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