Role of Ketamine in Managing Opioid-Induced Hyperalgesia

The role of opioid-induced hyperalgesia (OIH) in clinical situations of reduced opioid responsiveness has been increasingly recognized in chronic pain patients who experience increasing pain despite escalating doses of opioids. A considerable number of studies have investigated the cellular mechanisms of OIH. There is evidence of neuroplasticity occurring in the rostral ventromedial medulla of the brain as well as dorsolateral funiculus of the spinal cord (1-6). Among the neural mechanisms of opioid pronociceptive activity, there is substantial evidence describing the downregulation of glutamate transporters in the spinal cord and activation of N-methyl-D-aspartate (NMDA) receptors (7-10). It is not surprising that many researchers and clinicians have focused on investigating the potential role of NMDA receptor antagonists in treatment of OIH. Unfortunately, direct competitive NMDA receptor blockers and high-affinity noncompetitive NMDA antagonists exhibit inadequate therapeutic margins for human use when evaluated in clinical trials (11-14). On the other hand, low affinity blockers were shown to have a better therapeutic index (15). Ketamine appears to be in the middle of the affinity range of noncompetitive NMDA antagonists and is probably the most potent one available for clinical use. This chapter discusses the role of ketamine in treatment of OIH and other conditions such as cancer-related pain.