Introduction to Ketamine

Ketamine is a non-opioid, non-benzodiazipine, non-paralytic, and non-respiratory depressing anesthetic was first synthesized in 1962 by Calvin L. Stevens. It was FDA approval in 1970. Ketamine is one of the most widely used medication in modern medicine and one of the most important in anesthesia. Ketamine is a "core" medicine in the World Health Organization's Essential Drugs List, a list of minimum medical needs for a basic healthcare system. Ketamine has a remarkably safe track record in surgical settings and is frequently used in pediatric surgery.  It is also commonly used to treat the both mental and physical pain. The US military has used ketamine as a battlefield anesthetic since the Vietnam War.  Ketamine is also used in veterinary medicine.  

Ketamine is a highly lipophilic (44% non-ionized at physiological pH) molecule with a racemic mixture of two stereoisomers: S(+) and R(-).  The onset of action is 30 seconds IV, the route of administration during a ketamine infusion. The duration is 5-15 minutes IV. The elimination half-life is 2.5 hours and the distribution half-life is 11-16 hours. The metabolism is hepatic via hydroxylation and N-demethylation. The metabolite norketamine is 33% as potent as parent compound. Excretion is primarily via urine.

Ketamine has a complex mechanism of action, which is one of the reasons why most people, including physicians, do not understand how it works or why it works. Ketamine's primary mechanism of action is via NMDA receptor antagonism. The NMDA receptor (N-Methyl-D-Aspartate), a specific inotropic glutamate receptor, mediates neuronal signaling and regulates gene expression. It is present in all neurons in the CNS, including and specifically in the dorsal horn of the spinal cord. It is highly permeable to and allows flow of Na+ and Ca2+ into cell and K+ out of cell. Mg2+ blocks NMDA channels. NMDA signaling is important in anesthesia because it is intimately involved in pain processing, neuronal plasticity and generation of central sensitization. This is a key point that most physicians, including "pain management" physician miss, thus leading to the horrible mismanagement of patients that we currently see today. The NMDA receptor is very important for controlling synaptic plasticity and memory function. NMDAR antagonists reduce neuropathic, wind-up and spontaneous pain.



Various NMDAR compounds have differing relative potency on the different NMDA receptor subtypes (commonly termed GluN1, GluN2A, GluN2B, GluN2C, and GluN2Debut also called NR1, NR2A-D) with resultant different spectra of action. These subtypes show markedly heterogeneous distributions in the brain, which may account for the variations in clinical effects caused by different NMDA blocking compounds. The GluN2A subtype is found throughout the brain, whereas GluN2B is primarily confined to the limbic system, thalamus, and spinal cord, GluN2C to the thalamus and cerebellum, and GluN2D in the brain stem, diencephalon, and spinal cord. Ketamine has been shown to result in suppression of immediate early gene expression at the site of mechanical injury (zif/268, c-fos, junB, fosB, c-jun, junD). It also alters the regulation of NMDA receptor1 phosphorylation 22 and NMDA receptor1 mRNA expression in rat and mouse models of hyperalgesia, and also limits astrocytic and microglial activation as seen in reduced glialfibrillary acidic protein (GFAP) expression; effects that correlate with a reduction in neuropathic pain.

At concentrations within the clinical dose range, ketamine directly affects a wide range of cellular processes, including:

•  Blockade of NMDA channels
•  Neuronal hyperpolarisation-activated cationic currents (Ih, also known as hyperpolarisation-activated cyclic nucleotide channels (HCN1))
•  Nicotinic acetyl-choline ion channels
•  Delta and mu-opioid agonism and opioid potentiation
•  Nitric-oxide (NO) cyclic guanosine-mono-phosphate (cGMP) system
•  Non-NMDA glutamate receptors (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA))
•  Metabotropic glutamate receptors (mGluR)
•  Reduction in cholinergic neuromodulation
•  Increased release of aminergic neuromodulators (dopamine and noradrenaline)
•  Neurosteroids
•  L-type Ca2þ channels

Ketamine has also been shown to enhance brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) protein levels in the rat hippocampus, resulting in modification to the number and function of synaptic connections. Norketamine has been shown to actually have anti-analgesic effects and ketamine may actually facilitate endogenous pain pathways in some circumstances. In the setting of chronic neuropathic pain syndromes, there is some evidence for prolonged post-drug analgesia that markedly outlasts the effective drug levels, which would be mediated by downstream mechanisms.

Ketamine also has direct effects on the delta opioid receptor, and acts to augment opioid mu-receptor function. Ketamine’s analgesia is not reduced by naloxone; which would argue against the primary opioid mechanisms of action. In vitro, ketamine prevented and even reversed opioid mu-receptor desensitization. In other words, it can reset opioid tolerence and immediately reduce the need for opioids and make the opioids that are being taken, more effective for pain. Ketamine augments endogenous anti-nociceptive systems presumably, in part, via its aminergic (serotonergic and noradrenergic) activation and inhibition of re-uptake. Ketamine directly inhibits nitric-oxide synthase which probably contributes in part to its analgesic effects.

Ketamine has both acute and prolonged effects on chronic neuropathic pain syndromes. A single low analgesic dose of ketamine can rapidly and transiently reduce ongoing pain of neuropathic origin, including allodynia and hyperalgesia. This may be due to a reduction in NMDA-mediated “wind-up”. Ketamine applied around the time of surgery as a single infusion has even been reported to limit the development of chronic pain up to 180 days postoperatively. Ketamine’s pre-emptive reduction in neuropathic pain is a corollary of its antidepressant effect which endures well after the drug has been eliminated. Ketamine may set in chain cell signaling cascades that interrupt the gradual propagation of pathophysiological changes associated with chronic pain development.