This review raises the issue of better consumer protection by recommending that older first-generation H(1)-antihistamines should no longer be available over-the-counter as prescription- free drugs for self-medication of allergic and other diseases now that newer second- generation nonsedating H(1)-antihistamines with superior risk/benefit ratios are widely available at competitive prices.

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Summary Background The mediator mechanisms of the cutaneous wheal and flare response, which underlies allergic skin and urticarial conditions, are controversial. The wheal results primarily from a direct effect of histamine on the local vascular bed, but to what extent does histamine diffuse within the wheal? The flare is neurogenic in origin, being disseminated within the dermis by axon reflexes, but do the neuropeptides released from the nerve endings cause the vasodilatation directly or do they induce the further release of histamine which then transduces the fiare? Objective We have addressed these questions by inserting 216 μm diameter microdialysis fibres into the dermis within the different areas of the wheal and flare to monitor changes in histamine levels provoked by intradermal injections of histamine, allergen, codeine and substance P. Twenty‐one subjects participated in the investigations. Results The histamine concentration in unprovoked skin was 10.5 ± 0.6 nM. As the dialysis efficacy was 50%, this equates to tissue concentrations of 20 nM. All provicants released large amounts of histamine at the injection site, maximum histamine levels being 337–1293 nM. Diffusion of histamine within the wheai was poor, levels at 2.3 mm and 3.7 mm from the site of injection being 4–22% and 0.2–3.7% respectively of those 1 mm from the injection site. No increased histamine levels were detected in the flare with any provicant. Atraumatic delivery to the skin of histamine in infusion concentrations of 30–10000 nM caused concentration‐related effects, at least 100 nM being necessary to induce a significant increase in skin blood flow, a threshold of 300–1000 being required to stimulate a visible flare and a measurable erythema, and 3000–10000 nM being the minimum for induction of a wheal. Thus the skin blood vessels and nerves are responsive to histamine, but at relatively high concentrations Conclusions These data support the theory that the flare reaction to local histamine injection or release is a neurogenic reflex not involving histamine release at its effector end.