oral versus topical nsaids in rheumatic diseases

Oral versus Topical NSAIDs inRheumatic DiseasesA Comparison

Catherine A. Heyneman,1 Cara Lawless-Liday1 and Geoffrey C. Wall2

1 Department of Pharmacy Practice and Administrative Sciences, Idaho State University College ofPharmacy, Pocatello, Idaho, USA

2 Department of Pharmacy Practice, Drake University College of Pharmacy, Des Moines, Iowa, USA

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5551. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556

1.1 Rationale for the Use of Topical Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) . . . . . . . 5561.2 Overview of Rheumatic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5591.3 Mechanism of Action of NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5591.4 Objective Criteria for Topical Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559

2. Absorption and Distribution of Topically Administered NSAIDs . . . . . . . . . . . . . . . . . . . . . 5592.1 Basic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5592.2 In Vivo Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5602.3 Ex Vivo Studies on Human Skin Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5602.4 Human In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5602.5 Penetration Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562

3. Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5643.1 Topical NSAIDs versus Placebo and Active Controls . . . . . . . . . . . . . . . . . . . . . . . . 5643.2 Topical NSAIDs versus Oral NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568

4. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5705. Cost Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5706. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most com-monly prescribed drugs worldwide and are responsible for approximately one-quarter of all adverse drug reaction reports. NSAIDs are widely prescribed forpatients with rheumatic disease – a population at increased risk for serious gas-trointestinal (GI) complications. Topical administration of NSAIDs offers theadvantage of local, enhanced drug delivery to affected tissues with a reducedincidence of systemic adverse effects, such as peptic ulcer disease and GI haem-orrhage.

NSAIDs administered topically penetrate slowly and in small quantities intothe systemic circulation; bioavailability and maximal plasma NSAID concentra-tion after topical application are generally less than 5 and 15%, respectively,compared with equivalent oral administration. Product formulation may have adramatic impact, not only on absorption rates but also on penetration depth.

REVIEW ARTICLE Drugs 2000 Sep; 60 (3): 555-5740012-6667/00/0009-0555/$25.00/0

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Compared with oral administration, topical application leads to relatively highNSAID concentrations in the dermis. Concentrations achieved in the muscletissue below the site of application are variable, but are at least equivalent to thatobtained with oral administration. NSAIDs applied topically do reach the syno-vial fluid, but the extent and mechanism (topical penetration versus distributionvia the systemic circulation) remain to be determined. In addition, marked inter-individual variability was noted in all studies; percutaneous absorption may bestrongly influenced by individual skin properties.

In general, interpretation of clinical studies measuring efficacy of topicalNSAIDs in rheumatic disease states is difficult because of a remarkably highplacebo response rate, use of rescue paracetamol (acetaminophen), and signifi-cant variability in percutaneous absorption and response rates between patients.Overall efficacy rates attributable to topical NSAIDs in patients with rheumaticdisorders ranged from 18 to 92% of treated patients. Topically applied NSAIDshave a superior safety profile to oral formulations. Adverse effects secondary totopical NSAID application occur in approximately 10 to 15% of patients and areprimarily cutaneous in nature (rash and pruritus at site of application). GI adversedrug reactions are rare with topically applied NSAIDs, compared with a 15%incidence reported for oral NSAIDs. Available clinical studies suggest, but do notdocument, equivalent efficacy of topical over oral NSAIDs in rheumatic diseases.

1. Background

1.1 Rationale for the Use of TopicalNonsteroidal Anti-Inflammatory Drugs (NSAIDs)

The concept of transdermal application of non-steroidal anti-inflammatory drugs (NSAIDs) is notnew. Phenylbutazone cream was utilised over 30years ago to treat superficial thrombophlebitis.[1] Therenewed interest in topical delivery of NSAIDs forpatients with rheumatic diseases stems from the po-tential advantages of transdermal administration.

In theory, an NSAID applied topically couldachieve therapeutic concentrations in the tissues sub-jacent to the site of application while maintaininglow serum concentrations. This could provide nu-merous potential benefits to patients, includingavoidance of gastrointestinal (GI) tract and first-pass metabolism, as well as reduced risk of seriousadverse events related to elevated serum NSAID con-centrations. Avoidance of the GI tract should miti-gate the common direct toxicities of nausea, vomi-ting, dyspepsia and diarrhoea which occur secondaryto high local concentrations of NSAID in the ali-mentary tract.

NSAID-mediated toxicity is often dose related.Thus, reduction in serum concentrations should alsolessen the risk of potentially serious systemic ad-verse effects secondary to NSAID-induced pros-taglandin inhibition: acute renal insufficiency, ne-phrotic syndrome, NSAID gastropathy, prolongedbleeding time, and fluid retention. Finally, topicalapplication should mitigate the risk of drug-druginteractions, such as NSAID-mediated protein bind-ing displacement of warfarin.

In 1980, benzydamine was the first topical NSAIDto be licensed in the UK.[2] Since that time, severalother topical NSAIDs have been licensed in Eur-ope, Japan and South Africa for the treatment ofrheumatic diseases, and some of these transcutane-ous formulations are currently available without aprescription.[1,2] A list of commercially-availabletopical NSAID preparations is presented in table I.

The use of topical NSAIDs for acute musculo-skeletal conditions has been reviewed extensive-ly;[3,4] this review will therefore focus exclusivelyon the efficacy and safety of topical NSAIDs inchronic rheumatic diseases, including osteoarthri-tis, bursitis, tendinitis and epicondylitis. Unfortu-nately, no clinical trials have assessed the effective-

556 Heyneman et al.

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Table I. Commercially available preparations of topical nonsteroidal anti-inflammatory drugsa

Generic name Trade name Strength Dosage form

Benzydamine Difflam 3% Gel

Tantum 5% Cream

Bufexamac Croxaryl 5% Cream

Droxaryl 5% Cream

Malipuran 5% Cream

Parfenac 5% Cream

Parfenac-Fettsalbe 5% Ointment

Diclofenac Dealgic 1% Gel

Diclofenac GNR Gel 1% Gel

Dicloreum 1% Gel

Flector 1% Gel

Flogofenac 1% Gel

Solarase 3% Gel

Voltaren Emulgel 1% Emulsion gel

Voltarol Emulgel 1% Emulsion gel

Diclofenac hydroxyethyl-pyrrolidine(DHEP)

Dicloreum TissugelFlector EP TissugelFlector EP Gel

180mg185.5mg1%

PlasterPlasterGel

Etofenamate Etofen Gel 5% 5% Gel

Etofen Gel 10% 10% Gel

Reumagel 5% Gel

Flogoprofen 5% Gel

Felbinac Traxam 3% Gel

Napageln 1% Ointment

Dolinac Gel 3% Gel

Flurbiprofen TransAct LAT 40mg Patch

Froben 0.25% Spray

Ibuprofen Aciril 10% Gel

Arfen 10% Gel

Artrene 20% Gel

Bufen 5%, 10% Cream

Brufort 10% Ointment

Dolgit 5% Cream

Dolofast 10% Gel

Ibudros 5% Ointment

Ibugel 5% Gel

Ibuleve 5% Gel

Iprogel 5% Gel

Optifen Gel 5% Gel

Optifen Gel forte 10% Gel

Proflex 5% Cream

Indomethacin Adco-Indomethacin Gel 1% Gel

Elmetacin 1% Spray

Indocid 1% Gel

Ketoprofen Actron 2.5% Gel

Algogel 1% Gel

Atrosilene Gel 5% Gel

Fastum 1%, 2.5% Gel

Flexen 2.5%, 5% Gel

Ketalgin 2.5% Cream

Ketartrium 2.5% Gel

Ketoprofene GNR 5% Ointment

Oral versus Topical NSAIDs in Rheumatic Diseases 557


Table I. Contd

Generic name Trade name Strength Dosage form

Ketoprofen Ketoprofene Ibi 1% Cream

KLS Gel-Spray 15% Gel-spray

Oki 15% Gel

Orucote 2.5% Gel

Orudis 2.5%, 5% Gel

Orudis 1% Cream

Profenid 2.5% Gel

Salient 1% Cream

Thermalgen 2.5% Cream

Naproxen Aprenin 10% Gel

Artroxen Gel 10% Gel

Napreben 10% Gel

Naprossene 10% Gel

Naprosyn Gel 10% Gel

Neoeblimon 10% Gel

Numidan Gel 12% Gel

Prexan 10% Ointment

Ticoflex Gel 10% Gel

Xenar 10% Gel

Xenar 5% Ointment

Niflumic acid Niflugel R 2.5% Gel

Oxyphenbutazone Tanderil 10% Ointment

Piroxicam Antiflog 1% Gel

Atroxicam 1% Cream

Brexivel 1% Cream

Bruxicam 1% Cream

Ciclafast 2% Cream

Clevian Gel 1% Gel

Euroxi 1% Gel

Feldene Lipo 0.5% Cream

Feldene 1% Cream

Feldene Topico Gel 0.5% Gel

Flodol 1% Gel

Flogobene 1% Cream

Lampoflex 1% Cream

Oxicam 1% Gel

Piroxicam GNR 1% Cream

Pivaloxicam 2% Cream

Reucam 1% Cream

Reudene 1% Gel

Reumagil 1% Cream

Riacin 1% Cream

Roxene 1% Cream

Roxenil 1% Cream

Roxedin 1% Gel

Unicam 2% Cream

Salicylic acid/glycosaminoglycan/corticosteroid combination

Mobilat Gel 2% salicylic acid,0.2% glycosaminoglycan,1% suprarenal extract

Gel

Suprofen Sulprotin 1% Ointment

Tolmetin Tolectin Gel 5% Gel

a All percentages expressed are percentage weight to weight.

558 Heyneman et al.


ness of topically applied NSAIDs in rheumatoidarthritis, even though it has a prevalence rate of 1%in the adult population and oral NSAIDs are a main-stay of therapy.[5]

1.2 Overview of Rheumatic Diseases

The appellation ‘rheumatic disease’is an umbrellaterm encompassing a remarkably broad range of dis-orders characterised by varying degrees of inflam-mation, tissue damage and loss of function.[6] Theinflammatory process is a normal response to tis-sue insult. However, in chronic disease states suchas rheumatic disorders inflammation itself can fuelprogressive disease manifestations.[7] This reviewwill focus primarily on investigations in patientswith osteoarthritis (OA) and regional rheumaticpain syndromes such as bursitis, tendinitis, teno-synovitis and epicondylitis.

OA is one of the most common rheumatic dis-orders. This chronic, painful disease state is esti-mated to affect 15.8 million adults in the UnitedStates alone,[8] and is the principal source of painand disability in the elderly.[9] OA is characterisedby degeneration and loss of articular cartilage, man-ifesting as joint pain, stiffness and limitation ofmovement.[8] Regional rheumatic pain syndromesare classified as painful, inflammatory processesoccurring in muscles, tendons, joints, cartilage, liga-ments, fascia, bone and nerve tissues.[10]

First-line treatment of localised rheumatic painand joint stiffness generally consists of oral para-cetamol (acetaminophen) and/or topical counterir-ritants, such as capsaicin.[7,8,10,11] NSAIDs are ef-fective,[8] but are generally considered second-linetherapy because of their adverse effect profile.[12,13]

As mentioned earlier, adverse effects secondary toNSAID use include GI tract, renal, cutaneous, CNS,hepatic and haematopoietic system toxicities.[7]

1.3 Mechanism of Action of NSAIDs

The primary mechanism of action of NSAIDs isreversible inhibition of the cyclo-oxygenase (COX)enzyme responsible for synthesis of prostaglan-dins, which are mediators of the inflammatory pro-cess.[14] The relative potency of COX inhibition by

various NSAIDs in vitro tends to be proportionalto their anti-inflammatory potency in vivo.[15] Themode of COX inhibition by NSAIDs is complex andvaries considerably between agents in this class.[16]

1.4 Objective Criteria for Topical Administration

In order to confirm the validity of the postulatethat topical NSAID administration is superior tothe oral route, the following basic criteria shouldbe met:[2]

• therapeutic concentrations of NSAID must beachieved in the target tissues

• efficacy must be demonstrated in well-designedclinical trials

• the risk for serious adverse events secondary totopical NSAID therapy must be less than that oforal treatment,

• topical administration of NSAIDs must be costeffective.This review will attempt to address all of these

criteria as they apply to the treatment of rheumaticdiseases.

2. Absorption and Distribution ofTopically Administered NSAIDs

2.1 Basic Principles

The skin acts as an efficient barrier to the pas-sage of materials into and out of the body.[17] Thekeratinised stratum corneum is the outer, horny layerwhich consists primarily of multilaminate hydro-phobic and hydrophilic channels composed of non-polar fatty acid chains and polar head groups.[18,19]

Thus, the ideal drug candidate for transdermal de-livery would have a low molecular weight, be highlypotent, and have both hydrophobic and hydrophilicproperties.[17] In addition, the best delivery systemwould release the drug to the skin at a rate lowerthan the maximum rate of skin transport. This wouldcontrol for variability in skin permeability betweenindividuals and ensure a constant release rate.[17,20]

In several in vitro studies, a linear relationship hasbeen established between the initial topical NSAIDconcentration and the release rate from the vehicle,



suggesting a diffusion-controlled model.[20,21] Ve-hicle pH and penetration enhancers such as poly-ethylene glycol, limonene, emulsion preparations oriontophoresis can also have dramatic effects onNSAID release rates, increasing penetration ratesby up to 75-fold.[21-26]

2.2 In Vivo Animal Studies

In order to treat patients rationally with topicallyapplied NSAIDs, the issue of ‘local enhanced top-ical delivery’ of NSAIDs must be addressed. Thisconcept postulates that local accumulation of drugin target tissues occurs by direct diffusion to a greaterdegree than could have resulted by prior absorptionand redistribution through the cutaneous vascula-ture.[2] This issue has been addressed directly byMcNeill et al.,[27] who administered equivalent50µg doses of titrated piroxicam either intrave-nously or topically to the right shoulder of malerats. In the muscle tissue subjacent to the topicalpiroxicam application, 2 distinct piroxicam peakswere noted at 4 and 12 hours after application. Thecontralateral muscle tissue from the nondosed shoul-der produced a single peak at 12 hours. The authors’interpretation of this data was that the first peakcould only be accounted for by topical piroxicamdelivery; the second peak was attributed to redis-tribution from the general blood supply. The con-centrations of piroxicam achieved in the acromio-trapezius muscle subjacent to the treated shoulderat 2 hours after topical application exceeded thatfound in the same muscle of rats given equivalentintravenous piroxicam by 14-fold.

This work was confirmed by Mikulak et al.[28]

These authors reported that topical application ofindomethacin produced maximal tissue concentra-tions in the subjacent deltoid muscle, joint capsuleand rotator cuff 2 to 10 times greater than thatachieved with equivalent oral dosing.

Singh and Roberts[29] investigated the relativeepidermal permeabilities of salicylate, indometha-cin, naproxen, diclofenac and piroxicam solutionsin anaesthetised rat dermis. These authors con-cluded that ‘local direct penetration was evident forall NSAIDs up to a depth of about 3 to 4mm below

the applied site, with distribution to deeper tissuesbeing mainly though the systemic blood supply’.While this information seems to contradict thestudies by Mikulak et al.[28] and McNeill et al.[27]

with respect to deeper tissue penetration, it is im-portant to note that the drugs utilised in the studydesigned by Singh and Roberts[29] were in aqueoussolution, while Mikulak et al.[28] utilised a lipophilicpenetration enhancer and McNeill et al.[27] used acarbopol gel base. Thus, product formulation mayhave a dramatic impact, not only upon absorptionrates, but also on penetration depth.

2.3 Ex Vivo Studies on Human Skin Tissue

Ex vivo studies utilising cadaver skin tissue toinvestigate transdermal penetration of NSAIDs havedetermined that occlusion of the skin surface canenhance drug penetration by up to 2-fold.[30] In astudy of 7 different NSAIDs, Cordero et al.[31] de-termined that the flux across human cadaver skinwas related primarily to the lipophilic character ofthe drug. Roy and Manoukian[32] demonstrated thatthe flux of ketorolac through skin tissue in vitro de-creased exponentially as the solution pH was raisedform 3.5 to 7.0. This is consistent with the findingsof Cordero et al.,[31] given that this pH shift wouldincrease the unionised percentage of ketorolac byseveral orders of magnitude, making it more lipo-philic.

In essence, ex vivo studies suggest that occlusioncan enhance NSAID skin penetration, lipophilicityis an important characteristic, and the pH of thevehicle is extremely important. However, these datamust be interpreted with caution, as cadaver skinobviously has no functional blood supply and istherefore an incomplete model for true skin pene-tration.

2.4 Human In Vivo Studies

Many investigators have attempted to quantitatemaximum plasma concentrations (Cmax) and thetime required to reach this blood level (tmax) aftertransdermal administration of NSAIDs in healthyhumans.[32-40] These reports have been summarisedin table II for both single dose and multiple dose

560 Heyneman et al.


Oral versus Top

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Table II. Summary of single and multiple dose topical nonsteroidal anti-inflammatory drug absorption studies in healthy individuals. When the trial also involved an oral or intramuscularagent, only the results relating to the topical agent(s) are shown

Drug Dosage Route n Design Mean plasma Cmax

(µg/ml) ± SD or SE or%CV

Ratio of Cmax

observed toexpected Cmax fromequivalent oraladministrationa

Mean plasma tmax

(hours) ± SD or SEor %CV

Reference

Single dose studiesDiclofenac 300mg solution gel

300mg emulsion gelTopical over400cm2, occluded

12 Randomised, 2-way, crossover

0.081 ± 0.043 (SD)0.039 ± 0.017 (SD)

0.0070.003

3.50 ± 0.52 (SD)7.17 ± 1.59 (SD)

33

Ibuprofen 200mg solution gel Topical over 360cm2

occluded6 Randomised, 3-

way, crossover1.40 ± 0.40 (SD) 0.080 4.83 ± 1.83 (SD) 34

200mg hydrophilicointment

6 0.28 ± 0.11 (SD) 0.016 7.0 ± 1.67 (SD)

200mg oil in wateremulsion

6 0.39 ± 0.19 (SD) 0.022 6.8 ± 2.2 (SD)

Ketorolac 174mg in vehicle A Topical over 20cm2,occluded


1.265 ± 45% (CV) 0.081 5.3 ± 38% (CV) 35

239mg in vehicle B 9 0.696 ± 72% (CV) 0.032 7.1 ± 47% (CV)205mg in vehicle C 9 0.092 ± 63% (CV) 0.005 22.2 + 10% (CV)

Ketorolac 1.5g in device A(20cm2)

Topical over variablesurface areaaccording to device,occlusion unclear


0.20 ± 0.15 (SD) 0.001 8.4 ± 1.3 (SD) 32

1.5g in device B(20cm2)

10 0.18 ± 0.06 (SD) 0.001 12.4 ± 1.3 (SD)

0.86g in device C(7.5cm2)

10 0.82 ± 0.24 (SD) 0.011 8.8 ± 1.7 (SD)

Ketoprofen 50mg gel Topical over 70cm2

(occlusion not noted)5 Open Below detection Not available Below detection 36

Piroxicam 15mg gel Topical over289cm2, notoccluded

8 Open 0.147 ±0.034 (SE) 0.044 23 ± 1.7 (SE) 37

Multiple dose studiesDiclofenac 80mg bid for 7.5 days Topical over

200cm2, occluded12 Open 0.0189 ± 0.0172 (SD) 0.006 2.2 ± 2.3 (SD) 38

Diclofenachydroxy-ethylpyrrolidine(DHEP)

185.5mg plaster bidfor 7 days

Topical over150cm2, occluded


0.017 ± 0.013 (SD) 0.002 5.4 ± 3.7 (SD) 39

50mg gel bid for 7days

Topical (surfacearea not specified),occlusion not noted

0.028 ± 0.013 (SD) 0.019 3.1 ± 0.7 (SD)

Ketoprofen 30mg gel q 6 hours ×25 doses

Topical over 100cm2

on back, arm orknee, not occluded


0.119 + 78% (CV) fromback

0.066 3.00 + 73% (CV)from back

40

0.119 + 58% (CV) fromarm

0.066 2.67 + 75% (CV)from arm

0.085 + 65% (CV) fromknee

0.047 3.04 + 53% (CV)from knee

a Estimated from manufacturer’s reported Cmax values after oral administration, corrected for dosage differences.Cmax = maximum plasma concentration; SE = standard error; SD = standard deviation; tmax = time to Cmax; %CV = percentage coefficient of variance.

studies, along with a calculation comparing the re-ported mean Cmax values to expected plasma con-centrations after equivalent oral administration.These data indicate that systemic absorption aftertopical administration produces peak plasma valuesless than 10% of that obtained after oral adminis-tration (range 0.2 to 8.0%). Another importantpoint gleaned from table II is the significant inter-and intra-individual variability, which is consistentwith that seen in the ex vivo data.[31] This variabilityhas been attributed to individual skin differencesbetween study participants, including hydrationstatus,[41] permeability characteristics[31,38] and in-dividual differences in subcutaneous vasculature.[41]

Shah et al.[40] compared serum ketoprofen con-centrations after equivalent gel applications to theforearm, back or knee in a crossover design (seetable II). These authors found that anatomical siteof application had little effect on systemic absorp-tion. The study by Seth[34] comparing equivalentdoses of ibuprofen applied to equivalent skin surfaceareas emphasises the importance of the vehicle onpercutaneous drug absorption. This author demon-strated a 5-fold enhancement of maximal serumconcentration by changing the drug formulationfrom an ointment base to a gel base. Overall, giventhat different NSAIDs, vehicles, methods of occlu-sion and/or permeability enhancers were utilised inevery study described in table II, it is difficult todraw any conclusions regarding superior perme-ability of any one NSAID formulation.

As demonstrated by the available in vivo studies(see table II), topical NSAIDs penetrate slowly andin small quantities into the general circulation.Marked interindividual variability was noted in allstudies. Reported maximal plasma concentrationsof NSAIDs applied topically are generally less than15% of the concentration which would be expectedfrom equivalent oral administration. The reportedmaximal serum concentrations after topical admin-istration are uniformly below the accepted thera-peutic drug concentrations for NSAIDs, which isadvantageous when viewed from the vantage pointof systemic toxicity. The time required to achieveCmax is approximately 10 times longer than that of

equivalent oral administration, ranging from 2.2 to 23hours. Bioavailability studies suggest that NSAIDsadministered topically achieve only 3 to 5% of thetotal systemic absorption when compared with oraladministration.[33,42,43] Anatomical site of applica-tion does not appear to influence plasma concentra-tions,[40] but the formulation can enhance systemicabsorption by as much as 5-fold.[34] Steady state isachieved fairly rapidly after tmax (generally within2 to 5 days of initiation of repeated topical appli-cation),[41,42] and plasma concentrations after re-peated administration have been reported to rise to2.5 times the Cmax after a single application.[42]

2.5 Penetration Studies

The concept of local enhanced topical deliveryof NSAIDs requires proof not only that the drugreaches the systemic circulation, but that it reacheshigher and therapeutically effective concentrationsin the tissues localised below the site of application.Verification of local enhanced topical delivery isessential, given the proposed rationale behind theuse of topical NSAIDs – that enhanced, localisedconcentrations minimise systemic toxicity whilemaintaining efficacy.

Muller et al.[38] attempted to address the issue ofdepth of diclofenac penetration in vivo. In thisstudy, 12 healthy volunteers were given topical di-clofenac foam (diclofenac 80mg over 200cm2 ap-plied to the shaved surface of the thigh with occlu-sion) twice daily for 8 days. Immediately prior tothe last topical dose, 2 microdialysis probes wereinserted to a tissue depth of 11.7 ± 0.4mm withoutlocal anaesthesia into the medial vastus muscle atleast 4cm lateral from the margin of the applicationsite. Concentration versus time profiles were ob-tained for plasma and interstitial fluid of skeletalmuscle. Significant interindividual variability wasnoted. The mean Cmax in plasma was 18.75 ± 4.97µg/L, and corresponding interstitial concentrationsin skeletal muscle were 219.68 ± 66.36 µg/L (12-fold higher than the plasma level).

A similar study was conducted by Tegeder etal.[44] These investigators administered ibuprofen800mg either orally or topically over 323cm2 to the

562 Heyneman et al.


thighs of 11 healthy volunteers in a 2-way cross-over design, then monitored serum and tissue con-centrations by microdialysis probes inserted intothe thigh to a depth of 4 to 5mm (dermis) and 25to 30mm (muscle). Topical administration led to22.5-fold greater concentrations of ibuprofen inthe dermis than those obtained after oral adminis-tration (p value not reported). Ibuprofen concentra-tions achieved in the muscle after topical adminis-tration were almost identical to those obtained afteroral administration. There was significant interindi-vidual variability (for example, muscle ibuprofenconcentrations after topical administration ex-ceeded those from oral administration by over 2orders of magnitude in 1 volunteer). In approxi-mately 50% of the volunteers, ibuprofen concen-trations in the muscle tissue after topical adminis-tration were increased over concentrations after oraladministration. The authors attributed this varia-bility to differences in the microvasculature at thesite of drug administration.

Keeping in mind that the interstitial drug con-centration in the muscle tissue measured by Mulleret al.[38] was 11mm deep and 4cm lateral to the appli-cation site, these results directly contradict the invivo animal study by Singh and Roberts,[29] whichpostulated that distribution to tissues deeper than3 to 4mm below the applied site were accounted forby the systemic blood supply. The authors note thatthe microdialysis method employed measured onlythe pharmacologically active unbound drug frac-tion; total tissue drug concentrations were proba-bly higher. The study by Tegeder et al.[44] suggeststhat, for approximately 50% of patients, local en-hanced topical delivery of NSAIDs accounts for tis-sue concentrations of drug that are above that whichcan be obtained by equivalent oral administrationup to 25 to 30mm subjacent to the site of applica-tion.

In an elegant, nonblind study design, Dominkuset al.[45] compared topical administration of ibu-profen 375mg in a gel formulation applied 3 timesdaily for 3 days to oral administration of ibuprofen600mg given twice daily for 3 days in 17 patientswith degenerative knee disorders. Ibuprofen ad-

ministration occurred in the time period immedi-ately preceding knee surgery. Twelve patients re-ceived the topical preparation (1125 mg/day for 3days) and 5 received the oral formulation (1200mg/day for 3 days). Samples of blood, synovial fluid,muscle, fasciae and subcutaneous tissue were ob-tained during the operation, 15 hours after the lastadministration of ibuprofen. Mean plasma concen-trations of ibuprofen were 1.0 ± 0.5 mg/L in pa-tients receiving the topical preparation, and 1.6 ±1.3 mg/L in patients receiving oral ibuprofen (p =0.17). Given that the half-life of ibuprofen is 1.78to 2.5 hours,[46] at least 6 half-lives elapsed betweenthe last topical or oral dose and the time the serumand tissue samples were removed for analysis,making it very difficult, if not impossible, to com-pare the blood concentrations. However, it is inter-esting to note that similar ibuprofen concentrationswere achieved in the 2 treatment groups in the sy-novial fluid, fasciae and muscle tissues. The sub-cutis was the only tissue in which the ibuprofenconcentration derived from topical application ex-ceeded that obtained after oral administration(5.4 ± 3.3 vs 1.3 ± 0.3 µg/g; p = 0.03).

In a recent randomised, parallel investigation,Rolf et al.[47] compared ketoprofen concentrationsin plasma, synovial fluid and intra-articular tissuesin 100 patients undergoing knee arthroscopy. Fortypatients received a single topical plaster containingketoprofen 30mg, 30 received multiple 30mg plas-ter applications over 5 days and 30 received keto-profen 50mg orally. Ketoprofen concentrations weremeasured in plasma, synovial fluid, synovial tis-sue, meniscus and cartilage at time points up to 14hours after drug administration. Interestingly, whilesynovial fluid ketoprofen concentrations averaged70 to 80% of the plasma concentrations after topi-cal application, the meniscus and cartilage concen-trations were elevated 20- to 30-fold over those inplasma in the same patients. Median ketoprofen con-centrations achieved in meniscus and cartilage tis-sues after topical administration (single or multipleapplication) were 4.1- to 6.8-fold higher than thoseachieved after oral administration.



Dominkus et al.[45] reported that tissue and sy-novial fluid ibuprofen concentrations achieved af-ter topical application exceeded the in vitro IC50

(concentration of ibuprofen required to inhibit 50%of enzyme activity) for prostaglandin synthetase[48]

even 6 half-lives after last administration of drug.IC50 values for ibuprofen inhibition of COX-1 andCOX-2 have been determined in vitro to be 0.8 to3.8 mg/L and 0.0006 to 0.0012 mg/L.[16] COX-2 isthe isoform primarily associated with inflamma-tion;[16] thus, ibuprofen applied topically appearsto exceed the threshold quantity required for anti-in-flammatory activity. However, Gierse et al.[16] haverecommended caution when interpreting the COXIC50 data, because of the complex and distinct mech-anisms of enzyme inhibition of each COX isoformby NSAIDs (including competitive, covalent andtime-dependent variable binding mechanisms).These authors state that ‘comparison of inhibitoryactivity on COX-1 and COX-2 using IC50 ratios[are of] questionable validity’.[16] Judicious inter-pretation of IC50 data is reasonable, then, particularlywhen considering that COX-2 is an inducible en-zyme which increases in concentration during theinflammatory response.[8]

As noted with ibuprofen,[48] topically-applieddiclofenac hydroxyethylpyrrolidine (DHEP) hasalso been detected in the synovial fluid of patientswith monolateral knee joint effusion by Gallacchiand Marcolongo.[49] These authors treated 8 patientswith OA of the knee with plasters containing 180mgDHEP twice daily for 4.5 days. Four hours after thelast application, synovial fluid from the treated kneejoint was collected. Plasma diclofenac concentrationswere also assessed at 1, 4 and 8 hours after the lasttopical application. The mean concentration ofdiclofenac detected in the synovial fluid was 30%of that found in the plasma at the same 4-hour timepoint (1.02 ± 0.38 vs 3.62 ± 1.05 µg/L; p < 0.05).

It has been postulated that the major site of ac-tion for NSAIDs in the treatment of arthralgias isprobably within the synovial compartment.[50] Thesestudies prove that topically applied NSAIDs canindeed reach the synovial fluid. Orally administeredNSAIDs generally result in synovial drug concen-

trations approximately 60 to 80% of the mean plasmaconcentration;[47,50] this difference in concentrationhas been attributed to lower albumin levels in sy-novial fluid compared with plasma.[15] It is inter-esting to note that in the study conducted by Do-minkus et al.,[45] the mean NSAID concentration inthe synovial fluid actually exceeded that found inthe plasma, although statistical tests were not ap-plied to this data. Given the relatively slow transferrate of NSAIDs into and out of the synovial com-partment,[15] the sustained synovial NSAID levelsobserved,[49] and the fact that the levels in the studyconducted by Dominkus et al.[45] were taken 15 hoursafter the last topical administration, it is not possibleto state conclusively that topically applied NSAIDsare capable of concentrating in the synovium. How-ever, Rolf et al.[47] provide persuasive evidence thatketoprofen applied topically can concentrate in theintra-articular tissues, and that less vascularisedtissues (cartilage and meniscus) may actually act asa drug reservoir.

In summary, local enhanced topical delivery ofNSAIDs does occur. However, the maximal depthto which it occurs varies among individuals. Topi-cally applied NSAIDs do reach the synovial fluidcompartment and can concentrate in intra-articulartissues. However, without direct, objective meas-urement of contralateral tissue and synovial fluiddrug concentrations in well-designed trials, a de-termination of the mechanism of NSAID transport– whether it is direct or via the systemic circulationor both – cannot yet be made. While essentially alltissue concentrations of topically applied NSAIDsresult in subjacent tissue concentrations which ex-ceed the IC50 for COX-2, this data must be inter-preted cautiously based upon variable and complexmechanisms of COX enzyme inhibition.[16]

3. Efficacy

3.1 Topical NSAIDs versus Placebo and Active Controls

Table III includes a summary of published clinicaltrials which compared topically applied NSAIDswith vehicle controls or to other topical NSAIDS

564 Heyneman et al.


Table III. Summary of clinical trials investigating the efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatic conditions: versus placebo and active controls

Active drugtherapy

Formulation Treatment regimen Lengthofstudy(days)

Totalnumber ofparticipants(numbercompletingtrial)

Inclusiondiagnoses

Trialdesign

Efficacy vs control atend of trial

Overall clinical status % Adversereactions (%requiringdropout)

Rescuemed (dailymaximumallowed)

Ref.

pain ratings functionalratings

patientratings

physicianratings

activedrug

control

Comparative clinical trials: topical NSAID vs vehicle controlFlurbiprofen 40mg LAT

patch40mg patch over136cm2 bid overaffected shoulder,occluded

14 80 (70) Scapulohumeralperiarthritis withmild-moderatepain

r, db,p

Nodifference

Nodifference

Nodifference

Nodifference

22.2(0)

8.8(0)

Paracetamol[acetamino-phen] (up to2 g/day)

51

Flurbiprofen 40mg LATpatch

40mg patch over136cm2 bid overaffected areaoccluded

14 104 (89) Local, nonarticularform ofrheumatism withmoderate-severepain(epicondylitis,tendonitis, bursitis)

r, db,p

Nodifference

Nodifference

Nodifference

Flurbipro-fen; p =0.009

15(3.8)

6(3.9)

Paracetamol(up to 4g/day)

52

Ketorolac 0.6%aqueoussolution

30mg viaiontophoresis qod(surface area notreported, site notspecified), notoccluded

10 60 (60) 12 epicondylitis,30 scapulo-humeralperiarthritis, 10gonalgia, 8metatarsalgia

r, db,p

Nodifference

Notassessed

Ketorolac;p < 0.02

Ketorolac;p < 0.02

0 (0) 0 (0) Not reported 53

Copper-salicylate

Chelatedcopper-salicylate gel(4.3 mg/gcopper,43.8 mg/gsalicylate)

6.5mg copper +65.7mg salicylateto medial forearmbid (surface areanot specified), notoccluded

28 116 (93) Osteoarthritis ofthe hip and/orknee

r, db,p

Nodifference

Notassessed

Nodifference

Nodifference

85(24)

52(1.7)

Paracetamol(nomaximumreported)

54

DHEP 180mgplaster

180mg over150cm2 bid (sitenot specified),occluded

15 155 (142) Osteoarthritis ofthe knee (clinicallysymptomatic)

r, db,p

DHEP; p <0.0001

DHEP;p <0.0002

DHEP; p< 0.0001

DHEP; p< 0.0001

1.3(0)

5.2(1.3)


55

DHEP 180mgplaster

180mg over150cm2 bidapplied at site ofinflammation,occluded

14 60 (60) Localinflammatoryprocesses inperiarticular/tendinous and/orextra-articular sites

r, db,p

DHEP; p <0.01

Notassessed

Notassessed

DHEP; p< 0.01

0 (0) 0 (0) Paracetamol(nomaximumreported)

56

Oral versus Top

ical NSA

IDs in R

heumatic D

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Table III. Cont

Active drugtherapy

Formulation Treatment regimen Lengthofstudy(days)


Inclusiondiagnoses

Trialdesign


Overall clinical status % Adversereactions (%requiringdropout)

Rescuemed (dailymaximumallowed)

Ref.


patientratings

physicianratings

activedrug

control

Diclofenac/hyaluronate

3% diclo-fenac, 2.5%hyaluronangel

60mg diclofenac,50mg hyaluronandaily over affectedjoint (surface areanot specified), notoccluded

14 119 (112) Osteoarthritis r, db,p

Nodifference

Notassessed

Notassessed

Notassessed

20.3(0)

43.3(0)

Not allowed 57

Indomethacin 4% spraywith metereddose aerosolunit

10-20 mg/dose 3-5times daily overaffected area, notoccluded

14 30 (30) 28 peri-arthritis ofshoulder, 2epicondylitis

r, db,co

Indometha-cin; p <0.001

Indome-thacin; p< 0.014



6.7(0)

0 (0) Paracetamol(up to 3g/day)

58

Diclofenac 2% in lecithinorganogel

50 mg/dose tidover affectedknee, not occluded

14 74 (70) Osteoarthritis ofthe knee (clinicallysymptomatic andradiologicallyverified)

r, db,p

Diclofenacp = 0.05

Diclofe-nac p =0.05

Nodifference

Nodifference

2.7(2.7)

0 (0) Paracetamol(up to 4g/day)

59

Comparative clinical trials: topical NSAID vs topical NSAIDTopical indo-methacin vstopicaldiclofenac

Plaster(strength notspecified) vsemulsion gel(strength notspecified)

Plaster applied bidon lower back(surface area notspecified),occluded vs 2cmgel applied qid(surface area notspecified), notoccluded

28 30 vs 34(64 total)

Nonsurgicallumbago (discsyndrome, backpain, etc.)

r, sb,p

Nodifference

Nodifference

Nodifference

Notassessed

Indo-meth-acingroup6.7(3.3)

Diclo-fenacgroup0 (0)


60

Topicalflurbiprofenvs topicalpiroxicam

40mg LATpatch vs0.5% gel

40mg patch over136cm2 appliedbid over affectedarea vs 450mgapplied overaffected area(surface area notspecified), notoccluded

14a 137 total(122 atend)

Soft tissuerheumatism of theshoulder or elbow

r, nb,co

LAT;p < 0.001

LAT; p <0.004

LAT;p < 0.001

LAT;p < 0.04

LATgroup9.0(0.8)

Pirox-icamgroup6.7(2.4)


61

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566H

eyneman et al.

in the treatment of rheumatic conditions.[51-63] Acursory review of the placebo-controlled trialssummarised in table III would suggest that, withthe possible exception of DHEP and indomethacin,topical NSAIDs are not effective in chronic inflam-matory diseases. Indeed, the discouraging resultsreported by Shackel et al.[54] are not unexpected,given that patients with OA of the hip and/or kneewere instructed to apply the copper-salicylate gelto their forearms, instead of over the painful joint.

However, of the 5 studies that reported ‘no dif-ference’ in pain ratings between topical NSAIDand placebo treatments,[51-54,57] 2 reported decreasesin subjective pain scores by 35 to 60% from base-line which were attributable to placebo alone (p val-ues < 0.05 compared to baseline).[51,53] This highplacebo response rate is consistent with that seenin topical treatment of soft tissue injury.[3,51,64] Vaileand Davis[3] noted that the placebo response asso-ciated with topical treatment of soft tissue complaintscan be as high as 60 to 80%. While the natural pro-gression of healing may account for the high pla-cebo rate in patients with acute musculoskeletalcomplaints, the high rate reported in more chronicrheumatological diseases is more puzzling. Simplerubbing of the topical preparation over the affectedarea may have had some positive treatment results.Two of the studies noted in table III utilised men-tholated or camphorated placebo formulations,which may have contributed to the placebo ef-fect.[51,54]

The trend of significant pain resolution from base-line noted in the placebo-controlled studies contin-ued in the comparative topical NSAID versus topicalNSAID trials summarised in table III. Reportedpain scores decreased from 39[62] to 70%,[63] andthe percentage of patients who improved from base-line ranged from 26[61] to 87%[60] (p < 0.05 for allreported values). Looking at the comparative clin-ical trials summarised in table III, it is not possibleto draw conclusions regarding a superior drug.This is not surprising, given that there is high in-terindividual variability in patient response toNSAIDs administered orally, and the lack of pla-

Landscape table III to be placed here.



TopicalDHEP vstopical DDA

180mgplaster vs1.16%emulsion gelcontaining1% diclofenac

Plaster appliedover 150cm2 bidover affected area,occluded vs 20mgapplied qid overaffected area(surface area notspecified), notoccluded

14 96 vs 94(190 total)

Localisedperi-articular/tendinousinflammations

r, nb,p

DHEP;p < 0.001

Notassessed

DHEP;p < 0.001

DHEP;p < 0.001

DHEPgroup2.1(0)

DDAgroup3.2(0)

Not reported 62

Topical BPAAvstopicaldiclofenac

Gel (concen-tration notspecified) vsemulsion gel(concentrationnot specified)

30mg applied tidover affected area(surface area notspecified), notoccluded vs 40mgqid over affectedarea (surface areanot specified), notoccluded

7 20 vs 20(40 total)

Osteoarthritis r, nb,p

Nodifference

Notassessed

Notassessed

Notassessed

BPAAgroup0 (0)

Diclo-fenacgroup0 (0)

Not reported 63

a 4 days of one drug then 4 days of the other, then 6 days of preferred treatment.bid = twice daily; BPAA = biphenyl acetic acid; co = crossover; DDA = diclofenac diethyl diammonium; db = double-blind; DHEP = diclofenac hydroxyethyl-pyrrolidine; LAT = localaction transcutaneous; nb = nonblind; p = parallel; qid = 4 times daily; qod = every other day; r = randomised; sb = single-blind; tid = 3 times daily.

cebo controls provided no index of internal sensi-tivity.[8]

It is also difficult to deduce the optimal topicalNSAID formulation. In the sole study which di-rectly compared 2 different formulations of diclo-fenac, the total daily dosages were dramatically dif-ferent (360 vs 80mg), preventing any conclusionsregarding vehicle superiority from being drawn.[62]

3.2 Topical NSAIDs versus Oral NSAIDs

Objective, clinical evidence for the relative effi-cacy of topical versus oral NSAIDs in rheumaticdisorders is scant. Methodological issues cloud theresults presented here. Of the 4 studies summarisedin table IV,[65-68] 1 was nonblind, 3 failed to specifythe surface area of application and none utilised acrossover design. A crossover methodology, withthe advantage of utilising patients as their own con-trols, would have helped minimise the interpatientvariability that seems to plague these investiga-tions. Further, all 4 studies chose oral NSAID dos-ages on the lower end of the recommended dosagerange and compared these oral forms to topical prep-arations which have not demonstrated superiorityto vehicle controls (see table IV).

Documentation of compliance with the studyprotocol, application technique (the extent of ‘rub-bing in’), occlusion and skin surface area to be cov-ered are all important variables which need to bestandardised in these studies. The methods sectionof the study reported by Sandelin et al.[67] statedthat ‘in bilateral cases both knees were treated withsame treatment and treatment regimen’. Thus, pa-tients suffering from OA in both knees receivedtwice the dosage (and achieved presumably twicethe serum concentration) of patients with mono-lateral OA. However, the data analysis was notstructured to control for this variable. Furthermore,exclusion criteria common to these studies in-cluded a history of peptic ulcer disease, GI haem-orrhage or renal dysfunction. Thus, the safety andtolerability data may have been skewed in favourof oral NSAIDs.

The issue of allowance and tracking of rescuemedication is also very important. The study re-

ported by Dickson[68] is interesting in this respect.This author compared piroxicam gel and ibuprofentablets in patients suffering from OA of the knee.Patient ratings of efficacy were good to excellentin 64 and 60% of patients given topical piroxicamor oral ibuprofen, respectively. However, paraceta-mol rescue analgesia was required in 69 and 62% ofpatients in the topical and oral groups, respectively.This is the only study reviewed that reported suchhigh rescue analgesic use. Many of the efficacy stud-ies allowed rescue paracetamol and, of the studiesthat tracked rescue drug use,[52,54-56,66] most re-ported low incidences of use (under 5%).[56,66]

All studies reviewed here, while not consistentlydocumenting superiority of topical or oral admini-stration, reported clinical improvement attributableto topical NSAIDs ranging from 18[67] to 92%[66]

of treated patients. However, the placebo effect is-sue looms large, since only 1 study included a topi-cal placebo into its design.[67] In this investigationby Sandelin et al.,[67] oral diclofenac showed supe-rior efficacy to topical placebo as measured by in-vestigators’ and patients’ evaluation of overall ef-ficacy (p < 0.008); the efficacy values reported fortopical eltenac versus placebo, while showing atrend in favour of eltenac, did not reach statisticalsignificance.

One of the 4 studies comparing oral with topicalNSAID summarised in table IV documented supe-riority of the topical dosage form. Martens[66] com-pared local action transcutaneous (LAT) flurbi-profen to oral diclofenac in the treatment of softtissue rheumatism. In the investigator’s opinion,92% of patients treated with LAT showed clinicalimprovement, whereas 73% of those receiving oraldiclofenac showed improvement (p = 0.03). In ad-dition, the investigator’s ratings of severity of painand severity of tenderness were significantly betterin the LAT group (p ≤ 0.04). Unfortunately, whilethis was the only comparative study to show supe-riority of a topical formulation, it was also the onlystudy which was nonblind, and all assessments whichreached statistical significance were those of theinvestigator, not of the patients.

568 Heyneman et al.


Table IV. Summary of clinical trials investigating the efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) in rheumatic conditions: versus oral NSAIDs

Activedrug ther-apy

Formulation Treatmentregimen

Lengthofstudy(days)


Inclusiondiagnoses

Trialdesign


Overall clinical status % Adversereactions (%requiring dropout)

Rescue med(dailymaximumallowed)

Ref.


patientratings

physicianratings

activedrug

control

Topicalfelbinacvs oralfenbufen

Gel(concentrationnot specified)vs 200mgtablets

(Dosage,occlusion andsurface area notspecified) tid plusplacebo tablets tidvs 200mg po tidplus placebo geltid

14 275 total Osteoarthritisof the knee(clinicallyconfirmed)

r, db,p

Nodifference

Notassessed

Nodifference

Nodifference

Topicalfelbinacgroup1.4 (0)

Oralfenbufengroup10.2 (0)

Not reported 65

Topicalflurbiprofenvs oraldiclofenac

LAT patchcontaining40mgflurbiprofen vs50mg tablets

40mg patch over136cm2 appliedover affected areabid vs 50mg po bid

14 56 vs 53(109 total)

Localised,soft-tissuerheumatism

r, nb,p

Flurbiprofen;p < 0.04

Nodifference

Notassessed

Flurbipro-fen; p <0.03

Topicalflurbi-profengroup14.0(1.8)

Oraldiclofenacgroup17 (3.8)

Paracetamol(max notreported)flurbiprofengroup usedless thandiclofenacgroupp < 0.04

66

Topicaleltenac vsoraldiclofenac

1% gel vs50mg tablets

30mg appliedover affectedknee tid (surfacearea not specified) plus 1placebo tablet bidvs 50mg po bidplus placebo gelapplied tid

28 126 vs 82(208 total)

Osteoarthritisof the knee(radiographically confirmed)

r, db,p

Nodifference

Notassessed

Nodifference

Nodifference

Topicaleltenacgroup27.0(3.2)

Oraldiclofenacgroup24.4 (0)

Not allowed 67

Topicalpiroxicamvs oralibuprofen

0.5% gel vs400mg tablets

5mg applied overaffected knee(surface area notspecified) tid vs400mg tid

28 117 vs 118(235 total)

Mildosteoarthritisof the knee

r, db,p

Nodifference

Nodifference

Nodifference

Nodifference

Topicalpiroxicamgroup26.5(7.7)

Oralibuprofengroup22.9(5.9)

Paracetamol(up to4g/day)(62-69% ofpatients ineach grouprequiredrescueanalgesia)

68

bid = twice daily; db = double-blind; LAT = local action transcutaneous; nb = nonblind; p = parallel; r = randomised; tid = 3 times daily.

A nonblind study by Browning and Johson,[69]

in 191 elderly patients with mild to moderate OA,demonstrated that patients taking oral NSAIDs forOA could reduce their oral NSAID dose by a factorof 2 by concomitant use of piroxicam gel with noreduction in perceived efficacy. Thus, addition of atopical NSAID to an existing oral regimen may allowpatients to experience equivalent pain relief whiletapering down the dosage of the oral form (and thusreducing their risk of GI haemorrhage, peptic ulcerdisease, etc.)

In summary, the empirical evidence suggests,but does not prove, that NSAIDs administered top-ically are at least as efficacious as oral NSAIDs inthe treatment of rheumatic diseases. Larger, placebo-controlled, double-blind studies which control forthe variables discussed in detail in this section arenecessary before a conclusion can be reached.

4. Safety

Systemic COX inhibition by NSAIDs results ina cluster of well recognised adverse effects, partic-ularly affecting the GI tract and kidneys.[7] Someof the adverse effects secondary to oral NSAID useare dose related.[70-72] NSAID use approximatelydoubles the risk of acute renal failure,[72] and a lin-ear dose-response relationship has been estab-lished between oral NSAIDS and upper GI bleed-ing.[73] Thus, targeting therapeutic tissue/synovialfluid concentrations of NSAIDs via the topicalroute while minimising systemic exposure by low-ering serum concentrations makes good sense.

Figueras et al.[74] reviewed 194 adverse drug re-action reports attributed to topical NSAIDs. Ofthese, 95% were dermatological in nature and theremaining 5% were systemic reactions. This datais consistent with the information presented in ta-bles III and IV. On average, adverse drug reactions(ADRs) occurred in 12% of the patients in thesestudies (range 0 to 85%), and approximately 75%of ADRs were cutaneous, consisting of a rash and/or pruritus at the site of application. The mean per-centage of patients reporting adverse events aftertopical placebos was 14.4% (range 0 to 52%). Again,these events were primarily rash and pruritus, sug-

gesting that the vehicle itself may be responsiblefor a significant proportion of the adverse cutane-ous reactions.

The tolerability of topical NSAIDS in the el-derly has been reviewed.[72] While the majority ofadverse effects are skin disorders, there have beencase reports of topical NSAIDs associated withsystemic effects such as GI and renal toxicities,abnormal hepatic function, hematopoietic disordersand asthma.[72] However, the incidence of these se-rious systemic ADRs appears to be very low; noneof the studies summarised here reported a serioussystemic reaction attributable to topical NSAID use.Without considerable post-marketing surveillancedata, it will be difficult to assign a definite associ-ation between topical NSAID administration andsystemic adverse events, since many events mayoccur independently, and patients may have beentaking an oral NSAID at the time of their illness. Acase-control study conducted by Evans et al.[75]

demonstrated that once adjustments were made forthe confounding effects of concomitant oral NSAIDuse, topical NSAID administration was not signif-icantly associated with upper GI bleeding and per-foration.

In summary, topically applied NSAIDs are saferthan orally administered NSAIDs. ADRs can beexpected in approximately 10% of patients, the vastmajority being localised pruritus and/or rash at thesite of administration that resolves quickly upondiscontinuation of the product. Cross-sensitivitybetween different topical NSAIDs has been estab-lished.[76] Skin reactions secondary to oral NSAIDuse have been reported in 5 to 10% of patients.[77]

GI ADRs after topical NSAID use are rare; in com-parison, the incidence of serious GI events associ-ated with oral NSAIDs is 15%.[78]

5. Cost Effectiveness

By the year 2030, people over the age of 65 areexpected to constitute 17% of the US populationand to account for approximately 40% of total drugexpenditures.[79] OA is the most common of therheumatic diseases, and the overall disease preva-lence increases with age: 10 to 20% of people over

570 Heyneman et al.


65 have clinical OA of the knees and hips, and overhalf of these have radiographic evidence of OA.[8,80]

Currently, over 50% of oral NSAID prescriptionsare written for OA.[15] Furthermore, increasing ageis associated with an increased likelihood of ad-verse events after oral NSAID therapy, particularlywith respect to peptic ulcer disease. The overall oddsratio for the risk of serious GI toxicity associatedwith oral NSAID administration is 2.74 [95% CI(confidence interval): 2.54 to 2.97]; the risk assessedin people aged 60 years or greater (compared withthose under 60 years taking NSAIDs) has been es-timated to be 5.5 (95% CI: 4.6 to 6.6).[81] Thus, theissue of cost effectiveness of oral versus topicaladministration of NSAIDs is an important consid-eration.

Topical NSAIDs have been considered a costlyalternative to oral formulations.[64,82] However, inthe US alone, oral NSAID-induced GI damage hasbeen reported to account for 42% of hospital ad-missions of patients with rheumatic diseases andfor one-third of the total cost of rheumatic diseasetreatment.[83] When this ‘shadow’ cost of treatingadverse effects is taken into account, and assumingequal efficacy (which remains to be proven), thecost-benefit analysis shifts decidedly in favour oftopical over oral NSAIDs.[64] It remains to be seenif the new COX-2–specific NSAIDs can indeed re-duce the GI morbidity and mortality associated withoral NSAID treatment of rheumatic disorders.

6. Conclusions

Topical NSAIDs have been used to treat a widevariety of conditions: musculoskeletal injuries,[3,4]

postoperative pain,[84,85] herpetic neuralgia,[86] peri-odontitis,[87] aphthous ulcers[88] and actinic kerato-ses.[89] The anti-inflammatory efficacy of topicallyapplied NSAIDs, even remote from the site of ap-plication, has been well established in animal mod-els.[90] Evidence for anti-inflammatory activityfrom topical NSAIDs in humans is more equivocal,characterised by a considerable placebo effect (5 to60% in chronic rheumatic diseases[91]) and signifi-cant interpatient variability in response.

Local enhanced topical delivery of topically ap-plied NSAIDs does occur in humans, but the tissuedepth at which the systemic circulation takes overdistribution of the drug is highly variable amongindividuals. Individual variability in subcutaneousvasculature may account for the wide range of tis-sue depths reported after topical administration, aswell as inconsistency in patient response to topicalNSAIDs.

Few generalisations can be made regarding thebest drug or topical dosage form for enhancing cu-taneous NSAID penetration and efficacy. Opti-misation of vehicle formulation, pH and occlusionhave all been documented to enhance penetration.

Transdermal application gives rise to much lowerplasma concentrations than oral administration.NSAID concentrations in the synovium subjacentto the site of topical application are at least compa-rable to those achieved after equivalent oral admin-istration; subcutaneous concentrations after topicaladministration far exceed that which are normallyachieved after oral administration.

Adverse effects secondary to topical NSAIDapplication occur in approximately 10 to 15% ofpatients, and are primarily cutaneous in nature(rash and pruritus at site of application). GI ADRs arerare with topically applied NSAIDs, comparedwith a 15% incidence reported for oral NSAIDs.

Positive treatment outcomes reported in patientswith chronic rheumatic disorders range from 30 to95%, with considerable interpatient variability.[91]

On average, 1 out of 3 patients using topical NSAIDswill achieve a successful outcome who would nothave done so had they used a placebo.[91]

The clinical evidence suggests, but does notprove, that NSAIDs applied topically are as effec-tive as oral NSAIDs in the treatment of chronicrheumatic diseases. However, the contribution toefficacy by the rather dramatic placebo effect seenin these studies remains to be teased out by larger,well controlled, crossover studies comparing oraladministration of clinically effective doses with top-ical formulations with proven superiority over ve-hicle controls. The safety profile of topical NSAIDsin terms of cutaneous ADRs is approximately



equivalent to that of oral formulations, but topicalpreparations are clearly superior in terms of GI ad-verse effects. Given the relatively benign adverseeffect profile of topical NSAIDs and the increasingrisk of serious NSAID-mediated GI events with age,it seems rational to give patients with rheumaticdisorders a trial of topical NSAIDs prior to institu-tion of an oral NSAID if oral paracetamol fails tocontrol their pain.

References1. Grahame R. The NSAID patch [editorial]. Eur J Rheumatol

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Correspondence and offprints: Dr Catherine A. Heyneman,Assistant Professor of Pharmacy Practice, Idaho State Uni-versity College of Pharmacy, Campus Box 8356, Pocatello,ID 83209, USA.E-mail: [email protected]

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