Portal de Periódicos da CAPES

Effect of intravenous magnesium on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers

2001; Elsevier BV; Volume: 86; Issue: 6 Linguagem: Inglês

10.1093/bja/86.6.871

1471-6771

Søren Mikkelsen, Jesper Dirks, Pia Keinicke Fabricius, Karin L. Petersen, Michael C. Rowbotham, Jørgen B. Dahl,

Plant-based Medicinal Research

We investigated the effects of i.v. magnesium on secondary hyperalgesia following heat/capsaicin stimulation in human volunteers. Twenty-five volunteers were included in this double blind, randomized, crossover study. Sensitization was induced in the volunteers, who were then subjected to either i.v. saline or magnesium sulphate. No analgesic or antihyperalgesic effect could be demonstrated in sensitized skin during infusion of magnesium. In contrast, painfulness of thermal stimulation was increased in normal skin. These results suggest that i.v. magnesium has no important analgesic effects in clinically relevant doses. We investigated the effects of i.v. magnesium on secondary hyperalgesia following heat/capsaicin stimulation in human volunteers. Twenty-five volunteers were included in this double blind, randomized, crossover study. Sensitization was induced in the volunteers, who were then subjected to either i.v. saline or magnesium sulphate. No analgesic or antihyperalgesic effect could be demonstrated in sensitized skin during infusion of magnesium. In contrast, painfulness of thermal stimulation was increased in normal skin. These results suggest that i.v. magnesium has no important analgesic effects in clinically relevant doses. The N-methyl-d-aspartate (NMDA) receptor complex plays a significant role in a central sensitization, and has been implicated in mechanisms underlying both acute and chronic pain states.1Doubell TP Mannion RJ Woolf CJ The dorsal horn: state-dependent sensory processing, plasticity and the generation of pain.in: Wall PD Melzack R Textbook of Pain. 4th Edn. Churchill Livingstone, Edinburgh1999: 165-183Google Scholar 2Woolf CJ Somatic pain – pathogenesis and prevention.Br J Anaesth. 1995; 75: 169-176Abstract Full Text PDF PubMed Scopus (103) Google Scholar NMDA receptor antagonists reduce central sensitization.3Dickenson AH Spinal cord pharmacology of pain.Br J Anaesth. 1995; 75: 193-200Abstract Full Text PDF PubMed Scopus (279) Google Scholar The NMDA receptor complex contains a magnesium ion block at resting membrane potential that prevents inward current flux of sodium and calcium ions.1Doubell TP Mannion RJ Woolf CJ The dorsal horn: state-dependent sensory processing, plasticity and the generation of pain.in: Wall PD Melzack R Textbook of Pain. 4th Edn. Churchill Livingstone, Edinburgh1999: 165-183Google Scholar The magnesium block is removed as part of the molecular sensitization process. We hypothesized that magnesium could re-establish channel block following activation and, thus, potentially reduce sensitization. Reversible cutaneous sensitization can be induced with an intense noxious stimulation (thermal and/or chemical) creating a zone of primary hyperalgesia within the stimulated region. In the area surrounding the zone of primary hyperalgesia, there is a zone of secondary hyperalgesia.4Mikkelsen S Ilkjær S Brennum J Borgbjerg FM Dahl JB The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans.Anesthesiology. 1999; 90: 1539-1545Crossref PubMed Scopus (60) Google Scholar In this study, cutaneous sensitization was induced with a heat/capsaicin sensitization model, which combines thermal and chemical methods of nociceptor stimulation to produce stable and long-lasting hyperalgesia. Suppression of secondary hyperalgesia with opioid has been reliably demonstrated without skin injury using this model.5Petersen KL Jones B Segredo V Gaspar J Dahl JB Rowbotham MC The effect of remifentanil on pain and secondary hyperalgesia associated with the heat/capsaicin model in healthy volunteers.Anesthesiology. 2001; 94: 15-20Crossref PubMed Scopus (117) Google Scholar The aim of the study was to investigate the effects of i.v. magnesium on secondary hyperalgesia following heat/capsaicin sensitization, thermal thresholds and acute noxious thermal pain in healthy volunteers. This two-session, crossover, double blind, randomized, placebo controlled study was conducted in accordance with the Helsinki Declaration and approved by the local Ethics Committee and the Danish National Board of Health. After providing informed written consent, 25 healthy male volunteers, aged 21–42 (mean 26) yr were included in the study. All subjects were familiarized with the experimental protocol on a separate screening day. Heat/capsaicin sensitization was produced by heating the skin at the stimulation site to 45°C for 5 min. Immediately thereafter, the skin was covered with capsaicin cream (0.075% capsaicin, 7 g; Clay-Park Labs Inc, NY, USA) for 30 min. The sensitization was re-kindled twice throughout the infusion session with the thermode at 40°C for 5 min. The areas of secondary hyperalgesia were measured by stimulating with a von Frey hair (21.5 g) and a foam brush along four linear paths arranged radially around the stimulation site. Stimulation was initiated outside the hyperalgesic area and continued towards the stimulation site until the subjects reported a definite change in perception. Area calculations were made using vector algorithm. Areas of secondary hyperalgesia were measured immediately after the initial sensitization, before drug infusion (baseline), and immediately after each re-kindling. All thermal stimulations were performed using the Thermotest (Somedic A/B Sweden). The 25×50 mm thermode is a Peltier device that warms the skin surface at a linear rate (1.0°C s–1) from a probe temperature of 32°C to a safety cut-off of 52°C. The heat pain detection thresholds (HPDT) were determined in the stimulation site and in normal skin before the induction of the heat/capsaicin sensitization (baseline), and after each re-kindling. The thermode was applied with a standardized pressure. By activating a button, the subjects indicated when the temperature of the thermode was first perceived as painful. Another stimulation site was marked in normal skin on the non-dominant upper arm and in this site, subjects rated the pain associated with a 1 min long 45°C heat stimulation (long thermal stimulation, or LTS). Pain during LTS was determined before the induction of the heat/capsaicin sensitization (baseline), and after each re-kindling. On the two infusion days, the subjects received either i.v. infusion of saline placebo or magnesium sulphate (bolus 0.2 mmol kg–1 over a period of 15 min, followed by 0.2 mmol kg–1 h–1) for a total of 90 min. The study drugs were prepared according to a computer generated randomization list by an investigator who took no further part in the study. The subjects rated side-effects immediately after bolus infusion, and every 25 min on a scale from 0–3 (0=none, 1=slight, 2=moderate, 3=severe). The procedures were performed according to the following schedule. –10 min: Heat pain detection threshold (HPDT), normal skin (baseline); pain rating (VAS) during LTS (baseline). 0 min: Induction of hyperalgesia: heat stimulation followed by capsaicin cream. 40 min: Area of secondary hyperalgesia for von Frey hair and brush stimulation (baseline). 45 min: Magnesium or placebo. 75–80 min: Re-kindling. 80 min: Area of secondary hyperalgesia for von Frey hair and brush stimulation; HPDT, sensitized and normal skin; VAS during LTS. 115–120 min: Re-kindling. 120 min: Area of secondary hyperalgesia for von Frey hair and brush stimulation; HPDT, sensitized and normal skin; VAS during LTS; end of magnesium/placebo infusion. The sample size was based on a power calculation which showed that 25 volunteers were required to achieve 80% power to detect a difference of 20% in area of secondary hyperalgesia, with α=0.05 (two-tailed). Wilcoxon's test for paired data was used. Any significant P-values were corrected using Bonferroni's correction for repeated measurements. P 0.26) (Table 1). In sensitized skin, HPDT did not differ regardless of treatment regimen (P=0.88 at 80 min, P=0.97 at 120 min). Heat pain detection thresholds were reduced in normal skin during magnesium infusion (P=0.001). Likewise, LTS was rated as more painful during infusion of magnesium than placebo (P<0.002). Infusion of magnesium caused significantly more light-headedness (P<0.0001), and drowsiness (P<0.0001) than infusion of placebo.Table 1VAS ratings, area of secondary hyperalgesia, heat pain detection thresholds and side effects. *P=0.001, **P<0.002, ***P<0.0001. (Median (quartiles)).PlaceboMagnesium 0.2 mg kg–1+ magnesium 0.2 mg kg–1h–1VAS ratings during re-kindling (40°C for 5 min)80 min22 (8–33)21 (10–31)120 min7 (2–15)6 (2–11)Area of secondary hyperalgesia, pin-prick (cm2)Baseline104 (81–130)108 (88–135)80 min81 (70–107)83 (62–83)120 min79 (63–98)78 (63–107)Area of secondary hyperalgesia, brush (cm2)Baseline77 (61–114)94 (72–110)80 min59 (47–87)59 (47–87)120 min63 (41–83)56 (41–82)Heat pain detection threshold (°C) normal forearmBaseline44.0 (42.5–45.3)44.0 (42.8–45.1)80 min43.8 (42.1–44.7)42.2 (40.4–43.3)*120 min42.9 (41.7–44.2)42.3 (40.9–43.2)*Heat pain detection threshold (°C) sensitized forearmBaseline44.1 (42.9–46.3)45.2 (43.2–45.9)80 min42.6 (40.3–44.2)43.4 (39.6–44.8)120 min42.5 (41.6–43.8)42.2 (41.3–44.4)VAS ratings during long thermal stimulation (percentage of baseline value)80 min110 (91–138)149 (122–192)**120 min112 (94–138)149 (126–207)**Light-headedness0 (0–0)0.5 (0.25–1.0)***Drowsiness0 (0–0)0.75 (0.25–1.125)*** Open table in a new tab One study has assessed the effect of i.v. magnesium administration in patients with chronic pain. Felsby and coworkers failed to demonstrate significant reductions in pain and area of allodynia in 10 patients with chronic neuropathic pain.6Felsby S Nielsen J Arendt-Nielsen L Jensen TS NMDA receptor blockade in chronic neuropathic pain: a comparison of ketamine and magnesium chloride.Pain. 1996; 64: 283-291Abstract Full Text PDF PubMed Scopus (272) Google Scholar In our study, i.v. magnesium had no effect on sensitization. Furthermore, magnesium had no analgesic effect on thermal stimulation in hyperalgesic skin. In contrast, magnesium decreased HPDT and increased the pain of LTS in normal skin. These results suggest that i.v. magnesium has no important analgesic effects in clinically relevant doses. This study was supported by grants from the following foundations: Danish Medical Research Council, Copenhagen, Denmark (Reg. no. 28809); and Novo Nordisk Foundation, Bagsvaerd, Denmark. Dr Rowbotham is supported by Grants NS21445 and K24 NS02164 from the National Institute of Neurological Disorders. Dr Petersen is supported by a fellowship from the VZV Research Foundation.