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Combination therapy with H2 and H1 antihistamines in acute, non compromising allergic reactions

Three Part Question

In [an adult patient with allergic-type urticaria of less than 72 hours duration] does an [H2 antihistamine] improve [the subjective and objective resolution of the urticaria]?

Clinical Scenario

A gentleman attends the emergency department with a typically urticarial allergic reaction, which is not compromising either his airway, breathing, or circulation. You prescribe an H1 antihistamine and observe for resolution. At 2 hours he is no better. You wonder if you could have improved his chances of rapid relief with the use of an H2 antihistamine?

Search Strategy

Medline 1950 to November 2007 using the OVID interface.
{(Passive Cutaneous Anaphylaxis/ or exp Anaphylaxis/ or OR (anaphyla$.mp) OR (allerg$.mp) OR (exp Food Hypersensitivity/ or exp Drug Hypersensitivity/ or exp Hypersensitivity, Immediate/ or exp Hypersensitivity/ or acute allergic or exp Anaphylaxis/ or Urticaria/) OR (urtic$.mp.)} and {(histamine H2 or exp Histamine H2 Antagonists/) OR ( or exp Histamine H1 Antagonists/) OR ( or exp Nizatidine/) OR ( or exp Famotidine/) OR ( or exp Cimetidine/) OR ( or exp Ranitidine/)} Limit to human and English.

Search Outcome

The medline search brought up 629 citations. Anapahylaxis was used in the search strategy to ensure that no appropriate studies were missed. Only four were clinical studies relevant to the question.
Searching the Cochrane Library using the term "antihistamine" did not add to this.

Relevant Paper(s)

Author, date and country Patient group Study type (level of evidence) Outcomes Key results Study Weaknesses
Moscati RM and Moore GP,
93 ED patients with urticaria < 72 hours duration, randomised to receive either 50mg diphenhydramine (DPH) IM or 300mg cimetidine (CMT) IM. Exclusions: respiratory signs or symptoms, hypotension, pregnancy, allergy to study drugs, current use of steroids or antihistamines, history of chronic respiratory, cardiovascular, renal or hepatic disease.Prospective Double Blind RCTRelief of itch (scale 0 to 3)Scale fell by 1.174 CMT (P<.0001)and 1.489 DPH (P<.0001) (Difference NS)Small Numbers. Non-validated clinical measure. IM route no longer widely used. Overall score in favour of CMT likely due to less sedative effect rather than effect on rash.
Relief of wheal intensity (scale 0 to 3)Scale fell by 0.935 (P<.0001) CMT and 0.915 DPH (P<.0001) (Difference NS)
Relief of wheal extent (scale 1 to 3)Scale fell by 1.304 CMT and 1.426 DPH (Difference NS)
Sedation (scale 0 - 2)DPH 1.085 (P<.0001) vs. CMT 0.37 (P<.0006). DPH more sedating than CMT (P<.0001)
Overall improvement (pt asked if felt same, worse, or better)After 30 minutes CMT 87% vs. DPH 76% (NS). No patients felt worse.
Runge JW et al,
39 ED patients aged 18-50, with signs of allergic reaction (urticaria, pruritus etc…) <12 hours old, randomised to receive either cimetidine 300mg IV and placebo, or diphenhyramine 50mg IV and placebo, or cimetidine plus diphenhydramine. Patients rated their symptoms on a visual analog scale (VAS) before and 30 min after treatment.Double Blind Placebo controlled RCTRelief of urticaria33 patients with urticaria. Relief for 5/11 receiving DPH vs. 8/10 receiving CMT (NS); Relief for 5/11 receiving DPH vs 11/12 receiving DPH + CMT (P=0.027)Small Numbers Poor explanation of randomisation
Relief of pruritus35 patients with pruritus. Relief for 12/12 receiving DPH vs. 6/10 receiving CMT (P=0.029); Relief for 12/12 receiving DPH vs 12/13 receiving DPH + CMT (NS)
Lin RY et al,
100 ED patients aged >18, with signs of allergic reaction (urticaria, pruritus, acute angioedema, acute unexplained stridor) <12 hours old, randomised to receive either diphenhydramine 50mg and saline IV or diphenhydramine 50mg and ranitidine (RAT) 50mg IV. Effects rated by physician at 1 and 2 hours after injection.Double Blind Placebo controlled RCTAbsence of urticaria at 2h.53 patients with urticaria initially. Urticaria resolved in 91.7% RAT gp v 73.8% saline gp, P=0.02. MVM OR 4.7 (95% CI 1.2-22.2) in favour of RAT.Convenience sample, when study physician was available. Only 91 patients received the study medication. Non-validated clinical measure.
Absence of both angioedema and urticaria at 2h.72 patients with angioedema and urticaria initially. These symptoms resolved in 70.5.7% RAT gp v 46.5% saline gp, P=0.02. MVM OR 2.8 (95% CI 1.03-8.08) in favour of RAT.
Absence of angioedema irrespective of urticaria at 2h.Angioedema resolved in 77.1% in RAT gp v 67.4% saline gp, NS
Watson NT et al,
25 ED patients with urticaria <72 hours duration, randomised to either famotidine (FAM) 20mg IM or diphenhydramine 50mg IM. Patients rated their symptoms on a visual analog scale before and 30 min afte treatment. Exclusions: Allergies to famotidine or diphenhydramine, pregnant or lactating, bronchospasm or pharyngeal oedema, haemodynamically unstable, angioedema, unable to understand to complete the questionnaire or informed consent.Prospective Double Blind RCTIntensity of urticaria (100mm VAS by Dr)FAM improved 34mm, DPH 34mm (p<.0001 for each).Very small numbers Method of randomisation not clarified IM route no longer widely used
Sedation (100mm VAS)FAM no sedation (NS), DPH 20mm increase in sedation score (NS). Difference between drugs NS
% body surface affected by urticaria (rule of 9s by Dr)FAM improved by 20% (P<.01), DPH 8% (NS). Difference between drugs NS.
Relief of itch (100mm VAS)FAM improved 36mm, DPH 54 mm (<.0001 for each). Difference between drugs NS.


There is a theoretical rationale for the use of H2 antihistamines in allergic reactions. There are many studies of H2 antihistamines in histamine-induced wheal models of cutaneous allergy, and some of these suggest a benefit. Two studies have directly compared H1 against H2 (Moscati et al and Watson et al). Neither showed a benefit of H2 over H1 antihistamines. Two studies have compared H1 antihistamine against combined H1 and H2 antihistamines in the treatment of ongoing acute allergic reactions. Runge et al found no benefit. Only Lin et al have shown any benefit: relief of urticaria and improvement of angioedema . Although these studies were well conducted, larger scale trials would be desirable. H2 antihistamines are a widely used class of drug, with a proven safety record. As would be expected, none of these studies reported any serious adverse effects from their use. The use of H2 antihistamines in anaphylaxis or dermographism was not considered in this BET.

Clinical Bottom Line

There is no evidence to support the use of H2 antihistamines to speed the resolution of pruritus from non-compromising acute allergic reactions. There is some evidence to suggest that the combination of H1 and H2 antihistamines causes faster resolution of the rash and maybe angioedema.


  1. Moscati RM, Moore GP. Comparison of cimetidine and diphenhydramine in the treatment of acute urticaria. Ann Emerg Med 1990;19(1):12-5.
  2. Runge JW, Martinez JC, Caravati EM, et al. Histamine antagonists in the treatment of acute allergic reactions. Ann Emerg Med 1992;21(3):237-42.
  3. Lin RY, Curry A, Pesola GR, et al. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med 2000;36(5):462-68.
  4. Watson NT, Weiss EL, Harter PM. Famotidine in the treatment of acute urticaria. Clin Exp Dermatol 2000;25:186-9.