Chronic Pain

Drugs that modulate the N-methyl-d-aspartate (NMDA) may decrease perception of chronic pain, treat the depression often associated with chronic pain, and decrease craving for opioids. However, NMDA antagonist drugs have not been introduced as a mainstream approach to treating chronic pain because of the potential for many drugs in this class to cause addiction, neurotoxicity, and hallucinations. Extensive laboratory evidence and early human data suggest that D-cycloserine, a mixed NMDA agonist/antagonist drug, has the potential to provide clinical benefit with no potential to cause addiction or neurotoxicity. Off label use of ketamine demonstrates proof of concept that NMDA antagonist use ameliorates chronic pain in patients.1 Ketamine is toxic, addictive, and likely not suitable for long term use. Consequently, safe, oral, nonaddictive drugs that act at the NMDA receptor are needed.
Two in five adults suffer from chronic pain and represents the most common reason for seeking medical care.2,3,4 Estimates from 2010 indicate that medical costs and lost productivity from chronic pain costs Americans between $560 and $635 billion each year.5 Treatments include physical therapy/exercise, anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs), analgesic antidepressants, targeted injections, neuromodulation, psychotherapy, and – all too often – opioids. None of these treatments is ideal. The safest treatments tend to be least effective, while the most potent analgesics, particularly opioids, lead to physical and psychological dependence, use disorders, and increasingly death. More than 100,000 Americans will die next year from opioids.6

From Acute Pain to Chronic Pain

Chronic pain is a consequence of both peripheral and central sensitization (Figure 1). Peripheral sensitization is often driven by inflammation around the site of tissue damage. Mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts release numerous proalgesic compounds including neurotransmitters, peptides, eicosanoids, prostaglandins, thromboxanes, leukotrienes, neurotrophins, cytokines, and chemokines.7 Nociceptors sense these molecules through specific cell surface receptors.7 The peripheral nerves become far more sensitive than in their native state, sending a steady stream of abnormal stimuli to the spinal cord.
Repeated, abnormal stimuli from peripheral nerves cause changes at the level of the spinal cord in a process called central sensitization. The theory of central sensitization was articulated by Woolf and King in 1989 when they demonstrated that neurons in the spinal cord become hyperexcitable after injury.8 Central sensitization may produce hyperalgesia, a greater-than-usual pain sensation from a stimulus that usually provokes pain and/or allodynia, a sensation of pain from a stimulus that does not normally cause pain. Moreover, central sensitization can be maintained with or without ongoing input from the periphery. Neuroplastic changes cause a persistent, heightened state of neural reactivity.9,10 Higher order neurons and circuits can certainly adapt and maladapt to chronic pain, e.g., catastrophizing, avoidance, anxiety, depression, analgesic self-administration, etc. Indeed, the insula, which participates in role in multisensory integration, is hyperactive in most individuals with central sensitization in the spinal cord.10-12