Oral Ketamine as an Adjuvant to Opioids for Pain Treatment in Cancer Patients

It is estimated that 10%-15% of patients with cancer-related pain do not achieve acceptable levels of pain relief even when oral or parenteral opioids are skillfully combined with conventional adjuvant analgesics and intractable pain occurs in up to 2% of advanced cancer patients. Painful conditions arising from tumor-nerve structure involvement, neuropathic pain, skin lesions, iatrogenic (chemo-and radiotherapy lesion), or ischemic pain are those most likely to require more aggressive treatment, such as the use of unconventional agents or interventional management approaches.

Despite considerable progress in the technologies of cancer-related pain management and an increased broadening array of medications, many patients fail to achieve adequate pain relief. In others, the availability of these treatments may be limited by such factors as side effects, or lack of or pain-management expertise. Furthermore, the development of opioid tolerance and the high incidence of side effects with escalating dose of opioid dose may contribute to treatment failure.

The need to develop new pharmacologic approaches for refractory pain remains of critical importance. The most potent class of analgesics available for general use remains the opioids.

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.

Glutamate is the primary excitatory neurotransmitter of the central nervous system and is normally released by pain-signaling afferent neurons as they synapse on central pain pathways in the spinal cord. The persistent release of glutamate, due to peripheral injury or inflammation, leads to the activation of N-methyl-D-aspartate (NMDA) receptors. This process of activation has been shown to play a crucial role in mediating the phenomenon of "wind up" pain, a state in which spinal neurons become hyper-responsive to repetitive painful stimulation.