Comparison of five new antihistamines (H1-receptor antagonists) in patients with allergic rhinitis using nasal provocation studies and skin tests
Jeroen van Steekelenburg, MD
Department of ENT, Head and Neck Surgery
Free University Hospital Brussels
Oral antihistamines or H1-receptor antagonists are considered part of the first-line medical treatment of mild persistent as well as intermittent allergic rhinitis (1), and this is true for adults as well as for children (2). Histamine H1-receptor antagonists are divided into first generation drugs which often have sedating side-effects caused by blood-brain-barrier passage, and the newer second generation, nonsedating drugs.
In recent years, several new molecules have been developed, such as cetirizine, ebastine, fexofenadine, mizolastine and loratadine. All of these newer drugs seem to be safe, easy to use, and without important side-effects (3–7). Furthermore, for most of these newer drugs it is claimed that besides a strong H1-antagonist activity, they also have important anti-inflammatory properties (8, 9). For the ENT specialist and the general practitioner alike, it is not easy to make the best possible choice from these new nonsedating antihistamines, especially since little is known about the comparative efficacy of these drugs.
The purpose of this study was to evaluate any differences in efficacy of five of the newer antihistamines used for the treatment of allergic rhinitis, as compared to placebo. To compare the efficacy of these drugs intradermal histamine and grass pollen skin test reactivity, nasal grass pollen provocative concentrations, and nasal smear eosinophilia were determined before and after drug administration. Earlier studies comparing the efficacy of antihistamines were done using histamine skin tests in nonallergic patients (10, 11). In our study the drugs were compared in allergic patients using allergen as well as histamine skin testing, and also with nasal allergen provocation. By using nasal provocation as well as skin tests we tried to get a more complete picture of the effects of these drugs. We performed tests on allergic patients rather than normal test subjects, to observe drug effects in a setting that more closely resembles the situation in which the drugs are normally used. Suppression of nasal eosinophilia and nasal blockage after nasal allergen provocation also gives some insight into the clinical relevance of claims of anti-inflammatory activity of the newer antihistamines.
Material and methods
The subjects included in this study where 12 grass pollen allergic adult patients, whose allergy was confirmed by intradermal skin test. The study was performed entirely out of season with first tests being done three months after the end of the grass pollen season and the last at least two months before the start of the new grass pollen season.
Each of 12 patients was tested on six different visits with at least a one-week interval between visits. On these visits the protocol below was followed. A different drug was administered (cetirizine 10 mg, ebastine 10 mg, fexofenadine 120 mg, mizolastine 10 mg, loratadine 10 mg and placebo) in a randomised order, immediately after determination of the basal values, in one single dose. Patients were not aware of which drug they were given. The placebo was a white tablet of 1 cm diameter containing lactose but no active agent.
T0: basal values, before drug administration
1) Nasal smear for eosinophilia.
2) Nasal grass pollen provocation.
3) Intradermal skin tests, using grass pollen extract and histamine.
4) Administration of drug after performing tests.
T4: 4 h after drug administration
1) Nasal grass pollen provocation.
2) Intradermal skin tests, using grass pollen extract and histamine.
T8: 8 h after drug administration
1) Intradermal skin tests, using grass pollen extract and histamine.
The nasal smear
A sample of nasal mucus was taken with a common cotton swab, over the length of the concha inferior. The sample was spread out on an object carrier glass, air-dried and Giemsa-stained. All samples were examined by the same pathologist who was not aware of what drug the patient had been administered. Using light microscopy and examining several ‘high power fields’ (HPF) per specimen, the samples were scored semiquantitatively according to the number of eosinophils into classes 0–3. If no eosinophils were seen the score was 0, a few scattered cells or small clumps scored 1, larger clumps, which did not cover the entire field, scored 2; and if the entire field was covered the score was 3. The results were compared before drug administration and after 8 h (4 h after the last grass pollen provocation), and the results were expressed as the sum of the increases in nasal eosinophilia for each drug (where a lower increase in eosinophilia represents a better result).
The nasal allergen challenge
A constant quantity of grass pollen extract of increasing concentration (100, 1000, 10 000 AU/ml) was administered in the nose using a nasal spray, at intervals of 15 min.
Ten minutes after each concentration increase, the unilateral nasal resistance was measured using passive anterior rhinomanometry. The concentration of allergen inducing a 100% increase in unilateral nasal resistance vs baseline value was considered the positive concentration. Further sneezing was recorded and the concentration at which sneezing occurred was considered the provocative concentration for this symptom. For rhinorrhea, the concentration at which a clear increase in weight of nasal secretions occurred was considered the provocative concentration. The secretions were collected while letting the patient blow his or her nose.
For each parameter, the provocative concentrations before (T0) and after administration (T4) of the drug were compared, and the sums of the shifts in threshold were calculated for each drug.
Intradermal skin test
A constant quantity of grass pollen extract or histamine solution was injected intradermally, using a 1 ml syringe. The maximum wheal diameter (in mm) was measured 15 min after injection. The sum of the differences between the results 4 h and 8 h after drug administration and the result at T0, were calculated for each drug.
All P-values were calculated using the Wilcoxin signed rank test, comparing with placebo. P-values smaller then 0.05 were considered significant.
From Table 1, it follows that 8 h after the active drug administration all antihistamines showed significantly smaller increases of eosinophilia (as assessed by nasal smear), after two nasal allergen provocations, when compared to placebo. However, there was no significant difference in activity between the different antihistamines.
Table 1. Sum of the increases of nasal eosinophilia induced by two grass pollen provocations, 8 h after drug or placebo intake, in 12 patients
Nasal blockage after nasal grass pollen provocation
From Table 2, it follows that all antihistamines showed a significant reduction of the provocative concentration for nasal blockage, as compared to placebo. No significant differences in the provocative concentration could be found between different antihistamines.
Table 2. Nasal grass pollen provocative concentration decrease (expressed as the sum of threshold shifts for all 12 patients), for nasal blockage (determined by 100% increase in nasal resistance), 4 h after drug intake
Sneezing after nasal grass pollen provocation
Table 3 shows that for all histamines vs placebo there was a significant reduction in the allergen concentration that provoked sneezing, but once more no significant differences between the different antihistamines could be found.
Table 3. Nasal grass pollen provocative concentration decrease (expressed as the sum of threshold shifts for all 12 patients) for sneezing, 4 h after drug intake
Rhinorrhea after nasal grass pollen challenge
In our study design, as follows from Table 4, all active antihistamines tended to reduce rhinorrhea after nasal allergen provocation, when compared to placebo, but these trends were not significant. Nor were significant differences found between the different antihistamines when looking at rhinorrhea after nasal allergen provocation.
Table 4. Nasal grass pollen provocative concentration decrease (expressed as the of threshold shifts for all 12 patients), for rhinorrhea (determined as a clear increase of the weight of nasal secretions), 4 h after drug intake
Intradermal skin tests
From Tables 5 and 6, it follows that for both the histamine and the allergen skin tests, all antihistamines reduced the wheal diameter in a significant way, as compared to placebo. However, there were no significant differences between the action of the different antihistamines. Regarding the differences between T4 and T8, fexofenadine tended to be less active at T8, but this trend was not significant.
In our study design, for all antihistamines tested, there was a significant reduction in nasal smear eosinophilia after nasal allergen provocation as compared with placebo.
To date not many nasal provocation studies have been performed where a significant effect of antihistamines on nasal eosinophilia after nasal allergen challenge has been demonstrated. During natural allergen exposure, however, it has been suggested that certain antihistamines diminish eosinophil counts (12). There are several in vitro studies in which a reduction in eosinophil chemotaxis caused by certain antihistamines was found (13, 14). The number of local eosinophils in allergen skin tests has also been shown to be reduced by antihistamines (15).
The reduction in nasal eosinophilia after nasal allergen challenge might be an indication of the anti-inflammatory properties of these newer antihistamines. More studies are certainly necessary to show to what extent this reduction in nasal eosinophilia is clinically relevant.
For the nasal allergen provocation test, a significant reduction in nasal blockage and sneezing was found for all tested antihistamines. In this study, though the rhinorrhea induced by nasal allergen provocation tended to be reduced for all antihistamines vs placebo, this trend was not significant.
Normal exposure to grass pollen during the season is not entirely comparable to nasal challenge with grass pollen. During the season the patient is exposed continuously to grass pollen and therefore there is a constant hyperreactive state due to persistent eosinophilia (16, 17). The significant reduction of nasal blockage and sneezing is, however, a clear indication of the effectiveness of these new drugs in preventing symptoms in grass pollen allergic patients. The lack of significant reduction of rhinorrhea might be an indication that nose-blowing, as a method of collection of secretions during allergen provocation, is not sensitive enough.
Intradermal skin tests using either histamine or allergen (in an allergic patient) have long been used to assess the efficacy of antihistamines in the treatment of allergic rhinitis. Some authors doubt whether this is valid since the skin does not react completely in the same way as the shock organ in IgE-mediated allergic rhinitis (18, 19).
Also in our setting, in the histamine and the grass pollen skin test there was a significant reduction in wheal diameter caused by all antihistamines at 4 h as well as at 8 h after administration of the drug. Fexofenadine tended to be less effective after 8 h but even this trend was not significant; fexofenadine might better be administered twice a day instead of once daily.
A significant difference in action between the different antihistamines could not be found in any of the tests performed in our study (nasal smear, nasal allergen provocation, allergen/histamine skin tests), all antihistamines showed significant activity compared to placebo. By using allergic patients and allergen testing in our study we tried to make the test setting as similar as possible to the normal situation in which these drugs are used. However, the fact that the study was performed outside the grass pollen season in grass pollen allergic patients may have influenced the final results.
The authors do conclude, however, that when choosing a drug from this group of second generation histamine H1-antagonists for treatment of allergic rhinitis, the preference of the patients might be the one most important factor, because all the new histamine H1-antagonists appear to be comparable in their efficacy.
We wish to thank Prof. L Kaufman who helped with the statistical analysis.
Background: It was the aim of the authors to compare all of the latest second-generation antihistamines and to see if there were significant differences in their efficacy. It is important for ENT specialists to know if these differences exist, as it is for general practitioners trying to choose between these drugs.
Methods: In 12 confirmed grass pollen allergic patients the authors performed nasal smears to asses eosinophilia, histamine/grass pollen skin tests, and grass pollen nasal provocation tests. All tests were performed before and after administration of one of five different antihistamines (cetirizine, loratadine, ebastine, fexofenadine, mizolastine) or placebo. The order of administration of antihistamines and placebo was randomised, and patients were not aware of which drug they were given. A decrease in nasal eosinophilia (nasal smear), or nasal or skin reactivity (provocation tests) was looked for.
Results: A significant decrease in nasal eosinophilia was observed for all antihistamines but not for placebo. For the grass pollen nasal provocation tests, the decrease was significant for nasal blockage and sneezing; for rhinorrhea there was an insignificant decrease that was true for all antihistamines. A significant reduction in histamine/grass pollen skin test reactivity was also observed for all antihistamines, during an 8 h observation period. A significant difference in efficacy between the different antihistamines could not be found with any of the tests performed.
Conclusions: For the newer nonsedating H1-antagonists there appears to be no clinically relevant differences in activities – at least not in our study. Preference of the patient may be the most important factor in making a choice between these drugs.