A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation

Abstract

Persistent pain has been reported in up to 80% of patients after limb amputation. The mechanisms are not fully understood, but nerve injury during amputation is important, with evidence for the crucial involvement of the spinal N -methyl d -aspartate (NMDA) receptor in central changes. The study objective was to assess the effect of pre-emptively modulating sensory input with epidural ketamine (an NMDA antagonist) on post-amputation pain and sensory processing. The study recruited 53 patients undergoing lower limb amputation who received a combined intrathecal/epidural anaesthetic for surgery followed by a randomised epidural infusion (Group K received racemic ketamine and bupivacaine; Group S received saline and bupivacaine). Neither general anaesthesia nor opioids were used during the peri-operative period. Pain characteristics were assessed for 12 months. The primary endpoint was incidence and severity of post-amputation pain. Persistent pain at one year was much less in both groups than in comparable studies, with no significant difference between groups (Group K = 21% (3/14) and 50% (7/14); and Group S = 33% (5/15) and 40% (6/15) for stump and phantom pain, respectively). Post-operative analgesia was significantly better in Group K, with reduced stump sensitivity. The intrathecal/epidural technique used, with peri-operative sensory attenuation, may have reduced ongoing sensitisation, reducing the overall incidence of persistent pain. The improved short-term analgesia and reduced mechanical sensitivity in Group K may reflect acute effects of ketamine on central sensitisation. Longer term effects on mood were detected in Group K that requires further study. Keywords Phantom limb Epidural analgesia Ketamine NMDA receptors RCT 1 Introduction Persistent pain after amputation is an important clinical problem with no reliably effective treatment ( Halbert et al., 2002 ). Up to 80% of patients may experience persistent pain after lower limb amputation ( Nikolajsen and Jensen, 2001; Ephraim et al., 2005 ). This may either be stump pain (pain at the site of amputation that may have neuropathic elements) or phantom pain, which is a form of neuropathic pain, perceived where the limb was previously. The underlying mechanisms are not understood, but it is clear that major changes occur in the peripheral and central nervous system in response to peripheral nerve injury and subsequent alterations in peripheral sensory input ( Woolf and Mannion, 1999; Flor, 2002 ). Central sensitisation, occurring at the level of the spinal cord, is likely to play a key role in ongoing pain ( Woolf, 1995 ). Animal models of peripheral nerve injury have shown that activation of the ionotropic glutamate receptor, the N -methyl d -aspartate (NMDA) receptor, is integral to the process of central sensitisation, particularly in nerve injury models ( Woolf and Thompson, 1991 ). Laboratory studies implicate sensory input at the time of nerve injury with acute central neural plasticity leading to persistent neuropathic pain. In animals, NMDA antagonists given before nerve injury can reduce behavioural signs of neuropathic pain and associated neurochemical changes ( Burton et al., 1999 ; Munglani et al., 1999 ). Clinical studies of pre-emptive treatment interfering with spinal sensory input are inconsistent. One non-blinded, non-randomised study found a reduction in long-term phantom limb pain by using epidural analgesia with bupivacaine and morphine prior to surgery ( Bach et al., 1988 ). A larger randomised controlled trial found an incidence of ∼70% for phantom pain at one year regardless of whether epidural bupivacaine and morphine were commenced 18 h before surgery or immediately after surgery ( Nikolajsen et al., 1997 ). Neither of those studies aimed to specifically modulate spinal NMDA receptors, activated at the time of nerve injury and likely to be important in central sensitisation. Additionally, the route of administration of NMDA receptor antagonists may be clinically relevant in terms of efficacy. Superior analgesia after thoracotomy was achieved with epidural administration of ketamine, an NMDA antagonist, compared to intramuscular administration ( Ozyalcin et al., 2004 ). Intravenous ketamine used around the time of amputation in combination with general anaesthetic and morphine had no significant effect on the incidence of phantom limb pain ( Hayes et al., 2004 ). Modulation of sensory input to the spinal cord around the time of nerve injury may play a key role in altering neuronal plasticity. While there may be some NMDA receptor activation as a result of pre-operative pain, the aim of this study was to focus on NMDA receptor blockade at the time of nerve injury. At this time a massive excitotoxic injury discharge may occur, with excessive glutamate release. In this study we assessed the effect of pre-emptive treatment with an epidurally administered NMDA receptor antagonist, ketamine, in combination with local anaesthetic, on reducing spinal sensory transmission, acute central sensitisation and the development of persistent post-amputation pain. 2 Methods 2.1 Overview The study was approved by the local Research Ethics Committee and was in accordance with the Helsinki Declaration of 1975 (revised 1983). International Standard Randomised Controlled Trial Number (ISRCTN) 48374927 was assigned to this trial. 2.2 Subjects Patients scheduled to undergo lower limb amputation in the Vascular Surgery Unit, Royal Infirmary of Edinburgh, Scotland, were approached regarding participation in the trial. After written informed consent was obtained they were then entered into the trial. Trial recruitment took place over a 20-month period. Patients had to be able to participate in the questionnaire-based pain assessment and lower limb examination before they were invited to take part in the study. Exclusion criteria included: contraindication to spinal or epidural blockade; contraindication to the use of ketamine...