The Physician and Sportsmedicine: Volume 38: No.2

A Review of Recent Data and Current Treatment Options

Alan R. Brewer, DDS, MD; Bill McCarberg, MD; And Charles E. Argoff, MD

Abstract: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) have an emerging role in the treatment of certain types of acute pain. In addition to their convenience, efficacy, and safety, they are an attractive option, particularly when considering current concerns about the safety of traditional NSAIDs and cyclooxygenase-2 (COX-2) inhibitors (coxibs). Topical analgesics act largely within the peripheral nervous system. Studies have demonstrated that topical NSAIDs penetrate the skin and distribute to the target tissues underlying the application site. Because the pharmacologically effective dose is delivered at the site of pain, there is minimal systemic absorption and risk of related adverse events. Topical NSAIDs have been used for many years in Europe, with extensive post-marketing data available for some of the agents. Three topical NSAID formulations have recently been approved for use in the United States: the diclofenac epolamine topical patch 1.3% (DETP), diclofenac sodium 1% gel, and diclofenac sodium topical solution 1.5%. Topical NSAIDs provide a therapeutic option for treatment of acute, localized, soft tissue injuries or painful conditions in areas of the body that can be readily treated using the topical route of administration. This article reviews available data on the use of topical NSAID therapy.

Keywords: topical analgesic therapy; nonsteroidal anti-inflammatory drugs; diclofenac; pain; musculoskeletal pain; soft tissue injuries

Acute pain due to muscle and other types of minor injuries is common and accounts for significant disability in the general population because of its frequency.¹ Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors (coxibs) have been the mainstay of therapy for these types of acute pain. However, the risk for adverse events (AEs) with traditional NSAIDs and coxibs has led to a search for alternative treatment options, including a re-examination of the topical route of delivery for NSAIDs.^2,3 Topical analgesics act via peripheral mechanisms, and thus provide an opportunity to target peripheral receptors and neural pathways without additional mechanisms of systemic pain relief.⁴ Topical NSAIDs are best suited for treating painful conditions that affect localized superficial musculoskeletal soft tissues in areas that are accessible through topical delivery, such as the shoulder, elbow, knee, hip, or ankle (Table 1).⁵

In appropriate patients, topical NSAIDs have been shown to provide efficacy comparable with that of oral NSAIDs, with an apparent reduced rate of AEs.⁶ In addition to providing a potential safety advantage compared with oral NSAIDs, topical NSAIDs may be better accepted by patients, possibly leading to improved treatment adherence.⁵ To assess the currently available information on topical NSAIDs for treatment of painful conditions, we examined literature available on PubMed and the bibliographies of relevant articles. In addition, information from recent scientific meetings was reviewed for data published in abstract or poster format. All publications were then appraised for relevance to this topic and clinical importance to the health care providers treating patients with painful conditions. During the preparation of this article, another review was published that summarized the differences among available topical NSAIDs and provided evidence for their effectiveness and safety in musculoskeletal pain.⁷

Various topical formulations of NSAIDs have been examined, including diclofenac (gel, patch, spray, solution), ketoprofen (gel, patch, cream), felbinac gel, piroxicam gel, and ibuprofen cream and gel.⁶ Topical NSAID formulations approved by the US Food and Drug Administration (FDA) include the diclofenac epolamine topical patch 1.3% (DETP) for treatment of acute pain due to minor strains, sprains, and contusions; diclofenac sodium 1% gel for treatment of osteoarthritis (OA)-associated pain of joints amenable to topical treatment; and diclofenac sodium topical solution 1.5% for the treatment of signs and symptoms of OA of the knee (Table 2).^8-10 Additional topical NSAIDs being studied in clinical trials include 3 ketoprofen formulations (patch, gel, cream) and a diclofenac sodium patch.¹¹

Topical NSAIDs have been used in Europe for many years, and there is a large body of evidence to support the efficacy and safety of these topical agents in comparison with oral formulas.¹² Recently, in the 2008 guidelines for OA, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom recommended the use of topical NSAIDs prior to therapy with oral NSAIDs, coxibs, or opioids.¹¹

The pharmacology and pharmacokinetics of topical NSAIDs provide a rationale for their use in managing painful conditions. In general, NSAIDs inhibit the inflammatory response by inhibiting the enzyme COX, thus decreasing prostaglandin production. It is thought that the pharmacologic action of topical NSAIDs is not dependent on systemic absorption. Although all NSAIDs have the same mechanism of action (inhibition of prostaglandin synthesis), topical NSAIDs exert their pharmacologic effects predominantly in the tissues underlying the site of application.³ The anti-inflammatory actions of topical NSAIDs (DETP, naproxen gel, ketorolac tromethamine gel) have been demonstrated in soft tissue injuries and inflammatory rheumatoid diseases.^13-17 In acute pain from ankle sprains, use of topical NSAIDs significantly reduced periarticular edema in the malleolar perimeter, as assessed by measurement of the perimeter in millimeters versus the noninjured ankle (DETP vs placebo; P ≤ 0.02 on days 3 and 7)¹³ and statistically reduced ankle swelling, as determined by volumetric measurement of ankle volume compared with placebo (ketorolac tromethamine gel; P = 0.002).¹⁷ In a third study, which used a telethermographic index to assess local inflammation in peri- and extra-articular rheumatologic disease, application of a topical NSAID (DETP) resulted in consistent reduction in heat that was statistically significantly different from placebo at day 3 and through the end of the study.¹⁴ In patients treated with the DETP, periarticular swelling was significantly different from placebo starting on day 5 and through the end of the study; the mean swelling was rated as 0 (absent) from day 7 through study end.¹⁴

Pharmacokinetic studies have shown significantly lower plasma drug concentrations after administration of topical versus oral NSAID formulations.⁶ Peak plasma levels after administration of topical NSAIDs are typically < 10% of those following oral dosing and range from 0.2% to 8.0%.⁶ After 5 days of twice-daily application of the DETP 180 mg, plasma concentrations of diclofenac were in the range of 1.3 to 8.8 ng/mL.^8,18 For comparison, a single dose of oral diclofenac sodium (25 and 50 mg) resulted in peak plasma concentrations of 720 ng/mL to 1214 ng/mL, with up to 1600 ng/mL reported in young females (aged < 22 years) and older women (aged > 65 years).^19,20 The short plasma half-life of diclofenac and the slow diffusion in and out of synovial fluid eventually result in higher concentrations in the synovial fluid and tissue, versus plasma, after oral administration.²¹ This property of diclofenac may be an important factor when considering therapeutic options for site-specific analgesia use. The relatively low systemic bioavailability of topical NSAIDs in comparison with oral NSAIDs suggests a decreased potential for NSAID-related, dose-dependent AEs compared with higher plasma levels seen with oral dosage forms when given at therapeutically effective doses.^3,6,22 However, because topical NSAIDs achieve effective analgesia with lower systemic exposure than oral formulations, trials comparing topical and oral NSAIDs have been performed with high oral doses and low topical doses instead of doses that would result in similar systemic exposure. As far as we are aware, such studies have not been conducted, and it is unknown whether administering prolonged or excessive amounts of the topical NSAID formulation will produce higher systemic levels.⁷

Studies have demonstrated that diclofenac successfully penetrates the skin, as demonstrated by synovial fluid, meniscus, cartilage, and intra-articular adipose tissue concentrations.^23-26 In patients with bilateral joint effusions, diclofenac gel achieved significantly greater concentrations in the synovial fluid, meniscus, and cartilage compared with placebo.²⁶ Available data indicate that direct transport into tissue is not occurring. In a study of patients with bilateral knee joint effusions who received topical diclofenac gel to one knee and placebo gel preparation to the other knee, only the total concentration of diclofenac was significantly higher (15%; P < 0.05) in the diclofenac gel-treated knee than the contralateral placebo-treated knee. Because concentrations of free unbound diclofenac in synovial fluid were similar in the diclofenac- and placebo-treated knees and not significantly different from plasma concentrations, it was concluded that transport of diclofenac was primarily via the plasma.²⁷ Gallacchi and Marcolongo²⁸ found that after topical administration of DETP twice daily, synovial fluid concentrations were sustained at approximately 1.02 ng/mL, with corresponding plasma concentrations of 3 ng/mL.

Two meta-analyses have evaluated the efficacy of topical NSAIDs compared with placebo or active controls in patients with acute and chronic pain.^29,30 In the first meta-analysis, conducted in 1998, Moore et al³⁰ reviewed data from 86 controlled trials involving 10 160 patients and concluded that topical NSAIDs were effective in relieving pain in both acute and chronic conditions.³⁰ In addition, these authors found a very low incidence of systemic AEs with topical therapy (< 0.5%).³⁰ The second meta-analysis was performed to include more recent data and exclude topical salicylate and benzydamine, which are no longer classified as topical NSAIDs. Mason et al²⁹ analyzed the results from randomized double-blind studies that included 2853 patients and found that topical NSAID therapy provided greater pain relief than placebo, with results reaching statistical significance in 19 of 26 trials (Figure 1).²⁹ For additional information about topical NSAIDs that have been studied in small numbers of patients or exclusively in Europe, readers are encouraged to consult these reviews by Mason et al²⁹ and Moore et al.³⁰

The most recent studies on the use of topical NSAIDs, particularly the 3 diclofenac formulations recently approved for use in the United States, are reviewed in the following sections.

The DETP has been approved by the FDA for use in acute pain due to minor strains, sprains, and contusions. It is a semiocclusive adhesive patch containing diclofenac epolamine 1.3%, which provides a continuous release of diclofenac over a 12-hour period.⁸ The safety and efficacy of the DETP have been studied in soft tissue injuries, arthritic conditions, and connective tissue conditions.

Five controlled studies evaluated the efficacy of the DETP in soft tissue injuries.^13,15,31-33 The DETP provided significantly superior pain relief versus placebo starting at hour 4 after the first application (Figure 2).¹⁵ The time to resolution of pain was approximately 3 days shorter in patients treated with the DETP compared with placebo.^32,34

Three randomized controlled studies and a pooled analysis have shown the efficacy of the DETP in arthritic conditions.^14,35-37 Evaluation of data from 1 controlled study and a pooled analysis in patients with OA showed the DETP significantly improved Lequesne functional index (an index of functional ability measured by pain) and pain intensity.^35,36 In addition, the DETP was shown to significantly reduce pain (P < 0.001) and decrease night awakenings and the need for rescue medication compared with placebo (P < 0.005) in patients with OA.³⁷ In the pooled analysis, the effects of the DETP on pain and physical function were similar to those of oral NSAIDs, as indicated by relative benefit data and the number of patients needed to treat (3.0 for ≥ 50% reduction of pain) to observe additional benefit.³⁶

Two studies have reported the efficacy of the DETP in connective tissue conditions, including localized inflammatory disease (tendonitis and bursitis) and epicondylitis.^38,39 In these studies, patients treated with the DETP were significantly less likely to have moderate to very strong spontaneous pain versus those treated with placebo (26.8% vs 60.9%, respectively; P < 0.05), and a greater reduction in spontaneous pain verbal score versus diclofenac 1.16% gel (58.1% vs 39.5%; P < 0.001) after 2 weeks of treatment.^38,39 Because the 2 diclofenac formulations were considered to have equivalent concentrations of active drug, the authors theorized the improved efficacy of the DETP versus gel was due to more constant release of active substance to the target area by the DETP.³⁹

Diclofenac sodium is available in 3 topical formulations in various parts of the world, including drops, gels, and a patch. Diclofenac sodium gel 1% was approved by the FDA in 2007 for use in treating pain associated with OA in joints amenable to topical treatment. This formulation has been studied both in short-term (8–12 week) studies and up to 12 months in a long-term, open-label safety trial.⁹ The results of the short-term studies found that diclofenac sodium gel 1% applied to the knee or hand provided significantly greater improvement in Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain and physical function subscales, or the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) and global rating of disease pain scores on a visual analog scale (VAS) versus placebo.^40,41

Diclofenac sodium 1.5% drops¹⁰ were approved by the FDA in 2009 for the topical treatment of pain associated with knee OA. The efficacy of this formulation was analyzed in a systematic review of 4 randomized controlled trials having a mean duration of 8.5 weeks.⁴² In comparison with placebo, diclofenac drops significantly reduced pain and stiffness, and improved physical function in patients with OA.⁴² In a 12-week equivalence trial that used the WOMAC pain and physical function subscales to compare treatment response, diclofenac drops were as effective as oral diclofenac in patients with knee OA, but had improved tolerability.⁴³ The topical penetration of diclofenac in the drop formulation is enhanced by a carrier containing dimethylsulfoxide (DMSO); however, the absorption and metabolism of DMSO can occasionally lead to halitosis and changes in taste perception in some patients.⁴⁴

Finally, in Germany, diclofenac sodium has been studied in a patch formulation. In patients with traumatic, blunt soft tissue injury treated twice daily with either diclofenac patch or placebo, the diclofenac sodium patch was significantly more effective in relieving tenderness in the first 3 days.⁴⁵ In addition, the diclofenac sodium patch was associated with a significantly shorter time to reach resolution of pain versus placebo.⁴⁵

Topical ibuprofen 5% in a cream formulation has been studied in ankle sprains, knee OA, and soft tissue injuries. In ankle sprains, ibuprofen 5% cream was superior to placebo in reducing total VAS pain scores, which included pain at rest and on standing and walking, over the first 48 hours of treatment (P < 0.05).⁴⁶ In a second study, a larger percentage of patients with knee OA responded to treatment with ibuprofen 5% cream versus placebo (84% vs 40%; response defined as a decrease in pain score of ≥ 18 mm or ≥ 23% reduction from baseline) and achieved a greater reduction in Lequesne index scores than those in the placebo group (27.5% vs 10.7%).⁴⁷ Topical ibuprofen cream also had analgesic efficacy equivalent to oral ibuprofen over 24 months in elderly patients with chronic knee pain, as determined by WOMAC global scores.⁴⁸

In soft tissue injuries, ibuprofen 5% gel was more likely to achieve a clinically meaningful reduction in interference of physical activity versus placebo (79% vs 44%).⁴⁹ When the efficacy of ibuprofen 5% gel and ibuprofen 400 mg oral tablets (1200 mg daily) was compared in a double-blind, double-dummy, parallel-group study in patients with acute pain from soft tissue injuries, the treatment groups showed similar time to clinically significant relief (defined as a reduction from baseline VAS score of 3 cm, or a score of 0 if the initial pain score was < 3 cm) from pain at rest or on movement and swelling. The gel formulation also had improved tolerability compared with the oral formulation.⁵⁰

Topical ketoprofen has been studied in both patch and gel formulations. The ketoprofen patch maintains a continual release of drug over a 24-hour period, resulting in low plasma ketoprofen concentrations. The total systemic bioavailability of 100 mg of ketoprofen administered via a patch is no more than 10% of that reported for ketoprofen 100 mg administered orally. Phase 3 clinical trials in patients with nonarticular rheumatism (tendinitis, N = 172) and traumatic, painful, soft tissue injuries (ankle sprain, N = 163) showed that the topical ketoprofen patch was significantly more effective than placebo at reducing pain during daily activities and spontaneous pain after 7 days of treatment.⁵¹

One gel formulation of ketoprofen incorporates a Transfersome^® technology (IDEA-033) that improves drug penetration through the skin barrier while limiting systemic absorption. IDEA-033 Transfersome^® gel (110 mg in 4.8 g Transfersome^®) was compared with oral celecoxib 100 mg and placebo in patients with pain flare due to knee OA.⁵² At study end, IDEA-033 was shown to be significantly superior to placebo and similar to celecoxib 100 mg in pain reduction, as assessed by change from baseline score on WOMAC pain (P = 0.004 and 0.0004 vs placebo for IDEA-033 and celecoxib, respectively) and physical function subscales (Figure 3).⁵² A second study found that IDEA-033 50 mg applied twice daily for 12 weeks successfully managed pain flare in patients with knee OA.⁵³ Patients who participated in a 12-week extension of this study achieved significant additional improvement in scores on WOMAC pain, physical function, and stiffness subscales between weeks 12 and 24.⁵⁴ In 20 healthy subjects with muscle injury/soreness due to exercise, short-term treatment with IDEA-033 (50 or 100 mg) for 7 days was shown to have beneficial effects.⁵⁵

Topical NSAIDs, which have been marketed principally in Europe for > 10 years and since January 2007 in the United States, have been associated with good tolerability in both clinical trials and post-marketing experience. The incidence of AEs was low in clinical studies compared with placebo.^29,30,43,56 The most common AEs reported were mild local skin reactions, including pruritus, dermatitis, and burning.

It is important to remember that all NSAIDs, including topical formulations, contain black box warnings concerning increased risk of cardiovascular thrombotic events, myocardial infarction and stroke, and serious gastrointestinal (GI) AEs.^8,9 Nonsteroidal anti-inflammatory drugs should be administered at the lowest effective dose for the shortest duration possible.⁸ Topical NSAIDs should only be applied to healthy skin, free of lesions and/or current dermatologic conditions. Nonsteroidal anti-inflammatory drugs should not be used in patients who have experienced allergic-type reactions after taking aspirin or other NSAIDs, or in pregnant women, and use is contraindicated in patients undergoing coronary artery bypass graft surgery. In addition, the benefit/risk ratio should be carefully evaluated when considering NSAID use in patients prone to urticaria, angioedema, or bronchospasm.

Based on post-marketing reports of drug-induced hepatotoxicity, which included liver necrosis, jaundice, fulminant hepatitis, and liver failure, new warnings and precautions for hepatic effects have recently been added for all topical diclofenac products and are now consistent with oral diclofenac formulations. Patients receiving products containing diclofenac should be monitored within 4 to 8 weeks of initiating therapy, and periodically thereafter, for changes in transaminase levels and signs of hepatotoxicity.^8-10 Possible mechanisms proposed for diclofenac-induced hepatotoxicity include underlying disease, reactive diclofenac metabolites, diclofenac activation of redox-sensitive transcription factors, and immunoallergic reactions.⁵⁷ However, minimal data have been published on the etiology of diclofenac hepatotoxicity, and risk factors have not been identified.⁵⁷ Therefore, individual risk assessment and ongoing monitoring are recommended in all patients.

In a 2004 meta-analysis of placebo-controlled trials studying topical NSAIDs, the percentage of patients experiencing ≥ 1 local AEs (4%) or a systemic AE (2.5%) and the percentage of patients withdrawing because of an AE (0.8%) were similar between topical NSAIDs and placebo. Likewise, there were no differences in systemic AEs and discontinuations because of AEs between topical and oral NSAIDs.²⁹ However, a recent systematic review of topical NSAID therapies found a reduced risk of systemic AEs with topical versus oral NSAID treatment.⁷

In patients treated with the DETP, discontinuation rates due to AEs were the same as those seen with placebo patch (3%); the most common AEs leading to discontinuation were application site reactions, which occurred in 2% of both treatment groups.⁸ Post-marketing data for DETP use in Europe and the United States between June 1993 and January 2008 include approximately 175 million units and 6.25 million patients treated for an average of 14 days. During the 14-year period, a total of 108 patients reported 178 AEs, of which most were general disorders (drug ineffective) and application site conditions (n = 43) or skin and subcutaneous disorders (n = 53). Ten patients reported 13 GI AEs.⁵⁸

Similarly, data from an open-label study of diclofenac sodium gel (up to 32 g/day), in which patients were treated for 1 year, show that the incidence of AEs was comparable to that observed in placebo-controlled clinical trials. In this long-term study, most AEs were application site reactions (11%).⁹

In 1995, Zimmerman et al⁵⁹ reported 4 cases of upper GI hemorrhage associated with topical diclofenac gel. Gastrointestinal disorders, including nausea, dysgeusia, and dyspepsia, have been reported in a small proportion of patients treated with the DETP and diclofenac sodium gel (≤ 3%).^8,9

Application site AEs were significantly more common in patients receiving topical diclofenac solution than in patients who had received oral diclofenac. However, patients who had received the topical diclofenac solution had significantly fewer GI AEs compared with oral diclofenac.^7,43

Cutaneous AEs are the most commonly reported AEs in patients treated with topical NSAIDs, reported overall in 1% to 2% of patients.⁵⁶ Because the incidence of cutaneous reactions is similar to those seen with placebo,^8,9 it is thought that many of these reactions may be attributed to the vehicle rather than to the active ingredient with some formulations.⁵⁶

Aspects of pain processing and transmission that involve peripheral pathways may be amenable to therapeutic intervention by local application of an analgesic to the skin overlying the painful area. The advantages of this approach include a high level of patient acceptance, ease of administration, likely reduced risk of systemic side effects, and a reduced potential for drug–drug interactions.

Topical NSAIDs may be useful in a range of localized clinical conditions, including sprains, strains, soft tissue rheumatism, sports injuries, periarthritis, and tendinitis. The topical route of pain relief may be particularly useful for elderly patients, patients on polypharmacy, patients who have risk factors for GI toxicity, and those who are reluctant to take oral medications. Patients with hepatic and renal insufficiencies may have difficulty with the metabolism and clearance of systemic analgesics and, therefore, may also benefit from topical nonsystemic analgesic therapy.⁴⁴

The importance of topical NSAID formulations as part of the therapeutic armamentarium for the treatment of pain is reflected in the recent 2008 guidelines for OA from NICE in the United Kingdom. The NICE guidelines recommend use of topical NSAIDs, when possible, prior to therapy with oral traditional NSAIDs, coxibs, or opioids.¹¹ Topical NSAIDs provide valuable analgesic options for the treatment of localized painful conditions that have an inflammatory component. Their low relative bioavailability compared with oral NSAIDs is likely responsible for the low risk for AEs observed in controlled clinical trials compared with what would be expected from treatment with traditional NSAIDs via oral administration. Minor cutaneous irritation has been the most common AE observed across clinical trials and post-marketing safety surveillance.

Among the available formulation choices, topical patches offer some unique advantages, including provision of a constant fixed dose, local action, and light bandaging.⁵ Patches are also well accepted by patients; however, gel formulations may be preferred in areas of the body that are not easily treated with a patch, such as the fingers.

Writing and editorial assistance for this article was provided by Quintiles, Parsippany, NJ. Funding for writing and editorial support was provided by King Pharmaceuticals, Inc.^®, Bridgewater, NJ. Funders were involved in the review of the manuscript for accuracy of content.



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