The most common hypothesis for skin itch and also for the itch in the healed wound is the stimulation of skin sensory nerve fibers by HISTAMINE. The data is circumstantial but quite convincing. First of all, histamine is produced in the skin and especially in the burn wound by the increased number of mast cells present. Secondly, histamine applied in low concentrations to the epidermal-dermal junction causes intense itching. Third, histamine causes itch by binding to the H₁ receptor, found in large concentration in skin.^11-15

The healed partial thickness burn wound or donor site appears to be the most prone to itch due to some injury induced alteration in the superficial nerve fibers making them more sensitive to histamine and secondly, the presence of increased number of histamine factories, namely the mast cells. Depletion of mast cells, by experimental approaches, eliminates the itch.

A number of other agents, known to induce itch, appear to acts indirectly through stimulation of histamine release or potentiation of the itching effect of histamines.

• Antihistamine Resistance from Excess Histamine

Antihistamine resistance, a likely reason for only partial relief of itch seen with use of oral antihistamines can be produced by stimulation of excess histamine release. The locally available histamine competes with available antihistamine for H1 receptors and overwhelms the antihistamine. The use of more potent antihistamines would reverse the odds and be able to block the binding of histamine to the H1 receptor. Doxepin is one such antihistamine, 800 times more potent than diphenhydramine.15-21

• Antihistamine Resistance and Nerve Action

As described, there remains some controversy as to whether there are actual itch nerve fibers or whether nerve fibers, which cause itch, are the superficial skin C fibers, which also carry the pain response. Itch fibers have been identified by some investigators just beneath the surface of a healed wound.

There are several mechanisms by which these nerves could be resistant to oral antihistamines. These include:

• Close physical proximity of mast cells with nerve fibers
• Lack of access of histamine to be metabolized
• Production of histamine by nerve themselves

A topically applied agent with potent antihistamine properties would be more effective, to override these mechanisms, as the proximity of the topical antihistamine to the nerves would be far superior than the antihistamines which require blood flow for delivery. In addition, the concentration of a topical antihistamine would be far greater than that provided systemically.