Frequency of application of topical corticosteroids: an overview

B.R.LAGOS AND H.I.MAIBACHDepartment of Dermatology, University of California San Francisco, School of Medicine, Box 0989, Surge 110, San Francisco,California 94143-0989, U.S.A.

Accepted for publication 25 June 1998

Summary The frequency of application of topical corticosteroids has remained an unresolved issue through thedecades with most textbooks and physicians recommending multiple daily use. This review focuseson the rationale of once daily application of corticoids as an effective treatment in some patients.Dermatopharmacokinetic data relevant to the dosage and frequency of application of topicalcorticoids are discussed. Clinical trials on the efficacy of once daily vs. twice daily applications areevaluated.

The frequency of topical application of corticosteroidsdeveloped in an empirical manner. Until recently, mostphysicians recommended multiple daily applications.Sudilovsky et al., as early as the 1980s commentedthat the tradition of applying topical corticoids threeto four times daily in the treatment of inflammatorydermatoses reflects the inexactitude of the art and hadno scientific basis.1 A decade and a half later, the customof applying topical corticosteroids several times dailyprevails. This fact underlies the need to determine theminimum required frequency of application at givenconcentrations as logic dictates that administrationshould be limited to the least amount compatible witheffective treatment. Problems of tachyphylaxis, systemictoxicity, local side-effects, expense and patient compli-ance might be improved by less frequent use of topicalsteroids.2

Dermatopharmacokinetics

Knowledge of dermatopharmacokinetics allows a morerational approach. Several observations and hypothesesderived from data accumulated through the last fewdecades are relevant to the dosage and frequency ofapplication of topical corticoids. Owing to a ‘reservoireffect’, corticoids applied under occlusion can reside inthe stratum corneum for up to 2 weeks, and in theabsence of occlusion, for up to 2 days.3 The urinaryexcretion of topically applied hydrocortisone reaches aplateau for several days after a single application to

unoccluded skin.4 In view of the relatively slowprocess of corticosteroid absorption, it is not surprisingthat a single daily application may be effective in somepatients.

As early as the 1970s, it was known that increasedfrequency of application during 1 day is not an effectiveway to increase the penetration of topical corticoids.Experimental studies on the percutaneous absorption ofhydrocortisone failed to reveal a significant increase inabsorption when applied on a repetitive basis, comparedwith a single dose.5

In addition, du Vivier and Stoughton have demon-strated that an acute tolerance to the vasoconstrictioneffect of topical corticoids in normal subjects can beobserved after thrice daily application for 4 days.6 Inan animal model, the hairless mouse, a similar acutetolerance to the antimitotic effect of topical corticoidswas demonstrated.7 As vasoconstriction and antimito-tic effects of topical corticoids may be related to theirtherapeutic effects, these observations suggests that theresistance clinically observed after prolonged use mightbe prevented by less extensive therapy, such as dailyapplication and short resting periods between courses oftreatment.8

In the 1980s, Hehir and colleagues investigated thepharmacokinetics of clobetasol propionate and clobeta-sol butyrate after a single application of an ointment.9

Using radioimmunoassay methods, the plasma levels ofclobetasol propionate and clobetasol butyrate weremeasured following application of the ointment inpatients with psoriasis or eczema. The study showedmeasurable plasma levels of clobetasol propionate andclobetasol butyrate 48 h after a single application of

British Journal of Dermatology 1998; 139: 763–766.

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Correspondence: Howard I Maibach.

ointment, suggesting that once daily usage may give asgood or better clinical results as multiple daily applica-tions. This is especially critical for the potent corticoidswhich are associated with more side-effects.10

Investigations on the reservoir function of the skinby Turpeinen examined the percutaneous absorption ofhydrocortisone in patients with atopic dermatitis.11

Aside from confirming previous findings that topicallyapplied hydrocortisone may be absorbed at high levelsin severe and widespread dermatitis, Turpeinen showedthat topically applied hydrocortisone is stored in ecze-matous skin.12,13 Elevated plasma levels of hydrocorti-sone 24 h after application suggest that a single dailyapplication provides sufficient hydrocortisone for 24 h,in the topical treatment of atopic dermatitis. A relatedstudy, performed on the pharmacokinetics of topicalhydrocortisone at plasma level after application onceor twice daily in patients with widespread dermatitis,suggested that the treatment of an exacerbation ofatopic dermatitis can be improved by the topical appli-cation of hydrocortisone twice a day on the first day but,from the second day onward, one application a dayseems to suffice.14

Efficacy of corticosteroids

The optimum frequency for the application of topicalcorticoids has been investigated in only a few studies(Table 1). With regards to the class I superpotentcorticosteroids, several well controlled paired compari-son studies showed no difference in treatment responsein eczema or psoriasis between once or twice daily

application. In one study, 50 patients with moderateto severe atopic, contact or nummular dermatitis wererandomly allocated to two treatment groups, one receiv-ing betamethasone 17,21 dipropionate (Diprodem cream0·05%) 2 ×/day and the other receiving the base in themorning and betamethasone 17,21 dipropionate (Dipro-derm 0·05%) cream in the evening.15 There was nosignificant difference in effect between the two treat-ments after 1 week, showing that once a day treatmentwith betamethasone 17,21 dipropionate (Diprodermcream 0·05%) seems to be as effective as twice a dayin these types of dermatitis. In a double-blind 3-weekcomparison study of the efficacy of betamethasone dipro-pionate in the treatment of 97 patients with corticoid-responsive dermatoses (63 cases of eczema and 34 casesof psoriasis), English et al. found no statistical differencebetween once daily and twice daily application for allparameters examined in patients with either eczema orpsoriasis.16 Singh et al. studied 36 psoriatic patientswho had two stable equivalent indicator lesions on theflexor of each forearm.17 One indicator lesion in eachpatient was treated with topical betamethasone dipro-pionate 0·05% twice daily and the other was treatedonce daily. There was no statistical difference betweenthe results in the two groups for the onset of actionwhich occurred within 48 h, the score of each of thefour parameters (i.e. erythema, scaling, induration andthe local psoriasis area and severity index: PASI) on eachday of the observation, and the number of days requiredfor the parameter scores to become zero. This studydemonstrates that the generally recommended twicedaily application of 0·05% betamethasone dipropionate

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Table 1. Frequency and efficacy of topical application of corticosteroids

Author, year and reference Type of study Results

Gartner and Tarras, 198415 Randomized double blind, controlled No statistical difference between once daily vs. twice daily treatment withbetamethasone 17,21 dipropionate in eczema

English et al. 198916 Randomized double blind No statistical difference between once daily and twice daily application ofbetamethasone dipropionate in both eczema and psoriasis

Singh et al. 199517 Randomized double blind, controlled,bilateral paired comparison

No difference in results between once daily vs. twice daily application ofbetamethasone dipropionate 0·05% in psoriasis

Koopman et al. 199518 Randomized double blind Once daily and twice daily application of 0·1% hydrocortisone-17-butyrate reduced clinical features equally in atopic eczema patientsalthough clearance rate was higher with the twice daily application

Tharp, 199619 Randomized double blind, vehiclecontrolled

No statistical difference between once daily and twice daily application offluticasone propionate in moderate to severe eczema

Frederiksson et al. 198020 Double-blind study No statistical difference in response with once daily vs. thrice dailyapplication of halocinonide in psoriasis and atopic dermatitis, except foronset of action which was more rapid with thrice daily

Sudilovsky et al. 198121 Double-blind paired comparison No statistical significant difference between once daily vs. thrice dailyapplication of 0·1% halocinonide cream in atopic dermatitis patients

offers no therapeutic advantage over once daily treat-ment in psoriasis.

For corticosteroids in the potent or moderately potentcategories, several paired comparison studies showed nodifference or a slight difference only when comparing onceand twice daily application. For the treatment of derma-titis, recent studies revealed no difference between onceand twice daily application or slight differences which areprobably not of clinical significance. In a multicentrerandomized double-blind study, the twice daily applicationof 0·1% hydrocortisone-17-butyrate (Locoid Lipocream)was compared with 0·1% hydrocortisone-17-butyrate(Locoid Lipocream) once daily and its base once dailyin 150 patients with atopic eczema.18 Both treatmentssignificantly reduced all clinical features equally, but theclearance rate was significantly higher with the twicedaily regimen. In another study, Tharp compared theefficacy and safety of once and twice daily application of0·05% fluticasone propionate cream over a 28-daytreatment period in 238 patients with moderate tosevere eczema.19 There were no statistically significantdifferences between the once daily and twice dailyapplication groups at day 8 and at the end of the 28-day treatment period, suggesting that once daily appli-cation may be recommended for the treatment ofmoderate to severe eczema in most patients. With regardto the treatment of psoriasis using potent or moderatelypotent corticosteroids, two studies, both comparing 0·1%halocinonide (Halog), have been performed.20,21 Bothwere paired comparison investigations with one studyshowing no difference except for a relatively more rapidonset of action. However, the other study revealed that,although a once daily regimen of 0·1% halcinonidecream can be effective, application of the cream threetimes daily was slightly superior to once daily, especiallyfor severe psoriasis.

Conclusions

A review of the literature has shown that, for thesuperpotent corticosteroids, there was no significantdifference in treatment response with once or twicedaily application. Likewise, there was no difference oronly a slight difference with once or twice daily appli-cation of potent or moderately potent corticosteroids. Inview of these findings, once a day application of topicalcorticosteroids may be preferable as it also offers distinctadvantages over more frequent applications. In addition,the risk of developing adverse effects, which increaseswith excessive use, could be minimized, the cost of therapywill be halved, and patient compliance will improve.

Acknowledgments

Dr Ernst Epstein provided expert counsel.

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15 Gartner L, Tarras-Wahlberg C. A double-blind controlled evalu-ation of Diproderm cream 0.05% twice a day treatment in com-parison with once a day treatment in eczema. J Int Med Res 1984;12: 59–61.

16 English JS, Bunker CB, Ruthven K. A double blind comparison ofthe efficacy of betamethasone dipropionate cream twice dailyversus once daily in the treatment of steroid responsive derma-toses. Clin Exp Dermatol 1989; 14: 32–4.

17 Singh S, Gopal J, Mishra RN. Topical 0.05% betamethasonedipropionate: efficacy in psoriasis with once a day vs. twice aday application. Br J Dermatol 1995; 133: 497–8.

18 Koopman B, Lasthein Andersen B, Mork NJ et al. Multicentrerandomized double-blind study of Locoid lipocream fatty creamtwice daily versus Locoid lipocream once daily and locobase oncedaily. J Dermatol Treatment 1995; 6: 103–6.

19 Tharp M. Comparison of twice daily and once daily administration

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of fluticasone propionate cream 0.05% in the treatment of eczema.Cutis 1996; 57: 19–26.

20 Fredriksson T, Lassus A, Bleeker J. Treatment of psoriasis andatopic dermatitis with halocinonide cream applied once and threetimes daily. Br J Dermatol 1980; 102: 575–7.

21 Sudilovsky A, Muir JG, Bocobo FC. A comparison of single andmultiple applications of halcinonide cream. Int J Dermatol 1981;20: 609–13.

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