Ketamine is being recognized for its ability to treat therapy resistant chronic pain syndromes. Particularly those with a neuropathic component such as complex regional pain syndrome type 1 (CRPS-1), post-herpetic neuralgia and neuropathic pain from peripheral nerve damage. However, a lot of us still have questions. How is ketamine able to treat chronic pain?
Current data indicates that short term infusions produce potent analgesic effects that are short lived during the infusion, however, long term infusions (4-14 days) have been shown to produce long-term analgesic effects for up to 3 months. So, what is it that ketamine is doing to produce these effects?
In order to understand how ketamine works with pain, we first have to learn about NMDAR. NMDAR is an excitatory glutamatergic receptor present at spinal and supraspinal sites involved in afferent transmission of nociceptive signals. In chronic pain sites, prolonged nociceptive stimulation causes activation and upregulation of the NMDAR at dorsal horn synapses resulting in enhanced and amplified trafficking of pain signals to the brain (central sensitization). NMDAR antagonists that black the NMDAR are able to halt the excessive barrage of nociceptive input to the brain and are therefore potential alternatives to existing chronic pain treatment.
Luckily for us, ketamine is in fact a NMDAR antagonist. This basically means that ketamine is able to go into the body, reducing the release of NMDAR, which amplifies pain signals to the brain. Ketamine also works on the opioidergic, muscarinic and monoaminergic receptors, however little is known about their relationship.
Ketamine is also hypothesized to restore the physiological balance between pain inhibition and facilitation through activation of descending inhibitory pathways. Through use of RS-fMRI, we can see that ketamine activates the anterior cingulate cortex, the orbital frontal cortex, the insula and brainstem, which are all involved in descending inhibitory pathways. There is also evidence to suggest that ketamine is able to activate the condition pain modulation (CPM) in the descending inhibitory pathways. CPM is the central inhibition of a focal stimulus by administering a second noxious stimulus at a remote area.
Although ketamine appears very promising, there are a few concerns. First being that a follow-up infusion is needed typically between 4 and 6 weeks following a prolonged infusion. Although there have been no known serious side effects of ketamine in a clinical setting, we know through recreational users that abuse of the drug can result in organ damage. With that being said, prolonged infusions every 4-6 weeks are said to be relatively safe, however, extra attention should be paid to close monitoring of liver enzymes following repeated treatments.