I was wondering if a prolonged course of daily antihistamines (whether first or second generation) for allergic rhinitis can result in tolerance? Some patients seem to prefer taking oral antihistamines to using a daily corticosteroid (e.g. fluticasone).


Thank you for your inquiry.

Although there were early studies citing that tolerance to therapeutic effects of antihistamines could occur, more recent data, especially studies involving nonsedating antihistamines, as noted in the abstracts copied below, indicate that tolerance to the therapeutic effects of these drugs does not occur. Variations in symptoms while on a single antihistamine more than likely are due to differences in the natural course of the condition rather than tolerance to the drug in question.

Thank you again for your inquiry and we hope this response is helpful to you.

Otolaryngol Pol. 2007;61(5):898-901. doi: 10.1016/S0030-6657(07)70551-6.
[Does new antihistamines characterize tachyphylaxis phenomenon?].
Klos K1, Kruszewski J..
The Aim of the Study: was to estimate the skin microcirculation reactivity after histamine administration in patients treated with 10 mg daily dose of cetirizine for 180 days.
Material and Methods: Thirty seven young men age 27+12 year, patients suffering from persistent rhinitis were randomized into three groups which received 10 mg/day of cetirizine, 5 mg/day of levocetirizine or placebo respectively. Twenty eight completed the study. The skin microcirculation reaction after 10 mg/ml histamine administration was estimated visually on the forearm (diameter of wheal and flare) and by laser Doppler flowmetry before and after study drug or placebo administration 24 hours and every 30 days during the time of the study. The blood flow was measured by Periflux PF3, using a skin probe 5 mm away from the histamine-induced point.
Results: Statistically significant inhibition of skin reaction (over 92%) and blood flow (over 85%) in relation to the start values in cetirizine group as well as between the groups which received cetirizine or placebo (p<0.001), remained at the same level all the time during the examination.
Conclusion: Tachyphylaxis phenomenon for antihistamine effect of 10 mg/day cetirizine and 5 mg/day levocetirizine was not observed during the whole 180-days treatment.

Laryngorhinootologie. 2005 Jan;84(1):30-41.
Oral second generation antihistamines in allergic rhinitis].
Riechelmann Abstract
Background: Histamine is a key mediator of the allergic immediate reaction. Antihistamines belong to the most frequently used treatment modalities in allergic rhinitis.
Methods: The National Library of Medicine was searched for current data of the effects of histamine and antihistamines in allergic rhinitis.
Results: Histamine acts on 4 different histamine receptors. Activation of H1-receptors on nasal trigeminal nerve fibers transmits nasal itch and sneezing. Nasal hypersecretion is mainly mediated by an trigeminal-parasympathetic reflex. Activation of H1-receptors results in contraction of nasal endothelial cells with consecutive plasma extravasation and edema formation. Histamine also activates H2-receptors on smooth muscle cells surrounding nasal capacitance vessels. They transmit muscle relaxation, increased blood content and an enlarged volume of nasal mucosa. Via peripheral H3-receptors, histamine modulates neurogenic inflammation and via H4-receptors functions of immune cells. Oral second generation antihistamines inhibit histamine dependent activation of nasal H1-receptors. They mainly reduce nasal itch, sneezing, and hypersecretion. In addition, allergy related activity impairment is reduced resulting in improved physical and mental performance. Second generation antihistamines reduce proinflammatory effects mediated by H1-receptors, however, drug concentrations necessary for mast cell stabilization as observed in vitro are not reached in vivo. Oral second generation antihistamines are readily absorbed and reduce allergy symptoms for approximately 24 hours, allowing convenient once daily medication. Modern antihistamines are generally safe; tachyphylaxis, tolerance or rebound has not been observed.
Conclusion: Due to their minimal adverse effects and efficient symptom reduction oral second generation antihistamines are particularly useful for the treatment of less severe intermittent forms of nasal allergy.

Lack of subsensitivity to terfenadine during long-term terfenadine treatment
F.Estelle R. Simons et al
Journal of Allergy and Clinical Immunology
Volume 82, Issue 6, December 1988, Pages 1068-1075
Eleven healthy male volunteers ingested térfenadine, 60 mg, every 12 hours for 56 days. Compliance was monitored strictly throughout the study. Before the first terfenadine dose on day 0, and 12 hours after the evening terfenadine dose every seventh day and on randomly selected "unscheduled" days, wheal-and-flare areas were measured after intradermal injections of 0.01 ml of histamine phosphate (1.0 mg/ml and 0.1 mg/ml). On days 0, 28, and 56, six volunteers had skin tests hourly for 12 hours after the morning terfenadine dose. On all study days, serum terfenadine metabolite I concentrations were measured each time histamine skin tests were performed. On days 7, 14, 21, 28; 35, 42, 49, and 56, the mean areas of the histamine-induced wheals did not differ significantly from each other but were significantly decreased compared to the mean wheal area on day 0 (p < 0.01). On these days, the mean areas of the histamine- induced flares also did not differ significantly from each other but remained significantly suppressed compared to the mean flare areas on day 0 (p < 0.01). Wheal-and-flare suppression was noted in all unscheduled histamine skin tests performed 12 hours after the evening terfenadine dose. In the subgroup of volunteers who had hourly tests, on day 0, the mean wheal-and-flare areas were significantly suppressed from 2 to 12 hours after the dose, with maximal wheal suppression occurring at 5 hours (p < 0.05) and maximal flare suppression occurring from 3 to 9 hours (p < 0.01). On day 28 in the subgroup, the mean wheal area was significantly larger 12 hours after the dose than before the dose or at any other time (p < 0.01), but the mean flare areas did not differ significantly at any time (p = 0.01). On day 56 in the subgroup, the mean wheal areas did not differ significantly from before the dose to 12 hours after the dose, nor did the mean flare areas differ significantly at any time (p = 0.01). The mean serum concentration of terfenadine metabolite 112 hours after the evening dose did , not differ significantly on days 7, 14,21, 28, 35, 42, 49,adn 56 (p = 0.01). Unscheduled serum terfenadine metabolite I concentrations measured 12 hours after the dose provided additional confirmation of compliance. In the subgroup, the mean serum elimination half-life value and the mean area under the serum concentration versus time curve of terfenadine metabolite I did not differ significantly on day 0, day 28, or day 56 (p = 0.01). We conclude that subsensitivity to the antihistaminic effect of terfenadine did not develop during 56 days in compliant subjects, as evidenced by continued suppression of the histamine-induced wheals and flares. Also, the pharmacokinetics of terfenadine metabolite 1 remained unchanged after 56 days of terfenadine treatment.

Phil Lieberman, M.D.

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