessary adverse effects of therapy.³¹ The recognition of topical NSAIDs in current OA guidelines provides osteopathic physicians with a treatment option that offers pain relief and functional improvement for many patients with OA while avoiding the potential systemic adverse effects of oral formulations.