Naloxone Antagonizes the Local Antihyperalgesic Effect of Fentanyl in Burnt Skin of Healthy Humans

Abstract

The aim of this study was to investigate local opioid effects in the inflamed skin of healthy human volunteers. To induce inflammation, the circular tip of a 10-mm diameter probe was heated to 48ºC and applied for 120 s to a site on each forearm of 24 healthy participants. Thirty minutes later, 0.2 mL normal saline was injected subcutaneously into one inflamed site, and the opioid antagonist naloxone hydrochloride (80 µg in 0.2 mL)was injected subcutaneously into the other inflamed site. Participants completed tests of pain sensitivity (heat pain thresholds, heat pain ratings and mechanical pain ratings) before and after the injections. Fentanyl citrate (10 µg in 0.2 mL) was then injected into the pre-treated sites, and pain sensitivity was measured again. The thermal injuries produced thermal and mechanical hyperalgesia which did not differ between the saline and naloxone sites. After the fentanyl injections, decreases in thermal and mechanical hyperalgesia were greater at the saline site than the naloxone site. These findings demonstrate that pre-treatment with naloxone blocks local opioid effects produced by the subcutaneous injection of a low dose of fentanyl in the inflamed skin of healthy humans.Thus, peripheral opioid receptors could be a therapeutic target for painful cutaneous disorders.Perspective: This article demonstrates that activation of opioid receptors in the skin inhibits sensitivity to painful mechanical and thermal stimuli. Thus, local application of low-dose opioid medications could relieve painful skin disorders.

A literature review on the pharmacological sensitivity of human evoked hyperalgesia pain models

“…Opioids [69,70,74,75], intracellular sodium channel blockers [76,77], NSAIDs [78][79][80][81][82], corticosteroids [83,84], the calcium channel α2-δ ligand gabapentin [85], the glutamate antagonist riluzole [86], the opioid receptor antagonist naloxone [87] and the purinergic P1 receptor activator adenosine [15] were inconsistent at attenuating heat, mechanical and unprovoked hyperalgesia.…”

Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review

“…Research has focused on various receptors, e.g., α 2 -receptors, 5-HT 1A -receptors, NMDA-receptors and TRPV1-receptors, but above all, major interest has been dedicated to the endogenous mu-opioid-receptor (MOR). Selective MOR-antagonists have been used in a large number of human experimental [ 1 – 63 ] and clinical studies [ 64 ]. Early animal data demonstrated that MOR-antagonists increase nociceptive responding across various stimulation paradigms and species [ 61 ].…”

Pharmacokinetics of intra-articular morphine in horses with lipopolysaccharide-induced synovitis

“…One review on IA morphine's analgesic effect concluded that a 'systemic effect cannot be completely excluded' (Gupta et al 2001). However, the analgesic effect of IA morphine has been compared to systemically administered morphine in clinical studies in humans (Stein et al 1991;Richardson et al 1997); several laboratory studies have compared IA opioids, systemically administered opioids and/or no treatment to various combinations of peripherally or centrally acting opioid antagonists (Parsons et al 1990;Perrot et al 2001;Robertson et al 2007;Inglis et al 2008) and the results of all these studies have led to the general conception that IA morphine exerts both analgesic and anti-inflammatory effects through peripherally situated opioid receptors. A pharmacokinetic study in horses determining the concentration of morphine and its major metabolites, both in synovia and serum could give significant support to the concept for morphine's peripheral action after IA administration.…”