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      Does Naloxone Reinstate Secondary Hyperalgesia in Humans after Resolution of a Burn Injury? A Placebo-Controlled, Double-Blind, Randomized, Cross-Over Study

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          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.


          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.


          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.


          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.

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          Most cited references 54

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          Staircase bioassay: the up-and-down method.

           Marcus Dixon (1990)
          Experiments are conducted to estimate the threshold for an all-or-none response. Threshold is defined to be a point above which 50% of the subjects will respond and below which 50% of the subjects will not respond. Examples are death, death in a fixed time period, shock, fibrillation, emesis. Staircase designs, in particular up-and-down trials, produce median (ED50) estimates of given standard error with as few as one-fifth the number of subjects as the traditional designs with preset numbers of tests at each of several levels of stimulus. We discuss these estimates and their efficiency as well as procedures to estimate standard deviation and its use in designing up-and-down trails. The advantages in using several short series in factorial experiments are presented. Suggestions are given for minimizing the complications of sequential designs. Case studies indicate the efficiency of the design for various applications.
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            Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans.

            1. Capsaicin, the algesic substance in chilli peppers, was injected intradermally in healthy human subjects. A dose of 100 micrograms given in a volume of 10 microliters caused intense pain lasting for a few minutes after injection and resulted in a narrow area of hyperalgesia to heat and a wide surrounding area of hyperalgesia to mechanical stimuli (stroking) lasting for 1-2 h. 2. Nerve compression experiments with selective block of impulse conduction in myelinated (A) but not in unmyelinated (C) fibres indicated that afferent signals in C fibres contributed to pain from capsaicin injection and to heat hyperalgesia, whereas conduction in afferent A fibres was necessary for the perception of mechanical hyperalgesia. 3. Electrical intraneural microstimulation normally eliciting non-painful tactile sensations was accompanied by pain when the sensation was projected to skin areas within the region of mechanical hyperalgesia induced by capsaicin injection. 4. The threshold for pain evoked by intraneural microstimulation was reversibly lowered and pain from suprathreshold stimulation was exaggerated during the period of mechanical hyperalgesia, regardless of lidocaine anaesthesia of the cutaneous innervation territory of the stimulated fibres. 5. The results indicate that hyperalgesia to stroking on a skin area surrounding a painful intradermal injection of capsaicin is due to reversible changes in the central processing of mechanoreceptive input from myelinated fibres which normally evoke non-painful tactile sensations.
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              Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients.

              We have previously shown that fibromyalgia (FMS) patients have enhanced temporal summation (windup) and prolonged decay of heat-induced second pain in comparison to control subjects, consistent with central sensitization. It has been hypothesized that sensory abnormalities of FMS patients are related to deficient pain modulatory mechanisms. Therefore, we conducted several analyses to further characterize enhanced windup in FMS patients and to determine whether it can be centrally modulated by placebo, naloxone, or fentanyl. Pre-drug baseline ratings of FMS and normal control (NC) groups were compared with determine whether FMS had higher pain sensitivity in response to several types of thermal tests used to predominantly activate A-delta heat, C heat, or cold nociceptors. Our results confirmed and extended our earlier study in showing that FMS patients had larger magnitudes of heat tap as well as cold tap-induced windup when compared with age- and sex-matched NC subjects. The groups differed less in their ratings of sensory tests that rely predominantly on A-delta-nociceptive afferent input. Heat and cold-induced windup were attenuated by saline placebo injections and by fentanyl (0.75 and 1.5 microg/kg). However, naloxone injection had the same magnitudes of effect on first or second pain as that produced by placebo injection. Hypoalgesic effects of saline placebo and fentanyl on windup were at least as large in FMS as compared to NC subjects and therefore do not support the hypothesis that pain modulatory mechanisms are deficient in FMS. To the extent that temporal summation of second pain (windup) contributes to processes underlying hyperalgesia and persistent pain states, these results indirectly suggest that these processes can be centrally modulated in FMS patients by endogenous and exogenous analgesic manipulations. Copyright 2002 International Association for the Study of Pain

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                31 May 2013
                : 8
                : 5
                [1 ]Multidisciplinary Pain Center, Neuroscience Center, Rigshospitalet, Copenhagen University Hospitals, Copenhagen, Denmark
                [2 ]Department of Anaesthesia, Centre of Head and Orthopaedics, Copenhagen University Hospitals, Rigshospitalet, Copenhagen, Denmark
                [3 ]California Pacific Medical Center Research Institute, San Francisco, California, United States of America
                [4 ]Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky, United States of America
                University of Arizona, United States of America
                Author notes

                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.

                Conceived and designed the experiments: MPP MUW JBD MCR BKT. Performed the experiments: MPP TKR. Analyzed the data: MPP MUW JBD. Contributed reagents/materials/analysis tools: JBD MUW. Wrote the paper: MPP MUW JBD. Reviewed the manuscript: BKT MCR TKR.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 9
                The authors have no support or funding to report.
                Research Article
                Cognitive Neuroscience
                Pain Management
                Diagnostic Medicine
                Clinical Neurophysiology
                Drugs and Devices
                Pain Management
                Non-Clinical Medicine
                Academic Medicine



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