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Ketamine. Just the need to know.

Updated: Feb 18, 2021

Mechanism of action (1)

Non-competitive antagonist at phencyclidine binding site of N-methyl-D-aspartate (NMDA) in the CNS (particularly the prefrontal cortex and hippocampus)

Decreases the frequency of channel opening and the duration of time the gate is left in the 'open' state

NMDA receptor is a ligand-gated channel (ligand is a chemical that binds - and then opens an ion gate) whose main 'ligand' (endogenous agonist) is glutamate - the predominant excitatory neurotransmitter in the CNS

So by blocking the receptor with ketamine, you block the neuronal activity (reducing pain signalling)

NMDA USUALLY plays a role in cognition, chronic pain, opioid tolerance, and mood regulation - so thought to play a part in 'wind-up' and central sensitisation

BUT WAIT - There is more!

Ketamine has effects on opioid receptors in high doses (but not reversed by naloxone)

Ketamine also works on non-NMDA pathways including descending modulation pathways through GABA signaling. So other stuff too...


Can be used to lower opioid use - but studies have been variable (likely due to patient selection difficulties)

IASP article suggests Ketamine is THIRD line adjuvant drug for opioid-resistant pain in palliative care and intractable non-cancer pain

Used in: CRPS, fibromyalgia, neuropathic pain, phantom limb pain, postherpetic neuralgia, sickle cell disease, and spinal injury

- Evidence from ASRA and AAPM and ASA (American organisations) - weak to moderate support for ketamine's role in these conditions

- Interestingly they also state that '...adverse effects were few and rate of serious adverse effects was similar to placebo in most studies

Ketamine possibly has a role in PTSD and refractory depression

- Chronic pain patients due to undergo surgery

- Thought to work only in some patients who have the specific receptors ketamine works on, active

- Helps with sedation, analgesia and amnesic effects


- Commonly an IV infusion

- Can be taken orally or applied to the skin, inhaled in nose, or injected into muscle/bone

Common side effects (Sympathetic stuff)

- Sedation

- Increased heart rate, BP,

- Salivary and tracheobronchial secretions

- Bronchodilation


- Cardiovascular disease (unstable)

- Severe liver disease

- Poorly controlled psychosis

- Substance abuse problems

- Elevated intracranial pressure

- Glaucoma

Rare side effects - be aware!

Liver and kidney issues?

- Metabolism is via the liver through the P450 system

- It is water and lipid soluble - so rapidly goes around the body and through blood-brain barrier

- Ketamine excretion (only minimal after liver has done its stuff - 4% excreted as ketamine itself) and its metabolites, is via the urine

Golden pearls

- Commonly known as Special K, Vitamin K, Super K

- Long term use demonstrates minimal tolerance and tachyphylaxis (tachyphylaxis - acute, sudden decrease in response to a drug after its administration)

Evidence is difficult. For example...

Reference 1 - "The efficacy of ketamine for chronic neuropathic pain and conditions with features of neuropathic pain has been investigated in double-blind RCTs.44,117119,123,152169 Several of these trials found that ketamine, administered under ideal clinical conditions, was associated with significantly greater reductions in pain compared with the control condition. However, statistical measures of the treatment effect, or effect size, were not used in these studies. In the absence of measures of effect size, a comparison of pain scores between the ketamine and control groups could help guide decisions about the use of ketamine in clinical practice."


1. Cohen, S. P., Bhatia, A., Buvanendran, A., Schwenk, E. S., Wasan, A. D., Hurley, R. W., Viscusi, E. R., Narouze, S., Davis, F. N., Ritchie, E. C., Lubenow, T. R., & Hooten, W. M. (2018). Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Regional anesthesia and pain medicine, 43(5), 521–546.

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