Antihistamines (all classes) versus placebo.

Only one published study meeting the criteria for inclusion examined the role of antihistamines in the treatment of nonallergic rhinitis. Because the antihistamine was used as part of an antihistamine-decongestant combination product, outcomes related to the antihistamine component of this drug cannot be separately identified. Two additional studies published after the completion of the literature search (Banov and Lieberman, 2001, Gehanno, Deschamps, Garay et al., 2001) demonstrated the efficacy of azelastine nasal spray for the treatment of vasomotor rhintis.

Effect of nasal corticosteroids.

Though it is commonly assumed that many physicians recommend a therapeutic trial with nasal corticosteroids in the management of nonallergic rhinitis, there were only three studies identified which examined the efficacy of nasal corticosteroids in the treatment of nonallergic rhinitis. Two of the three studies employed budesonide and the other used beclomethasone. One study indicated that the symptoms of nasal congestion could be improved by budesonide without alteration in other symptoms of nonallergic rhinitis. In the other two studies, comparison was made between the nasal corticosteroid and nasal ipratropium bromide. One study favored the nasal corticosteroid and the other study failed to differentiate between the two on the basis of symptom relief. Intranasal corticosteroids have been recommended for long term therapy for nonallergic rhinitis (Settipane and Lieberman, 2001) and two nasal corticosteriods have FDA approval.

Sympathomimetics versus placebo.

Only two randomized controlled studies were identified which looked at the role of oral decongestants (phenylpropanolamine) in treatment of nonallergic rhinitis. In both studies emphasis was placed on relief of symptoms of nasal congestion. Phenylpropanolamine was demonstrated in both trials to be helpful in the management of nasal congestion when used at sufficient dosages (e.g. 100 mg per day dosage). No major impact on the other associated symptoms experienced by patients with nonallergic rhinitis was observed in these studies.

While small in number, these studies do suggest a role for decongestants in treatment of nonallergic rhinitis with specific emphasis on the symptoms of nasal congestion. However, the FDA has urged companies marketing phenylpropanolamine to voluntarily withdraw the drug from the market while the FDA initiated regulatory actions to mandate such withdrawals. The only currently available orally active decongestant, pseudoephedrine, was not identified in any of the clinical trials concerning management of nonallergic rhinitis.

Leukotriene modifiers.

No studies were identified looking at the efficacy of leukotriene modifiers in the treatment of nonallergic rhinitis.

Anticholinergics.

Each of five studies identified in the analysis indicated a significant benefit from use of nasal ipratropium bromide (a topically applied anticholinergic agent) in the treatment of the symptom of rhinorrhea (increased nasal secretions) associated with nonallergic or vasomotor rhinitis. Relief of the symptom is dose-dependent - dosing often up to four times a day was required to achieve a significant clinical benefit. Other symptoms such as nasal congestion, nasal itching and sneezing do not appear to be benefited by ipratropium bromide.

Cromoglycate.

Both of the two RCTs that examined the effects of cromoglycate in nonallergic rhinitis recorded improvement in symptoms of rhinitis with active treatment compared to placebo. Not all symptoms were improved by cromoglycate in either study and the specific symptoms which benefited most differed between these two studies. However, although small in quantity, the data appear to indicate that sodium cromoglycate may have a role in the management of nonallergic rhinitis.

Side-effects/adverse events.

There were no side-effects or adverse events reported in the studies of antihistamines or nasal corticosteroids. However, a recent study (Skoner, Rachelefsky, Meltzer et al, 2000) reported on the suppressive effect of belcomethasone nasal spray on bone growth in children and all nasal steroid preparations in the United States now warn of this adverse event. Agents with less systemic bio-availability may be devoid of these risks (Allen, 2000).

In the two studies examining cromoglycate, no significant adverse events were associated with use. In only one of the two studies involving sympathomimetics were adverse events such as drowsiness, nausea and headache described. This study (Broms and Malm, 1982), involving a combination product (antihistamine plus decongestants) also had patients who described micturition difficulties, which were presumed to be related to the anticholinergic activity of the antihistamine component. Significant side-effects of nasal dryness and nasal irritation were recorded in three of the five studies looking at ipratropium in the treatment of nonallergic rhinitis. Overall, these treatment modalities are very well tolerated and devoid of major side-effects.

In conclusion, the literature concerning treatment of nonallergic rhinitis is scant and no single agent is identified as being uniformly effective in controlling all the symptoms associated with this condition. All treatments appear relatively free of major side-effects. Oral decongestants are effective in controlling the symptom of nasal congestion and ipratropium bromide is beneficial in the management of rhinorrhea. With the exception of azelastine for treatment of vasomotor rhinitis, there is little published evidence for use of antihistamines or nasal corticosteroids for the management of nonallergic rhinitis.

Antihistamines versus nasal corticosteroids.

There is strong evidence for the beneficial effects of nasal corticosteroids in the management of allergic rhinitis, and these agents are significantly superior to antihistamines.

The recent meta-analysis by Weiner (Weiner, Abramson, and Puy, 1998) of 17 RCTs published up to 1997 compared intranasal corticosteroids with antihistamines in the treatment of seasonal and/or perennial allergic rhinitis. The analysis included several different nasal corticosteroid preparations and several different antihistamines including both nonsedating and sedating antihistamines. For the six nasal symptoms studied as well as for overall nasal symptoms score, nasal corticosteroids produced significantly greater relief than did oral antihistamines. The specific symptoms that were improved included nasal blockage, nasal discharge, sneezing, nasal itching, and postnasal drainage. There were no significant differences identified between treatments for nasal discomfort, nasal resistance, or eye symptoms.

Our search identified eight additional studies that were not included in the Weiner meta-analysis. Seven of the studies favored intranasal corticosteroids over antihistamines both with respect to improvement in global nasal symptoms as well as most individual nasal symptoms. One study showed better symptom improvement with cetirizine alone over fluticasone alone. Thus, the overwhelming majority of studies show very clear benefits for the use of intranasal corticosteroids over either sedating or nonsedating antihistamines for relief of symptoms of nasal allergy. These results are similar for seasonal allergic rhinitis and perennial allergic rhinitis.

Antihistamines versus immunotherapy.

No RCTs were identified directly comparing immunotherapy with antihistamines in the treatment of seasonal and/or perennial allergic rhinitis. Immunotherapy is generally considered a long-term disease modifying treatment measure requiring months to years of treatment whereas antihistamines are often used for immediate symptom relief. Therefore direct comparisons with respect to effectiveness/efficacy are not likely to be undertaken.

Nasal corticosteroids versus immunotherapy.

For reasons similar to those above, no RCTs were identified which directly compared immunotherapy with intranasal corticosteroids in the treatment of seasonal and/or perennial allergic rhinitis.

Sedating versus nonsedating antihistamines.

With respect to symptom alleviation in allergic (seasonal) rhinitis, study results indicate no consistent benefit of sedating antihistamines over nonsedating antihistamines. In the eight randomized controlled clinical trials comparing sedating and nonsedating antihistamines in the treatment of seasonal allergic rhinitis, approximately equivalent numbers of patients seemed to benefit in terms of symptom relief from nonsedating antihistamines as from sedating antihistamines, though the side effect profile favors nonsedating antihistamines. Similar observations were seen with perennial allergic rhinitis except perhaps for a tendency to favor sedating antihistamines. The benefits were seen across a range of symptoms with no specific symptom appearing to be better improved by one class of treatment or the other.

Other agents (cromolyn, leukotriene modifiers sympathomimetics, ipratropium).

Studies provide strong support for the beneficial effect of cromoglycate in the management of both seasonal and perennial allergic rhinitis. Eighteen studies (14/18 studies of seasonal allergic rhinitis and 4/11 studies of perennial allergic rhinitis) included documentation of patient preference or patient willingness to use the drug in the future. In 17 studies there was a clear-cut preference for the active ingredient (cromoglycate). Cromoglycate seems to have higher efficacy in seasonal allergic rhinitis than it does in perennial allergic rhinitis. In those studies that looked at different dosing regimens, higher doses (including higher frequency of dosing) were more effective.

Two clinical trials were identified looking at the effects of decongestant drugs in allergic rhinitis and suggest some benefit in relief of nasal congestion but not other symptoms. The trial of ipratropium documented no significant differences between dosages of ipratropium but significant reduction in rhinorrhea and postnasal drip.

Side-effects/adverse events.

A majority of the studies reported no major adverse events associated with the use of antihistamines. In those studies where major adverse events were reported, somnolence, dry mouth, dizziness, and headache were identified most frequently. These symptoms were seen almost exclusively with the sedating antihistamines.

Epistaxis, headache, and pharyngitis were the most frequently reported side-effects of nasal corticosteroids. None of the studies reported systemic side-effects from intranasal corticosteroids in the short-term treatment studies analyzed. However, a recent study (Skoner, Rachelefsky, Meltzer et al, 2000) reported on the suppressive effect of belcomethasone nasal spray on bone growth in children and all nasal steroid preparations in the United States now warn of this adverse event. Agents with less systemic bio-availability may be devoid of these risks (Allen, 2000).

No major adverse events were reported in studies of cromolyn; minor reported side-effects included a high frequency of nasal irritation, headache, and nasal congestion.