NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have therapeutic applications that "have spanned several centuries," according to Rao and Knaus (J. Pharm. Pharm. Sci. 2008;11:81s-110s). NSAIDs are among the increasing number of anti-inflammatory agents used to target bioactive lipids produced from arachidonic acid. Although this drug class is one of the most often used in practice and has been well studied by investigators, the role of NSAIDs for cutaneous purposes has been relatively limited (J. Cutan. Med. Surg. 2002;6:241-56). Indeed, only three topical NSAIDs are approved for use in the United States, for a narrow range of conditions.

Diclofenac sodium 1.5% topical solution (containing dimethyl sulfoxide to enhance penetration) and diclofenac sodium gel 1% are currently approved in the United States for hand and knee osteoarthritis (Postgrad. Med. 2010;122:98-106). The diclofenac hydroxyethylpyrrolidine (epolamine) 1.3% patch was approved by the U.S. Food and Drug Administration for soft-tissue injuries in January 2007, although it has long been available in more than 40 countries (Int. J. Clin. Pract. 2010;64:1546-53; Clin. Ther. 2010;32:1001-14).

A winning adverse event profile

Significantly, topical NSAIDs have not been associated with the adverse events resulting from oral NSAIDs, which engender various dose-related side effects (Semin. Arthritis. Rheum. 2009;39:203-12). Mild and self-limiting local skin reactions are the most common adverse side effects from topical NSAID products. The diclofenac products are approved in the European Union, as are ibuprofen creams and gels, ketoprofen gel, felbinac gel and cutaneous foam, and piroxicam gel.

The efficacy and safety of these products have been established through meta-analyses. In a recent study, researchers cautioned that the patient, the drug, and the drug delivery mechanism should be considered in topical NSAID selection, because the pharmacokinetic absorption from topical preparations can vary with different formulations of the same drug, depending on the agent, the underlying disorder, and the application site (Am. J. Ther. 2012 Feb 22 [Epub ahead of print]).

Easing osteoarthritis

Although oral NSAIDs have been the mainstays of hand and knee osteoarthritis treatment regimens, their dose- and age-related side effect profiles (including adverse effects on the cardiovascular, renal, and gastrointestinal systems) have prompted the use of topical NSAIDs, which yield comparable efficacy with far less systemic risk. Results of a Jan. 1, 2005, to March 31, 2010, literature review showed that topical products exhibited superior efficacy compared with placebo, with similar adverse event profiles. Topicals also showed efficacy comparable to that of oral diclofenac, with side effects seen primarily at the application site and no ulcers, perforations, or bleeding (Postgrad. Med. 2010;122(6):98-106).

In 2009, Barthel et al. evaluated the efficacy and safety of topical diclofenac sodium gel (DSG) 1% in a randomized, double-blind, vehicle-controlled trial of 492 adults (aged 35 years and older) with mild to moderate symptomatic knee osteoarthritis lasting at least 6 months. Patients received 4 g of topical treatment of DSG or vehicle four times daily for 12 weeks. The investigators noted significant reductions in the DSG group compared with the vehicle group according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function subscales, as well as global rating of disease. They also observed significantly better efficacy results with DSG as early as week 1 of treatment. Gastrointestinal reactions occurred in 5.9% of the DSG group and 5.0% of the vehicle group, and application site reactions emerged in 5.1% of the DSG group and 2.5% of the vehicle group (Semin. Arthritis Rheum. 2009;39:203-12).

In 2010, Baraf et al. also conducted a 12-week efficacy and safety study of topical DSG 1% for symptomatic knee osteoarthritis. This randomized, double-blind, parallel-group, multicenter trial of patients at least 35 years of age with symptomatic Kellgren-Lawrence grade (KLG) 1 to 3 osteoarthritis in one or both knees for at least 6 months assigned 208 subjects to DSG treatment and 212 to vehicle. The investigators found significant improvement according to WOMAC metrics in the DSG patients compared with placebo patients. Unlike the Barthel report, no gastrointestinal upset was noted in this study. Application site reactions were the most common side effect, occurring in 4.8% of the DSG group and 0% of the vehicle group (Phys. Sportsmed. 2010;38:19-28).

In 2012, Baraf et al. extended their previous work and assessed the safety of topical DSG 1% for the treatment of knee and hand osteoarthritis in older and younger patients. They also compared the treatment in those with or without comorbid hypertension, type 2 diabetes, or cerebrovascular or cardiovascular disease. This post hoc analysis of pooled data from five randomized, double-blind, placebo-controlled trials included 1,426 patients 35 years of age and older with mild to moderate osteoarthritis of the knee and 783 patients 40 years of age and older with mild to moderate osteoarthritis of the hand. Participants applied 4 g of DSG or vehicle to affected knees q.i.d. for 12 weeks or 2 g of DSG or vehicle to affected hands q.i.d. for 8 weeks. The investigators found that the adverse event profile was similar across comparisons of patients with knee osteoarthritis. Among patients with hand osteoarthritis, the only differences were that the adverse event profile was lower in patients with type 2 diabetes than in patients without the condition, and higher in patients with cerebrovascular or cardiovascular disease than in patients without those conditions. The authors concluded that the rates of adverse side effects were similar and low between the two groups (Am. J. Geriatr. Pharmacother. 2012;10:47-60).

To further examine the efficacy and tolerability of the diclofenac epolamine topical patch (DETP), investigators reviewed data from eight studies from 1984 to 2009, including data on patients with acute pain from soft-tissue injuries or localized periarticular disorders. Significant reductions in spontaneous pain from baseline due to DETP were seen (range, 26%-88% on day 7 and 56%-61% on day 14). In addition, significant decreases in pain scores were linked to DETP use compared with a placebo patch in two studies and compared with diclofenac diethylammonium topical gel in one study. Adverse events were low across studies; reactions at the application site and nausea were the most common events (Clin. Ther. 2010;32:1001-14).

Oral ibuprofen and combination therapy

Notably, ibuprofen has demonstrated effectiveness in the treatment of acne, as inflammatory acne lesions are infiltrated with neutrophils and ibuprofen suppresses leukocyte chemotaxis (Dermatology. 2003;206:68-73). Ibuprofen is generally considered safe, with low potential for causing gastrointestinal, cardiovascular, or renal risks compared with other NSAIDs and selective cyclooxygenase-2 inhibitors (coxibs), which have been removed from the market (Inflammopharmacology 2009;17:275-342; J. Pharm. Pharm. Sci. 2008;11:81s-110s).

In a double-blind study of 60 patients aged 15-35 years with acne vulgaris, patients were randomly assigned to one of four groups: oral ibuprofen (600 mg) plus tetracycline (250 mg) four times daily; ibuprofen (600 mg) plus placebo four times daily; tetracycline (250 mg) plus placebo four times daily; and two placebos four times daily. Interestingly, the combination therapy was the only approach that yielded an effect statistically superior to that of placebo in reducing total lesion counts. The use of ibuprofen alone netted improvements comparable to those afforded by tetracycline but with fewer side effects (J. Am. Acad. Dermatol. 1984;11:1076-81).

NSAIDs are also used for the treatment of sunburn. In 1992, Hughes et al. investigated ameliorating UVB-induced skin injury by nonsteroidal drugs (oral ibuprofen or indomethacin) plus topical betamethasone dipropionate in 24 subjects. Measurements of erythema and increased skin blood flow, performed serially, revealed a synergistic effect of oral NSAIDs combined with topical corticosteroids to repair UVB-induced skin damage (Dermatology 1992;184:54-8).

Conclusion

An ideal anti-inflammatory agent has not yet been developed, but topical NSAIDs appear to fit the bill in terms of reducing or eliminating the adverse side effects associated with oral NSAID regimens. However, topical NSAIDs are approved for only a narrow range of indications, and more research is necessary to determine whether they are appropriate for a wider array of dermatologic conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) have therapeutic applications that "have spanned several centuries," according to Rao and Knaus (J. Pharm. Pharm. Sci. 2008;11:81s-110s). NSAIDs are among the increasing number of anti-inflammatory agents used to target bioactive lipids produced from arachidonic acid. Although this drug class is one of the most often used in practice and has been well studied by investigators, the role of NSAIDs for cutaneous purposes has been relatively limited (J. Cutan. Med. Surg. 2002;6:241-56). Indeed, only three topical NSAIDs are approved for use in the United States, for a narrow range of conditions.

Diclofenac sodium 1.5% topical solution (containing dimethyl sulfoxide to enhance penetration) and diclofenac sodium gel 1% are currently approved in the United States for hand and knee osteoarthritis (Postgrad. Med. 2010;122:98-106). The diclofenac hydroxyethylpyrrolidine (epolamine) 1.3% patch was approved by the U.S. Food and Drug Administration for soft-tissue injuries in January 2007, although it has long been available in more than 40 countries (Int. J. Clin. Pract. 2010;64:1546-53; Clin. Ther. 2010;32:1001-14).

A winning adverse event profile

Significantly, topical NSAIDs have not been associated with the adverse events resulting from oral NSAIDs, which engender various dose-related side effects (Semin. Arthritis. Rheum. 2009;39:203-12). Mild and self-limiting local skin reactions are the most common adverse side effects from topical NSAID products. The diclofenac products are approved in the European Union, as are ibuprofen creams and gels, ketoprofen gel, felbinac gel and cutaneous foam, and piroxicam gel.

The efficacy and safety of these products have been established through meta-analyses. In a recent study, researchers cautioned that the patient, the drug, and the drug delivery mechanism should be considered in topical NSAID selection, because the pharmacokinetic absorption from topical preparations can vary with different formulations of the same drug, depending on the agent, the underlying disorder, and the application site (Am. J. Ther. 2012 Feb 22 [Epub ahead of print]).

Easing osteoarthritis

Although oral NSAIDs have been the mainstays of hand and knee osteoarthritis treatment regimens, their dose- and age-related side effect profiles (including adverse effects on the cardiovascular, renal, and gastrointestinal systems) have prompted the use of topical NSAIDs, which yield comparable efficacy with far less systemic risk. Results of a Jan. 1, 2005, to March 31, 2010, literature review showed that topical products exhibited superior efficacy compared with placebo, with similar adverse event profiles. Topicals also showed efficacy comparable to that of oral diclofenac, with side effects seen primarily at the application site and no ulcers, perforations, or bleeding (Postgrad. Med. 2010;122(6):98-106).

In 2009, Barthel et al. evaluated the efficacy and safety of topical diclofenac sodium gel (DSG) 1% in a randomized, double-blind, vehicle-controlled trial of 492 adults (aged 35 years and older) with mild to moderate symptomatic knee osteoarthritis lasting at least 6 months. Patients received 4 g of topical treatment of DSG or vehicle four times daily for 12 weeks. The investigators noted significant reductions in the DSG group compared with the vehicle group according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function subscales, as well as global rating of disease. They also observed significantly better efficacy results with DSG as early as week 1 of treatment. Gastrointestinal reactions occurred in 5.9% of the DSG group and 5.0% of the vehicle group, and application site reactions emerged in 5.1% of the DSG group and 2.5% of the vehicle group (Semin. Arthritis Rheum. 2009;39:203-12).

In 2010, Baraf et al. also conducted a 12-week efficacy and safety study of topical DSG 1% for symptomatic knee osteoarthritis. This randomized, double-blind, parallel-group, multicenter trial of patients at least 35 years of age with symptomatic Kellgren-Lawrence grade (KLG) 1 to 3 osteoarthritis in one or both knees for at least 6 months assigned 208 subjects to DSG treatment and 212 to vehicle. The investigators found significant improvement according to WOMAC metrics in the DSG patients compared with placebo patients. Unlike the Barthel report, no gastrointestinal upset was noted in this study. Application site reactions were the most common side effect, occurring in 4.8% of the DSG group and 0% of the vehicle group (Phys. Sportsmed. 2010;38:19-28).

In 2012, Baraf et al. extended their previous work and assessed the safety of topical DSG 1% for the treatment of knee and hand osteoarthritis in older and younger patients. They also compared the treatment in those with or without comorbid hypertension, type 2 diabetes, or cerebrovascular or cardiovascular disease. This post hoc analysis of pooled data from five randomized, double-blind, placebo-controlled trials included 1,426 patients 35 years of age and older with mild to moderate osteoarthritis of the knee and 783 patients 40 years of age and older with mild to moderate osteoarthritis of the hand. Participants applied 4 g of DSG or vehicle to affected knees q.i.d. for 12 weeks or 2 g of DSG or vehicle to affected hands q.i.d. for 8 weeks. The investigators found that the adverse event profile was similar across comparisons of patients with knee osteoarthritis. Among patients with hand osteoarthritis, the only differences were that the adverse event profile was lower in patients with type 2 diabetes than in patients without the condition, and higher in patients with cerebrovascular or cardiovascular disease than in patients without those conditions. The authors concluded that the rates of adverse side effects were similar and low between the two groups (Am. J. Geriatr. Pharmacother. 2012;10:47-60).

To further examine the efficacy and tolerability of the diclofenac epolamine topical patch (DETP), investigators reviewed data from eight studies from 1984 to 2009, including data on patients with acute pain from soft-tissue injuries or localized periarticular disorders. Significant reductions in spontaneous pain from baseline due to DETP were seen (range, 26%-88% on day 7 and 56%-61% on day 14). In addition, significant decreases in pain scores were linked to DETP use compared with a placebo patch in two studies and compared with diclofenac diethylammonium topical gel in one study. Adverse events were low across studies; reactions at the application site and nausea were the most common events (Clin. Ther. 2010;32:1001-14).

Oral ibuprofen and combination therapy

Notably, ibuprofen has demonstrated effectiveness in the treatment of acne, as inflammatory acne lesions are infiltrated with neutrophils and ibuprofen suppresses leukocyte chemotaxis (Dermatology. 2003;206:68-73). Ibuprofen is generally considered safe, with low potential for causing gastrointestinal, cardiovascular, or renal risks compared with other NSAIDs and selective cyclooxygenase-2 inhibitors (coxibs), which have been removed from the market (Inflammopharmacology 2009;17:275-342; J. Pharm. Pharm. Sci. 2008;11:81s-110s).

In a double-blind study of 60 patients aged 15-35 years with acne vulgaris, patients were randomly assigned to one of four groups: oral ibuprofen (600 mg) plus tetracycline (250 mg) four times daily; ibuprofen (600 mg) plus placebo four times daily; tetracycline (250 mg) plus placebo four times daily; and two placebos four times daily. Interestingly, the combination therapy was the only approach that yielded an effect statistically superior to that of placebo in reducing total lesion counts. The use of ibuprofen alone netted improvements comparable to those afforded by tetracycline but with fewer side effects (J. Am. Acad. Dermatol. 1984;11:1076-81).

NSAIDs are also used for the treatment of sunburn. In 1992, Hughes et al. investigated ameliorating UVB-induced skin injury by nonsteroidal drugs (oral ibuprofen or indomethacin) plus topical betamethasone dipropionate in 24 subjects. Measurements of erythema and increased skin blood flow, performed serially, revealed a synergistic effect of oral NSAIDs combined with topical corticosteroids to repair UVB-induced skin damage (Dermatology 1992;184:54-8).

Conclusion

An ideal anti-inflammatory agent has not yet been developed, but topical NSAIDs appear to fit the bill in terms of reducing or eliminating the adverse side effects associated with oral NSAID regimens. However, topical NSAIDs are approved for only a narrow range of indications, and more research is necessary to determine whether they are appropriate for a wider array of dermatologic conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) have therapeutic applications that "have spanned several centuries," according to Rao and Knaus (J. Pharm. Pharm. Sci. 2008;11:81s-110s). NSAIDs are among the increasing number of anti-inflammatory agents used to target bioactive lipids produced from arachidonic acid. Although this drug class is one of the most often used in practice and has been well studied by investigators, the role of NSAIDs for cutaneous purposes has been relatively limited (J. Cutan. Med. Surg. 2002;6:241-56). Indeed, only three topical NSAIDs are approved for use in the United States, for a narrow range of conditions.

Diclofenac sodium 1.5% topical solution (containing dimethyl sulfoxide to enhance penetration) and diclofenac sodium gel 1% are currently approved in the United States for hand and knee osteoarthritis (Postgrad. Med. 2010;122:98-106). The diclofenac hydroxyethylpyrrolidine (epolamine) 1.3% patch was approved by the U.S. Food and Drug Administration for soft-tissue injuries in January 2007, although it has long been available in more than 40 countries (Int. J. Clin. Pract. 2010;64:1546-53; Clin. Ther. 2010;32:1001-14).

A winning adverse event profile

Significantly, topical NSAIDs have not been associated with the adverse events resulting from oral NSAIDs, which engender various dose-related side effects (Semin. Arthritis. Rheum. 2009;39:203-12). Mild and self-limiting local skin reactions are the most common adverse side effects from topical NSAID products. The diclofenac products are approved in the European Union, as are ibuprofen creams and gels, ketoprofen gel, felbinac gel and cutaneous foam, and piroxicam gel.

The efficacy and safety of these products have been established through meta-analyses. In a recent study, researchers cautioned that the patient, the drug, and the drug delivery mechanism should be considered in topical NSAID selection, because the pharmacokinetic absorption from topical preparations can vary with different formulations of the same drug, depending on the agent, the underlying disorder, and the application site (Am. J. Ther. 2012 Feb 22 [Epub ahead of print]).

Easing osteoarthritis

Although oral NSAIDs have been the mainstays of hand and knee osteoarthritis treatment regimens, their dose- and age-related side effect profiles (including adverse effects on the cardiovascular, renal, and gastrointestinal systems) have prompted the use of topical NSAIDs, which yield comparable efficacy with far less systemic risk. Results of a Jan. 1, 2005, to March 31, 2010, literature review showed that topical products exhibited superior efficacy compared with placebo, with similar adverse event profiles. Topicals also showed efficacy comparable to that of oral diclofenac, with side effects seen primarily at the application site and no ulcers, perforations, or bleeding (Postgrad. Med. 2010;122(6):98-106).

In 2009, Barthel et al. evaluated the efficacy and safety of topical diclofenac sodium gel (DSG) 1% in a randomized, double-blind, vehicle-controlled trial of 492 adults (aged 35 years and older) with mild to moderate symptomatic knee osteoarthritis lasting at least 6 months. Patients received 4 g of topical treatment of DSG or vehicle four times daily for 12 weeks. The investigators noted significant reductions in the DSG group compared with the vehicle group according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function subscales, as well as global rating of disease. They also observed significantly better efficacy results with DSG as early as week 1 of treatment. Gastrointestinal reactions occurred in 5.9% of the DSG group and 5.0% of the vehicle group, and application site reactions emerged in 5.1% of the DSG group and 2.5% of the vehicle group (Semin. Arthritis Rheum. 2009;39:203-12).

In 2010, Baraf et al. also conducted a 12-week efficacy and safety study of topical DSG 1% for symptomatic knee osteoarthritis. This randomized, double-blind, parallel-group, multicenter trial of patients at least 35 years of age with symptomatic Kellgren-Lawrence grade (KLG) 1 to 3 osteoarthritis in one or both knees for at least 6 months assigned 208 subjects to DSG treatment and 212 to vehicle. The investigators found significant improvement according to WOMAC metrics in the DSG patients compared with placebo patients. Unlike the Barthel report, no gastrointestinal upset was noted in this study. Application site reactions were the most common side effect, occurring in 4.8% of the DSG group and 0% of the vehicle group (Phys. Sportsmed. 2010;38:19-28).

In 2012, Baraf et al. extended their previous work and assessed the safety of topical DSG 1% for the treatment of knee and hand osteoarthritis in older and younger patients. They also compared the treatment in those with or without comorbid hypertension, type 2 diabetes, or cerebrovascular or cardiovascular disease. This post hoc analysis of pooled data from five randomized, double-blind, placebo-controlled trials included 1,426 patients 35 years of age and older with mild to moderate osteoarthritis of the knee and 783 patients 40 years of age and older with mild to moderate osteoarthritis of the hand. Participants applied 4 g of DSG or vehicle to affected knees q.i.d. for 12 weeks or 2 g of DSG or vehicle to affected hands q.i.d. for 8 weeks. The investigators found that the adverse event profile was similar across comparisons of patients with knee osteoarthritis. Among patients with hand osteoarthritis, the only differences were that the adverse event profile was lower in patients with type 2 diabetes than in patients without the condition, and higher in patients with cerebrovascular or cardiovascular disease than in patients without those conditions. The authors concluded that the rates of adverse side effects were similar and low between the two groups (Am. J. Geriatr. Pharmacother. 2012;10:47-60).

To further examine the efficacy and tolerability of the diclofenac epolamine topical patch (DETP), investigators reviewed data from eight studies from 1984 to 2009, including data on patients with acute pain from soft-tissue injuries or localized periarticular disorders. Significant reductions in spontaneous pain from baseline due to DETP were seen (range, 26%-88% on day 7 and 56%-61% on day 14). In addition, significant decreases in pain scores were linked to DETP use compared with a placebo patch in two studies and compared with diclofenac diethylammonium topical gel in one study. Adverse events were low across studies; reactions at the application site and nausea were the most common events (Clin. Ther. 2010;32:1001-14).

Oral ibuprofen and combination therapy

Notably, ibuprofen has demonstrated effectiveness in the treatment of acne, as inflammatory acne lesions are infiltrated with neutrophils and ibuprofen suppresses leukocyte chemotaxis (Dermatology. 2003;206:68-73). Ibuprofen is generally considered safe, with low potential for causing gastrointestinal, cardiovascular, or renal risks compared with other NSAIDs and selective cyclooxygenase-2 inhibitors (coxibs), which have been removed from the market (Inflammopharmacology 2009;17:275-342; J. Pharm. Pharm. Sci. 2008;11:81s-110s).

In a double-blind study of 60 patients aged 15-35 years with acne vulgaris, patients were randomly assigned to one of four groups: oral ibuprofen (600 mg) plus tetracycline (250 mg) four times daily; ibuprofen (600 mg) plus placebo four times daily; tetracycline (250 mg) plus placebo four times daily; and two placebos four times daily. Interestingly, the combination therapy was the only approach that yielded an effect statistically superior to that of placebo in reducing total lesion counts. The use of ibuprofen alone netted improvements comparable to those afforded by tetracycline but with fewer side effects (J. Am. Acad. Dermatol. 1984;11:1076-81).

NSAIDs are also used for the treatment of sunburn. In 1992, Hughes et al. investigated ameliorating UVB-induced skin injury by nonsteroidal drugs (oral ibuprofen or indomethacin) plus topical betamethasone dipropionate in 24 subjects. Measurements of erythema and increased skin blood flow, performed serially, revealed a synergistic effect of oral NSAIDs combined with topical corticosteroids to repair UVB-induced skin damage (Dermatology 1992;184:54-8).

Conclusion

An ideal anti-inflammatory agent has not yet been developed, but topical NSAIDs appear to fit the bill in terms of reducing or eliminating the adverse side effects associated with oral NSAID regimens. However, topical NSAIDs are approved for only a narrow range of indications, and more research is necessary to determine whether they are appropriate for a wider array of dermatologic conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest.