Updosing of Nonsedating Anti-histamines in Recalcitrant Chronic Urticaria.

Chronic urticaria (CU) is a persistent, debiliating condition that causes severe impairment on the quality of life (QoL) of patient by interrupting work productivity. Current guidelines recommend second-generation (nonsedating) anti-histamines for the treatment for all forms of urticaria. In patients who do not respond adequately to conventional doses of anti-histamines, it is recommended to increase the dose to up to four times to obtain control. But there are only few controlled studies that have assessed the efficacy and safety of nonsedating anti-histamines. Though sedating histamines are frequently used as an add-on therapy in severe cases, they have a negative impact on QoL by compromising sleep and performance. The use of other suggested therapeutic options (omalizumab, cyclosporine A, montelukast and dapsone) is also limited by paucity of data on their efficacy and adverse effect profile. Second-generation anti-histamines which are relatively safer require more proven data to support their judicious use to improve disease in patients with CU.

What was known?

Nonsedating second-generation H1 anti-histamines are the first-line therapeutic options for chronic urticaria. However, when the disease control is inadequate with standard doses, dose escalation of anti-histamines to up to four-folds is advised.

Introduction

Chronic urticaria (CU) is defined as recurrence of transient wheals accompanied by redness, itching and frequently, angioedema, daily or almost daily ≥6 weeks.[1] The recurrent symptoms are extremely distressing causing severe impairment in quality of life (QoL) of patients. The symptoms affect the everyday life in terms of physical functioning, bodily pain, general health, sleep disturbances leading to social isolation and emotional disturbances.[23]

Current international guidelines by European Academy of Allergology and Clinical Immunology / Global Allergy and Asthma European Network / European Dermatology Forum / World Allergy Organization (EAACI / GA2LEN / EDF / WAO) recommend a three-step algorithm for treatment. Standard dose of second-generation (nonsedating) H1 anti-histamines constitute the first-line treatment. If there is insufficient response, the conventional dose is progressively increased to up to four times. In therapy-resistant cases, omalizumab, cyclosporine A or leukotriene antagonist is advised. A short-term course of systemic corticosteroids is administered for acute exacerbation for up to 3–7 days (maximum 10 days).[145]

Nonsedating anti-histamines have a longer half-life with less incidences of side effects such as sedation, cholinergic side effects and cardiotoxicity than first-generation anti-histamines. Thus, the former are better tolerated.[6] Patient safety should be the prime consideration while choosing and updosing anti-histamines. This review highlights the treatment of CU with higher than conventional doses of second-generation anti-histamines in patients who do not respond to conventional doses with relevant studies performed. We included studies of refractory urticaria treated with updosing second-generation anti-histamines.

Methodology

A comprehensive pubmed search (http://www.ncbi.nlm.nih.gov/pubmed) of literature was conducted on treatment of chronic recalcitrant urticaria. MeSH terms included in search were ‘chronic urticaria’, ‘treatment’, ‘updosing’, ‘anti-histamines’. All clinical trials of CU treated with higher than standard doses of anti-histamines till date were included in the review. This included clinical trials done in last 20 years.

Second-generation anti-histamines at higher than conventional doses

Various controlled studies on higher than conventional doses of anti-histamines suggest that they increase the chances on disease control and improvement in QoL in patients of CU with lesser incidence of adverse effects.

Cetirizine

Zuberbier et al.[7] (1996) conducted a double-blind, placebo-controlled trial with cetirizine. It was a 3-week treatment period using either 20 mg/day of cetirizine or placebo in 11 patients with cholinergic urticaria. Statistical analysis was done on 11 patients which showed that cetirizine caused a statistically significant reduction of wheals (P = 0.015), erythema (P = 0.033), pruritus (P = 0.006) and all symptoms (P = 0.013). No adverse events were observed. Cetirizine in dose of 20 mg induced significant reduction in wheals, erythema and pruritus as compared to placebo with no additional adverse effects. A similar study on cetirizine for chronic idiopathic urticaria (CIU) was also conducted. Kameyoshi et al.[8] obtained good results in an open-label study using 20 mg of cetirizine in CIU patients in alleviating symptoms.

In another study, 22 adult patients with moderate/severe CU not controlled with the usual anti-histamine doses were included. These patients recorded urticaria severity on a visual analogue scale (range 0–10) for 2 weeks. In the first week of the study, they were treated with cetirizine at the standard dose (10 mg/day). During second week the dose was increased to three-fold (30 mg). Only one patient improved with increased dose, whereas others had to be treated with steroids and immune-suppressants to gain disease control. The results of this study were not consistent with increasing the doses of second-generation anti-histamines as compared to previous two studies mentioned.[9]

Levocetirizine and Desloratidine

One double-blind study included 80 patients with CU treated with levocetirizine or desloratadine. Treatment was started with a conventional dose of 5 mg for 1 week. Doses were increased weekly to 10 mg or 20 mg if response was not satisfactory. Patients not responding to 20 mg of one of the anti-histamines were switched to 20 mg of the other drug. Wheal and pruritus scores, QoL, somnolence, safety and patient discomfort were assessed. Thirteen patients became symptom-free at 5 mg (nine levocetirizine and four desloratadine). 21 patients responded to 10 mg dose (8 levocetirizine and 7 desloratadine) and 20 mg dose (5 levocetirizine and 1 desloratadine). Out of 28 patients nonresponsive to 20 mg desloratadine, 7 patients responded and became symptom-free with 20 mg levocetirizine. In contrast, none of the 18 levocetirizine nonresponders benifited with 20 mg desloratadine. No serious or severe adverse effects warranting the discontinuation of treatment with either drug were noted. Increasing the dose of anti-histamines improved symptoms in patients along with improvement in QoL without increasing somnolence.[10]

Desloratadine

Siebenhaar et al.[11] evaluated effects of high-dose desloratadine in patients with acquired cold urticaria. A total of 30 patients were treated with desloratadine 5 mg or 20 mg or placebo daily for 7 days in a randomized, double-blind study. 5 mg and 20 mg of desloratadine was administered every day each for 7 days separated by 14-day washout periods. At the end of each treatment, responses of urticarial reactions were assessed using digital three-dimensional time-lapse photography and thermography, cold provocation with the TempTest 2.0/2.1 system, and the critical temperature threshold (CTT) and critical stimulation time threshold (CSTT) were measured. Desloratadine 20 mg significantly reduced cold-induced wheal volume, CTT, and the CSTT. Adverse effects reported by the patients were studied. Higher dose was not associated with increased somnolence and patient performed significantly better with higher doses. Authors supported current guidelines stating that increased desloratadine dosing might benefit patients with urticaria who do not respond to standard doses.

Fexofenadine

In 1999–2000, 2 to 4 weeks, double-blind, placebo-controlled study done by Finn et al.[12] and Nelson et al.[13] assessed the efficacy of fexofenadine (20, 60, 120 and 240 mg) in 439 and 418 patients, respectively. Efficacy was measured in terms of mean daily changes from baseline in number of wheals, pruritus severity, and interference with sleep and daily activities due to urticaria. In both the studies, fexofenadine hydrochloride was well tolerated and was statistically superior to placebo in reducing signs and symptoms of chronic spontaneous urticaria. But in both the trials there was similar improvement with 60, 120 and 240 mg doses twice daily. Adverse events were mild and occurred with similar incidence in all treatment groups. There was no dose-related increase in adverse effects. Also, patients receiving fexofenadine hydrochloride also experienced significantly less interference with sleep and daily activities than patients receiving placebo (P ≤ 0.0001). Authors in both trials recommended a dose of 60 mg twice a day or greater in treatment of chronic urticaria.

Godse et al.[14] also conducted similar trial on fexofenadine (180, 360, 540 mg) in chronic spontaneous urticaria patients. Thirty-seven patients with chronic spontaneous urticaria were started with fexofenadine 180 mg tablet. Patients were reviewed once a week for a 4 week period. For symptomatic patients, the dose of fexofenadine was doubled to 360 mg at the end of 1 week and 540 mg at the end of 2 weeks. Urticaria severity score (UAS) was recorded at the beginning, then at 1, 2 and 4 weeks of treatment. The authors concluded that fexofenadine in higher doses effectively controlled urticaria in majority of the patients. Side effects noted were headache and sedation.

Rupatadine

Rupatadine, a newer second-generation H1 anti-histamine has rapid onset of action and is nonsedating. It has potent anti-platelet activating factor activity.[15] A randomized, double-blind, placebo-controlled, multicenter study in which CU patients (N = 333) were treated with rupatadine at different doses suggests the superior effificacy of rupatadine 10 mg and 20 mg. The mean pruritus score (MPS) reduction was assessed. 57.5% (P < 0.005) and 63.3% (P < 0.0001) MPS reduction was observed from baseline, at week 4 with 10 and 20 mg rupatadine, respectively, compared with placebo (44.9%). Rupatadine 10 mg had an overall better adverse event profile.[16]

Another pooled data from two randomized, placebo-controlled, double-blind, trial of 538 patients using responder analysis to identify meaningful differences between the groups (10 and 20 mg rupatadine) showed that rupatadine 20 mg daily resulted in a higher percentage of patients with response of 75% symptom reduction or better than rupatadine 10 mg. The efficacy of rupatadine 10 and 20 mg is significantly better as compared to placebo in the treatment of CU patients. Authors supported the use of higher than standard doses of nonsedating anti-histamines in CU.[17]

In another study, Dubertret et al.[18] investigated the effect of rupatadine 5, 10, and 20 mg once daily for 4 weeks in patients (N = 277) with moderate to severe chronic idiopathic urticaria. The reductions in total symptom scores with rupatadine (54.8% with 10 mg and 65.9% with 20 mg) were superior to placebo (38.6%). But there was no significant difference in improvement with 10 and 20 mg doses. The main adverse effects noted were somnolence and headache.

Metz et al.[19] investigated the efficacy of rupatadine 20 mg in 21 patients with acquired cold urticaria in a double-blind, placebo-controlled trial. In 11 patients, complete response was obtained with reduced score for wheals, pruritus, burning sensation, and subjective complaints. Authors concluded that rupatadine 20 mg given daily resulted in reduction of symptoms of 75% in a higher percentage of patients than treatment with rupatadine 10 mg.

Ebastine

Ebastine is an oxypiperidine-based, long-acting, nonsedating, second-generation H1 anti-histamine. Its active metabolite is carebastine. It is recommended orally once daily for the treatment of allergic rhinitis and chronic idiopathic urticaria.

It has no adverse effects on cognitive performance. Supratherapeutic doses of up to five times usual dose does not significantly affect QTc interval.[2021]

Godse[22] treated 30 patients of chronic spontaneous urticaria with Ebastine. Treatment was started with 10 mg Ebastine and dose was increased to 20 mg in nonresponders at the end of first week and two tablets of ebastine 20 mg in two divided doses at the end of 2 weeks. UAS was used to grade response to treatment. Average UAS was 4.6 at 0 weeks which reduced to 2.2 at 1 week and to less than 1 at the end of 4 weeks. Author reported superior efficacy of 20 mg Ebastine as compared to 10 mg without increase in somnolence. It was concluded that ebastine is safe and effective in higher doses to control chronic spontaneous urticaria.

Bilastine

Bilastine is a new nonsedative, long-acting, H1 anti-histamine approved recently for the symptomatic treatment for allergic rhinoconjunctivitis and urticaria. It is a substrate of p-glycoprotein. It does not cross blood-brain-barrier and hence has no central nervous system side effects. It is non cardiotoxic. Recommended dose is 10 mg per day.[2324]

Krause et al.[25] evaluated the effect of Bilastine in 20 patients with cold contact urticaria (CCU). The study was randomized, crossover, double-blind, placebo-controlled for a duration of 12 weeks. Patients were given placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. Bilastine 20 mg was highly effective (P < 0.0001) in reducing CTT. Updosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming totally symptom-free. Only one patient did not respond to treatment. Authors supported current urticaria treatment guidelines which demonstrated the increased efficacy of bilastine with fourfold updosing without sedation.

The various studies on anti-histamines updosing in CU are summarized in Table 1.

Table 1

Studies done to evaluate the effect of updosing antihistamines in chronic urticaria

How safe are higher than standard dose of second-generation H1 anti-histamine?

Sedating first-generation H1 anti-histamines are lipophilic compounds which cross the blood–brain barrier causing significant sedation due to blockade of the histaminergic neuronal system. They impair cognitive function, learning and performance and alter rapid eye movement sleep. They also have pronounced anti-cholinergic effects and some exhibit cardiotoxicity at overdose. Also, overdosing in infants and young children may result in death.[26]

There are several untoward side effects induced by first-generation sedating H1 anti-histamines. Because of this, nonsedating second-generation H1 anti-histamines are favored. The latter have very low incidence of somnolence, drowsiness/sedation and impairment of cognitive or psychomotor functions.[6] They are now the first line therapy for CU.

Nonsedating second generation H1 anti-histamines have lower propensity to cross the blood-brain-barrier. This is due to the P-glycoprotein (P-gp)-mediated efflux system. P-gp is an energy-dependent efflux pump which extracts the drug out of the cell.[27] A second hypothesis on P-gp em hasizes on the indirect mechanism involved, via the regulation of pH and/or electric gradients.[28]

In studies mentioned above, higher-than-standard dose of anti-histamines were not associated with increase in adverse effect profile in most cases. There are few studies evaluating the sedative effects of desloratadine and fexofenadine at higher than standard doses in healthy volunteers.

In one study, fexofenadine in a range of doses from 80 to 180 mg was studied for any disruptive effects on aspects of cognitive function and psychomotor function in comparison with placebo, loratadine and promethazine. It was found that fexofenadine at all doses tested was not statistically different from placebo in any of the tests used and loratadine did not cause any significant impairment of cognitive function. Significant impairments were observed following promethazine.[29] Hindmarch et al.[30] investigated the acute effects of fexofenadine (360 mg) on various aspects of cognitive and psychomotor function in comparison to placebo and promethazine in healthy volunteers. Authors concluded that fexofenadine at a dose of 360 mg is demonstrably free from disruptive effects on aspects of psychomotor and cognitive function. Two long-term trials in healthy volunteers on fexofenadine HCl have demonstrated that doses up to 240 mg once daily for up to 12 months is safe and well tolerated. No dose-related prolongations in corrected QT interval (QTc) were found with fexofenadine doses up to 800 mg once daily or 690 mg twice daily for 28 days.[3132] Fexofenadine does not lead to sedation at therapeutic as well as supra-therapeutic doses. Desloratadine and levocetirizine usually do not cause sedation at approved doses but have potential to cause sedation at supra-therapeutic doses. Cetirizine has potential of causing sedation at both approved and supra-therapeutic doses.[62627]

Anti-histamines at higher than therapeutic doses also possess anti-inflammatory effects that will have synergistic effects on treatment of urticaria. The anti-inflammatory activity of H1 anti-histamines may be a consequence of their ability to influence the activation of genes responsible for the expression and synthesis of proinflammatory mediators.[33]

Conclusion

Nonsedating second-generation H1 anti-histamines are the first-line therapeutic option for chronic urticaria. However, disease control in some patients is inadequate with standard doses. In such patients, dose escalation of anti-histamines to up to four times is advised. The current literature provides convincing data of good therapeutic response with dose escalation. Two similar reviews also concluded that supra-therapeutic dose of nonsedating second-generation H1 anti-histamines represent the safest therapeutic approach in treatment of chronic urticaria patients who do not respond to recommended doses.[3435] Patient safety should be the most important parameter while using particular anti-histamines and increasing its dose. More studies are required to evaluate the therapeutic effect of newer anti-histamines and the side effect profiles of drugs when used in higher than standard doses.

What is new?

In maximum patients, escalating the dose of anti-histamines improved urticarial symptoms and quality of life without increasing the side effects.