The Effect of Perioperative Intravenous Low-dose Ketamine on Acute and Chronic Neuropathic Pain After Major Back Surgery. A Randomised, Placebo-controlled, Double-blind Study

Background

1. Ketamine as an adjuvant to multimodal postoperative analgesia and its impact on the development of chronic neuropathic pain:

Ketamine, a phenylcyclidine derivate, was developed in the 1960's to be used as a general anesthetic. The pharmacological mechanism of ketamine remained unclear for a long time. However, more recently, the antagonistic role of ketamine at the N-methyl-D-aspartate (NMDA) receptor was identified. Consequently, it has been suggested that ketamine should be used as an adjuvant for multimodal pain treatment.

During the last 15 years, a large number of clinical trials have been published that tested ketamine for the management of acute postoperative pain. Three meta-analyses have confirmed an opioid sparing effect in the immediate postoperative period, a decrease in post-operative pain intensity, and an increase in the delay until the first request of rescue analgesia in patients who were randomised to intraoperative ketamine [Elia & Tramèr, 2005; Bell et al, 2005; Himmelseher & Durieux, 2005]. There was no evidence of an increase in the incidence of nightmares or unpleasant dreams when patients received low-dose ketamine as an adjuvant to a general anesthetic [Elia & Tramèr, 2005].

Additionally to these short-term perioperative effects, ketamine is supposed to reduce the development of chronic neuropathic postoperative pain through NMDA receptor blockade and a reduction of wind-up and central sensitization [Woolf 2000]. Chronic postoperative pain is a major source of morbidity [Perkins & Kehlet, 2000]. Certain types of surgery, such as breast surgery, thoracotomy, inguinal hernia repair and limb amputation are considered as "high risk" interventions for developing neuropathic pain. After thoracotomy, for instance, incidences of chronic neuropathic pain up to 60% have been reported. A few studies only have looked at long-term outcomes. In a small pilot study, a beneficial effect of ketamine on persistent painful sensations around the scar was observed for up to 6 months after surgery [De Kock et al, 2001]. Chronic neuropathic pain remains an important therapeutic challenge. The pathophysiology of neuropathic pain has shown that central sensitisation might play an important role through hyperactivity/ hyperexcitability of spinal/supraspinal nociceptive neurons. Ketamine, which modulates NMDA receptors, is known to reduce neuropathic pain and might even prevent it. Furthermore, opioid resistance of neuropathic pain is a common feature and thermal sensory deficits within the painful area are predictive of the intensity of opioid response.