Several lines of investigation have focused on the neuro-physiological as well as neuro-chemical mechanisms that may underlay opioid resistant pain, such as opioid induced hyperalgesia and opioid tolerance cause certain types of pain to be relatively resistant to the opioids or that may underlie the tolerance that can develop to their beneficial effects. Particular attention has been paid to the role played by glutamate neurotransmission in promoting and maintaining chronic pain states.