Peripheral analgesic receptor systems
In this issue of the British Journal of Anaesthesia, Bondok and Abd El-Hady1 report the effect of intra-articular magnesium administration on pain after arthroscopic knee surgery. Studying 60 patients in a randomized and blinded manner, they injected either 1 g of magnesium sulphate or an equivalent volume of saline into the knee joint at the end of surgery and followed pain scores over 24 h. Magnesium administration resulted in a pronounced reduction of pain scores during the first 8 h after surgery and a similarly impressive lengthening of time to first administration of rescue analgesic.The remarkable effect of this simple intervention will require confirmation before it can be recommended as common practice. In particular, the safety aspects of the approach were not investigated, and the study was not powered to assess the incidence of significant side-effects. Nonetheless, it suggests that peripheral administration of magnesium can have profound analgesic effects and fits nicely within a growing body of literature on peripheral analgesic receptor systems. Over the past 10 yr or so, we have learned that a number of receptors for which the target site was thought to be solely in the central nervous system (CNS) are equally present and active in peripheral tissues.
This peripheral role has been elucidated in most detail for the analgesic actions mediated through opioid receptors. That their peripheral presence was initially missed is not surprising, as opioid receptor expression on peripheral nerves is normally very low.2 Hence, the CNS was seen as the primary target location for opiates. However, we now know that receptor levels in the periphery increase rapidly in settings of inflammation. In addition, inflammatory cells—moving into the inflamed area, in response to chemotactic signals—start releasing endogenous opiates. In essence, therefore, inflammation leads to the rapid deployment of a peripheral pain control system. We can enhance the effects of this system by administering exogenous opioids, and, indeed, it has been shown that opioids are effective analgesics even when applied only in peripheral tissues.3 In the setting of arthroscopy, intra-articular morphine has been shown to be effective.4 Therapy selectively targeted at peripheral opioid receptors would have the potential benefit of being devoid of the central side-effects of opioids, in particular respiratory depression. Understandably, therefore, these systems are of major investigational interest.
The analgesic actions of 
2 agonists such as clonidine have also classically been considered to take place in the CNS, particularly in the dorsal horn. However, 10 yr ago it was shown that intra-articular clonidine was analgesic.5 The mechanism for this action is not as clearly defined as is the case with the peripheral opioid receptors. The sympathetic nervous system may play a role in sensitizing nociceptors, and presynaptic 2 receptors may prevent or reverse this effect. Whatever the exact mechanism will turn out to be, a number of investigations have demonstrated analgesia after peripheral administration of 2 agonists.
The study by Bondok and Abd El-Hady1 addresses a third group of receptors on the list: glutamate receptors of the N-methyl-D-aspartate (NMDA) type. It had been demonstrated previously that the NMDA antagonist MK-801, when administered peripherally, reduced spinal cord responses to noxious stimulation.6 The clinically available NMDA receptor antagonists ketamine and magnesium were subsequently shown to reduce sensitivity to mechanical stimuli in humans when administered peripherally,7 and, returning to the arthroscopy setting, intra-articular ketamine has been shown to provide analgesia as well.8
That magnesium would be as potent an analgesic as shown in the present paper is somewhat surprising, as after systemic administration it has generally been found less effective than ketamine. However, after systemic administration only limited doses can be used because of magnesium's side-effects at higher concentrations. The relatively greater amounts that can be administered intra-articularly (1 g in a single joint, whereas a typical systemic analgesic dose would be 2 g for a 70 kg patient) may allow a much greater effect. In addition, the compound may function better in the setting of injured and inflamed tissue, as would be present immediately after operation.
The authors appropriately point out that they did not control for systemic absorption of the drug. They did not measure plasma levels, nor did they include a treatment group where magnesium was administered systemically. Hence, it cannot be ruled out that at least part of the analgesic effect was attributable to systemic absorption. However, based on previous studies with systemic administration, one would expect the analgesia obtained by less than 1 g of systemic magnesium to be limited. Therefore, it seems likely that at least a major portion of the action was attributable to a local effect. It should also be pointed out that the authors did not formally demonstrate that the analgesic action was because of NMDA receptor blockade. Other interactions may play a role.
But whatever the mechanism of the intra-articular effect, and whatever the contribution of a systemically absorbed fraction may be, the authors suggest a simple and practical approach to analgesia after a common, outpatient surgical procedure. In addition, they have added another piece of evidence to a growing body of literature showing that many of the receptors we always thought of as belonging to the CNS are just as active and effective mediators of analgesia in peripheral locations. Further research will be needed to determine the importance of their role as compared with central receptors. If this role is significant (and the present paper suggests it may well be), they may very well become targets for novel approaches to pain therapy.
Charlottesville, USA
E-mail: durieux{at}virginia.edu
References
1 Bondok RS and Abd El-Hady AM. Intra-articular magnesium is effective for postoperative analgesia in arthroscopic knee surgery. Br J Anaesth 2006; 97:389–92
2 Hassan AH, Ableiter A, Stein C, Herz A. Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neurosci 1993; 55:185–95[CrossRef][Web of Science][Medline]
3 Tegeder I, Meier S, Burian M, Schmidt H, Geisslinger G, Lotsch J. Peripheral opioid analgesia in experimental human pain models. Brain 2003; 126:1092–102
4 Rosseland LA, Stubhaug A, Skoglund A, Breivik H. Intra-articular morphine for pain relief after knee arthroscopy. Acta Anaesthesiol Scand 1999; 43:252–7[CrossRef][Web of Science][Medline]
5 Gentili M, Juhel A, Bonnet F. Peripheral analgesic effect of intra-articular clonidine. Pain 1996; 64:593–6[CrossRef][Web of Science][Medline]
6 Ushida T, Tani T, Kawasaki M, Iwatsu O, Yamamoto H. Peripheral administration of an N-methyl-D-aspartate receptor antagonist (MK-801) changes dorsal horn neuronal responses in rats. Neurosci Lett 1999; 260:89–92[CrossRef][Web of Science][Medline]
7 Iwatsu O, Ushida T, Lawand NB, Yamaoto H. Peripheral administration of magnesium sulphate and ketamine hydrochloride produces hypesthesia to mechanical stimuli in humans. J Health Sci 2002; 48:69–72[CrossRef]
8 Dal D, Tetik O, Altunkaya H, Tetik O, Doral MN. The efficacy of intra-articular ketamine for postoperative analgesia in outpatient arthroscopic surgery. Arthroscopy 2004; 20:300–5[Web of Science][Medline]
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