Intranasal corticosteroids for allergic
`rhinitis: How do different agents
`compare?
`
`Jonathan Corren, MD Los Angeles, Calif
`
`Intranasal steroids have proved to be an effective and safe
`form of therapy for allergic rhinitis. However, as the number
`of new glucocorticoid compounds has increased over the past
`decade, it has become important to consider whether signifi-
`cant differences exist between these agents. Pharmacologically,
`newer drugs such as mometasone furoate and fluticasone pro-
`pionate appear to have substantially higher topical potencies
`and lipid solubilities and lower systemic bioavailabilities than
`do older compounds. In clinical use, however, all the available
`drugs appear to be equally effective in controlling symptoms
`of seasonal and perennial allergic rhinitis. With respect to
`adverse effects, emerging data suggest that mometasone
`furoate and fluticasone propionate may have less potential for
`systemic effects during prolonged use, particularly in children.
`Newer intranasal steroids appear to have practical advantages
`over older agents that may favor their use in some groups of
`patients with allergic rhinitis. (J Allergy Clin Immunol
`1999;104:S144-9.)
`
`Key words: Intranasal steroids, potency, lipophilicity, systemic
`bioavailability, onset of action
`
`Since their introduction more than 2 decades ago,
`intranasal steroids have become established as first-line
`treatment for allergic rhinitis.1 All the available agents,
`including beclomethasone dipropionate, budesonide, flu-
`nisolide, fluticasone propionate, mometasone furoate,
`and triamcinolone acetonide have been shown to be effi-
`cacious in the treatment of both seasonal and perennial
`allergic rhinitis and other chronic inflammatory nasal
`diseases. Despite the efficacy of these medications, how-
`ever, some physicians have remained reluctant to pre-
`scribe them because of concerns about potential local and
`systemic adverse effects.2 When an attempt is made to
`develop intranasal steroids that are safe and maximally
`efficacious for long-term use, several pharmacologic and
`clinical attributes must be considered, including topical
`potency, lipophilicity, systemic bioavailability, onset of
`action, and potential for local and systemic adverse
`effects. This article will compare the available intranasal
`glucocorticoid compounds in the context of these impor-
`tant issues.
`
`From the University of California, Los Angeles, and the Allergy Research
`Foundation, Inc, Los Angeles, Calif.
`Supported by an unrestricted educational grant from Schering/Key Pharma-
`ceuticals, Schering Corporation.
`Reprint requests: Jonathan Corren, MD, University of California, Los Ange-
`les, Allergy Research Foundation, 11620 Wilshire Blvd, Suite 200, Los
`Angeles, CA 90025.
`Copyright © 1999 by Mosby, Inc.
`0091-6749/99 $8.00 + 0 1/0/101680
`
`S144
`
`Abbreviation used
`HPA: Hypothalamic-pituitary-adrenal
`
`PHARMACOLOGIC PROFILES OF TOPICAL
`INTRANASAL STEROIDS
`Topical potency
`
`Topical potencies of glucocorticoids are most often
`compared with use of the McKenzie assay, which assess-
`es skin-blanching responses as a measure of cutaneous
`vasoconstriction.3 With use of this assay, newly devel-
`oped compounds such as fluticasone propionate and
`mometasone furoate have been shown to be more potent
`than other corticosteroids used intranasally.4 Although
`the McKenzie assay is highly relevant to the vasocon-
`strictive effects of glucocorticoids, it is unknown to what
`extent these results correlate with the various anti-
`inflammatory properties of a drug.
`Another recent method for comparing the biologic
`effects of topical corticosteroids has been to evaluate the
`inhibitory effects of various compounds on the produc-
`tion of T lymphocyte–derived cytokines. In one recent
`study purified peripheral blood CD4+ cells were stimu-
`lated with immobilized anti-CD3 or soluble anti-CD28
`antibodies to induce the release of IL-4, IL-5, and IFN-γ
`(Fig 1).5 This study demonstrated that mometasone
`furoate and fluticasone propionate were equally and
`highly effective in preventing the release of IL-4 and
`IL-5 and were substantially more active than the other
`compounds tested. With use of an assay of T-cell prolif-
`eration, English et al6 demonstrated that fluticasone pro-
`pionate was more potent
`than dexamethasone,
`beclomethasone dipropionate, and budesonide. Although
`these data are derived from an in vitro system, they do
`provide a potentially meaningful way of comparing
`selective anti-inflammatory effects of glucocorticoid
`compounds.
`Glucocorticoid potencies have been postulated to be
`most highly related to glucocorticoid receptor binding
`affinity. A study by Smith and Kreutner7 compared the
`relative binding affinities of several intranasal steroids
`and determined that the ranked order of binding to the
`glucocorticoid receptor was, from highest to lowest,
`mometasone furoate, fluticasone propionate, budes-
`onide, triamcinolone acetonide, and dexamethasone (Fig
`2). In that same study mometasone furoate was also
`found to be the most potent stimulator of glucocorticoid
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`Corren S145
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`FIG 1. Potency of glucocorticoids as measured by inhibition of IL-5 (A), interferon-γ (B), and IL-4 (C). (Adapted with permission from
`Umland SP, Narhebne DK, Razac BS, Beavis A, Pinnline KJ, Egan RW, et al. The inhibitory effects of topically active glucocorticoids on
`IL-4, IL-5, and interferon-γ production by cultured primary CD4+ cells. J Allergy Clin Immunol 1997;100:511-9.)
`
`receptor–mediated transactivation of gene expression. In
`another publication, Hogger and Rohdewald8 demon-
`strated that fluticasone propionate had a higher binding
`affinity than did dexamethasone, budesonide, and
`beclomethasone-17-monopropionate, the active metabo-
`lite of beclomethasone dipropionate. Importantly, the
`results of these 2 studies reflect the results of in vitro
`assessments of anti-inflammatory activities.5,6
`
`Lipid solubility
`Lipophilicity is an index of the lipid-partitioning
`potential of glucocorticoid compounds. As such, highly
`lipophilic agents will demonstrate a higher and faster rate
`of uptake by the nasal mucous membrane, a higher level
`of retention within the nasal tissue, and an enhanced abil-
`ity to reach the glucocorticoid receptor. The ranked order
`of lipid solubility of available topical intranasal steroids
`is, from highest to lowest, mometasone furoate, fluticas-
`one propionate, beclomethasone dipropionate, budes-
`onide, triamcinolone acetonide, and flunisolide.4
`
`Systemic bioavailability
`Systemic bioavailability is the sum of 2 components,
`including the portion of the drug that is swallowed plus
`the portion of the drug that is absorbed via the nasal
`mucosa. Because most of the dose of an intranasal
`steroid is swallowed, systemic bioavailability is primari-
`ly determined by the amount of the drug that is absorbed
`by the gastrointestinal tract. With the exception of dexa-
`methasone, all the first-generation intranasal steroids
`
`have significant first-pass hepatic metabolism, with oral
`bioavailabilities ranging between approximately 20%
`and 50% (Fig 3).9,10 In contrast, neither mometasone
`furoate nor fluticasone propionate are readily absorbed
`by the gastrointestinal tract, and, subsequently, both have
`been found to have extremely low oral bioavailabilities
`respectively).11-13 Systemic
`(ie, <0.1% and <2%,
`bioavailability values of the intranasal steroids are simi-
`lar to the oral values noted above, and studies of both
`mometasone furoate and fluticasone propionate have
`demonstrated extremely low plasma drug levels in the
`systemic circulation.
`
`CLINICAL PROFILES OF INTRANASAL
`STEROIDS
`Therapeutic efficacy
`
`Intranasal steroids have been compared in a large
`number of clinical trials in patients with both seasonal
`and perennial allergic rhinitis. In general, these studies
`have consisted of 2- to 8-week parallel-group trials of
`patients with moderately severe rhinitis.
`Comparisons of older agents. There have been rela-
`tively few trials comparing beclomethasone dipropi-
`onate, budesonide, flunisolide, and triamcinolone ace-
`tonide. Welsh et al14 compared beclomethasone
`dipropionate (168 µg twice daily) versus flunisolide (100
`µg twice daily) in patients with seasonal allergic rhinitis
`and found the 2 drugs to be equally effective.
`Older agents versus fluticasone propionate. Multip-
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`S146 Corren
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`J ALLERGY CLIN IMMUNOL
`OCTOBER 1999
`
`FIG 2. Binding affinities of glucocorticoids for the glucocorticoid receptor. Relative binding affinity is
`expressed as the reciprocal of the relative amount of test ligand needed to displace 50% of bound [3H] dex-
`amethasone. (Adapted with permission from Smith CL, Kreutner W. In vitro glucocorticoid receptor binding
`and transcriptional activation by topically active glucocorticoids. Arzneim-Forsch/Drug Res 1998;48:956-60.)
`
`studies have compared beclomethasone dipropionate
`with fluticasone propionate. In a 2-week study of sub-
`jects with seasonal allergic rhinitis, beclomethasone
`dipropionate (168 µg twice daily) and fluticasone pro-
`pionate (200 µg once daily) had comparable efficacy.15
`In patients with perennial allergic rhinitis a 3-month16
`and a 6-month17 study demonstrated clinical equiva-
`lence between beclomethasone dipropionate (168 µg
`twice daily) and fluticasone propionate (200 µg once
`daily), whereas a 12-month study showed fluticasone
`propionate (200 µg once daily) to be substantially
`superior to beclomethasone dipropionate (200 µg twice
`daily).18
`Budesonide and fluticasone propionate have also been
`compared in a number of trials. In a 6-week study of
`patients with seasonal allergic rhinitis, budesonide (256
`µg once daily) was more effective in reducing sneezing
`than fluticasone propionate was (200 µg once daily).19 In
`2 separate 6-week studies of patients with perennial aller-
`gic rhinitis, budesonide (256 µg once daily) was demon-
`strated to be more effective than fluticasone propionate
`(200 µg once daily),20 whereas another trial found budes-
`onide (200 and 400 µg once daily) to be as efficacious as
`fluticasone propionate (200 µg once daily).21
`Small et al compared triamcinolone acetonide (220 µg
`once daily) with fluticasone propionate (200 µg once
`daily) in seasonal rhinitis and noted no significant differ-
`ences between the 2 treatments.22
`Older agents versus mometasone furoate. In a 4-
`week23 and 8-week24 study of patients with seasonal
`rhinitis, beclomethasone dipropionate (168 µg twice
`daily) was found to be equivalent to mometasone furoate
`(200 µg once daily). In patients with perennial allergic
`rhinitis the 2 drugs were again found to be equally effec-
`tive given in the above dosages.25
`
`Mometasone furoate versus fluticasone propionate.
`Mandl et al26 compared mometasone furoate (200 µg
`once daily) with fluticasone propionate (200 µg once
`daily) in patients with seasonal allergic rhinitis and found
`that the 2 drugs were clinically equivalent.
`When all the above studies are considered, there do
`not appear to be clinically significant differences in effi-
`cacy among the available intranasal steroid preparations.
`This is somewhat surprising given the marked pharmaco-
`logic differences among the various agents. It may be
`that the inflammatory processes occurring in allergic
`rhinitis are easily inhibited by glucocorticoids of varying
`potencies and that the pharmacologic advantages of flu-
`ticasone propionate and mometasone furoate are not crit-
`ical in most patients with nasal allergy. Alternatively,
`clinical trials primarily include patients with moderate
`symptoms, many of whom are able to remain in a trial for
`2 to 4 weeks, taking only a placebo as treatment for their
`symptoms. To determine whether the newer agents are
`more effective than the older drugs, it would be neces-
`sary to study patients with rhinitis whose symptoms were
`poorly controlled on one of the older agents.
`
`Onset of action
`For many years it was a commonly held belief that
`intranasal steroids require several days of use to achieve
`symptom control. This belief existed, in part, because
`onset of action was considered unimportant in drugs that
`were to be used regularly for control of chronic symp-
`toms. Subsequently, few clinical studies were designed to
`accurately determine the onset of action of these medica-
`tions. Increasingly, however, it has become widely rec-
`ognized that many patients use intranasal steroids on an
`as-needed basis only, stopping the drug when symptoms
`substantially abate. In support of this approach are recent
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`FIG 3. Bioavailability of intranasally administered first- and second-generation intranasal steroids. (Adapted
`from manufacturers’ prescribing information. Bioavailability of intranasal triamcinolone acetonide and
`beclomethasone are not provided in labeling.)
`
`studies demonstrating that intermittent use of intranasal
`steroids is moderately effective in many patients.27
`Because of this emerging style of use, it has become
`more important to determine the onset of action of these
`agents in allergic rhinitis. Historically, package inserts
`for older intranasal steroids have stated that several days
`to up to 2 weeks of use are usually required for clinical
`improvement. Recent clinical studies with budesonide,
`fluticasone propionate, mometasone furoate, and triam-
`cinolone acetonide have demonstrated clinical improve-
`ment within 1 to 2 days of the first dose.9-12,28,29 In a
`placebo-controlled study of mometasone furoate, 28% of
`patients treated with active therapy had symptom relief
`within the first 12 hours, in contrast to 13% of patients in
`the placebo group.30 The median time to symptomatic
`relief was 36 hours with mometasone furoate and 72
`hours with placebo. Future studies comparing the onset
`of action for all the topical glucocorticoids will be
`required to definitively show superiority of one agent
`over another.
`
`Dosing frequency
`Clinical trials have demonstrated the efficacy of once-
`daily dosing with many of the available intranasal
`steroids, including beclomethasone dipropionate, budes-
`onide, fluticasone propionate, mometasone furoate, and
`triamcinolone acetonide.10-12,28,29 In this regard, there do
`not appear to be significant advantages of one agent over
`another.
`
`Adverse effects
`Local side effects. Use of intranasal steroids frequent-
`ly results in symptoms of dryness, stinging, and burning
`in 5% to 10% of patients, irrespective of the compound
`or formulation used. Epistaxis is another common local
`
`side effect, occurring in approximately 5% of patients; its
`incidence has not been shown to increase with use of the
`newer, more potent agents. Septal perforations have been
`reported to occur rarely and may best be averted by
`directing the spray toward the inferior turbinate rather
`than the septum. Atrophy of the nasal mucosa was once
`a concern with chronic use of topical steroids, particular-
`ly with the introduction of higher-potency compounds.
`However, long-term histologic studies with mometasone
`furoate and fluticasone propionate have demonstrated
`restoration of normal histologic features with no evi-
`dence of atrophy or metaplasia after 12 months of thera-
`py in patients with perennial allergic rhinitis.31,32 There
`do not appear to be any increased risks of local side
`effects with more potent intranasal steroids.
`Systemic side effects. As discussed above, all the avail-
`able intranasal steroids except dexamethasone undergo
`substantial first-pass hepatic metabolism. As would be
`expected, systemic bioavailabilities of these drugs are
`universally low, reducing the risk of systemic exposure to
`glucocorticoid effects. Although intranasal steroids have
`a long track record of safety with no reports of serious
`side effects, the introduction of more potent glucocorti-
`coid compounds to younger patient populations has
`renewed interest in the potential systemic effects of these
`medications. Laboratory evaluations of hypothalamic-
`pituitary-adrenal (HPA) axis function are frequently used
`to determine the systemic effects of intranasal steroids.
`As would be expected in patients absorbing extremely
`small doses of glucocorticoids, there have been no
`reports of acute adrenal crisis or chronic adrenal insuffi-
`ciency with intranasal steroids. Therefore, rather than
`serving as an indicator of the risk of clinical adrenal dys-
`function, measures of HPA axis function are of greater
`interest as biologic markers of systemic glucocorticoid
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`S148 Corren
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`activity. Evaluations of the HPA axis can be divided into
`tests that assess basal (eg, morning plasma cortisol, inte-
`grated plasma cortisols, urinary cortisol) versus dynamic
`(ACTH stimulation, insulin tolerance tests) function.
`Studies that have sought to determine the effects of
`intranasal steroids on basal index values of HPA axis
`function have generally shown no significant effects with
`beclomethasone dipropionate at 200, 336, 400, and 800
`µg per day33,35; triamcinolone acetonide at 220 µg per
`day33,34; fluticasone propionate at 200 µg per day33; and
`mometasone furoate at 200 µg per day.34 In one study,
`budesonide at 200, 400, and 800 µg per day caused sig-
`nificant suppression of urinary cortisol,35 whereas in
`another study at 200 µg per day it did not.34 Studies with
`ACTH stimulation have similarly shown no significant
`effects of intranasal corticosteroids, including beclo-
`methasone dipropionate at 336 µg per day,36 fluticasone
`propionate at doses of 200 and 400 µg twice daily,37 and
`triamcinolone acetonide at 220 and 440 µg per day.38
`Few data exist regarding HPA axis effects of intranasal
`steroids in children; one study of children with allergic
`rhinitis failed to show any significant suppression of
`ACTH stimulation after the use of triamcinolone ace-
`tonide at 220 and 440 µg per day.39 Overall, these data
`suggest that intranasal steroids have no or minimal
`effects on the HPA axis, even when given in relatively
`high doses.
`Other investigators have evaluated intranasal steroids
`with use of techniques that are potentially more sensitive
`than measures of HPA axis function. Osteocalcin, com-
`monly used as a peripheral blood marker of bone metab-
`olism, was not significantly affected by short-term use of
`budesonide at 200 µg per day, mometasone furoate at 200
`µg per day, or triamcinolone acetonide at 220 µg per
`day.34 Using another approach, Fokkens et al40 quantitat-
`ed peripheral blood B cells, T cells, and lymphocyte sub-
`populations as a measure of systemic glucocorticoid
`activity and were unable to identify any effect with either
`budesonide or fluticasone propionate at dosages of 200
`and 800 µg per day. Knuttson et al41 examined the effects
`of budesonide and fluticasone propionate on specific gene
`expression in peripheral blood lymphocytes and noted
`that both drugs caused a decrease in glucocorticoid recep-
`tor messenger RNA and an increase in methallothionein
`messenger RNA, indicating a significant systemic effect.
`Although the results of this study suggest an effect of
`intranasal steroids on systemic immune cell function, the
`clinical relevance of this finding is uncertain.
`Recent observations that inhaled steroids may alter
`growth velocity in young asthmatic children have
`prompted similar concerns regarding the chronic use of
`intranasal steroids.42 A 12-month, double-blind, placebo-
`controlled study of young children with perennial aller-
`gic rhinitis demonstrated that beclomethasone dipropi-
`onate 168 µg twice daily caused a small (0.9-cm
`difference) but statistically significant reduction in
`growth velocity.43 In contrast, a recent 12-month trial of
`mometasone furoate in young children with perennial
`rhinitis failed to show any reduction in growth velocity at
`
`J ALLERGY CLIN IMMUNOL
`OCTOBER 1999
`
`dosages of either 100 or 200 µg once daily. Although
`there have been no studies of intranasal fluticasone pro-
`pionate on growth rates in children, data extrapolated
`from trials of inhaled fluticasone propionate, 100 µg
`twice daily suggest that there are no significant effects.11
`Several important questions remain regarding the use of
`intranasal steroids in children, including (1) which spe-
`cific agents can significantly affect growth velocity, (2)
`whether and how quickly growth velocity returns to nor-
`mal after the medication is stopped, (3) whether ultimate
`attainment of height is equivalent in children who are
`treated with these drugs, and (4) whether there is an addi-
`tive effect with inhaled steroids taken concomitantly for
`bronchial asthma. Comparative data regarding all the
`available agents are needed to resolve these issues, and
`only large, long-term clinical trials will be able to accom-
`plish this.
`
`CONCLUSION
`
`Advances in our understanding of the structural-func-
`tional relationships of glucocorticoids have allowed for
`the development of new compounds with higher poten-
`cies and lower oral bioavailabilities. Although it has been
`difficult to demonstrate differences in symptom control
`between these agents and older drugs, future studies of
`patients with more severe rhinitis may reveal clinically
`relevant differences between intranasal steroids. With
`respect to safety, preliminary data from young children
`have demonstrated that beclomethasone dipropionate
`caused a reduction in growth velocity, whereas mometa-
`sone furoate and fluticasone propionate did not. Differ-
`ences among available agents may be an even more
`important issue in children with asthma being treated
`concomitantly with an inhaled steroid. Until more infor-
`mation is available regarding the other available com-
`pounds, the new agents may be the most reasonable
`choices in young children requiring chronic treatment
`with intranasal steroids.
`
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