1 Department of Anaesthetics and Pain Management, University Hospital Lewisham, Lewisham High Street, London SE13 6LH, UK. 2 Department of Public Health Sciences, St Georges Hospital Medical School, London SW17 ORE, UK. 3 GKT School of Medicine, Pain Management Unit, Guys and St Thomas Hospital, London SE1 9RT, UK *Corresponding author
Accepted for publication: May 24, 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Method. A double-blind, placebo-controlled, cross-over study was conducted in which magnesium sulphate was administered as an i.v. infusion. Spontaneous pain was recorded and qualitative sensory testing with cotton wool was performed in seven patients with postherpetic neuralgia before and after the i.v. administration of either magnesium sulphate 30 mg kg1 or saline.
Results. During the administration, pain scores were significantly lower for magnesium compared with placebo at 20 and 30 min (P=0.016) but not at 10 min. I.V. magnesium sulphate was safe, well-tolerated and effective in patients with postherpetic neuralgia.
Conclusion. The present study supports the concept that the N-methyl-D-aspartate receptor is involved in the control of postherpetic neuralgia.
Br J Anaesth 2002; 89: 71114
Keywords: pain, neuropathic; pain, postherpetic neuralgia
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The typical features of PHN are burning, aching or itching and continuous pain, with additional sharp and shooting components, often associated with hyperalgesia and allodynia. PHN is the consequence of the extensive peripheral and spinal damage caused by the reactivation of the dormant virus.3 Continuous activation of C-nociceptor fibres causes the release of glutamate from central terminals acting on the amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and the N-methyl-D-aspartate (NMDA) receptor.4
The NMDA receptor plays an important role in the mechanisms underlying central sensitization (wind-up) in the spinal cord and is critically important for the establishment of several chronic neuropathic pain states.5 In its inactive state, it is blocked by the presence of a centrally positioned magnesium ion.6 Afferent activity in nociceptor fibres dislodges the central magnesium ion from the NMDA receptor, thus allowing calcium influx into the cell.
The NMDA receptor antagonist ketamine reduces neuropathic pain and allodynia in patients with chronic PHN.7 However, the psychomimetic side-effects limit its use in clinical practice.8
Magnesium has been shown to exert a physiological block of the ion channel on the NMDA receptor, preventing extracellular calcium ions from entering the cell and contributing to secondary neuronal changes.9 This double-blind, placebo-controlled, cross-over study evaluated the analgesic properties of magnesium sulphate in patients with PHN.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients with cardiac failure (New York Heart Association grade III or IV), atrioventricular conduction block (grade II or III), serum creatinine in excess of 110 mol litre1 and severe liver disease were excluded from the study. Subjects above 18 yr of age with PHN for more than 3 months after healing of the HZ rash and showing a pain score of 4 on a numerical visual analogue scale (VAS) (0=no pain, 10=worst possible pain) were assigned randomly to receive either an i.v. infusion of 0.9% saline 100 ml or magnesium sulphate 30 mg kg1 (magnesium 0.06 mmol kg1) over 30 min (the required amount was added as a 50% magnesium sulphate solution to 100 ml of saline). One week later, the other solution was infused. The magnesium concentration used in the study was well below what is widely administered in suspected myocardial infarction, for the emergency treatment of serious arrhythmias and to prevent recurrent seizures in eclampsia.
The severity of pain was recorded using a numeric VAS at baseline and at 10, 20 and 30 min during the infusion. The patients were also asked about the degree of pain relief at the time of discharge, 1 h later and the following morning. Mechanical stimulation with cotton wool to test for mechanical dynamic allodynia was performed before and immediately after the infusions. Serum magnesium concentrations were measured before the start of the study and found to be within normal limits in all patients.
The Wilcoxon signed rank test was used to ascertain if pain scores were the same between magnesium and placebo within individuals, sequentially in time, at 10, 20 and 30 min during the infusion. As three sequential statistical tests were performed, Bonferronis correction factor was applied to adjust for multiple testing. The critical significance level was adjusted from 0.05 to 0.017 accordingly. All reported P-values are two-tailed.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Magnesium could be expected to modulate neuropathic pain by blocking the NMDA receptor calcium ionophore. This mechanism may prevent nociceptive-associated central sensitization5 and lessen the increased activity of wide-dynamic range neurones in the dorsal horn after prolonged activation. Assuming extracellular distribution of magnesium, plasma concentrations in our patients would have risen by approximately a third during the infusion, causing a block of the NMDA receptor with subsequent pain relief.
Magnesium therapy has been shown to be potentially beneficial in eclampsia12 and, more recently, in headache13 14 and acute migraine attacks.15 The systemic and intrathecal injection of magnesium suppresses neuropathic pain responses in different rat models.1521 In man, an i.v. infusion of magnesium sulphate caused a reduction of postoperative analgesic requirement2224 and an oral daily dose of magnesium sulphate was shown to be effective in neuropathic pain.25
In our study, magnesium clearly reduced PHN pain in comparison with placebo. This effect was initially observed 10 min after the start of the infusion, reaching statistical significance after 20 min. The majority of subjects achieved substantial pain relief during the magnesium infusion, whereas none of them had any relief during the placebo infusion. Although the study had a small sample size, its cross-over design increased its statistical power.
We did not observe an inhibitory effect on allodynia, as would have been predicted from postsynaptic action of magnesium. However, dynamic allodynia does not rely on the wind-up effect, which is mediated through the NMDA receptor. It is therefore not surprising that there was a different response to i.v. magnesium between ongoing pain and pain caused by brief mechanical stimulation.
Our results show that the physiological action of magnesium on NMDA receptors can be translated into a viable concept for pain control in some patients with PHN.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Kost RG, Strauss SE. Postherpetic neuralgiapathogenesis, treatment, and prevention. New Engl J Med 1996; 335: 3242
3 Mahalingam R, Wellish M, Wolf W, et al. Latent varicella-zoster viral DNA in human trigeminal and thoracic ganglia. New Engl J Med 1990; 323: 62731[Abstract]
4 Nurmikko T. Pathophysiology of acute herpes zoster and postherpetic neuralgia. Pain Forum 1998; 4: 23840
5 Woolf CJ, Thompson WN. The induction and maintenance of central sensitisation is dependent on N-methyl-D-aspartic acid receptor activation: implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 2989
6 Dickenson AH. NMDA receptor antagonists as analgesics. In: Fields HL, Liebeskind JC. Progress in Pain Research and Management, Volume 1. Seattle: IASP Press, 1994; 17387
7 Hoffmann V, Coppejans H, Vercauteren M, Adriaensen H. Successful treatment of postherpetic neuralgia with oral ketamine. Clin J Pain 1994; 10: 2402[ISI][Medline]
8 Byas-Smith MG, Max MB, Gracely RH, Bennett GJ. Intravenous ketamine and alfentanil in patients with chronic causalgic pain and allodynia [abstract]. 7th World Congress on Pain 1993; 4545
9 Fawcet WJ, Haxby EJ, Male DA. Magnesium: physiology and pharmacology. Br J Anaesth 1999; 83: 30220
10 Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997; 73: 12339[ISI][Medline]
11 Rowbotham MC, Petersen KL, Fields HL. Is postherpetic neuralgia more than one disorder? Pain Forum 1998; 7: 2317[ISI]
12 Eclampsia Trial Collaborative Group. Which anticonvulsant for women with preeclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet 1995; 345: 145563[ISI][Medline]
13 Ginder S, Oatman B, Pollack M. A prospective study of i.v. magnesium and i.v. prochlorperazine in the treatment of headaches. J Emerg Med 2000; 18: 3115[ISI][Medline]
14 Mauskop A, Altura BT, Cracco RQ, Altura BM. Intravenous magnesium sulfate alleviates headaches of various types. Headache 1996; 36: 15460[ISI][Medline]
15 Demirkaya S, Vural O, Dora B, Topcuoglu MA. Efficacy of intravenous magnesium sulphate in the treatment of acute migraine attacks. Headache 2001; 41: 1717[ISI][Medline]
16 Begon S, Pickering G, Eschalier A, Dubray C. Magnesium and MK-801 have a similar effect in two experimental models of neuropathic pain. Brain Res 2000; 887: 4369[ISI][Medline]
17 Feria M, Abad F, Sanchez A, Abreu P. Magnesium sulphate injected subcutaneously suppresses autonomy in peripherally deafferented rats. Pain 1993; 53: 28793[ISI][Medline]
18 Karesawa S, Ishizaki K, Goto F. The effect of intrathecal administration of magnesium sulphate in rats. Anaesthesia 1998; 53: 87986[ISI][Medline]
19 Takano Y, Sato E, Kaneko T, Sato I. Antihyperalgesic effects of intrathecally administered magnesium sulfate in rats. Pain 2000; 84: 1759[ISI][Medline]
20 Tsai P, Cheng J, Marsala M, Lin C, Wen G, Yang LC. Intrathecal magnesium sulphate attenuates algogenic behavior and spinal amino acids release after kainic acid receptor activation in rats. Neuroscience Lett 2001; 301: 1158[ISI][Medline]
21 Xiao WH, Bennett GJ. Magnesium suppresses neuropathic pain responses in rats via a spinal site of action. Brain Res 1994; 666: 168172[ISI][Medline]
22 Koinig H, Wallner T, Marhofer P, Andel H, Horauf K, Mayer N. Magnesium sulphate reduces intra-and postoperative analgesic requirements. Anesth Analg 1998; 87: 20610[Abstract]
23 Schultz-Stubner S, Wettmann G, Reyle-Hahn SM, Rossaint R. Magnesium as part of balanced general anaesthesia with propofol, remifentanil and mivacurium: a double-blind, randomised prospective study in 50 patients. Eur J Anaesthesiol 1991; 18: 7239
24 Tramer MR, Schneider J, Marti RA, Rifat K. Role of magnesium sulfate in postoperative analgesia. Anesthesiology 1996; 84: 3407[ISI][Medline]
25 Crosby V, Wilcock A, Corcoran R. The safety and efficacy of a single dose (500 mg or 1 g) of intravenous magnesium sulfate in neuropathic pain poorly responsive to strong opioid analgesics in patients with cancer. J Pain Symptom Manage 2000; 19: 359[ISI][Medline]