The non-anesthetic applications of ketamine, a nonselective NMDA receptor antagonist primarily known for its use as an anesthetic agent has caught the interest of researchers across the world for the last few years. While ketamine has been used as an anesthetic for over 65 years, its mechanisms of action lead to widespread physiological effects that are now being researched for the treatment of diverse medical disorders.
- Depression: Investigated for its rapid-onset antidepressant and antisuicidal properties in unipolar and bipolar depression, including treatment-resistant cases. Research encompasses different administration routes (IV, intranasal, sublingual), maintenance strategies, and use in specific populations like the military, cancer patients, and those with Alzheimer’s disease. Ketamine’s mechanisms in depression are thought to involve glutamatergic, dopaminergic, and serotonergic systems, as well as the mTOR pathway and glutamate transporters.
- Pain Syndromes: Explored for acute pain, chronic pain, and headaches. In acute pain, ketamine can reduce analgesic requirements, prevent opioid tolerance, and mitigate opioid-related side effects in settings like postoperative care and emergency departments.
o For chronic pain, moderate evidence suggests efficacy in noncancer pain, particularly neuropathic pain such as Complex Regional Pain Syndrome (CRPS). Different administration routes like oral, subcutaneous, and topical are being studied. In headaches, IV ketamine shows potential for reducing acute pain in refractory migraine, and intranasal ketamine may alleviate migraine
aura. Research is also looking at its use in cluster headaches. - Neurologic Applications: Investigated for neuroprotection in conditions like traumatic brain injury (TBI), stroke, and subarachnoid hemorrhage, as well as for the treatment of seizures, particularly status epilepticus (SE) and refractory
status epilepticus (RSE). Ketamine’s neuroprotective effects are thought to
involve reducing glutamate excitotoxicity and inflammation. In seizures, it may
work synergistically with benzodiazepines, especially in prolonged or
refractory cases, potentially avoiding the need for intubation. - Alcohol and Substance Use Disorders: Researched for its role in treating
alcohol and substance use disorders, including reducing relapse rates in
alcohol and cocaine dependence and improving opioid withdrawal symptoms.
Important Considerations and Limitations: - While showing promise across these diverse areas, research on nonanesthetic
ketamine use is generally considered to be in its early stages. - Many studies have small sample sizes, and results can be conflicting,
necessitating further large-scale prospective studies to confirm efficacy and
establish optimal protocols. - Ketamine has a significant side-effect profile, including psychotomimetic and
dissociative symptoms, potential for abuse and addiction, cognitive deficits,
and other adverse reactions like tachycardia, hypertension, liver injury, and
urogenital pathology. These side effects can limit its long-term use and require
careful consideration of risks and benefits. - The duration of ketamine’s effects in nonanesthetic uses, particularly in
depression and chronic pain, can be relatively short, requiring repeated
administrations, which poses practical challenges and raises concerns about
long-term safety. Alternative routes of administration are being explored to
address this. - Further research is needed to determine optimal dosing, timing, and routes of
administration for various nonanesthetic applications.
In conclusion, there is an ongoing broad and active area of research exploring the
nonanesthetic uses of ketamine across a wide range of medical disorders. While
initial findings are promising, especially in areas like rapid-onset treatment for
depression and management of refractory pain and seizures, significant further
research is required to fully elucidate ketamine’s role, optimize its use, and mitigate
its potential risks.
Author
Dr Jithin TN
Senior Consultant Anaesthesiologist
Baby Memorial Hospital