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

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

Is the Experience of Thermal Pain Genetics Dependent?

It is suggested that genetic variations explain a significant portion of the variability in pain perception; therefore, increased understanding of pain-related genetic influences may identify new targets for therapies and treatments. The relative contribution of the different genes to the variance in clinical and experimental pain responses remains unknown. It is suggested that the genetic contributions to pain perception vary across pain modalities. For example, it has been suggested that more than 60% of the variance in cold pressor responses can be explained by genetic factors; in comparison, only 26% of the variance in heat pain responses is explained by these variations. Thus, the selection of pain model might markedly influence the magnitude of the association between the pain phenotype and genetic variability. Thermal pain sensation is complex with multiple molecular and cellular mechanisms operating alone and in combination within the peripheral and central nervous system. It is thus highly probable that the thermal pain experience is affected by genetic variants in one or more of the pathways involved in the thermal pain signaling. This review aims to present and discuss some of the genetic variations that have previously been associated with different experimental thermal pain models

Review Article Is the Experience of Thermal Pain Genetics Dependent?

Copyright © 2015 E. Horjales-Araujo and J. B. Dahl. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. It is suggested that genetic variations explain a significant portion of the variability in pain perception; therefore, increased understanding of pain-related genetic influences may identify new targets for therapies and treatments. The relative contribution of the different genes to the variance in clinical and experimental pain responses remains unknown. It is suggested that the genetic contributions to pain perception vary across painmodalities. For example, it has been suggested that more than 60 % of the variance in cold pressor responses can be explained by genetic factors; in comparison, only 26 % of the variance in heat pain responses is explained by these variations.Thus, the selection of painmodelmightmarkedly influence themagnitude of the association between the pain phenotype and genetic variability. Thermal pain sensation is complex with multiple molecular and cellular mechanisms operating alone and in combination within the peripheral and central nervous system. It is thus highly probable that the thermal pain experience is affected by genetic variants in one or more of the pathways involved in the thermal pain signaling. This review aims to present and discuss some of the genetic variations that have previously been associated with different experimental thermal pain models. 1

Effect of Gabapentin on morphine demand and pain after laparoscopic sterilization using Filshie clips. A double blind randomized clinical trial

Abstract Background A considerable number of patients require opioids during recovery after laparoscopic sterilization. This implies nausea, dizziness and sedation and increases the number of unplanned admissions. Gabapentin has shown excellent postoperative analgesic effect in a number of recent studies with few side effects. This study was designed to test whether gabapentin given preoperatively can reduce the number of patients needing morphine in the recovery period. Methods 80 females scheduled for laparoscopic sterilization using Filshie clips were randomized to two treatment groups (Gaba group and control group). All patients received lornoxicam 8 mg p.o. 30 min. before the procedure. Patients in the Gaba group received gabapentin 1200 mg p.o. and patients in the control group received placebo capsules prior to the procedure. All patients were anesthetized according to a protocol, using remifentanil and propofol. Postoperative analgesia was obtained with patient controlled infusion of morphine. Pain, nausea, dizziness and sedation were scored at 2 and 4 hours after end of anesthesia. The expenditure of morphine was the primary measure for the effect of analgesia and the number of patients demanding morphine was the primary endpoint. Results Three patients were excluded because of procedural errors and one because of conversion to open surgery. 38 patients completed the study in each group. 32 (84%) patients in the gabapentin group and 37 (97%) patients in the control group did require morphine in the recovery period. (p = 0,049). There was no significant difference between mean morphine consumption, pain scores and frequency of adverse effects (nausea, dizziness, sedation and vomiting) Conclusion The postoperative analgesic effect of gabapentin given preoperatively was confirmed in this study. For this procedure, with pain predominantly in the immediate recovery period, and of less intensity than after major surgical procedures, the effect demonstrated is much less pronounced than in similar studies of major surgery. General use of gabapentin as analgesic for laparoscopic sterilization is not supported by this study. Trial Registration Current Controlled Trials ISCRTN39209275</p

WDT, WDT and PPT.

<p>Mean value and standard deviation of WDT and HPT are shown in this table, as well as median values and 25–75% IQR of PPT. On Day 2 and 4, pin-prick assessments were performed before and after i.v. administration of naloxone or placebo, whereas HPT and WDT were only assessed after drug infusion. Naloxone administration was not associated with changes in WDT (<i>P = </i>0.39), HPT (<i>P = </i>0.21) and PPT (<i>P = </i>0.98). There were no significant differences in WDT and HPT, assessed in the BI-area, between Day 1 and 2 ([baseline <i>vs.</i> 73 hrs PB, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064608#pone-0064608-g002" target="_blank">Fig. 2</a>] <i>P = </i>0.10, <i>P = </i>0.27, respectively), and between Day 3 and 4 (<i>P = </i>0.13, <i>P = </i>0.12, respectively).</p><p>HPT = Heat pain thresholds, PPT = Pin-prick thresholds, WDT = Warmth detection thresholds.</p

Size of secondary hyperalgesia areas after naloxone or placebo administration.

<p>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 (<i>P = </i>0.25).</p

Cumulative VAS scores (0–100).

<p>VAS/minute and standard deviation reported by the volunteers during the burn injury (Day 1+3) and BTS (Day 1+2+3+4). No difference in cumulative VAS was observed between Day 1 and 3 during the burn injury (<i>P = </i>0.21) and during BTS (<i>P = </i>0.09). There was a significant difference between Day 1 and 2 (<i>P</i><0.01), and Day 3 and 4 in VAS ratings during BTS (P<0.05). BTS = Brief thermal stimulation.</p