Allergic rhinitis (AR) is a common medical condition and its prevalence is increasing worldwide.1 In the United States, up to 15% to 30% of the population is affected with AR.2 The onset of symptoms is highest in adolescents, although symptoms may begin at any age. Studies have shown that as many as 10% of children and 20% to 30% of adolescents suffer from AR.3 The symptoms can adversely affect the quality of life of patients and thus are associated with significant morbidity.4 Patients can experience fatigue, sleep disturbances, mood changes, anxiety, and learning difficulties that decrease work or school performance and productivity. Some of the medications used to treat AR can also cause drowsiness as well as memory and learning impairment.5 Moreover, it may be associated with other comorbid conditions such as asthma, atopic dermatitis, sinusitis, and otitis media with effusion, which can further impair quality of life.
The goals of treatment of AR are effective prevention and symptom relief. The initial treatment approach is prevention, which includes identification and avoidance of triggers. This helps in reducing the symptoms as well as the need for medications, but allergen avoidance is not always possible.
Pharmacotherapy is often required for the relief of symptoms and associated morbidity. This includes agents such as antihistamines, decongestants, mast cell stabilizers, leukotriene modifiers, and intranasal steroids (INS) (Figure 1).6 Mild intermittent AR (symptoms less than 4 days per week for less than 4 consecutive weeks) can be treated effectively with oral or intranasal antihistamine and/or an oral or intranasal decongestant. However, oral decongestants should be avoided in the pediatric population due to concerns of adverse effects. Leukotriene modifiers are also now approved to treat seasonal AR. In patients with moderate or severe intermittent AR, initial treatment with INS is preferred. For persistent symptoms (symptoms occurring more than 4 days per week and for more than 4 consecutive weeks), INS is the first line of treatment. Irrespective of the severity of AR, appropriate follow-up is important. Symptom response should be monitored and therapy should be stepped up or down as required.6
Algorithm for the diagnosis of allergic rhinitis. Reprinted from Bousquet et al.,6 with permission of John Wiley and Sons.
INS are more effective and offer significant advantages compared to other medications that are used to treat AR, such as antihistamines.7 They are more cost effective than nonsedating antihistamines, which are the most commonly prescribed AR medications. A meta-analysis of 2,267 patients showed that INS provide much greater relief of nasal symptoms such as nasal blockade, rhinorrhea, sneezing, itching, and postnasal drip as compared to antihistamines.7 They have also been shown to be more effective than leukotriene modifiers.8 INS have been shown to be significantly more effective compared to antihistamine nasal spray in controlling the symptoms of perennial allergic rhinitis.9 A prescription combination of the nasal steroid fluticasone and the nasal antihistamine azelastine appears to improve symptoms of AR better than either drug alone.10 It is approved for use in people older than age 6 years, and the recommended dose is 1 spray in each side of the nose twice a day. Common side effects include bad taste, nose bleed, and headache.
Benefits of INS
Therapy with INS improves all nasal symptoms of AR including nasal congestion, itching, rhinorrhea, and sneezing.6 INS are more effective than other available agents and improve health-related quality of life without causing sedation.11 Currently, several INS, including beclomethasone dipropionate, flunisolide, triamcinolone acetonide, and budenoside, are approved for clinical use. Newer formulations include fluticasone propionate and mometasone furoate. All the available agents are effective in the treatment of both seasonal and perennial AR and other chronic inflammatory nasal diseases. The newer drugs, such as mometasone furoate and fluticasone propionate, have higher lipid solubility and topical potencies as well as lower systemic bioavailability compared to older molecules, and thus are associated with fewer systemic effects.
INS have also been shown to relieve ocular symptoms. Studies have shown significant reduction in total ocular symptom scores including itching, tearing, redness, and puffiness in patients treated with fluticasone propionate12 and mometasone furoate.13
Mechanism of Action
Corticosteroids exert their effect by controlling the rate of protein synthesis. The corticosteroid molecules bind to specific intracellular receptors, which results in formation of a complex. This complex then enters into the nucleus and binds to glucocorticoid response elements on DNA. This, in turn, suppresses gene transcription. The glucocorticoid receptor binding affinity is shown to be directly related to the glucocorticoid potency.14 Mometasone has the highest affinity to bind to the receptor and is the most potent stimulator of glucocorticoid receptor-mediated transactivation of gene expression.15
Glucocorticoids act on different components of the allergic process including the inflammatory cells as well as the mediators involved. They inhibit the influx of mast cell and eosinophils in the nasal epithelium, which play an important role in allergic inflammation. They also mitigate the release of inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-4, and tumor necrosis factor-alpha. Vascular permeability and mucus production is also decreased. These factors together play a role in diminished symptomatology and clinical benefits related to the use of INS.16 Fokkens et al.16 reported that intranasal fluticasone reduced the numbers of antigen-presenting cells, eosinophils, and IL-4 and IL-5 in the nasal mucosa of patients with AR.
INS inhibit the early as well as the late phase allergic response in the nasal mucosa. INS have been shown to limit the early phase response when they are used prophylactically prior to onset of seasonal symptoms. This results in delayed onset of symptoms and thus decreases the need for high-dose therapy when pollen season begins.17 In another study, daily use of budenoside nasal spray for 1 week inhibited the early phase response to allergen challenge. Patients reported a decrease in nasal secretions and nasal blockade as measured by rhinomanometry.18
INS also exert anti-inflammatory effects on the late phase events after allergen exposure. They tend to exert direct influence on the immune response to seasonal allergens by downregulation of allergen-specific immunoglobulin E (IgE) production. Thus, INS can potentially alter the course of the allergic process. Naclerio et al.19 conducted two seasonal studies to evaluate the effect of continuous treatment with the INS beclomethasone and triamcinolone. The treatment was initiated 1 week before the appearance of ragweed pollen. Continuous use of INS through the allergy season inhibited the rise in allergen-specific IgE. Patients also experienced significantly less rhinorrhea and mucosal edema.19
Various formulations of INS are available (Table 1). Newer formulations of INS such as mometasone furoate and fluticasone propionate have higher lipid solubility than the older compounds such as betamethasone, beclomethasone dipropionate, and dexamethasone. Higher lipid solubility results in faster absorption as well as higher retention by the nasal mucosa. Multiple studies have compared beclomethasone dipropionate and fluticasone. In a 2-week study of patients with seasonal AR, both agents had similar effects.20 In patients with perennial AR, both formulations were noted to have similar effects after 3 months and 6 months of use. However, at 12 months, fluticasone was found to be superior to beclomethasone.21 Similarly, beclomethasone and mometasone have been shown to have similar clinical effects in patients with seasonal and perennial AR.22 Mandl et al.23 reported mometasone and fluticasone to be equivalent in their clinical effect. Many patients experience some relief of symptoms on the first day of INS use.24
Currently Available Intranasal Steroid Formulations
Aqueous pump sprays are the most commonly used delivery devices for INS. These devices deliver the drug to the ciliated as well as nonciliated regions of the nasal mucosa.25 With these devices, intranasal distribution can be affected by the volume of nasal spray and the spray cone angle. Improper direction of the spray can damage the nasal tissue and cause nasal irritation or epistaxis. Preferably, the spray should be directed away from the nasal septum. When using INS, the patient's head should be bending forward and down. For maximal benefit, INS should be used daily. Other delivery devices include metered-dose aerosols and pump sprays. Symptom relief has been comparable with different delivery devices.26
INS differ from each other in regard to their sensory attributes (perceived discomfort, taste, or smell), which tend to affect patient acceptance and compliance.27 A recent survey showed that in patients who use INS, the most important sensory attribute is aftertaste.28 Other factors include nose runout, throat rundown, smell, and feel of the spray. Patients tend to have higher preference for INS that have lower intensity of unfavorable sensory attributes. These sensations are caused by the additives and preservatives used in INS preparations. INS that contain benzalkonium chloride (BKC) tend to be less acceptable than INS without BKC, because BKC has an unpleasant, bitter taste.28 Most of the available INS are isotonic formulations that cause decreased local concentration and absorption of the active ingredient into the nasal mucosa. On the other hand, hypotonic formulations increase the pharmacologic activity and absorption of nasally administered drugs, thereby potentially affecting the efficacy.
Most commercially available INS have spray volumes of about 100 mcL per actuation; however, the spray volumes of budesonide and ciclesonide are less (Table 1). A smaller spray volume decreases the amount of drug that can run down the back of the throat or leak out of the nose.
Clinical trials have shown that symptomatic relief can be achieved with once-daily dosing of different INS, including fluticasone propionate, mometasone furoate, budesonide, and triamcinolone acetonide.29 All available formulations appear to exert similar effects in this context.
Adverse effects associated with topical application of INS include burning sensation, stinging, and dryness irrespective of the formulation used. These occur in 5% to 10% of patients.30 Epistaxis is another common local side effect that occurs in approximately 5% of patients. Septal perforations can be averted by directing the spray toward the inferior turbinate, away from the septum.30 Localized fungal infections have occurred on rare occasions, requiring discontinuation of therapy. Prolonged use of intranasal steroids has not been shown to cause any change in epithelial thickness or signs of atrophy of the nasal mucosa.31
Systemic side effects are generally not common. These occur when the INS enter into the systemic circulation either by direct absorption through nasal mucosa or through gastrointestinal absorption of the swallowed fraction. Patients may be exposed to corticosteroids by other routes such as oral or inhaled for coexisting conditions such as asthma, which may result in cumulative dose effect and suppression of the hypothalamic-pituitary-axis (HPA). The older formulations such as beclomethasone have significant oral bioavailability after systemic absorption, varying from 20% to 50%.27 Newer molecules such as fluticasone and mometasone have negligible oral and intranasal bioavailability due to poor absorption from the gastrointestinal tract. This minimizes the risk for systemic side effects such as growth suppression, decreased bone growth, and suppression of the HPA.32 Intranasal budesonide, mometasone, and traimcinolone do not affect osteocalcin, which is a marker of bone turnover, suggesting minimal systemic effects of INS.33
Nevertheless, concerns regarding the effects of INS on linear growth in children have been voiced. Older molecules such as beclomethasone have been shown to cause small but significant reduction in growth velocity.34 In contrast, use of newer molecules does not seem to be associated with these effects. A placebo-controlled study of fluticasone propionate in prepubertal children with perennial rhinitis failed to show any reduction in growth velocity even with maximum recommended doses.35 In a similar study, mometasone furoate failed to demonstrate any suppression of growth velocity in prepubertal patients with perennial allergic rhinitis.36
To minimize the potential for systemic side effects, it is important to use INS properly. Some of the measures include once-daily dosing as compared to twice-daily dosing. In cases of acute inflammation, high doses of INS can be used initially and then steped down to a lower dose when the acute inflammation has subsided. Administering the corticosteroids in the morning minimizes the effects on the HPA axis.
INS are highly effective drugs for treatment of AR and are more efficacious than other groups of medications such as antihistamines, leukotriene modifiers, and decongestants. There are several formulations now approved for clinical use. Corticosteroids have a delayed onset of action and should be used daily for maximal benefits. INS can alter the immune response to allergen exposure and thus have the potential to alter the clinical course of AR. Systemic absorption is low, so systemic effects are rare. Attempts should be made to use lowest doses of INS to decrease potential for side effects.
- Ninan TK, Russell G. Respiratory symptoms and atopy in Aberdeen schoolchildren: evidence from two surveys 25 years apart. BMJ. 1992;304(6831):873–875. doi:10.1136/bmj.304.6831.873 [CrossRef]
- Wheatley LM, Togias A. Clinical practice. Allergic rhinitis. N Engl J Med. 2015;372(5):456–463. doi:. doi:10.1056/NEJMcp1412282 [CrossRef]
- Hagy GW, Settipane GA. Bronchial asthma, allergic rhinitis and allergy skin tests among college students. J Allergy Clin Immunol. 1969;44:323–332.
- Storms WW. Treatment of allergic rhinitis: effects of allergic rhinitis and antihistamines on performance. Allergy Asthma Proc. 1997;18(2):59–61. doi:10.2500/108854197778605473 [CrossRef]
- Milgrom H, Bender B. Adverse effects of medications for rhinitis. Ann Allergy Asthma Immunol. 1997;78(5):439–444. doi:10.1016/S1081-1206(10)63230-9 [CrossRef]
- Bousquet J, Khaltaev N, Cruz AA, et al. World Health OrganizationGA(2)LENAllerGen. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63(Suppl 86):8–160. doi:. doi:10.1111/j.1398-9995.2007.01620.x [CrossRef]
- Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ. 1998;317(7173):1624–1629. doi:10.1136/bmj.317.7173.1624 [CrossRef]
- Rodrigo GJ, Yañez A. The role of antileukotriene therapy in seasonal allergic rhinitis: a systematic review of randomized trials. Ann Allergy Asthma Immunol. 2006;96(6):779–786. doi:. doi:10.1016/S1081-1206(10)61339-7 [CrossRef]
- Stern MA, Wade AG, Ridout SM, et al. Nasal budesonide offers superior symptom relief in perennial allergic rhinitis in comparison to nasal azelastine. Ann Allergy Asthma Immunol. 1998;81(4):354–358. doi:10.1016/S1081-1206(10)63128-6 [CrossRef]
- Berger W, Bousquet J, Fox AT, et al. MP-AzeFlu is more effective than fluticasone propionate for the treatment of allergic rhinitis in children. Allergy. 2016;71(8):1219–1222. doi:. doi:10.1111/all.12903 [CrossRef]
- Meltzer EO. Quality of life in adults and children with allergic rhinitis. J Allergy Clin Immunol. 2001;108(suppl 1):S45–S53. doi:10.1067/mai.2001.115566 [CrossRef]
- DeWester J, Philpot EE, Westlund RE. The efficacy of intranasal fluticasone propionate in the relief of ocular symptoms associated with seasonal allergic rhinitis. Allergy Asthma Proc. 2003;24(5):331–337.
- Hebert J, Danzig M, Gates D. Mometasone furoate improves total ocular symptom score in patients with allergic rhinitis. J Allergy Clin Immunol. 2007;119:S61. doi:. doi:10.1016/j.jaci.2006.11.263 [CrossRef]
- Luisi BF, Xu WX, Otwinowski Z, et al. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature. 1991;352(6335):497–505. doi:10.1038/352497a0 [CrossRef]
- Smith CL, Kreutner W. In vitro glucocorticoid receptor binding and transcriptional activation by topically active glucocorticoids. Allergy. 1997;52(suppl 36):S29–S32.
- Fokkens WJ, Godthelp T, Holm AF, et al. Allergic rhinitis and inflammation: the effect of nasal corticosteroid therapy. Allergy. 1997;52(suppl 36):29–32. doi:10.1111/j.1398-9995.1997.tb04819.x [CrossRef]
- Graft D, Aaronson D, Chervinsky P, et al. A placebo- and active-controlled randomized trial of prophylactic treatment of seasonal allergic rhinitis with mometasone furoate aqueous nasal spray. J Allergy Clin Immunol. 1996;98(4):724–731. doi:10.1016/S0091-6749(96)70119-7 [CrossRef]
- Pipkorn U. Budesonide and nasal allergen challenge testing in man. Allergy. 1982;37(2):129–134. doi:10.1111/j.1398-9995.1982.tb01886.x [CrossRef]
- Naclerio RM, Adkinson NF Jr, Creticos PS. Intranasal steroids inhibit seasonal increases in ragweed-specific immunoglobulin E antibodies. J Allergy Clin Immunol. 1993;92(5):717–721. doi:10.1016/0091-6749(93)90015-8 [CrossRef]
- Ratner PH, Paull BR, Findlay SR. Fluticasone propionate given once daily is as effective for seasonal allergic rhinitis as beclomethasone dipropionate given twice daily. J Allergy Clin Immunol. 1992;90:285–291. doi:10.1016/S0091-6749(05)80005-3 [CrossRef]
- Haye R, Gomez EG. A multicentre study to assess long-term use of fluticasone propionate aqueous nasal spray in comparison with beclomethasone dipropionate aqueous nasal spray in the treatment of perennial rhinitis. Rhinology. 1993;31(4):169–174.
- Drouin M, Yang WH, Bertrand B. Once daily mometasone furoate aqueous nasal spray is as effective as twice daily beclo methasone dipropionate for treating perennial allergic rhinitis patients. Ann Allergy Asthma Immunol. 1996;77(2):153–160. doi:10.1016/S1081-1206(10)63502-8 [CrossRef]
- Mandl M, Nolop K, Lutsky BN. Comparison of once daily mometasone furoate (Nasonex) and fluticasone propionate aqueous nasal sprays for the treatment of perennial rhinitis. 194-079 Study Group. Ann Allergy Asthma Immunol. 1997;79(4):370–378. doi:10.1016/S1081-1206(10)63030-X [CrossRef]
- Berkowitz RB, Nolop RB, Mesarina-Wicki BE. Onset of action of mometasone furoate (Nasonex) nasal spray in seasonal allergic rhinitis [abstract 1790]. J Allergy Clin Immunol. 1997;99(Suppl):S441.
- Newman SP, Moren F, Clarke SW. Deposition pattern of nasal sprays in man. Rhinology. 1988;26:111–120.
- Day J, Alexander M, Drouin M, et al. Budesonide aqueous nasal spray and pressurized metered dose inhaler in the treatment of adult patients with seasonal allergic rhinitis. Am J Rhinol. 1997;11:77–83. doi:10.2500/105065897781446847 [CrossRef]
- Meltzer EO. Formulation considerations of intranasal corticosteroids for the treatment of allergic rhinitis. Ann Allergy Asthma Immunol. 2007;98(1):12–21. doi:. doi:10.1016/S1081-1206(10)60854-X [CrossRef]
- Mahadevia PJ, Shah S, Leibman C, et al. Patient preferences for sensory attributes of intranasal corticosteroids and willingness to adhere to prescribed therapy for allergic rhinitis: a conjoint analysis. Ann Allergy Asthma Immunol. 2004;93:345–350. doi:. doi:10.1016/S1081-1206(10)61393-2 [CrossRef]
- Herman H. Once-daily administration of intranasal corticosteroids for allergic rhinitis: a comparative review of efficacy, safety, patient preference, and cost. Am J Rhinol. 2007;21(1):70–79. doi:10.2500/ajr.2007.21.2896 [CrossRef]
- Corren J. Intranasal corticosteroids for allergic rhinitis: how do different agents compare?J Allergy Clin Immunol. 1999;104(suppl):S144–S149. doi:10.1016/S0091-6749(99)70310-6 [CrossRef]
- Minshall E, Ghaffar O, Cameron L, et al. Assessment by nasal biopsy of long-term use of mometasone furoate aqueous nasal spray (Nasonex) in the treatment of perennial rhinitis. Otolaryngol Head Neck Surg. 1998;118(5):648–654.
- Wilson AM, McFarlane LC, Lipworth BJ. Effects of repeated once daily dosing of three intranasal corticosteroids on basal and dynamic measures of hypothalamic-pituitary-adrenal-axis activity. J Allergy Clin Immunol. 1998;101:470–474. doi:10.1016/S0091-6749(98)70354-9 [CrossRef]
- Wilson AM, Sims EJ, McFarlane LC, et al. Effects of intranasal corticosteroids on adrenal, bone, and blood markers of systemic activity in allergic rhinitis. J Allergy Clin Immunol. 1998;102:598–604. doi:10.1016/S0091-6749(98)70275-1 [CrossRef]
- Rachelefsky GS, Chervinsky P, Meltzer EO, et al. An evaluation of the effects of beclomethasone dipropionate aqueous nasal spray (Vancencase AQ [VNS]) on long term growth in children [abstract]. J Allergy Clin Immunol. 1998;101(suppl):S236.
- Allen DB, Meltzer EO, Lemanske RF Jr, et al. No growth suppression in children treated with the maximum recommended dose of fluticasone propionate aqueous nasal spray for one year. Allergy Asthma Proc. 2002;23(6):407–413.
- Schenkel EJ, Skoner DP, Bronsky EA, et al. Absence of growth retardation in children with perennial allergic rhinitis after one year of treatment with mometasone furoate aqueous nasal spray. Pediatrics. 2000;105(2):E22. doi:10.1542/peds.105.2.e22 [CrossRef]
Currently Available Intranasal Steroid Formulations
|INS (Dose of Steroid)||Trade Name||Dosing Regimen||Common Adverse Events|
|Pediatric (age 2–12 y)||Adult (age ≥12 y)|
|Mometasone furoate (50 mcg/spray)||Nasonex (Merck & Co.; Kenilworth, NJ)||2 SEN daily||2 SEN daily||Headache, nosebleeds|
|Fluticasone propionate (50 mcg/spray)||Flonase (GlaxoSmithKline; Parsippany NJ)||1–2 SEN daily||2 SEN daily||Headache, sore throat, epistaxis|
|Triamcinolone acetonide (55 mcg/spray)||Nasacort, Nasacort AQ (Sanofi; Bridgewater, NJ||2 SEN daily||2–4 SEN daily||Sore throat, epistaxis, cough|
|Budenoside (32 mcg/spray)||Rhinocort AQ (AstraZeneca; Cambridge, UK)||1 SEN daily (age >6 y)||2 SEN twice per day||Epistaxis, throat dryness|
|Flunisolide (25 mcg/spray)||Nasarel/Nasalide (Teva; Petah Tikva, Israel)||1 SEN 3 times per day (age >6 y)||2 SEN 2–3 times per day||Aftertaste, nose dryness, epistaxis|
|Beclomethasone dipropionate (42 mcg/spray)||Beconase AQ (GlaxoSmithKline; Parsippany NJ)||1–2 SEN twice per day (age >6 y)||1–2 SEN twice per day
1–2 SEN daily||Nose/throat dryness, sneezing, headache|
|Ciclosonide (50 mcg/spray)||Omnaris (Covis Pharma; Zug, Switzerland)||2 SEN daily (age >6 y)||2 SEN daily||Headache, epistaxis, nasopharyngitis|
|Fluticasone furoate (27.5 mcg/spray)||Veramyst (GlaxoSmithKline; Parsippany NJ)||1 SEN daily||2 SEN daily||Headache, sore throat, epistaxis|
|Fluticasone (50 mcg/spray and azelastine (137 mgc/spray||Dymista (Mylan; Canonsburg, PA)||1 SEN twice per day (age >6 y)||1 SEN twice per day||Headache, epistaxis|