How to get your patient's allergic rhinitis under control

Allergic rhinitis is a widespread condition, affecting 20 to 40 million persons in the United States each year, including up to 40% of children.¹ The direct costs of treatment and indirect costs related to worker absences and loss of productivity are significant. In 1995, the total economic impact of allergic rhinitis was estimated at $2.7 billion, not including the costs of associated problems, such as rhinosinusitis and asthma.¹ Among children, rhinitis is a significant cause of lost school days.¹

In part 1 of this article, I will discuss the use of antihistamines, decongestants, anticholinergics, and cromolyn in the management of allergic rhinitis. In part 2, to be published in a coming issue of The Journal of Respiratory Diseases, I will review the use of intranasal corticosteroids, leukotriene modifiers, and combination therapy; I also will discuss the role of allergen immunotherapy.

PATHOPHYSIOLOGY

Allergic rhinitis is an inflammatory disease of the nasal mucosa; symptoms include sneezing, itching, rhinorrhea, and nasal congestion. Active symptoms and the underlying inflammation are the result of a process that begins when mast cells in the nasal mucosa of sensitized persons bind allergens through IgE expressed on the cell surface. Binding causes mast cell degranulation and the release of a host of preformed and newly formed mediators, including histamine and cysteinyl leukotrienes, which are important targets for drug intervention (Figure).

The events immediately following allergen binding to IgE cause the early-phase allergic response and provoke symptoms within minutes of allergen exposure. Increased vascular permeability of nasal vessels, along with glandular stimulation and vessel dilation, results in watery rhinorrhea, mucinous secretion, and nasal airways occlusion; nerve stimulation leads to nasal itching and sneezing.

A late-phase response develops hours later. In this phase, the mediators that were generated dur- ing the early response induce a variety of migratory cells--including eosinophils, basophils, and neutrophils--to infiltrate the nasal mucosa.² Activation of these cells elicits and sustains an inflammatory response that causes the tissue damage and persistent nasal blockage characteristic of chronic allergic reaction.

Allergic rhinitis is characterized as seasonal or perennial according to whether symptoms appear in a predictable cyclic pattern or throughout the year. Seasonal allergic rhinitis is the result of IgE-mediated responses to seasonal aeroallergens, typically pollens and molds. In perennial allergic rhinitis, the response is to aeroallergens that persist in the environment year-round, such as house dust mites, molds, and animal dander. Nasal obstruction may be the dominant symptom of chronic rhinitis, which is attributable to the ongoing inflammatory response associated with perennial allergy.¹

EVALUATION

Allergic rhinitis can sometimes be confused with nonallergic, non-IgE-mediated forms of rhinitis, which include infectious rhinitis, vasomotor rhinitis, occupational rhinitis, and nonallergic rhinitis with eosinophilia syndrome.¹ The evaluation of rhinitis begins with a careful history, followed by a physical examination that includes examination of the nasal passageways and secretions and determination of whether nasal polyps are present.

An important step in making an unequivocal diagnosis of allergic rhinitis is testing for specific IgE. This is usually accomplished by skin testing to allergens, although in vitro tests for specific subclasses of IgE can also be performed. Identification of a specific allergen(s) is an invaluable guide to appro- priate avoidance measures and to immunotherapy.¹

ALLERGEN AVOIDANCE

Where practicable, allergen avoidance should be recommended.³ For some patients, allergen avoidance can provide a drug-free means of minimizing the symptoms of allergic rhinitis. For patients with pollen allergies, monitoring of pollen counts, avoiding high-pollen areas, and staying indoors on days when pollen counts are high can provide a limited amount of relief.

With regard to indoor antigens, house dust mite control measures are perhaps the most valuable avoidance strategies that can be undertaken for patients with perennial allergic rhinitis who have dust mite allergy. Minimizing house dust, reducing indoor humidity, and using mite-proof covers are examples of recommended environmental measures.³ An analysis of 4 randomized controlled trials indicated that house dust mite avoidance measures for perennial allergic rhinitis significantly reduced dust mite load and could reduce some symptoms.⁴

PHARMACOTHERAPY

The complex pathophysiology of allergic rhinitis provides multiple opportunities for intervention at various stages in the disease pathway. Some medications, such as topical corticosteroids, have potent anti-inflammatory effects, which make them appropriate for controlling persistent rhinitis.

First-generation oral antihistamines and nasal decongestants provide symptomatic relief, although adverse effects can limit their value. The widely used second-generation oral antihistamines are generally considered effective for mild to moderate allergic rhinitis. For patients with seasonal allergies, prophylactic use of medications should be considered.

The number of medications available to treat allergic rhinitis can be bewildering, with both over-the-counter (OTC) and prescription drugs used as monotherapy or in various combinations. Moreover, the specific symptoms that need to be controlled vary among patients,³ and the activity profiles of the different drugs can complement or overlap each other.

Oral antihistamines

Antihistamines are among the most widely used medications for allergic rhinitis. Their effectiveness reflects the importance of histamine in eliciting acute allergic response. Histamine binding to H₁ receptors has a vasodilating effect on nasal blood vessels that swells nasal tissue to increase congestion. Histamine also stimulates sensory nerves in the nose, causing itching and sneezing.⁵

The first-generation oral antihistamines, which include clemastine, chlorpheniramine, and diphenhydramine, are effective for alleviating rhinorrhea, itching, and sneezing. In one study, patients given a low (0.5 mg) dose of clemastine 1, 4, or 6 hours before allergen challenge reported a significant reduction in the number of sneezes compared with placebo.⁶ Antigen-induced increases in rhinorrhea were significantly reduced, compared with placebo, when clemastine was administered 4 or 6 hours before challenge, but not 1 hour before challenge.

While first-generation antihistamines can provide multiple benefits, their inability to alleviate nasal congestion means that they are likely to be only one component of a combination therapy approach. The first-generation oral antihistamines have a sedative effect that can impair performance and psychomotor skills. This side effect can be a significant drawback to their use, particularly when it affects work or driving an automobile.

The second-generation oral antihistamines loratadine, desloratadine, fexofenadine, and (to a lesser extent) cetirizine are less sedating than the first-generation agents (Table). Because of the potential risks associated with CNS depression and impairment, second-generation antihistamines should be considered before sedating antihistamines.The second-generation antihistamines have gained widespread acceptance, and loratadine is now available OTC. These agents are considered minimally effective against nasal congestion, but they are effective in relieving other symptoms and have been reported to reduce challenge-induced mucinous secretion and plasma exudation in allergic rhinitis.⁷

While the second-generation, nonsedating antihistamines have similar properties, head-to-head trials have uncovered some differences. For example, while cetirizine and loratadine have similar efficacy in patients with allergic rhinitis 4 hours after ingestion, cetirizine has a more rapid onset of action.⁸

One double-blind, placebo-controlled 2-week study demonstrated no differences in efficacy between fexofenadine (120 or 180 mg qd) and cetirizine (10 mg qd) in relief of sneezing, rhinorrhea, itchy nose, and itchy/watery eyes, although the combined incidence of drowsiness and fatigue was greater with cetirizine.⁹ However, another clinical trial determined that while cetirizine and fexofenadine had comparable onset of action, cetirizine demonstrated greater efficacy and longer duration of effect with similar safety and incidence of somnolence.¹⁰

Intranasal antihistamines

Azelastine, a topical second-generation antihistamine, is an H₁- receptor antagonist available in the United States as a nasal spray. It is approved for treatment of seasonal allergic rhinitis and nonallergic vasomotor rhinitis. Azelastine has a broader pharmacologic profile than other antihistamines used to treat allergic rhinitis. In addition to its antihistamine effects, azelastine possesses anti-inflammatory activity, and its direct delivery to the site of the allergic reaction may contribute to its efficacy in alleviating a wide range of rhinitis symptoms, including nasal congestion.

In more than 1300 persons with seasonal allergic rhinitis in 5 randomized, placebo-controlled clinical trials (2 onset of action, 3 long-term efficacy studies), azelastine nasal spray improved major symptom complex (runny nose, sneezing, itchy nose, watery eyes, nose blowing) and the total symptom complex (major symptom plus postnasal drip, cough, itchy eyes/ ears/throat/palate) scores.^11-15 Two additional double-blind placebo-controlled trials in persons with nonallergic vasomotor rhinitis documented the efficacy of azelastine in the overall reduction of individual and total symptom scores, including rhinorrhea, sneezing, postnasal drip, and nasal congestion.¹⁶

Azelastine nasal spray has been shown to be a potent agent in patients with moderate to severe rhinitis symptoms who remain symptomatic after treatment with either loratadine or fexofenadine. In 2 studies involving more than 600 patients, no additional bene- fit was observed with combinations of oral loratadine plus azelastine or oral fexofenadine plus azelastine, compared with azelastine monotherapy, in treating moderate to severe symptoms of seasonal allergic rhinitis.^17,18 In both studies, azelastine monotherapy achieved significant improvement compared with placebo in total nasal symptom score and in individual scores for rhinorrhea, sneezing, and itchy nose; the degrees of improvement were similar to those seen with the combinations of azelastine plus loratadine or fexofenadine.^17,18

Decongestants

The decongestant properties of a-adrenergic agonist nasal decongestants derive from their vasoconstrictor activity and make these OTC agents useful for treating the nasal congestion that is a significant complaint of patients with allergic rhinitis. These drugs are relatively short-acting.

Pseudoephedrine is a commonly used nasal decongestant that is available in oral formulation that has been shown to reduce the effect of histamine challenge on nasal airway resistance compared with placebo. However, small but statistically significant increases in pulse and systolic blood pressure have occurred in patients who received pseudoephedrine in doses of 120 mg.¹⁹ Side effects such as these have led some to caution against the use of oral a-adrenergic agonists in certain at-risk populations, such as persons with coronary disease or hypertension.

Oxymetazoline is an example of a topically active a-adrenergic agonist that is available as a nasal spray. It significantly reduces superficial nasal blood flow and thereby reduces subjective nasal stuffiness.²⁰Even when oxymetazoline use is limited to once a day, there is a risk of nasal hyperreactivity and rebound swelling (rhinitis medicamentosa).²¹

Anticholinergics

Because glandular secretion in the nose is under cholinergic control, anticholinergic agents can effectively control rhinorrhea in patients with allergic rhinitis.²² In a study of methacholine-induced rhinorrhea, the anticholinergic ipratropium significantly reduced rhinorrhea when applied topically before the challenge.²³ Stimulated rhinorrhea was suppressed for up to 8 hours after a single dose of ipratropium from a pressurized aerosol inhaler. In addition, 70% of patients with perennial allergic rhinitis who used an aqueous nasal spray formulation of ipratropium 3 times daily thought it had a good or excellent effect on rhinorrhea.²⁴

Ipratropium appears safe for long-term use, as was demonstrated in a 1-year study of patients with perennial allergic rhinitis.²⁵ Its activity appears to be mostly confined to the control of nasal hypersecretion; the drug had little or no effect on nasal congestion, sneezing, or itching in patients with vasomotor rhinitis.²⁶

Cromolyn

Topical cromolyn inhibits the degranulation of sensitized mast cells, thereby blocking the release of proinflammatory and allergic response mediators. This medication is reported to reduce the symptoms of allergic rhinitis, and it can be used prophylactically.²⁷

In a 2-week, placebo-controlled trial, patients who had seasonal allergic rhinitis found cromolyn na-sal solution to be significantly more effective than placebo in control- ling allergy symptoms, providing overall symptom relief, and reliev-ing sneezing and nasal congestion.²⁸ In this study, intranasal cromolyn needed to be applied every 4 to 6 hours, indicating a short duration of action.

In another study, patients who had ragweed seasonal allergic rhinitis were treated with either cromolyn or nedocromil, up to 4 times daily for 8 weeks (in season).²⁹ Both treatments were more effective than placebo, as measured by clinical parameters at study visits and in global evaluations of treatment.In addition, patients who were in the cromolyn and nedocromil groups used less rescue medication than did patients in the placebo group. There was no significant difference between cromolyn and nedocromil.²⁹

References:

REFERENCES

1. Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in Allergy, Asthma and Immunology. American Academy of Allergy, Asthma, and Immunology.

Ann Allergy Asthma Immunol.

1998;81(5 pt 2):478-518.
2. Togias A, Naclerio RM, Proud D, et al. Studies on the allergic and nonallergic nasal inflammation.

J Allergy Clin Immunol.

1988;81(5 pt 1):782-790.
3. International Consensus Report on the diagnosis and management of rhinitis. International Rhinitis Management Working Group.

Allergy.

1994;49(19 suppl):1-34.
4. Sheikh A, Hurwitz B. House-dust mite avoidance measures for perennial allergic rhinitis.

Cochrane Database Syst Rev.

2001;4:CD001563.
5. Malmberg H, Binder E, Fraki J, et al. Nasal reactions elicited by unilateral allergen challenge.

Acta Otolaryngol.

1989;107:446-449.
6. Chung JH, deTineo ML, Naclerio RM, et al. Low dose clemastine inhibits sneezing and rhinorrhea during the early nasal allergic reaction.

Ann Allergy Asthma Immunol.

1997;78:307-312.
7. Greiff L, Persson CG, Andersson M. Desloratadine reduces allergen challenge-induced mucinous secretion and plasma exudation in allergic rhinitis.

Ann Allergy Asthma Immunol.

2002;89:413-418.
8. Frossard N, Lacronique J, Melac M, et al. Onset of action in the nasal antihistaminic effect of cetirizine and loratadine in patients with allergic rhinitis.

Allergy.

1997;52:205-209.
9. Howarth PH, Stern MA, Roi L, et al. Double-blind, placebo-controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis.

J Allergy Clin Immunol.

1999;104:927-933.
10. Day JH, Briscoe MP, Rafeiro E, et al. Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis.

Allergy Asthma Proc.

2004;25:59-68.
11. Connell JT. A novel method to assess antihistamine and decongestant efficacy.

Ann Allergy.

1979;42:278-285.
12. Weiler JM, Meltzer EO, Benson PM, et al. A dose-ranging study of the efficacy and safety of azelastine nasal spray in the treatment of seasonal allergic rhinitis with an acute model.

J Allergy Clin Immunol.

1994;94(6 pt 1):972-980.
13. Ratner PH, Findlay SR, Hampel F Jr, et al. A double-blind, controlled trial to assess the safety and efficacy of azelastine nasal spray in seasonal allergic rhinitis.

J Allergy Clin Immunol.

1994; 94:818-825.
14. Storms WW, Pearlman DS, Chervinsky P, et al. Effectiveness of azelastine nasal solution in seasonal allergic rhinitis.

Ear Nose Throat J.

1994;73:382-386, 390-394.
15. LaForce C, Dockhorn RJ, Prenner BM, et al. Safety and efficacy of azelastine nasal spray (Astelin NS) for seasonal allergic rhinitis: a 4-week comparative multicenter trial.

Ann Allergy Asthma Immunol.

1996;76:181-188.
16. Banov CH, Lieberman P; Vasomotor Rhinitis Study Groups. Efficacy of azelastine nasal spray in the treatment of vasomotor (perennial nonallergic) rhinitis.

Ann Allergy Asthma Immunol.

2001;86:28-35.
17. Berger WE, White MV; Rhinitis Study Group. Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine.

Ann Allergy Asthma Immunol.

2003; 91:205-211.
18. LaForce CF, Corren J, Wheeler WJ, Berger WE; Rhinitis Study Group. Efficacy of azelastine nasal spray in seasonal allergic rhinitis patients who remain symptomatic after treatment with fexofenadine.

Ann Allergy Asthma Immunol.

2004;93:154-159.
19. Empey DW, Young GA, Letley E, et al. Dose-response study of the nasal decongestant and cardiovascular effects of pseudoephedrine.

Br J Clin Pharmacol.

1980;9: 351-358.
20. Witek TJ Jr, Canestrari DA, Hernandez JR, et al. Superficial nasal mucosal blood flow and nasal patency following topical oxymetazoline hydrochloride.

Ann Allergy.

1992;68: 165-168.
21. Graf P, Hallen H, Juto JE. Four-week use of oxymetazoline nasal spray (Nezeril) once daily at night induces rebound swelling and nasal hyperreactivity.

Acta Otolaryngol.

1995; 115:71-75.
22. Mullol J, Raphael GD, Lundgren JD, et al. Comparison of human nasal mucosal secretion in vivo and in vitro.

J Allergy Clin Immunol.

1992;89:584-592.
23. Borum S, Becker B, Mygind N, Borum P. Comparison between the effect of ipratropium bromide as a pressurized aerosol and as an aqueous pump spray on methacholine-induced rhinorrhoea.

Rhinology.

1996;34: 198-200.
24. Meltzer EO, Orgel HA, Bronsky EA, et al. Ipratropium bromide aqueous nasal spray for patients with perennial allergic rhinitis: a study of its effect on their symptoms, quality of life, and nasal cytology.

J Allergy Clin Immunol.

1992;90:242-249.
25. Kaiser HB, Findlay SR, Georgitis JW, et al. Long-term treatment of perennial allergic rhinitis with ipratropium bromide nasal spray 0.06%.

J Allergy Clin Immunol.

1995;95(5 pt 2):1128-1132.
26. Jokinen K, Sipila P. Intranasal ipratropium in the treatment of vasomotor rhinitis.

Rhinology.

1983;21:341-345.
27. Ratner PH, Ehrlich PM, Fineman SM, et al. Use of intranasal cromolyn sodium for allergic rhinitis.

Mayo Clin Proc.

2002;77:350-354.
28. Meltzer EO; NasalCrom Study Group. Efficacy and patient satisfaction with cromolyn sodium nasal solution in the treatment of seasonal allergic rhinitis: a placebo-controlled study.

Clin Ther.

2002;24:942-952.
29. Schuller DE, Selcow JE, Joos TH, et al. A multicenter trial of nedocromil sodium, 1% nasal solution, compared with cromolyn sodium and placebo in ragweed seasonal allergic rhinitis.

J Allergy Clin Immunol.

1990; 86(4 pt 1):554-561.