Treatment of Urticaria

Urticaria is a cutaneous syndrome characterized by dermal edema (wheal) and erythema (flare) that blanches with pressure. The lesions typically last less than 24 hours and are usually pruritic. In 1983, Christensen and Maibach summarized the theory behind the use of histamine H₁ receptor antagonists (antihistamines) in clinical dermatology. These agents remain the mainstay of treatment for urticaria. This article reviews the medical literature on the effectiveness of antihistamines in urticarial syndromes, including acute, chronic idiopathic and the physical urticarias. Older antihistamines, such as chlorpheniramine and hydroxyzine, are effective in the treatment of urticarias, but they also have marked sedative and anticholinergic effects. Newer nonsedating antihistamines (second-generation antihistamines) have been developed that have reduced adverse effects because they do not cross the blood-brain barrier; these agents (acrivastine, cetirizine, loratadine, mizolastine, fexofenadine, ebastine, azelastine and epinastine) cause significantly less sedation and psychomotor impairment than their older counterparts. A review of the literature reveals that there are few studies which document the efficacy of second-generation antihistamines in the treatment of acute urticaria, a biologic entity that usually resolves within 3 weeks. We did not identify controlled studies that suggested superiority of any antihistamine in the treatment of acute urticaria. Loratadine or cetirizine, and possibly mizolastine, appear to be treatments of choice for chronic idiopathic urticaria. For symptomatic dermatographism, the combination of an antihistamine and an H₂ antagonist, e.g. chlorpheniramine and cimetidine, appears to be effective. Very few studies have been conducted on the use of antihistamines in the treatment of cold, cholinergic, and pressure urticaria. Antihistamines are the mainstay of urticarial therapy. This evidence-based review suggests that there are efficacy differences between newer, nonsedating antihistamines and older agents in some forms of the disorder. Clearly, further well-controlled clinical trials in larger numbers of patients are needed to clarify the role of these agents in the treatment of urticaria.     

Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil

Background:Several dermatoses are mediated by histamine, such as urticaria, angioedema, and papular urticaria. There are no Brazilian studies comparing the potency of antihistamines.Objectives:To evaluate the tolerability and efficacy of the main commercial brand and generic H1 antihistamines, regarding the suppression of the wheal and flare to the histamine test.Methods:A quasi-experimental, open study with 10 healthy adults submitted to the histamine test on the ventral aspect of the forearms. After 20 minutes, wheal and flares were measured. The tests were performed after two hours of intake of dexchlorpheniramine, hydroxyzine, levocetirizine, fexofenadine, cetirizine, loratadine, ebastine, desloratadine, epinastine and rupatadine, as well as generics of loratadine, cetirizine and fexofenadine.Results:All antihistamines presented a reduction in the wheal compared to the control (p <0.02), as well as in the flare, except for rupatadine (p = 0.70). In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1). As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1). The most common adverse effect was drowsiness, which was more prevalent among first-generation drugs (p < 0.01). Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p >0.03)..Study limitations:A single-center study evaluating only aspects related to histamine.Conclusions:Brazilian commercial antihistamines presented different profiles of inhibition of wheal and flares in the histamine test, as well as adverse effects. Generic loratadine, fexofenadine and cetirizine presented larger flares than brand drugs.     

Therapy of acute and chronic urticaria

Background The drug management of chronic urticaria can be divided into three approaches: (i) blockade of released histamine at the receptor sites; (ii) blockade of histamine release from mast cells; and (iii) blockade of other mediators and possible inflammatory and cellular components. The first approach is the most successful and widely used. It primarily involves the use of H₁-antihistamines, although tricyclic antidepressants and H₂-antihistamines also have a place. Treatments The usefulness of classic H₁-antihistamines, such as hydroxyzine, may be limited by side-effects (most notably, sedation). The four most widely used of the newer antihistamines are loratadine, terfenadine, astemizole and cetirizine. These antihistamines are significantly superior to placebo and have similar efficacies comparable with hydroxyzine. Novel agents and methods, including nifedipine, sulphasalazine and plasmapheresis have been tried with some success in refractory patients. Guidelines If acute cases are inadequately controlled, short-term oral corticosteroids may be added. Systemic corticosteroids are occasionally indicated for the management of severe acute urticaria, severe serum sickness, pressure urticaria or urticarial vasculitis, or to break the cycle of a resistant case, but have no place in regular therapy for chronic urticaria. For those with severe acute urticaria with signs of respiratory distress, possible treatments include subcutaneous epinephrine, systemic corticosteroids and intramuscular H₁-antihistamines. Patients with chronic urticaria inadequately controlled on H₁-antihistamines alone may benefit from the addition of a classic antihistamine, a tricyclic antidepressant or an H₂-antihistamine. A short course of systemic corticosteroids may help those with severe chronic refractory disease.     

Second- and third-generation antihistamines in the treatment of urticaria

ABSTRACT: Chronic urticaria is mainly idiopathic in nature and can be difficult to treat. While less responsive to antihistamine therapy than acute urticaria, antihistamines still play a key role in the management of symptomatology. While many of the antihistamines still commonly used to treat urticaria are first generation H₁ antagonists (e.g., diphenhydramine, hydroxyzine), the more recently developed second-generation agents (e.g., loratadine, cetirizine) and their metabolites—the third-generation antihistamines (e.g., fexofenadine, norastemizole, descarboxyloratadine)—possess many of the desirable clinical effects of the first-generation agents with a more tolerable side effect profile. This review discusses the advantages and disadvantages of each of the various second- and third-generation agents available, and presents some of the data showing the differences among these agents in the treatment of chronic urticaria.     

High dose cetirizine: a case report

We report the case of a 46-year-old man who tolerated 50 mg per day of cetirizine for the treatment of chronic idiopathic urticaria. The patient denied any sedation or somnolence and had no difficulty performing routine daily functions including driving. He had tried other antihistamines, including fexofenadine, loratadine, and hydroxyzine without improvement.     

Effects of loratadine and cetirizine on serum levels of neuropeptides in patients with chronic urticaria

H1‐receptor inhibiting drugs, namely loratadine and cetirizine, were frequently used in treatment of chronic urticaria. Urticarial weal and flare reactions, a neurogenic reflex due to neuropeptides, were reported to be more effectively inhibited by cetirizine than loratadine. The aim of this study was to determine and compare the effects of systemic loratadine and cetirizine treatments on serum levels of selected neuropeptides in chronic urticaria. Treatment groups of either systemic loratadine or cetirizine (10 mg/d), consisting of 16 and 22 patients, respectively, were included. Serum levels of stem cell factor (SCF), neuropeptide Y (NPY), calcitonin gene‐related peptide (CGRP), nerve growth factor (NGF), vasoactive intestinal peptide (VIP), and substance P (SP) were detected before and after one week of treatment with antihistamines. Serum NPY and VIP levels were significantly decreased when compared before and after treatment with antihistamines (P < 0.001 and P < 0.01, respectively). SCF and NGF values were also decreased after antihistamine treatment (P < 0.05). Post‐treatment levels of CGRP were significantly higher compared with pretreatment values, while no significant difference was detected between pre and post treatment levels of SP. Cetirizine was significantly more effective than loratadine on lowering serum levels of SCF among the other neuropeptides. Systemic loratadine and cetirizine treatments in patients with chronic urticaria precisely caused variations in serum levels of neuropeptides. The predominant effect of cetirizine compared to loratadine on reducing serum SCF levels might be explained with anti‐inflammatory properties of cetirizine.     

Chronic urticaria: a role for newer immunomodulatory drugs?

Chronic urticaria is now recognized as an autoreactive disorder in a substantial fraction of patients. A serologic mediator of whealing has been demonstrated in 50-60% of patients with chronic urticaria, and autoantibodies against the high affinity IgE receptor or IgE have been detected in about half of these patients. The demonstration that chronic urticaria is frequently autoimmune has encouraged a more aggressive therapeutic approach, with the use of immunomodulatory drugs.A step-by-step approach to the management of chronic urticaria is proposed, based on our personal experience and review of current medical literature, identified through Medline research and hand searching in medical journals. The non- or low-sedating H(1) receptor antagonists (antihistamines), such as cetirizine, fexofenadine, loratadine, mizolastine and, more recently, levocetirizine, desloratadine and ebastine, represent the basic therapy for all chronic urticaria patients. Older sedating antihistamines, such as hydroxyzine and diphenhydramine, may be indicated if symptoms are severe, are associated with angioedema, and if the patient is anxious and disturbed at night.Corticosteroid therapy with prednisone or methylprednisolone can be administered for a few days (7-14) if urticarial symptoms are not controlled by antihistamines and a rapid clinical response is needed. In cases of relapse after corticosteroid suspension, leukotriene receptor antagonists, such as montelukast and zafirlukast, should be tried. In our experience, remission of urticarial symptoms can be achieved in 20-50% of chronic urticaria patients unresponsive to antihistamines alone. When urticaria is unremitting and is not controlled by combined therapy with antihistamines and leukotriene receptor antagonists, prolonged corticosteroid therapy may be needed. Long-term corticosteroid therapy should be administered at the lowest dose able to control urticarial symptoms, in order to minimize adverse effects. In a few patients, however, high-dose corticosteroid therapy may have to be administered for long periods. In these patients, immunosuppressive treatment with low-dose cyclosporine can be started. This type of treatment has a corticosteroid-sparing effect and is also generally effective in patients with severe, unremitting urticaria, but requires careful monitoring of cyclosporine plasma concentration and possible adverse effects. Other immunomodulating drugs that have been tried in chronic urticaria patients include hydroxychloroquine, dapsone, sulfasalazine and methotrexate, but their efficacy has not been proven in large controlled studies. Warfarin therapy may also be considered in some patients with chronic urticaria and angioedema unresponsive to antihistamines.     

Efficacy and safety of antihistamines in allergic skin disorders

Background For patients with urticaria, H₁-antihistamines remain the gold standard medical treatment of choice. They act by blocking H₁ receptors on the vascular endothelial cell surface. Newer, non-sedating antihistamines such as loratadine also act to some extent by blocking the release of histamine from mast cells, basophils and human skin tissue. Efficacy All of the newer antihistamines (loratadine, terfenadine, astemizole and cetirizine) have been shown to have comparable efficacy to the classic sedating antihistamines and to be significantly superior to placebo in terms of symptom improvement. Loratadine has been shown to be at least as effective as the other non-sedating agents and cetirizine. Antihistamines also have a potential benefit in the management of patients with atopic dermatitis. In two studies, loratadine was found to be significantly superior to placebo in the reduction of pruritus. Safety In terms of safety, the newer antihistamines have important differences. Cetirizine, for example, causes dose-related sedation and functional impairment compared to placebo. In contrast, loratadine has no such sedative effects. Terfenadine and astemizole have also been shown to be free of sedative effects, but exceeding the recommended dose of either may increase the risk of a serious cardiac arrhythmia, torsades de pointes. Plasma levels of both terfenadine and astemizole may also be increased as a result of interaction with various drugs. In contrast, loratadine has not been shown to induce ECG changes, even at doses of 40 mg o.d. for 90 days.     

Effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced wheal-and flare-response, sedation, and psychomotor performance

Although many antihistamines are now in clinical use, few studies directly compare their pharmacodynamic and sedative activities in humans in vivo. We designed a double-blind, placebo-controlled, crossover study to compare the inhibitory effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced flare-and-wheal response. Systemic sedative effects and impaired psychomotor activities by these drugs were also evaluated. Bepotastine (10 mg twice a day), cetirizine (10 mg once a day), fexofenadine (60 mg twice a day), and olopatadine (5 mg twice a day) or placebo was given in a double-blind manner to seven healthy volunteers before histamine challenge by iontophoresis. At 0, 1, 2, 4, 8, 12, and 24 h following the oral administration of these drugs, histamine iontophoresis-induced wheal-and-flare response was measured. Sedative effects by the drugs were also evaluated by a visual analogue scale for subjective sedation, and by word processor test for psychomotor activity. Each volunteer was tested with all of the drugs (including placebo), administered in a random order with a washout period of at least 1 week. Histamine iontophoresis induced marked wheal-and-flare response in all participants. Bepotastine, cetirizine, fexofenadine, and olopatadine yielded significant reduction of histamine-induced wheal-and-flare response compared to placebo (P < 0.01). Among the drugs, olopatadine and cetirizine suppressed most markedly and persistently histamine-induced wheal-and-flare response, while bepotastine and fexofenadine produced a significant, but less persistent suppression. Olopatadine, fexofenadine, and cetirizine showed a significant systemic sedative effect in this order with bepotastine showing the least sedative effect. Moreover, olopatadine affected psychomotor performance most markedly, which was followed by fexofenadine and cetirizine. These results indicate that bepotastine, cetirizine, fexofenadine, and olopatadine inhibit histamine-induced wheal-and-flare response of humans in vivo and induce a variable systemic sedative effect and impaired psychomotor activity. Although olopatadine and cetirizine showed the strongest and most persistent suppression of histamine-induced wheal-and-flare response, olopatadine showed a considerable sedative effect with impaired psychomotor performance.     

A comparison of cetirizine and terfenadine in the management of solar urticaria.

Many solar urticaria patients may benefit from the use of antihistamines. Historically, the value of such therapy was limited by sedation. Newer agents such as terfenadine and cetirizine that are relatively non-sedating appear to be better tolerated by patients. The latter drug, in addition to its antihistamine effect, also appears to inhibit eosinophil migration, which terfenadine and other potent H1 antagonists do not significantly affect. Eosinophils have been reported as early migrating cells in induced solar urticaria, raising the possibility that the dual action of cetirizine may provide a greater potential benefit in the management of solar urticaria. Six patients with idiopathic solar urticaria were entered into a double-blind, phototest study to compare cetirizine and terfenadine. Using the minimal urticarial dose as a phototest end-point, both drugs were equally effective in raising the threshold of sensitivity in 4 patients. Two patients failed to respond to either therapy, which is in keeping with the known variable response to histamine blockade in solar urticaria. At the dosage used, cetirizine therapy appears to be no more effective than terfenadine.     

Pharmacology of Antihistamines

H_1-antihistamines, the mainstay of treatment for urticaria, were developed from anticholinergic drugs more than 70 years ago. They act as inverse agonists rather than antagonists of histamine H₁-receptors which are members of the G-protein family. The older first generation H_1-antihistamines penetrate readily into the brain to cause sedation, drowsiness, fatigue and impaired concentration and memory causing detrimental effects on learning and examination performance in children and on impairment of the ability of adults to work and drive. Their use should be discouraged. The newer second-generation H₁-antihistamines are safer, cause less sedation and are more efficacious. Three drugs widely used for symptomatic relief in urticaria, desloratadine, levocetirizine and fexofenadine are highlighted in this review. Of these levocetirizine and fexofenadine are the most potent in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals, whereas fexofenadine has a relatively short duration of action and may be required to be given twice daily for all round daily protection. Although desloratadine is less potent, it has the advantages of rarely causing somnolence and having a long duration of action.     

Cutaneous drug eruption from cetirizine and hydroxyzine

Topical application of the antihistamines commonly leads to sensitization for patients, but skin reactions provoked by their systemic use are very rare. The antihistamines cetirizine and hydroxyzine are piperazine derivatives, on the structural basis of an ethylenediamine, but the cross-reactions between the 2 have rarely been reported. A 44-year-old man visited because of the generalized morbilliform eruptions with pruritus over his whole body, after intake of hydroxyzine (Ucerax) and azelastine (Azeptine), administered during a 2-day period for chronic urticaria. Previously, he had presented the same cutaneous reactions after oral administration of cetirizine (Lotec). Oral challenge tests performed with cetirizine and hydroxyzine led to the same cutaneous reactions. He was given the diagnosis of drug eruption from cetirizine and hydroxyzine, which suggests that there were cross-reactions among cetirizine, hydroxyzine, and ethylenediamine.     

Cutaneous drug eruption induced by antihistamines

Topical application of antihistamines commonly leads to sensitization for patients, but systemic administration of antihistamines rarely induces allergic hypersensitivity, which is mainly linked to phenothiazine‐derived and piperazine‐derived compounds. We report a 70‐year‐old woman whose medical history included lichen planus, and who was referred by the dermatology department of our hospital for suspected allergy to corticosteroids. The reason for referral was that on the fourth day of treatment with prednisone and hydroxyzine, the patient presented a bilateral highly pruritic palmar erythema that evolved to a generalized morbilliform rash with subsequent complete desquamation. At a later time, she took cetirizine for a cold, and developed palmar erythema and desquamation. Skin tests (prick and intradermal tests) were performed with steroids, and patch tests (read after 48 and 96 h) with corticosteroids and antihistamines. Controlled oral challenge tests were performed with prednisone and with an alternative antihistamine. Skin tests were negative for all corticosteroids. Patch tests were negative for all corticosteroids, but the antihistamine test was positive for hydroxyzine. Oral challenge with prednisone and dexchlorpheniramine was negative. The patient was diagnosed with cutaneous drug eruption from hydroxyzine and cetirizine. We consider it is important to assess every patient whose skin condition worsens after treatment with antihistamines, especially hydroxyzine, because it is known that antihistamines are often not recognised as the culprit in cases of cutaneous eruption.     

Effects of acrivastine, loratadine and cetirizine on histamine-induced wheal and flare responses

It is accepted that studies evaluating histamine-induced wheal and flare reactions in the skin represent a simple and reliable method for demonstrating pharmacodynamic activity and pharmacokinetics of the H1-receptor antagonists. In this study, the effects of single oral doses of acrivastine (8 mg), loratadine (10 mg) and cetirizine (10 mg) on the histamine-induced wheal and flare reactions were compared in 60 healthy volunteers. The wheal and flare responses were produced by prick test using 1% histamine solution. Measurements were performed before the ingestion of antihistamines (baseline values) and afterwards at 15, 30, 90, 240, 360 min and 24 h. The values obtained for each antihistamine were compared with each other and with baseline values. Cetirizine was found to be superior to acrivastine and loratadine for the suppression of wheal and flare responses at 240, 360 min and 24 h (P < 0.05) and acrivastine was superior to the other two antihistamines for the suppression of flare response at 30 min (P < 0.05). Our results indicate that a single dose of cetirizine provides a more effective and long acting suppression on wheal and flare reactions in urticaria when compared to acrivastine and loratadine.     

Use and safety of antihistamines in children

ABSTRACT: Although first-generation antihistamines remain popular for the treatment of seasonal allergic rhinitis, atopic dermatitis, and urticaria in children, second- and third-generation antihistamines hold clear advantages over the first-generation agents, especially for the pediatric patient. The less frequent dosing schedule of the second- and third-generation agents makes administration easier for the parent. With less sedation and lower risk of adverse effects, the safety profile of second- and third-generation agents appears superior to that of first-generation agents. After briefly discussing the use of first-generation antihistamines, the pharmacokinetics, safety, and use of the newer antihistamines loratadine, cetirizine, and fexofenadine in the pediatric patient are reviewed.     

Selected urticaria patients benefit from a referral to tertiary care centres – results of an expert survey

Background Urticaria is a frequent reason for consultations. Recently, it has been demonstrated that the management of chronic spontaneous urticaria (csU) in the practice setting does not fully comply with published guidelines. In addition, it was shown that one of four csU patients is referred to specialized centres. Objective To analyse the management of urticaria patients in tertiary referral centres. Methods During a standardized expert‐to‐expert interview, 41 specialists from German tertiary care centres were asked for different aspects of urticaria patient care with a special focus on csU. Results On average, the participating centres saw 25 csU patients per month. All ran programmes for the identification of underlying causes with an average success rate of 45 ± 3% which is considerably higher as has been found in the practice setting. In those patients where an identification succeeds, infections, drugs, intolerance and autoreactivity were reported to be causes in 41%, 20%, 17% and 16%. In their symptomatic treatment the majority of centres (71%) followed the guidelines by using regular dosed non‐sedating H₁‐antihistamines as first line and higher doses (61%) as second line option. In contrast to the practice setting, meaningful experience also existed for alternative therapies in antihistamine‐resistant patients, such as dapsone, cyclosporin and omalizumab. The expenditure of time, laboratory costs and frequency of follow‐up visits was reported to be above average in case of csU. Conclusion This study indicates that some urticaria patients, especially those with unknown causes or with an H₁‐antihistamine‐resistant disease, may benefit from a referral to tertiary care centres.     

In dermographic urticaria H2 receptor antagonists have a small but therapeutically irrelevant additional effect compared with H1 antagonists alone

Two studies of the additional effect of an H₂ receptor antagonist when given in combination with an H₁ antagonist were undertaken in dermographic urticaria. Using a randomized, double-blind, crossover design in 19 patients, a combination of cetirizine (10 mg at night) and ranitidine (150 mg twice daily) was compared with a combination of cetirizine (10 mg at night) and placebo. The addition of ranitidine did not produce any significant difference in linear analogue scores for weal, Itch or sleep disturbance. There was a significant depression of the frictional force/wealing response curve with an increase in wealing threshold (P<0.0001) following the addition of H₂ blockade. The wealing threshold was 54.7 ± 4.4 (mean ± SEM) g/mm² for the H₁ antagonist alone, and 73.2 ± 5.7 for the combination of H₁ and H₂ antagonists. In a second similar study involving nine different patients, comparing terfenadine (120 mg twice daily) with a combination of terfenadine and ranitidine (150 mg twice daily), the weal threshold was 59.8 ± 6.6 for the H₁ antagonist alone, and 73.0 ± 6.4 for the combination of H₁ and H₂ antagonists. Thus, in dermographic urticaria, adding an H₂ antagonist to treatment with a potent H₁ antagonist gives a small, significant reduction in wealing response, but no symptomatic benefit. We conclude that involvement of the H₂ receptor in this urticarial disease is minimal, and does not justify the use of H₂ receptor antagonists.     

Solar urticaria: a case with good therapeutic response to cimetidine

A 25-year-old woman developed urticarial lesions after visible light irradiation. Orally administered cimetidine significantly inhibited the induction of urticaria, but H1 antihistamines did not suppress the weal formation. Our case suggests that a trial with H2 antihistamine should be considered for the treatment of solar urticaria.     

Combined H1 and H2 antihistamine therapy in chronic urticaria

Chronic urticaria is a frustrating problem for the patient and the physician. The cause is usually undetermined, and the therapy is directed toward controlling symptoms. Recent evidence that human skin blood vessels possess H2 receptors, as well as the commonly recognized H1 receptors, suggests a possible reason for the frequent failure of H1 antihistamines in controlling this disorder. Eighteen patients with refractory chronic idiopathic urticaria participated in a double-blind, cross-over study to evaluate the efficacy of combined H1 (hydroxyzine hydrochloride) and H2 (cimetidine) antihistamines vs H1 antihistamines alone. This study indicates that combined H1 and H2 antihistamine therapy is statistically more effective than H1 antihistamines alone in controlling the symptoms of chronic urticaria.     

Bilastine: a new H1‐antihistamine with an optimal profile for updosing in urticaria

This review set out to examine published papers detailing the efficacy of bilastine in skin models and urticaria to assess whether it meets the optimal profile for updosing in urticaria, that is, strong clinical efficacy and freedom from unwanted side effects, particularly sedation. Bilastine is a highly effective H₁‐antihistamine even when used at the basic dose of 20 mg daily. Its facilitated uptake after oral dosage gives it a rapid onset and long duration of action. In both wheal and flare studies and in urticaria updosing fourfold showed increased effectiveness. With respect to somnolence, bilastine is a substrate for P‐glycoprotein, a membrane pump which prevents it crossing the blood–brain barrier. Consequently, bilastine is a practically ‘non‐sedating’ H₁‐antihistamine. In conclusion, the excellent profile of bilastine in both efficacy and safety make it the ideal H₁‐antihistamine for updosing the daily dose fourfold in difficult‐to‐treat urticaria as recommended by the EAACI/GA²LEN/EDF/WAO guideline for the management of urticaria.