Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury? A placebo-controlled, double-blind, randomized, cross-over study

Abstract

Introduction: Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of μ-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury.

Methods: Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47°C, 7 minutes, thermode area 12.5 cm(2)) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45°C, 3 minutes, area 12.5 cm(2)), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds.

Results: Secondary hyperalgesia areas were demonstrable in all volunteers 1-3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73-86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects.

Conclusion: Naloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization.

Conflict of interest statement

Competing Interests: Bradley K. Taylor is a PLOS ONE Editorial Board member. This does not alter his adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Study algorithm.

The study was performed on 5 separate days. Day 0 corresponded to the screening day; Day 1 and Day 3 were the burn injury days separated by 72 hrs from the drug administration days, Day 2 and Day 4.

Figure 2. Detailed timetable algorithm of the study.

(Study Days 1 and 2, and, Study Days 3 and 4 are identical). BL = baseline (warmth detection thresholds, heat pain thresholds, pinprick pain thresholds, secondary hyperalgesia areas in brief thermal stimulation and burn injury sites), Nx-INF = Naloxone target-controlled infusion (see text for detailed explanation). 1/2/3 PB = postburn assessments 1, 2 and 3 hrs after the burn injury (secondary hyperalgesia areas on brief thermal stimulation and burn injury sites), 72 PB = postburn assessments 72 hrs after the burn injury (pinprick pain thresholds, secondary hyperalgesia areas on brief thermal stimulation and burn injury sites), 73 PB = postburn assessments 73 hrs after the burn injury (warmth detection thresholds, heat pain thresholds, pinprick pain thresholds, secondary hyperalgesia areas on brief thermal stimulation and burn injury sites).

Figure 3. Size of secondary hyperalgesia areas after naloxone or placebo administration.

Individual secondary hyperalgesia areas (▵-values = post-infusion area – pre-infusion area) at burn injury site in cm2 after administration of naloxone and placebo, 72 hrs post-burn. The median (25–75% interquartile range) change in secondary hyperalgesia areas after naloxone administration was 1.87 cm2 (0.74–7.00) and after placebo administration 3.10 cm2 (1.48–11.42). Magnitude of secondary hyperalgesia areas was not associated with naloxone-treated compared to placebo-treated subjects (P = 0.25).