H1‐antihistamines for chronic spontaneous urticaria
Chronic spontaneous urticaria (CSU) is characterised by the development of crops of red, itchy, raised weals or hives with no identifiable external cause.
To assess the effects of H1‐antihistamines for CSU.
We searched the following databases up to June 2014: Cochrane Skin Group Specialised Register, CENTRAL (2014, Issue 5), MEDLINE (from 1946), EMBASE (from 1974) and PsycINFO (from 1806). We searched five trials registers and checked articles for references to relevant randomised controlled trials.
We included randomised controlled trials of H1‐antihistamines for CSU. Interventions included single therapy or a combination of H1‐antihistamines compared with no treatment (placebo) or another active pharmacological compound at any dose.
Data collection and analysis
We used standard methodological procedures as expected by The Cochrane Collaboration.
Our primary outcome measures were proportion of participants with complete suppression of urticaria: 'good or excellent' response, 50% or greater improvement in quality of life measures, and adverse events. We present risk ratios (RR) with 95% confidence intervals (CIs).
We identified 73 studies (9759 participants); 34 studies provided data for 23 comparisons. The duration of the intervention was up to two weeks (short‐term) or longer than two weeks and up to three months (intermediate‐term).
Cetirizine 10 mg once daily in the short term and in the intermediate term led to complete suppression of urticaria by more participants than was seen with placebo (RR 2.72, 95% CI 1.51 to 4.91). For this same outcome, comparison of desloratadine versus placebo in the intermediate term (5 mg) (RR 37.00, 95% CI 2.31 to 593.70) and in the short term (20 mg) (RR 15.97, 95% CI 1.04 to 245.04) favoured desloratadine, but no differences were seen between 5 mg and 10 mg for short‐term treatment.
Levocetirizine 20 mg per day (short‐term) was more effective for complete suppression of urticaria compared with placebo (RR 20.87, 95% CI 1.37 to 317.60), and at 5 mg was effective in the intermediate term (RR 52.88, 95% CI 3.31 to 843.81) but not in the short term, nor was 10 mg effective in the short term.
Rupatadine at 10 mg and 20 mg in the intermediate term achieved a 'good or excellent response' compared with placebo (RR 1.35, 95% CI 1.03 to 1.77).
Loratadine (10 mg) versus placebo (RR 1.86, 95% CI 0.91 to 3.79) and loratadine (10 mg) versus cetirizine (10 mg) (RR 1.05, 95% CI 0.76 to 1.43) over short‐term and intermediate‐term treatment showed no significant difference for 'good or excellent response' or for complete suppression of urticaria, respectively.
Loratadine (10 mg) versus desloratadine (5 mg) (intermediate‐term) showed no statistically significant difference for complete suppression of urticaria (RR 0.91, 95% CI 0.78 to 1.06) or for 'good or excellent response' (RR 1.04, 95% CI 0.64 to 1.71). For loratadine (10 mg) versus mizolastine (10 mg) (intermediate‐term), no statistically significant difference was seen for complete suppression of urticaria (RR 0.86, 95% CI 0.64 to 1.16) or for 'good or excellent response' (RR 0.88, 95% CI 0.55 to 1.42).
Loratadine (10 mg) versus emedastine (2 mg) (intermediate‐term) showed no statistically significant difference for complete suppression (RR 1.04, 95% CI 0.78 to 1.39) or for 'good or excellent response' (RR 1.09, 95% CI 0.96 to 1.24); the quality of the evidence was moderate for this comparison.
No difference in short‐term treatment was noted between loratadine (10 mg) and hydroxyzine (25 mg) in terms of complete suppression (RR 1.00, 95% CI 0.32 to 3.10).
When desloratadine (5 to 20 mg) was compared with levocetirizine (5 to 20 mg), levocetirizine appeared to be the more effective (P value < 0.02).
In a comparison of fexofenadine versus cetirizine, more participants in the cetirizine group showed complete suppression of urticaria (P value < 0.001).
Adverse events leading to withdrawals were not significantly different in the following comparisons: cetirizine versus placebo at 10 mg and 20 mg (RR 3.00, 95% CI 0.68 to 13.22); desloratadine 5 mg versus placebo (RR 1.46, 95% CI 0.42 to 5.10); loratadine 10 mg versus mizolastine 10 mg (RR 0.38, 95% CI 0.04 to 3.60); loratadine 10 mg versus emedastine 2 mg (RR 1.09, 95% CI 0.07 to 17.14); cetirizine 10 mg versus hydroxyzine 25 mg (RR 0.78, 95% CI 0.25 to 2.45); and hydroxyzine 25 mg versus placebo (RR 3.64, 95% CI 0.77 to 17.23), all intermediate term.
No difference was seen between loratadine 10 mg versus mizolastine 10 mg in the proportion of participants with at least 50% improvement in quality of life (RR 3.21, 95% CI 0.32 to 32.33).
Although the results of our review indicate that at standard doses of treatment, several antihistamines are effective when compared with placebo, all results were gathered from a few studies or, in some cases, from single‐study estimates. The quality of the evidence was affected by the small number of studies in each comparison and the small sample size for many of the outcomes, prompting us to downgrade the quality of evidence for imprecision (unless stated for each comparison, the quality of the evidence was low).
No single H1‐antihistamine stands out as most effective. Cetirizine at 10 mg once daily in the short term and in the intermediate term was found to be effective in completely suppressing urticaria. Evidence is limited for desloratadine given at 5 mg once daily in the intermediate term and at 20 mg in the short term. Levocetirizine at 5 mg in the intermediate but not short term was effective for complete suppression. Levocetirizine 20 mg was effective in the short term, but 10 mg was not. No difference in rates of withdrawal due to adverse events was noted between active and placebo groups. Evidence for improvement in quality of life was insufficient.
Maulina Sharma, Cathy Bennett, Stuart N Cohen, Ben Carter
Plain language summary
H1‐antihistamines for chronic spontaneous urticaria
Chronic spontaneous urticaria (CSU) is a condition characterised by a rash of red itchy raised weals or hives, which appear for no identifiable reason. Other names include chronic idiopathic or chronic ordinary urticaria. 'Spontaneous' differentiates this type of urticaria from 'inducible' or 'physical' urticaria, for which there are specific triggers such as cold or pressure. 'Chronic' indicates that the condition has continued for at least six weeks. Hives may be intensely itchy, and the appearance may be unsightly and distressing to sufferers. In some cases, hives can be accompanied by deeper swelling, known as angio‐oedema, which is most common around the eyes and mouth.
Antihistamine drugs, specifically H1 antihistamines, are the mainstay of treatment for urticaria, although they control the condition rather than cure it. Many antihistamines are available to buy without a prescription, including brand names such as Clarityn, Piriton, Zirtek, Benadryl and Phenergan (brand names may differ by country).
Which H1‐antihistamines are effective and safe for CSU?
We included 73 randomised controlled trials, with 9759 participants of all ages and looked for complete suppression of urticaria. The duration of the intervention was up to two weeks (short‐term) or longer than two weeks and up to three months (intermediate‐term).
We investigated clinical trials in which one therapy was compared against another or against placebo (direct comparisons). We found that for general use, 10 mg once daily of cetirizine for short‐term and intermediate‐term duration was effective in completely suppressing urticaria, although not in all individuals. Some benefit may be associated with use of desloratadine at 5 mg for at least an intermediate term and at 20 mg in the short term. Levocetirizine at 5 mg was effective for complete suppression in the intermediate term but not in the short term. A higher dose of 20 mg was effective in the short term, but 10 mg was not.
Adverse events, such as headache or dry mouth, are tolerable with most antihistamines. Evidence is less clear for improvement in quality of life (e.g. reduction in sleep disturbance from itching, less distress from the appearance of hives) as many studies did not address this.
We cannot say whether one antihistamine works better than all the rest, as we did not have head‐to‐head evidence for every possible treatment comparison.
Quality of the evidence
The overall quality of the evidence found for most outcomes was low. Further well‐designed and carefully reported comparative studies are required, if we are to find out how well these medicines work, and if any adverse effects are reported, especially over periods of up to several months.
Maulina Sharma, Cathy Bennett, Stuart N Cohen, Ben Carter
Implications for practice
This review has found limited quality evidence to establish the efficacy of H1‐antihistamines compared with placebo in the treatment of CSU. Several antihistamines were found to be superior to placebo at standard (licensed) doses of treatment. Although the quality of evidence for adverse events was low, the direction of effects in most of the analyses suggest that users generally found these medicines tolerable.
Symptomatic relief has been demonstrated to a variable extent with different antihistamines. However, only few studies have assessed their effects on quality of life in urticaria.
On the basis of our data collection and analysis, it is evident that a clear message does not emerge regarding whether one antihistamine is better than another. Given the quality of trials and of their reporting, as well as the wide variation in comparisons and few opportunities to combine results in meta‐analyses, we must be guarded in putting forward specific treatment algorithms.
For general use, cetirizine at 10 mg once daily for short‐ and intermediate‐term duration was found to be effective in completely suppressing urticaria. However, three of the four trials that compared this treatment against placebo did have factors that we rated as suggesting high risk of bias. The two trials of loratadine 10 mg once daily versus placebo failed to demonstrate efficacy and were also at some risk of bias. Only two trials compared these two drugs: They failed to show a difference in efficacy, although they were not designed to demonstrate equivalence. Cetirizine and loratadine offer the advantages of being cheap and widely available. It would be reasonable to regard cetirizine as a first‐line option.
Some benefit (for complete suppression of urticaria) may be derived from using desloratadine at 5 mg once daily for at least an intermediate term of intervention and 20 mg desloratadine in the short term. Once again, risks of bias in trials of this drug were significant.
Levocetirizine at 5 mg once daily in the intermediate term appears to be effective in achieving complete suppression of CSU. This is based on the results of only three trials. We rated two of these as carrying an unclear risk of bias in every domain, although the third, whilst small, was relatively well conducted and reported. Evidence of benefit from increasing the dose to a ceiling of 20 mg per day is limited. It is common practice to use higher than licensed doses of various H1‐antihistamines, at least in Europe, where the guidelines recommend this (Zuberbier 2012). We included very few RCTs that assessed the effects of this and found insufficient evidence to support the practice, especially over longer durations. For clarity, the maximum licensed dose for both cetirizine and loratadine is 10 mg once daily, and for both levocetirizine and desloratadine, 5 mg once daily.
Although we included trials on various other drugs, their data are too sparse to allow firm conclusions about their relative efficacy. Furthermore, very few trials assessed combinations of antihistamines at conventional or higher doses; although such prescribing does occur in clinical practice, we have no basis on which to make recommendations.
Implications for research
We found little research on the use of higher doses of H1‐antihistamines, and no included studies continued over longer durations. Very few assessed whether responses were sustained after the intervention was stopped; future work should address these gaps.
Study investigators should provide information about the duration of urticaria for each participant before entry into a trial, as it is conceivable that urticaria that has persisted for many years may be more refractory to treatment than urticaria of only six weeks' duration.
We would welcome trials with two (or more) active treatment arms rather than a placebo that performed comparisons of different doses over longer periods. Although trials including a placebo yield useful data, particularly for new compounds, participants receiving placebo may find little benefit from taking part and seem to be more likely to withdraw or to fail to comply with the medication schedule. This can lead to very high levels of dropout and resulting difficulties in interpretation of study results. Trials should preferably be conducted independently of involvement of pharmaceutical companies.
Many dermatologists recommend higher, unlicensed doses of H1‐antihistamines in difficult cases of urticaria. Future studies should address whether this is justified in terms of effectiveness and safety.
In this review, primary outcome scores were variable for several of the trials, making it difficult for review authors to draw direct comparisons. This would be enabled by the use of a standardised outcome score such as the Urticaria Activity Score. This instrument is recommended in the European guidelines (Zuberbier 2012) and comprises the sum of 4‐point scales (0‐3) for number of weals and pruritus over a 24‐hour period. In several studies, outcome measures were not clearly defined, and for some measures, it was not clear how improvements in composite scores really correlated with symptomatic relief. For example, level of pruritus is likely to be of far greater importance to an individual with urticaria than the size of the largest weal.
In terms of reporting of results, we find that it is more meaningful to the clinician and to the participant if outcomes can be related to numbers of individuals who achieve a particular response. For example, five out of 10 of those with CSU will attain complete symptom relief, and a further three will experience greater than 50% improvement, rather than a particular drug will, on average, lead to a 3‐point reduction in total symptoms score. The latter approach is often accompanied by a P value < 0.05, but clinical significance and the spread of responses may be less clear: Was there some improvement for all participants, or were complete responses noted for a few and no response for others? We favour clear outcomes such as number of participants achieving complete suppression of urticaria, or 75% reduction in itch severity (which could be equated with a good response).
Wider use of standardised and validated quality of life (QoL) scores for trial participants diagnosed with this often disabling condition would provide measurable data to aid treatment decisions. For example, QoL scores would help investigators to monitor change in dosage or drug, or cessation of therapy.
Virtually no long‐term studies have looked at treatment and outcomes over much longer periods of time. Longer‐term studies should be designed, so that the extent of relief from symptoms from participants' perspective (symptoms, quality of life) and safety and efficacy should be included in the design of such studies. We do recognise that long‐term studies may be difficult to perform for reasons including expense and attrition, with fewer participants remaining in the study over long periods of time.