Ketamine Therapy Indications: Why This NMDA Antagonist Is Not Your Average Anesthetic

If you’ve been doing procedures long enough, you know that ketamine is one of the OR’s main go-to sedatives. It was first introduced in the 1970s as a quick-acting non-barbiturate anesthetic. But it has found many uses outside of the surgical suite since then, thanks to its effect on multiple receptors.

Ketamine is primarily a noncompetitive NMDA inhibitor. However, its other actions give it unique advantages for treating various conditions. In this article, we talk about the different settings where ketamine treatment is known to be useful or even critical.

Procedural Sedation

Not everyone has a high pain tolerance or responds to verbal anesthesia. And patient anxiety and awareness may set back a much-needed but potentially painful treatment. To get around this problem, clinicians often sedate their patients preoperatively.

Procedural sedation using ketamine alone is useful for both elective and emergency cases. It has proven to be as efficacious as propofol sedation but with less risk of clinically significant respiratory depression. Since it simultaneously acts on opioid receptors, ketamine administration also gives better pain relief (Morrison et al., 2017; Miner et al., 2010; Oh and Kingsley, 2018).

In TIVA procedures, propofol’s anesthetic effect, onset and duration improve when given with low-dose ketamine. This combination’s side effect profile was also found to be better (Hiremath, 2021). Preliminary studies show that intranasal dosing is just as effective and safe as IV infusion in children (Poonai et al., 2017). You can manage young patients better if you can give them medication without a fuss.

Pain Management

Picture injured soldiers and laboring mothers in the old days when surgery was done without anesthesia or potent analgesics. Then imagine yourself fixing them up, torn between wanting to give good care and stopping midway because of their heartbreaking screams.

Not fun, is it? We’ve obviously come a long way from that. However, in modern practice, another concern has reared its ugly head as a consequence of excellent pain control. We’re talking about drug dependence, for which opiates are the most notorious. Fortunately, low-dose ketamine infusion was found to be as effective as IV morphine for acute pain of various causes (Balzer et al., 2020; Lubega et al., 2018). It likewise produces fewer adverse events (Mashidfar et al., 2017). Perioperative ketamine infusion was also proven to reduce postoperative opioid requirement (Garcia-Henares et al., 2018; Riddell et al., 2019) and the risk of developing opioid dependency (Nielsen et al., 2018). For chronic pain, ketamine has been shown to be more effective than methadone in the treatment of refractory neuropathic pain (Rigo et al., 2017). Central sensitization underlies neuropathic pain. It arises from greater neuronal excitability and synaptic efficacy, as well as the reduced inhibition of NMDA-activated pain afferents. Pain hypersensitivity is its main symptom. Central sensitization is characteristic of complex regional pain syndrome (CRPS) and neuropathic cancer pain, both of which respond to subanesthetic ketamine (Zhao et al., 2018; Bredlau et al., 2013).


Although they make up less than 5% of ED consults (Munoz-Ceron et al., 2019; Cerbo et al., 2005), migraines can be so bad that they can keep many patients from functioning properly.

Treatment is challenging because of the unpredictability of patient response. And you can see that from the wide differences in the mechanisms used by migraine-busting drugs. We’ve used triptans, NSAIDs, steroids, ergotamines, opiates, etc., but none has proven to be a consistently reliable cure.

Meanwhile, piling evidence shows ketamine’s promise in alleviating migraines (Lauritsen et al., 2016; Afridi et al., 2013). Further research can help standardize dosing levels and improve safety and efficacy in the treatment of this condition.

Depression and Other Mental Health Issues

Suicidality plagues not only people diagnosed with psychiatric disorders but also those that are not. Suicidal ideation can be triggered by a lot of things—bad health news, relationship abuse, catastrophes, feelings of failure, loss of a loved one, and many others. Getting rid of depressive symptoms, such as suicidality, eating disorders, and sleep disturbance, is lifesaving. Conventional antidepressants and ECT have been the main therapeutic options for many decades, but it takes weeks before the effects of these treatments kick in. Care providers may treat acute agitation with fast-acting anxiolytics or antipsychotics, but these are fraught with distressing complications. In recent years, there has been an explosion of research supporting ketamine’s antidepressant potential.

Ketamine infusion therapy has been found to provide quicker symptomatic relief compared to midazolam in patients with treatment-resistant depression (Murrough et al., 2013) and cancer-related suicidal ideation (Fan et al., 2017). Moreover, it is effective in treating major depressive disorder across age groups (Dwyer et al., 2021; Kim et al., 2020; O’Brien et al., 2019). Single infusions only transiently benefit the patients. However, repeated sessions can sustain ketamine’s antidepressant effects and decrease its dissociative side effects (Phillips et al., 2019). Ketamine therapy can also treat bipolar depression (Grunebaum et al., 2017), PTSD symptoms (Feder et al., 2014), and substance abuse (Jones et al., 2018). Patients who respond to ketamine therapy also experience neurocognitive function and sleep improvement. Evidence points to the drug’s BDNF-stimulating ability, which is presumed to cause rapid neuroplastic changes that improve memory, learning, and mood (Wang et al., 2021; Murrough et al., 2015) In 2019, the FDA approved the use of Spravato, a brand of intranasal esketamine, for treatment-resistant depression. It is self-administered, but patients must take it under medical supervision at a certified doctor’s clinic (US Food and Drug Administration, 2019).

Emergency and Critical Care Medicine

Not all anesthetic drugs are suitable for unstable patients as most of them tend to worsen their condition. But ketamine is one of a kind because it is less likely to compromise pulmonary and hemodynamic functions. Its applications in emergency and critical care medicine include the following:

  • Prehospital Trauma Care

Ketamine can be given in place of morphine to reduce the risk of

hypotension and respiratory depression in this setting (Tran et al., 2014).

  • Rapid-Sequence Intubation of Patients in Shock

This NMDA receptor antagonist also has sympathomimetic effects. It has been

shown to be a safe alternative to etomidate, which can cause adrenal insufficiency

(Jabre et al., 2009).

  • Acute Asthma Attacks

Ketamine infusion improves patient response to the standard treatment compared

to placebo (Esmailian et al., 2018). It is as effective as intravenous aminophylline in

treating pediatric asthma unresponsive to conventional therapies (Tiwari et al.,

2016). Sympathomimetic action is also thought to be involved.

  • Refractory Status Epilepticus

Early ketamine infusion has been shown to decrease mortality and to have

neuroprotective effects in patients with intractable seizures (Gaspard et al., 2013;

Rosati et al., 2018).

Growing evidence proves that ketamine treatment can be a vital alternative to standard emergency and critical care interventions.


As you can see, ketamine is a unique anesthetic agent, with many non-anesthetic uses. Ketamine therapy would make a great addition to your clinical practice especially as it relates to its use for mental health and chronic pain relief.

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