Allergic rhinitis is a disease characterized by nasal obstruction, rhinorrhea, sneezing and nasal itch and often accompanied by conjunctivitis. It is elicited by IgE-mediated allergic inflammation of the nasal mucosa. The disease prevalence is 10–20% of the population in industrialized countries[1] and seems to be increasing.[2,3] Although allergic rhinitis is not a life-threatening disease, it can severely affect patients’ quality of life[4–6] and can cause comorbidity from other diseases, such as asthma, sinusitis, otitis media and conjunctivitis.[7] Allergic rhinitis can be either seasonal, i.e. present at certain times of the year such as during the pollen season, or perennial, i.e. present at all times of the year.

Applicable therapeutic initiatives in allergic rhinitis are allergen avoidance, allergen immunotherapy and pharmacological intervention. This review considers first-line pharmacological treatment of allergic rhinitis, in which two main treatment options have evolved, i.e. antihistamines and intranasal corticosteroids. The choice between these options has been extensively discussed since the introduction of intranasal corticosteroid treatment.[8] Evidence presented in this review considers only data obtained in patients with allergic rhinitis. Medical literature including abstracts and randomized trials published in the English language during the period 1966–2001 on antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis were identified using Medline.

1. Antihistamines

1.1 General Considerations

Histamine is the major pathophysiological mediator of allergic rhinitis, almost exclusively exerting its action through stimulation of the H1 receptor. Whether other histamine receptors have any effect in allergic rhinitis remains to be clarified. Antihistamines in the treatment of allergic rhinitis are, thus, H1 receptor antagonists.[9,10] An additional anti-inflammatory effect of H1 antihistamines has been proposed, as some newer compounds seem to influence cytokine production, mediator release or inflammatory cell flux.[11–19] However, other studies have been unable to reproduce such findings.[20–23] Whether antihistamines offer additional and clinically relevant anti-inflammatory effects along with their inhibition of histamine action needs further clarification.

1.2 Oral Antihistamines

Numerous H1 receptor antagonists have been developed over the years. For oral use, these can roughly be divided into older, first-generation (e.g. chlorpheniramine, diphenhydramine, promethazine and tripolidine) and newer, second-generation antihistamines (acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine and terfenadine). This review deals with the newer antihistamines, as use of the older drugs in allergic rhinitis is limited by their adverse effects, mainly sedation and anticholinergic activity.

All of the newer antihistamines are effective in the treatment of allergic rhinitis by decreasing nasal itching, sneezing and rhinorrhea, but have a poor effect upon nasal congestion.[24–31] They are also effective upon conjunctivitis and recent results seem to indicate some influence on lower airway symptoms which often co-exists with allergic rhinitis.[32,33]

Moreover, the pharmacokinetic profile of these drugs is advantageous when compared with that of the older ones.[34] They have an onset of action within 1–2 hours, lasting for 12–24 hours, except for acrivastine, which has to be given at 8-hour intervals. With the exception of cetirizine and fexofenadine, which are excreted almost unchanged, the drugs in this group are metabolized via the hepatic cytochrome P450 (CYP) system by CYP3A. As a number of other compounds (antimycotic conazoles, macrolide antibacterials and grapefruit juice) are substrates for this enzyme, this obviously provides a theoretical risk for interactions.[35] This is probably a contributing factor to the occurrence of severe cardiac arrhythmias (such as ‘torsade de pointes’) and deaths, which have been described following treatment with terfenadine and astemizole.[36–38] These effects seem to be enabled through a quinidine-like action, causing a prolongation of the QT interval.[39,40] At present, no clinical evidence has demonstrated cardiac adverse effects from other second-generation antihistamines, when considered at therapeutically appropriate levels. However, in a consensus statement on the treatment of allergic rhinitis the European Academy of Allergology and Clinical Immunology recommends that antihistamines that are metabolized by CYP450 or have quinidine-like actions be avoided in risk groups, i.e. patients with impaired hepatic function or cardiac arrhythmia.[41]

Astemizole can also act as an appetite stimulant and result in increased bodyweight.[42,4243] The cause of this action remains obscure, although a CNS-mediated mechanism, such as serotonin antagonism, could be speculated. However, whether this adverse effect is seen exclusively with astemizole remains unclear, as data regarding this parameter are lacking for other second-generation antihistamines.

While CNS-related adverse effects were a major characteristic of the first-generation antihistamines, the piperazine/piperidine-derived structures of the newer generation reduce their CNS penetration, although sedative effects have been described for some of the compounds, e.g. acrivastine[44] and cetirizine.[45] The binding affinity to muscarinic receptors is also decreased. With the exception of cardiac adverse effects, this leaves second-generation antihistamines with a therapeutic index superior to that of first-generation antihistamines.

1.3 Intranasal Antihistamines

Azelastine and levocabastine are two newer H1 receptor antagonists for topical use. When applied intranasally, both have proven effective in the treatment of allergic rhinitis, mainly relieving nasal itching and sneezing.[46,47] They act within 15–30 minutes, which is faster than oral antihistamines. They are applied twice daily. No sedative effects have been seen for either drug,[46,48] whereas the occurrence of a short-lasting perversion of taste has been described for azelastine.[49]

2. Corticosteroids

2.1 General Considerations

Inflammation of the nasal mucosa is the main characteristic of allergic rhinitis, and of currently available medications, corticosteroids have the most profound effect on this inflammatory process.[50] Corticosteroids exert their effect by combining with a glucocorticoid receptor localized in target cell cytoplasm. The resulting activated glucocorticoid receptor complex interacts with cellular DNA, thereby enabling regulation of cellular functions.[51–53]

Corticosteroids act on many of the cell types and inflammatory mediators participating in allergic inflammation. Antigen-presenting Langerhans cells are reduced in number by intranasal corticosteroids.[54,55] Moreover, such treatment seems to impair their processing of antigen.[56] Likewise, the migration of basophils and mast cells to the nasal epithelium is inhibited by corticosteroids[57–59] and their release of mediators (i.e. histamine) seems to be reduced.[60] Several pivotal aspects of eosinophil function are interfered with by corticosteroid therapy. Apoptosis is accentuated and degranulation propensity of cytotoxic proteins, i.e. eosinophil cationic protein and eosinophil peroxidase, is inhibited.[61,62] In addition, formation of cytokines and chemokines vital to eosinophil lifespan is reduced: e.g. interleukin (IL)-5 (formation),[63] IL-4 (adhesion)[64] andRANTES (chemotaxis).[65] Corticosteroids have also been shown to affect lymphocytes. In one study, intranasal corticosteroids inhibited activated T lymphocytes of nasal epithelium.[66] In two other studies, the increase of specific IgE in individuals with pollen allergy during the pollen season was abolished.[67,68]

2.2 Intranasal Corticosteroids

Several corticosteroids have been developed for intranasal application, all characterized by a high receptor affinity. Efficacy on the symptoms of allergic rhinitis, including nasal congestion, has been demonstrated for intranasal beclomethasone dipropionate,[69] budesonide,[70] flunisolide,[71] fluticasone propionate,[72] mometasone furoate[73] and triamcinolone acetonide.[74] In addition, some reports have indicated that intranasal corticosteroids may have a beneficial effect towards bronchial hyperresponsiveness and asthma symptoms which may co-exist with allergic rhinitis.[75–80]

It has been generally considered that intranasal corticosteroids have a slow onset of action. However, they usually act within 12–24 hours.[81–83] Recent results have even indicated that intranasal budesonide begins to act after 3 hours.[84] However, maximum treatment efficacy occurs after days or even weeks.[85] Application once daily has proven sufficient to treat most allergic rhinitis patients,[86–90] although severe cases may benefit from a double dose given twice daily.[91]

The different potencies of intranasal corticosteroids are important, when considering comparative data. It is well established that intranasal fluticasone propionate is twice as potent as intranasal beclomethasone dipropionate.[72] Regarding other relative potencies between intranasal corticosteroids, results have been controversial. However, the newer drugs, i.e. fluticasone propionate and mometasone furoate, seem to be more potent than others.[82]

Currently available intranasal corticosteroids are generally well tolerated. Sneezing caused by nasal hyperreactivity can occur at the beginning of therapy, but usually disappears with time.[92] Occasionally, mild and transient dryness, crusting and blood-stained secretions occur, often responsive to a reduction of dose.[85,93,94] Septal perforation has been described as a rare complication.[95,96] Atrophy of the mucosa, corresponding to dermal atrophy, after prolonged use of intranasal corticosteroids has not occurred.[97,98]

The risk of systemic adverse effects has been a concern for this class of drugs. A proportion of intranasally applied corticosteroid ends up in the gastrointestinal tract and thereby is systemically absorbed. Likewise, direct absorption across the nasal mucosa could contribute to systemic bioavailability. However, these compounds, especially the newer fluticasone propionate and mometasone furoate, have low systemic bioavailability, mainly because of their massive first-pass metabolism in the liver.[82] When used exclusively intranasally at therapeutic dose levels, the drugs in this class do not seem to exhibit any particular influence on the hypothalamic-pituitary-adrenal (HPA) axis.[99–102] Lack of HPA-axis suppression does not guarantee against other kinds of systemic adverse effects. Data demonstrating an inhibitory effect on the short-term growth rate of children have been presented for intranasal beclomethasone dipropionate and budesonide,[103,104] although the result for intranasal budesonide was achieved only by giving an adult dose of 200µg twice daily. Moreover, this could not be reconfirmed in a more recent study, in which budesonide 400µg daily was equal to placebo with respect to effect on child growth, expressed by lower-leg knemometry.[105] Newer intranasal compounds (fluticasone propionate and mometasone furoate) have not shown evidence of any effect on growth rate in children when given in therapeutic doses.[106] This difference has been explained by a difference of bioavailability between the drugs, although dosing frequency probably plays a major role, thus disfavoring beclomethasone dipropionate and budesonide.[106] However, more data are needed before drawing firm conclusions on the superiority of a drug regarding growth suppression. Current evidence seems to advocate once-daily administration of the minimum effective dose. Other systemic adverse effects that have been linked to intranasal therapy, such as cataract, glaucoma and dermal thinning, do not seem to occur in patients receiving treatment exclusively by the intranasal route.[106]

3. Comparing Antihistamines and Intranasal Corticosteroids in Allergic Rhinitis

3.1 Perennial Allergic Rhinitis

A number of studies have compared antihistamines and intranasal corticosteroids in allergic rhinitis (table I and table II). However, only a few of these have been performed in perennial allergic rhinitis. Two 4-week studies compared terfenadine with intranasal beclomethasone dipropionate[107] and astemizole with intranasal budesonide.[108] Both demonstrated intranasal corticosteroids to be superior on nasal symptoms. Only one small (n = 8) nonblind study on astemizole and beclomethasone dipropionate for 12 weeks each, was unable to show differences between the two drugs.[109]

Table I
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Comparative studies of oral antihistamines and intranasal corticosteroids in allergic rhinitis

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Table II
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(landscape table) to be inserted here 902908x

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Concerning differences between intranasal antihistamines and intranasal corticosteroids, azelastine has been compared with beclomethasone dipropionate, with no demonstrable differences for symptoms, physician’s assessment of efficacy or nasal blockage measured by rhinomanometry.[124] However, when azelastine was compared with budesonide in another study, budesonide had a significantly superior effect on all nasal symptoms.[125] A single-blind comparison of intranasal levocabastine and intranasal beclomethasone dipropionate, which was a follow-up on a double-blind comparison of levocabastine and placebo, demonstrated a better effect of beclomethasone dipropionate on nasal obstruction.[126]

3.2 Seasonal Allergic Rhinitis

Several comparisons have been done on antihistamines and intranasal corticosteroids in patients with seasonal allergic rhinitis, almost all being randomized, double-blind studies. Considering oral antihistamines (table I), results of 15 comparative studies, in total involving more than 2600 patients, have been presented, involving: terfenadine compared with beclomethasone dipropionate[110,111] or fluticasone propionate;[20,112,113] loratadine with beclomethasone dipropionate,[114] triamcinolone acetonide[115,116] or fluticasone propionate;[117–119] astemizole with beclomethasone dipropionate[120,121] or triamcinolone acetonide;[122] and cetirizine with fluticasone propionate.[123] With the exception of two studies,[111,121] all were able to demonstrate intranasal corticosteroids as significantly more effective than oral antihistamines on nasal symptoms. In fact, only one study, comparing astemizole and beclomethasone dipropionate in 74 patients, showed similar effect on nasal symptoms.[121] A possible explanation could be that a very long study period of approximately 15 weeks for the grass pollen season was used, thereby imposing a risk of diluting differences depending on pollen exposure. Actually, the paper lacks pollen data for the last 17 days of the study period.

Although the second exception was unable to disclose differences in symptoms, it revealed intranasal corticosteroids as superior when applying an objective measure of nasal obstruction, i.e. rhinomanometry.[111] This difference in nasal obstruction measured objectively was also seen in one of the studies demonstrating difference in nasal symptomatology.[20] The one study in adolescents showed a better effect of fluticasone propionate on nasal peak inspiratory flow rate in a subgroup of patients.[118] Two studies were able to demonstrate significant reductions in the number of nasal mucosal eosinophils only with intranasal corticosteroids.[20,113]

Most studies compare treatments given on a regular daily basis. However, a recent randomized, open study compared loratadine with fluticasone propionate, when both drugs were given as needed throughout the season in patients with ragweed-induced allergic rhinitis.[119] Interestingly, fluticasone propionate, given as needed, seemed superior to loratadine with regard not only to nasal symptoms, but also to quality-of-life estimates (Rhinitis Quality of Life Questionnaire [RQLQ]) and number of eosinophils in nasal lavage.

Conjunctivitis is often a major problem in seasonal allergic rhinitis. One of the reasons for using oral antihistamines rather than intranasal corticosteroids has been an expected better effect on eye symptoms. Of the previously mentioned studies, only two have been able to verify this.[114,121]

The apparent superiority of intranasal corticosteroids over oral antihistamines on nasal symptoms was confirmed by a meta-analysis of 16 studies involving 2 267 subjects,[134] which showed a better effect of intranasal corticosteroids on nasal obstruction, secretion, itching and sneezing as well as total nasal symptom score. However, the meta-analysis was unable to demonstrate any difference between the two drug classes on ocular symptoms.

Data on the comparative efficacy of intranasal antihistamines and intranasal corticosteroids in seasonal allergic rhinitis are also available (table II). Azelastine has been compared with beclomethasone dipropionate in two studies, one of which showed beclomethasone dipropionate to be more effective on nasal symptoms,[127] and the other revealed fewer eosinophils in nasal lavage but no differences on nasal symptoms.[128] Two small nonblind studies comparing azelastine with budesonide were unable to discriminate between treatments. [129,130] Three studies involved levocabastine, compared with budesonide[131] and fluticasone propionate.[132,133] All three demonstrated intranasal corticosteroids as superior regarding nasal symptoms. Moreover, fluticasone propionate reduced the number of eosinophils in nasal lavage fluid in both, as well as eosinophil and mast cell markers of nasal lavage in one study.[132]

3.3 Combination of Antihistamines and Intranasal Corticosteroids

The combination of antihistamines and intranasal corticosteroids is often used in clinical practice. Four studies have included a treatment arm of such combination therapy in addition to treatment arms of antihistamine and intranasal corticosteroids (table III). Three of these, including almost 800 patients, showed that the combination therapy, although better than antihistamine alone on nasal symptoms, offered no advantages over intranasal corticosteroids alone.[135–137] The fourth study, in 60 patients, demonstrated the combination of loratadine and beclomethasone dipropionate as significantly superior to beclomethasone dipropionate alone when considering sneezing and nasal itching.[138] One study has compared the combination of terfenadine and flunisolide with terfenadine alone and discovered a better effect of the combination on nasal symptoms and investigator assessment of treatment.[139] Another study with an open design, which assessed terfenadine and fluticasone propionate, offering the opposite drug on an as-needed basis, was unable to demonstrate any difference when measuring quality of life.[140] This parameter was also applied in two other studies, where it demonstrated that the treatments containing intranasal corticosteroids offered a better quality of life.[115,136]

Table III
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Comparative studies on combinations of oral antihistamines and intranasal corticosteroids in seasonal allergic rhinitis

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3.4 Safety

In contrast to the differences demonstrated for efficacy between antihistamines and intranasal corticosteroids in all these comparative studies, no quantitative differences have been observed regarding the occurrence of adverse effects. Minor qualitative differences can be observed: for example, nasal crusting for intranasal corticosteroids and sedation for antihistamines. In general, occurrence of adverse events is low for both treatments. This includes results of morning plasma cortisol measurements, albeit not an ideal indicator of HPA-axis interference, which were performed in three studies.[20,113,133] No data on increasing or additional adverse effects have, so far, been presented for long-term use of either treatment. Especially, when considering intranasal corticosteroids, no data on increasing impact on HPA-axis was seen over a study period of 5.5 years.

3.5 Cost-Effectiveness

The perspective of economy (i.e. cost-effectiveness) is naturally dependent on local prices for the respective medications. However, two analyses seem to favor intranasal corticosteroids over oral antihistamines. In a US study, fluticasone propionate was found to be more cost-effective than terfenadine when medications were used on an as needed basis for more than 11–22 days and direct costs of medication were compared to symptom-free days and overall patient assessment.[141] In a Canadian study, fluticasone propionate was 2.5 and 5.7 times as cost-effective as terfenadine and loratadine, respectively, when comparing direct costs of medication to days without nasal blockage.[142]

The combination of oral antihistamines and intranasal corticosteroids, merely offering no or a marginal clinical benefit compared with intranasal corticosteroids alone, cannot be considered to be cost-effective.

4. Conclusion

A comparative review[143] was unable to conclude that there are any differences in efficacy between oral second-generation antihistamines, when considering the results of the relatively few existing randomized, double-blind, placebo-controlled studies of seasonal allergic rhinitis. This view is largely supported by data from randomized, double-blind comparator studies over the last decade for both seasonal allergic rhinitis and perennial allergic rhinitis. Moreover, no differences have been documented by comparisons of systemic and topical second-generation antihistamines, when the latter were administered both in the nose and in the eyes.[144]

Considering present data on intranasal corticosteroids, no striking differences in efficacy against allergic rhinitis have been demonstrated at recommended doses. Likewise, existing clinical evidence on adverse effects does not convincingly support the theoretically based superiority of newer compounds, such as fluticasone propionate and mometasone furoate. On the other hand, beclomethasone dipropionate and budesonide offer the greatest amount of experience accumulated during more than 20 years. In all, the available clinical evidence does not support one drug among intranasal corticosteroids as superior.[144]

With regard to comparative efficacy of intranasal corticosteroids and antihistamines, present data clearly support intranasal corticosteroids as being more effective on nasal symptoms in allergic rhinitis. Moreover, this is substantiated by results on other endpoints, i.e. inflammatory parameters, acoustic rhinometry, rhinomanometry and quality-of-life assessments. Interestingly, present evidence does not support a difference of efficacy on eye symptoms. Considering safety data, no difference has been demonstrated between intranasal corticosteroids and antihistamines. The common clinical practice of combining intranasal corticosteroids and oral antihistamines in the treatment of allergic rhinitis has no support in clinical evidence; the combination has not provided effects beyond intranasal corticosteroids alone, and so it cannot be considered cost-effective.

International consensus reports[41,145,146] recommend intranasal corticosteroids as first-line treatment in seasonal allergic rhinitis and in perennial allergic rhinitis (adults) for patients with moderate to severe disease with regular or daily symptoms. Antihistamines are recommended as first-line treatment in patients with mild disease with infrequent symptoms and in children with perennial allergic rhinitis.

This review supports the notion that intranasal corticosteroids offer superior relief for the symptoms of allergic rhinitis. As long-term experience has shown the treatment to be very well tolerated, intranasal corticosteroids have a high therapeutic index and can be recommended as a well tolerated and effective treatment for allergic rhinitis.