Does intraoperative remifentanil infusion really make more postoperative pain?

Corresponding author: Seonghoon Ko, M.D., Ph.D., Department of Anesthesiology and Pain Medicine, Chonbuk National University Medical School, 634-18, Keumam-dong, Jeonju 561-712, Korea. Tel: 82-63-250-1979, Fax: 82-63-250-1240, E-mail: [email protected] This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. CC In the current issue of the Korean Journal of Anesthesiology, two articles demonstrate that N-methyl-D-aspartate (NMDA) receptor antagonists prevent remifentanil-induced hyperalgesia. Hong et al. [1] showed that continuous infusion of low dose ketamine decreased early postoperative pain score and analgesic requirement in patients with sevoflurane and remi fentanil anesthesia. Lee et al. [2] also found that wound infiltration of magnesium sulfate decreased opioid consumption and reduced opioid-induced hyperalgesia (OIH). Ketamine is a non-competitive and magnesium is a physiologic NMDA receptor blocker. NMDA receptor blockers might prevent central sensitization by inhibiting activation of excitatory amino acids such as glutamate on NMDA receptors. The administration of opioids is often related to the development of paradoxical and pathologic pain termed as OIH and tolerance. Tolerance is a pharmacologic concept which defined as a progressive decrease in response to a drug [3]. A variety of drugs, not a specific to the opioid family, can cause tolerance. Tolerance can be overcome by increasing dose of the drug. OIH is a paradoxical response to an opioid, whereby a patient receiving opioid for the treatment of pain might actually have an increase in pain perception to certain painful stimuli. OIH may complicate the clinical course of a patient who receives opioid treatment for pain control. The pronociception may occur in the same area as the underlying pain or away from the original site of the pain. The nature of pain often is associated with neuropathic pain such as hyperalgesia or allodynia. OIH is different from tolerance and it cannot be overcome by increasing dose of the drug because OIH is a pain sensitization of nerve system induced by the drug. Pain is aggravated with increased opioid dosage and improved by reducing or cessation of the drug. Therefore, OIH is clinical challenge to acute and chronic pain treatment. Although there has been a controversy about its clinical implication, substantial evidence has been reported to support the development of OIH in experimental and clinical studies. There are several proposed mechanisms for OIH. Both central and peripheral sensitization to pain occurs in the nervous system. Central sensitization in the spinal cord involves the glutamate receptor, the NMDA receptor. The excitatory neurotransmitter plays a key role in the development of OIH. Spinal dynorphin levels were increased with continuous infusions of opioids and increased dynorphin levels lead to the release of spinal excitatory neuropeptides [4]. Neurons within the descending pathway in the spinal cord may facilitate spinal nocioceptive processing [5]. In cultured rat spinal neurons, remifentanil induce persistent increases in NMDA responses which is inducible by δ-opioid receptor activation with a dynorphin agonist [6]. Gabapentin and pregabalin, which have a presynaptic effect on glutamate release, prevent OIH in rats and humans [7,8]. Also, these pro-nociceptive processes were facilitated in the spinal cord by increasing the synthesis of excitatory neuropeptides including 5-HT3, cholecystokinin, and substance P. Spinal dynorphin and facilitation of descending pathway in the spinal cord play important roles in OIH. Peripheral receptors also play a role in OIH, with evidence that the transient receptor potential vanilloid receptor 1 (TRPV1) is important in the development of hyperalgesia [9,10]. A TRPV1