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

S. Mikkelsen1, J. Dirks1, P. Fabricius1, K. L. Petersen2, M. C. Rowbotham2,3 and J. B. Dahl1

1Laboratory of Pain Physiology, Department of Anaesthesiology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark. 2Department of Neurologyand 3Department of Anesthesiology, UCSF Pain Clinical Research Center, University of California, San Francisco, CA 94115, USA*Corresponding author

Accepted for publication: January 2, 2001


    Abstract
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
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.

Br J Anaesth 2001; 86: 871–3

Keywords: pain, experimental


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
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.1 2 NMDA receptor antagonists reduce central sensitization.3 The NMDA receptor complex contains a magnesium ion block at resting membrane potential that prevents inward current flux of sodium and calcium ions.1 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.4

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.5 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.


    Methods and results
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
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 25x50 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 {alpha}=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<0.05 was considered statistically significant. Before statistical analyses, areas of secondary hyperalgesia, HPDT, and pain of LTS in individual volunteers were normalized in relation to the baseline values obtained before administration of the study drugs. The pain of LTS (45°C for 1 min) was calculated as area under the curve and then converted to VAS values (0–100).

Infusion of magnesium did not change the size of the areas of secondary hyperalgesia compared with placebo (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.


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Table 1 VAS ratings, area of secondary hyperalgesia, heat pain detection thresholds and side effects. *P=0.001, **P<0.002, ***P<0.0001. (Median (quartiles)).
 

    Comment
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
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.6

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.


    Acknowledgements
 
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.


    References
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
1 Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: state-dependent sensory processing, plasticity and the generation of pain. In: Wall PD and Melzack R, eds. Textbook of Pain. 4th Edn. Edinburgh: Churchill Livingstone, 1999; 165–83

2 Woolf CJ. Somatic pain – pathogenesis and prevention. Br J Anaesth 1995; 75: 169–76[Free Full Text]

3 Dickenson AH. Spinal cord pharmacology of pain. Br J Anaesth 1995; 75: 193–200[Free Full Text]

4 Mikkelsen 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: 1539–45[ISI][Medline]

5 Petersen 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: 15–20

6 Felsby 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: 283–91