Wheal and flare responses to opioids in humans

Certain opioids release histamine from cutaneous mast cells to produce local wheal and flare responses and adverse hemodynamic effects. In vivo responses to opioids suggest that cutaneous responses result from the interaction of opioids with opioid receptors on human mast cells. There are no data evaluating or comparing the opioids currently used in anesthesia. Volunteers were injected intradermally with different opioids as well as with naloxone and antihistamines to evaluate their effects on cutaneous mast cell reactivity and cutaneous vascular responses. Fentanyl and morphine produced concentration-dependent wheal and flare responses in the range of 5 x 10^-6 M to 1.5 x 10^-3 M. Volunteers were then tested intradermally with different opioids and histamine at a 5 x 10^-4 M concentration to determine their relative cutaneous effects. Morphine, meperidine, fentanyl, and sufentanil produced both wheal and flare responses that were significantly greater than those due to saline (P < 0.05). Naloxone, alfentanil, and nalbuphine did not produce significant wheal or flare responses. Butorphenol was followed by a significant wheal but no flare. Naloxone attenuated cutaneous wheal and flare responses to fentanyl and the flare response to morphine. Intradermal antihistamines (diphenhydramine and cimetidine) produced significant wheal and flare responses. Electron micrographs of biopsies from fentanyl-induced wheals demonstrated normal mast cell architecture with no evidence of mast cell degranulation. Opioid effects on wheal and flare responses and mast cell degranulation appear independent of opioid analgesic potency. Opioids produce cutaneous vascular responses dependent on both histamine release from mast cells and direct effects on the vasculature. Wheal and flare responses of opioids appear to represent an indicator of systemic histamine release only if they are of the same magnitude as that produced by an equimolar intradermal histamine injection.