Morphine-induced skin wheals: A possible model for the study of histamine release

Abstract

We evaluated the ability of morphine to release histamine when injected intradermally in man. Mathematic analysis of the dose-response (wheal) relationship suggested that two different effects were involved. The effect of low doses of morphine (0.05 to 1 microgram) was clearly antagonized by naloxone (0.4 or 1.2 mg im 30 minutes before), whereas the effect of higher doses (5 to 50 micrograms) was not modified. The median effective doses of morphine (ED50) for the low dose range effect were 0.07 +/- 0.01 and 0.08 +/- 0.01 microgram before naloxone and 0.14 +/- 0.02 and 0.15 +/- 0.03 microgram after 0.4 and 1.2 mg doses, respectively. Astemizole (45 mg po 30 minutes before) and oxatomide (60 mg po 120 minutes before) produced similar inhibition of histamine-induced wheals, but there were clear differences in their effects on wheals elicited by morphine. Morphine ED50 values for the low dose range effect rose from 0.09 +/- 0.01 to 0.20 +/- 0.01 microgram after astemizole and from 0.08 +/- 0.01 to 0.46 +/- 0.04 microgram after oxatomide. Opiate receptors may be involved in some of the effects produced by morphine injection in the human skin, but morphine-induced wheals seem to offer a suitable model for the evaluation of agents capable of inhibiting histamine release in man.

Transcutaneous iontophoresis of methadone provokes local flushing and thermal hyperalgesia

“…However, flaring around the methadone site was minimal in the present study, and wheals did not form. The absence of wheals and flares after the methadone iontophoresis (present study) and intradermal injection of alfentanil [10], together with the persistence of these responses to morphine after naloxone administration [7,9,10], suggests that a nonopioid mechanism contributes to the formation of wheals and flares provoked by some m-receptor agonists. This mechanism might involve mast cell degranulation [7][8][9][10] or direct effects on the vascular endothelium [10].…”

“…Cutaneous flares and wheals develop after intradermal administration of m-receptor agonists such as morphine, meperidine and fentanyl [7,9,10]. We previously found that wheals developed routinely when morphine was administered by iontophoresis at half the present dose of methadone (de Silva-Rossdeutscher, unpublished doctoral dissertation, Murdoch University, 2000).…”

“…In human skin, signs of inflammation are particularly pronounced for the m-receptor agonist morphine, due to both opioid and non-opioid influences [7 -10]. For example, Levy et al [10] reported that intradermal injection of the opioid antagonist naloxone attenuated the cutaneous flare but not the wheal to morphine, whereas Saucedo and Erill [9] found that intradermal injection of naloxone inhibited wheal formation to low (0.05 to 1 mg) but not high doses of morphine. Similar findings have been reported for various other opioid drugs (e.g., fentanyl, meperidine and sufentanil) [7,10].…”

Pharmacologic advances in the systemic treatment of itch

“…Initial studies showed that intradermal injections of opioid agonists caused localized itching and histamine wheal‐and‐flare reactions (5). In addition, H1‐antihistamines were effective in relieving the local itch induced by dermal morphine injection (6). It appeared from these studies that histamine release was the cause of opioid‐induced pruritus.…”

No cutaneous histamine release with buprenorphine?

“…Histamine release by morphine is well documented (4,5,6,9). To our knowledge, buprenorphine, which resembles morphine structurally ( Fig.…”