Nonsteroidal anti-inflammatory drugs (NSAIDs) have been an important therapy in the treatment of a large number of cutaneous pathologies for more than three decades.
Objective:
In this retrospective review, we document the use of NSAIDs in more than 15 common and uncommon dermatoses, including acne, psoriasis, sunburn, erythema nodosum, cryoglobulinemia, Sweet's syndrome, systemic mastocytosis, as well as urticarial, livedoid, and nodular vasculitis. NSAIDs act mainly by inhibiting prostaglandin synthesis by the cyclooxygenase (COX) pathway.
Conclusion:
Recent studies link prostaglandin to cutaneous carcinogenesis, thus expanding the dermatologic use of NSAIDs. They may be effective in the treatment and prevention of non-melanoma skin cancer, and specific COX-2 inhibitors promise safer, broader, long-term use of these pharmacologically innovative drugs.
Get full access to this article
View all access options for this article.
References
1.
LichtensteinJFlowerFSherertzEF. Nonsteroidal anti-inflam matory drugs. Their use in dermatology. Int J Dermatol1987; 26(2):80–87.
2.
FischerSMLoHHGordonGB. Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol Carcinog1999; 25(4):231–240.
3.
VoorheesJJ. Leukotrienes and other lipoxygenase products in the pathogenesis and therapy of psoriasis and other dermatoses [Editorial]. Arch Dermatol1983; 119:541–547.
4.
KragballeKHerlinT. Benoxaprofen improves psoriasis: A double-blind study. Arch Dermatol1983; 119:548–552.
5.
AllenBRLittlewoodSM. Benoxaprofen: Effect on cutaneous lesions of psoriasis. Br Med J1982; 285:1241.
6.
HindsonCLawlorFWacksH. Benoxaprofen for nodular acne. Lancet1982; 1:1415.
7.
FentonDAWilkinsonJD. Benoxaprofen: Effect on cutaneous lesions in psoriasis. Br Med J1982; 285:1420–1421.
8.
HalseyJPCardoeN. Benoxaprofen: Side-effect profile in 300 patients. Br Med J1982; 284:1365–1368.
9.
StewartIC. Gastrointestinal haemorrhage and benoxaprofen. Br Med J1982; 284:163–164.
10.
TaggartHAlderdiceJM. Fatal cholestatic jaundice in elderly patients taking benoxaprofen. Br Med J1982; 284:1372.
11.
MillnsJLRandleHWSolleyGO. The therapeutic response of urticarial vasculitis to indomethacin. J Am Acad Dermatol1980; 3(4):349–355.
12.
BarrWGRobinsonJA. Chronic erythema nodosum treated with indomethacin. Ann Intern Med1981; 95:659.
13.
UbogyZPersellinRH. Suppression of erythema nodosum by indomethacin. Acta Derm Venereol1982; 62(3):265–266.
14.
KellyAP. Acne and related disorders. In: SamsWMLynchPJ, eds. Principles and Practice of Dermatology. New York: Churchill Livingstone, 1996, pp 801–818.
15.
WongRCKangSHeezenJL. Oral ibuprofen and tetracycline for the treatment of acne vulgaris. J Am Acad Dermatol1984; 11(6):1076–1081.
16.
SutejPJorizzoJL. Rheumatoid arthritis, rheumatic fever, and gout. In: FreedbergIMEisenAZ, eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw–Hill, 1999, pp 2061–2067.
17.
ShresthaMMorganDLMoredenJM. Randomized double-blind comparison of the analgesic efficacy of intramuscular ketorolac and oral indomethacin in the treatment of acute gouty arthritis. Ann Emerg Med1995; 26(6):682–686.
18.
PittmanJRBrossMK. Diagnosis and management of gout. Am Fam Physician1999; 59(7):1799–1806,1810.
19.
CorneliusLALawleyTJ. Cryoglobulinemia and cryofibrino-genemia. In: FreedbergIMEiseniAZ, eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw–Hill, 1999, pp 2053–2058.
20.
WeinbergerABerlinerSPinkhasJ. Articular manifestations of essential cryoglobulinemia. Semin Arthritis Rheum1981; 10(3):224–229.
21.
LorcerieBArveuxIChauffertB. Aspirin and systemic mastocytosis. Lancet1989; 2(8672):1155.
22.
RobertLJSweetmanBJLewisRA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med1980; 303(24):1400–1404.
23.
FjellnerBHagermarkO. Pruritus in polycythemia vera: Treatment with aspirin and possibility of platelet involvement. Acta Derm Venereol1979; 59(6):505–512.
24.
Sarzi-PuttiniPSantandreaSBoccassiniB. The role of NSAIDs in psoriatic arthritis: Evidence from a controlled study with nimesulide. Clin Exp Rheum2001; 19(1Suppl 22):S17–20.
25.
SmithDReganM. Ibuprofen in psoriatic arthritis. Arthritis Rheum1980; 23(8):961–962.
LonauerGWirthW. Controlled double blind study on the effectiveness and adverse effects of acemetacin and indomethacin in the treatment of psoriatic arthritis. Arzneimittelforschung1980; 30(8A):1440–1444.
28.
KellyRI. Cutaneous vasculitis and cutaneous vaculopathies. Australas J Dermatol1995; 36(3):109–117.
29.
JeanfilsSJolyPYoungP. Indomethacin treatment of eighteen patients with Sweet's syndrome. J Am Acad Dermatol1997; 36(3 pt 1):436–439.
30.
YamamotoMDannoKShioH. Antithrombotic treatment in livedo vasculitis. J Am Acad Dermatol1988; 18(1):57–62.
31.
SoterNA. Cutaneous Vasculitis. In: LeungDYMGreavesMW, eds. Allergic skin disease. New York: Marcel Dekker, 2000; p 301.
32.
WinchesterR. Reiter's syndrome. In: FreedbergIMEisenAZWolffK, eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw–Hill, 1999, pp 2085–2094.
33.
JuvakoskiTLassusA. A double-blind cross-over evaluation of ketoprofen and indomethacin in Reiter's disease. Scand J Rheumatol1982; 11(2):106–108.
34.
PlummerNAHensbyCNBlackA Kobza. Prostaglandin activity in sustained inflammation of human skin before and after aspirin. Clin Sci Mol Med1977; 52:615–620.
35.
MillerWSRudermanFRSmithJGJr. Aspirin and ultraviolet light-induced erythema in man. Arch Dermatol1967; 95(4):357–358.
36.
BlackA KobzaGreavesMWHensbyCN. The anti-inflammatory and pharmacological effects of topically applied flurbiprofen on human skin 24 h after irradiation. Prostaglandin Med1980; 5:405–413.
37.
SnyderDSEaglesteinWH. Topical indomethacin and sunburn. Br J Dermatol1974; 90:91–93.
38.
BlackA KobzaGreavesMWHensbyCN. Effects of indomethacin on prostaglandins E2, F2alpha and arachidonic acid in human skin 24 h after UV-B and UV-C irradiation. Br J Clin Pharmacol1978; 6:261–266.
PerazellaMErasJ. Are selective COX-2 inhibitors nephrotoxic?Am J Kidney Dis2000; 35(5):937–940.
52.
WheltonA. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: Physiologic foundations and clinical implications. Am J Med1999; 106:13S–24S.
53.
McCordJMFridovichI. The biology and pathology of oxygen radicals. Ann Intern Med1978; 89:122–127.
54.
GreavesMW. Prostaglandins and dermatology. J R Coll Physicians Lond1982; 16:219–225.
55.
TrangLE. Prostaglandins and inflammation. Semin Arthritis Rheum1980; 9:153–159.
56.
VaneJR. Inhibition of prostaglandin synthesis as a mechanism of aspirin-like drugs. Nat New Biol1971; 231:233–235.
57.
SteinbrinkKParagnikLJonuleitH. Induction of dendritic cell maturation and modulation of dendritic cell-induced immune responses by prostaglandins. Arch Dermatol Res2000; 292:437–445.
58.
MatasicRDietzBPavlovicS. Cyclooxygenase-independent inhibition of dendritic cell maturation by aspirin. Immunology2000; 101:53–60.
59.
HiggsGAMoncadaSVaneJR. The role of arachidonic acid metabolites in inflammation. In: WeissmanGSamuelssonBPaolettiR, eds. Advances in Inflammation Research, Vol 1. New York: Raven Press, 1979; 413–418.
60.
SamuelssonB. Leukotrienes: A new class of mediators of immediate hypersensitivity reactions and inflammation. Adv Prostaglandin Thromboxane Leuko Res1983; 11:1–13.
61.
SamuelssonBBorgeatPHammarstromS. Leukotrienes: A new group of biologically active compounds. Adv Prostaglandin Thromboxane Leukot Res1980; 6:1–18.
62.
SamuelssonBHammarstromSBorgeatP. Pathways of arachidonic acid metabolism. Adv Inflamm Res1979; 1:405–412.
63.
SmithMJH. Biological activities of leukotriene B4 (isomer III). In: SamuelssonBPaolettiR, eds. Leukotrienes and Other Lipoxygenase Products. New York: Raven Press, 1982, pp 283–292.
64.
BrainSDCampRDRLeighIM. The synthesis of leukotriene B4-like material by cultured human keratinocytes [Abstract]. J Invest Dermatol1982; 78:328.
65.
GrabbeJCzarnetzkiBMMardinM. Release of lipoxygenase products of arachidonic acid from freshly isolated human keratinocytes. Arch Dermatol Res. 1984; 276:128–130.
66.
FinchamNCampRLeighI. Synthesis of arachidonate lipoxygenase products by epidermal cells [Abstract]. J Invest Dermatol1985; 84:447.
67.
GoetzlEJ. Mediators of immediate hypersensitivity derived from arachidonic acid. N Engl J Med1980; 303:822–825.
68.
CampRDRJonesR RussellBrainS. Production of in-traepidermal microabscesses by topical application of leukotriene B4. J Invest Dermatol1984; 82:202–204.
69.
KragballeKVoorheesJJ. Arachidonic acid and leukotrienes in clinical dermatology. Curr Probl Dermatol1985; 13:1–10.
70.
KragballeKDesjarlaisLDuellEA. In vitro synthesis of 12-hydroxy-eicosatetraenoic acid is increased in uninvolved psoriatic epidermis. J Invest Dermatol1986; 87:47–52.
71.
BarrRMBrainSCampRDR. Human allergic and irritant contact dermatitis; levels of arachidonic acid and its metabolites in involved skin. Br J Dermatol1984; 111:23–28.
72.
WongEGreavesMWO'BrienT. Increased concentrations of immunoreactive leukotrienes in cutaneous lesions of eosinophilic cellulitis. Br J Dermatol1984; 110:653–656.
73.
BlackA KobzaBarrRMWongE. Lipoxygenase products of arachidonic acid in human inflamed skin, Br J Clin Pharmacol1985; 20:185–190.
74.
SteeleVEHolmesCAHawkET. Lipoxygenase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Bio-markers Prev1999; 8:467–483.
75.
NukiG. Non-steroidal analgesic and anti-inflammatory agents. Br Med J1983; 287(6384):39–43.
76.
CryerBFeldmanM. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med1998; 104(5):413–421.
77.
PaajanenHMannistoJUotilaP. Aspirin inhibits arachidonic acid metabolism via lipoxygenase and cyclooxygenase in hamster isolated lungs. Prostaglandins1982; 23:731–741.
78.
DawsonWBootJRHarveyJ. The pharmacology of benoxaprofen with particular reference to effects on lipoxygenase product formation. Eur J Rheumatol Inflamm1982; 5:61–68.
79.
RaoCVRivensonASimiB. Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent. Cancer Res1995; 55(7):1464–1472.
80.
FunkCDFunkLBKennedyME. Human platelet/erythroleukemia cell prostaglandin G/H synthase: Cdna cloning, expression, and gene chromosomal assignment. FASEB J1991; 5:2304–2312.
81.
BuckmanSYGreshamAHaleP. COX-2 expression is induced by UVB exposure in human skin: Implications for the development of skin cancer. Carcinogenesis1998; 19(5):723–729.
82.
Muller-DeckerKReinerthGKriegP. Prostaglandin-H-synthase isozyme expression in normal and neoplastic human skin. Int J Cancer1999; 82(5):648–656.
83.
KosakaTMiyataAIharaH. Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem1994; 221:889–897.
84.
KujubuDAFletcherBSVarnumBC. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cycilooxygenase homologue. J Biol Chem1991; 266:12866–12872.
85.
MaierJAHlaTMaciagT. Cyclooxygenase is an immediate-early gene induced by interleukin-1 in human endothelial cells. J Biol Chem1990; 265:10805–10808.
86.
XieWRobertsonDLSimmonsDL. Mitogen-inducible prostaglandin G/H synthase: A new target for nonsteroidal antiinflammatory drugs. Drug Devel Res1992; 25:249–265.
87.
O'BanionMKWinnVYoungDA. cDNA cloning and functional activity of a glucocorticoid-regulated inflammatory cyclooxygenase. Proc Natl Acad Sci USA1992; 89:4888–4892.
88.
GabrielSEJaakkimainenLBombardierC. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflamm atory drugs: A meta analysis. Ann Intern Med1991; 115:787–796.
89.
MacDonaldTMMorantSVRobinsonGC. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: Cohort study. BMJ1997; 315:1333–1337.
90.
HenryDDobsonATurnerC. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal antiinflammatory drugs. Gastroenterology1993; 105:1078–1088.
91.
GriffinMRPiperJMDaughertyJR. Nonsteroidal antiinflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med1991; 114:257–263.
92.
SilversteinFEGrahamDYSeniorJR. Misoprostol reduces serious gastrointestinal complication in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: A randomized, double-blind, placebo-controlled trial. Ann Intern Med1995; 123:241–249.
93.
GrahamDYWhiteRHMorelandLW. Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs. Ann Intern Med1993; 119:257–262.
94.
SimonLSWeaverALGrahamDY. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: A randomized controlled trial. JAMA1999; 282(20):1921–1928.
95.
SilversteinFFaichGGoldsteinJ. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. JAMA2000; 284(10):1247–1255.
96.
BombardierCLaineLReicinA. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med2000; 343:1520–1528.
97.
MukherjeeDNissenSTopolE. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA2001; 286(8):954–959.
98.
CroffordLOatesJMcCuneJ. Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors: A report of four cases. Arthritis Rheum2000; 43(8):1891–1896.
99.
PerazellaMTrayK. Selective cyclooxygenase-2 inhibitors: A pattern of nephrotoxicity similar to traditional nonsteroidal antiinflammatory drugs. Am J Med2001; 111:64–67.
100.
Physicians Desk Reference, 54th ed.Montvale, NJ: Medical Economics, 2000.
101.
BennettACharlierEMMcDonaldAM. Prostaglandins and breast cancer. Lancet1977; 2:624–626.
102.
BennettA. The production of prostanoids in human cancers, and their implications for tumor progression. Prog Lipid Res1986; 25:539–542.
103.
BennettACarrollMAStamfordIF. Prostaglandins and human lung carcinomas. Br J Cancer1982; 46:888–893.
104.
BennettACivierAHensbyCN. Measurement of arachidonate and its metabolites extracted from human normal and malignant gastrointestinal tissues. Gut1987; 28:315–318.
105.
RigasBGoldmanISLevineL. Altered eicosanoid levels in human colon cancer. J Lab Clin Med1993; 122:518–523.
106.
VanderveenEEGrekinRCSwansonNA. Arachidonic acid metabolites in cutaneous carcinoma. Arch Dermatol1986; 122:407–412.
107.
BennettACarterLStamfordIF. Prostaglandin-like material extracted from squamous carcinomas of the head and neck. Br J Cancer1980; 41:204–208.
108.
JungTTKBerlingerNTJuhnSK. Prostaglandins in squamous cell carcinoma of the head and neck: A preliminary study. Laryngoscope1985; 95:307–312.
109.
LupulescuA. Prostaglandins, their inhibitors and cancer. Prostaglandins Leukot Essent Fatty Acids1996; 54:83–94.
110.
WeitzmanSAGordonLI. Inflammation and cancer: Role of phagocyte-generated oxidants in carcinogenesis. Blood1990; 76:655–663.
111.
TsujiiMDuBoisRN. Alteration in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2. Cell1995; 83:493–501.
112.
CeruttiPATrumpBF. Inflammation and oxidative stress in carcinogenesis. Cancer Cells1991; 3:1–7.
113.
LeihrJWangM. Lipid hydroperoxide-induced endogenous DNA adducts in hamsters: Possible mechanisms of lipid hydroperoxide-mediated carcinogenesis. Arch Biochem Biophys1995; 316:38–46.
114.
PlesciaOJSmithAHGrinwichK. Subversion of immune system by tumor cells and role of prostaglandins. Proc Natl Acad Sci USA1975; 72:1848–1851.
115.
BaichCMDoghertPACloudGA. Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients. Surgery1984; 95:71–77.
116.
GoodwinJSCeuppensJL. Regulation of immune response by prostaglandins. J Clin Immunol1983; 3:295–315.
117.
GoodwinJSBankhurstADMessnerRP. Suppression of human T-cell mitogenesis by prostaglandin; Existence of a prostaglandin producing suppressor cell. J Exp Med1977; 146:1719–1734.
118.
BrundaMJHerbermanRBHoldenHT. Inhibition of murine natural killer cell activity by prostaglandins. J Immunol1980; 124:2682–2688.
119.
TaffetSMRussellSW. Macrophage-mediated tumor cell killing: Regulation of expression of cytolytic activity by prostaglandin E. J Immunol1980; 126:424–427.
120.
BakerPEFaheyJVMunckA. Prostaglandin inhibition of T-cell proliferation is mediated at two levels. Cell Immunol1981; 61:52–61.
121.
MinakuchiRWacholtzMDavisL. Delineation of the mechanism of inhibition of human T cell activation by PGE2. J Immunol1990; 145(8):2616–2625.
122.
KunkelSLWigginsRCChensueSW. Regulation of macrophage tumor necrosis factor production by prostaglandin E2. Biochem Biophys Res Commun1986; 137:404–410.
123.
KambayashiTAlexanderARFongM. Potential involvement of IL-10 in suppressing tumor-associated macrophages. Colon-26-derived prostaglandin E2 inhibits TNF-alpha release via a mechanism involving IL-10. J Immunol1995; 154:3383–3390.
124.
MasferrerJLLeahyKMKokiAT. Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res2000; 60(5):1306–1311.
125.
PentlandAPSchogginsJWScottGA. Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis1999; 20(10):1939–1944.
126.
FrostCAGreenAC. Epidemiology of solar keratoses. Br J Dermatol1994; 131:455–464.
127.
MarksR. An overview of skin cancers. Incidence and causation, Cancer1995; 75(2 Suppl):607–612.
128.
HruzaLLPentlandAP. Mechanisms of UV-induced inflammation. J Invest Dermatol1993; 100:35s–41s.
129.
EberhartCECoffeyRJRadhikaA. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology1994; 107:1183–1188.
130.
KargmanSLO'NeillGPVickersPJ. Expression of prostaglandin G/H synthase-1 and −2 protein in human colon cancer. Cancer Res1995; 55:2556–2559.
131.
SteinbachGLynchPMPhillipsRK. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med2000; 342(26): 1946–1952.
132.
HanahanDFolkmanJ. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell1996; 86:353–364.
133.
JiangHYamamotoSKatoR. Inhibition of two-stage skin carcinogenesis as well as complete skin carcinogenesis by oral administration of TMK688, a potent lipoxygenase inhibitor. Carcinogenesis1994; 15(5):807–812.
134.
BooneCWKelloffGJSteeleVE. Natural history of intraepithelial neoplasia in human with implications for cancer chemo-prevention strategy. Cancer Res1992; 52(7):1651–1659.
135.
DenkertCKobelMBergerS. Expression of cyclooxygenase 2 in humane malignant melanoma. Cancer Res2001; 61(1):303–308.
