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.
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.
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.
Afridi, S. K., Griffin, N. J., Kaube, H. & Goadsby, P. J. (2013). A Randomized Controlled Trial of Intranasal Ketamine in Migraine with Prolonged Aura. Neurology, 80(7), 642-647. https://doi.org/10.1212/wnl.0b013e3182824e66
Balzer, N., McLeod, S. L., Walsh, C. & Grewal, K. (2020). Low-Dose Ketamine for Acute Pain Control in the Emergency Department: A Systematic Review and Meta-Analysis. Academic Emergency Medicine, 28(4), 444-454. https://doi.org/10.1111/acem.14159
Bredlau, A. L., Thakur, R., Korones, D. N. & Dworkin, R. H. (2013). Ketamine for Pain in Adults and Children with Cancer: A Systematic Review and Synthesis of the Literature. Pain Medicine, 14(10), 1505-1517. https://doi.org/10.1111/pme.12182
Cerbo, R., Villani, V., Bruti, G., Di Santi, F. & Mostardini C. (2005). Primary Headache in Emergency Department: Prevalence, Clinical Features and Therapeutical Approach. The Journal of Headache and Pain, 6, 287-289. https://doi.org/10.1007/s10194-005-0210-1
Dwyer, J. B., Landeros-Weisenberger, A., Johnson, J. A., Tobon, A. L., Flores, J. M., Nasir, M., Couloures, K., Sanacora, G. & Bloch, M. H. (2021). Efficacy of Intravenous Ketamine in Adolescent Treatment-Resistant Depression: A Randomized Midazolam-Controlled Trial. The American Journal of Psychiatry, 178(4), 352-362. https://doi.org/10.1176/appi.ajp.2020.20010018
Esmailian, M., Esfahani, M. K. & Heydari, F. (2018). The Effect of Low-Dose Ketamine in Treating Acute Asthma Attack: A Randomized Clinical Trial. Emergency, 6(1), 1-5. http://dx.doi.org/10.22037/aaem.v6i1.64
Fan, W., Yang, H. K., Sun, Y., Zhang, J., Li, G., Zheng, Y. & Liu, Y. (2017). Ketamine Rapidly Relieves Acute Suicidal Ideation in Cancer Patients: A Randomized Controlled Clinical Trial. Oncotarget, 8(2), 2356-2360. https://doi.org/10.18632/oncotarget.13743
Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., Kirkwood, K., Rot, M., Lapidus, K. A. B., Wan, L., Isosifescu, D. & Charney, D. S. (2014). Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder A Randomized Clinical Trial. JAMA Psychiatry, 71(6), 681-688. https://doi.org/10.1001/jamapsychiatry.2014.62
Garcia-Henares, J. F., Moral-Munoz, J. A., Salazar, A. & Del Pozo, E. (2018). Effects of Ketamine on Postoperative Pain after Remifentanil-Based Anesthesia for Major and Minor Surgery in Adults: A Systematic Review and Meta-Analysis. Frontiers in Pharmacology, 9, 1-14. https://dx.doi.org/10.3389%2Ffphar.2018.00921
Gaspard, N., Foreman, B., Judd, L. M., Brenton, J. N., Nathan, B. R., McCoy, B. M., Al-Otaibi, A., Kilbride, R., Fernandez, I. S., Mendoza, L., Samuel, S., Zakaria, A., Kalamangalam, G. P., Legros, B., Szaflarski, J. P., Loddenkemper, T., Hahn, C. D., Goodkin, H. P. Claassen, J… Laroche, S. M. (2013). Intravenous Ketamine for the Treatment of Refractory Status Epilepticus: A Retrospective Multicenter Study. Epilepsia, 54(8), 1498-1503. https://doi.org/10.1111/epi.12247
Grunebaum, M. F., Ellis, S. P., Keilp, J. G., Moitra, V. K., Cooper, T. B., Marver, J. E., Burke, A. K., Milak, M. S., Sublette, M. E., Oquendo, M. A. & Mann, J. J. (2017). Ketamine versus Midazolam in Bipolar Depression with Suicidal Thoughts: A Pilot Midazolam-Controlled Randomized Clinical Trial. Bipolar Disorders, 19(3), 176-183. https://doi.org/10.1111/bdi.12487
Hiremath, S. (2021). A Clinical Comparative Study of Propofol and Ketamine Combination (Ketofol) versus Either Drug Alone in Short Surgeries and Procedures. IAR Journal of Anesthesiology and Critical Care, 2(3), 17-23.
Jabre, P., Combes, X., Lapostolle, F., Dhaouadi, M., Ricard-Hibon, A., Vivien, B., Bertrand, L., Beltramini, A., Gamand, P., Albizzati, S., Perdrizet, D., Lebail, G., Chollet-Xemard, C., Maxime, V., Brun-Buisson, C., Lefrant, J., Bollaert, P., Megarbane, B., Ricard, J… KETASED Collaborative Study Group (2009). Etomidate versus Ketamine for Rapid Sequence Intubation in Acutely Ill Patients: A Multicentre Randomised Controlled Trial. The Lancet, 374(9686), 293-300. https://doi.org/10.1016/s0140-6736(09)60949-1
Jones, J. L., Mateus, C. F., Malcolm, R. J., Brady, K. T. & Back, S. E. (2018). Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review. Frontiers in Psychiatry, 9, 1-10. https://doi.org/10.3389/fpsyt.2018.00277
Kim, S., Rush, B. S. & Rice, T. R. (2020). A Systematic Review of Therapeutic Ketamine Use in Children and Adolescents with Treatment-Resistant Mood Disorders. European Child and Adolescent Psychiatry, 2020. https://doi.org/10.1007/s00787-020-01542-3
Lauritsen, C., Mazuera, S., Lipton, R. B. & Ashina, S. (2016). Intravenous Ketamine for Subacute Treatment of Refractory Chronic Migraine: A Case Series. The Journal of Headache and Pain, 17. 1-5. https://doi.org/10.1186/s10194-016-0700-3
Lubega, F. A., De Silva, M. S., Munube, D., Nkwine, R., Tumukunde, J., Agaba, P. K., Nabukenya, M. T., Bulamba, F. & Luggya, T. S. (2018). Low-Dose Ketamine versus Morphine for Acute Severe Vaso-Occlusive Pain in Children: A Randomized Controlled Trial. Scandinavian Journal of Pain, 18(1), 19-27. https://doi.org/10.1515/sjpain-2017-0140
Mashidfar, B., Mofidi, M., Fattahi, M., Farsi, D., Moghadam, P. H., Abbasi, S. & Rezai, M. (2017). Acute Pain Management in Emergency Department, Low Dose Ketamine versus Morphine, a Randomized Clinical Trial. Anesthesiology and Pain Medicine, 7(6), 1-6. https://dx.doi.org/10.5812%2Faapm.60561
Miner, J. R., Gray, R. O., Bahr, J., Patel, R. & McGill, J. W. (2010). Randomized Clinical Trial of Propofol versus Ketamine for Procedural Sedation in the Emergency Department. Academic Emergency Medicine, 17(6), 604-611. https://doi.org/10.1111/j.1553-2712.2010.00776.x
Morrison, T., Carender, C., Kilbane, B. & Liu, R. W. (2017). Procedural Sedation with Ketamine versus Propofol for Closed Reduction of Pediatric Both Bone Forearm Fractures. Orthopedics, 40(5), 288-294. https://doi.org/10.3928/01477447-20170824-01
Munoz-Ceron J., Marin-Careaga, V., Pena, L., Mutis, J. & Ortiz, G. (2019). Headache at the Emergency Room: Etiologies, Diagnostic Usefulness of the ICHD 3 Criteria, Red and Green Flags. PLOS One, 14(1), 1-8. https://doi.org/10.1371/journal.pone.0208728
Murrough, J. W., Burdick, K. E., Levitch, C. F., Perez, A. M., Brallier, J. W., Chang, L. C., Foulkes, A., Charney, D. S., Mathew, S. J. & Iosifescu, D. V. (2015). Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial. Neuropsychopharmacology, 40(5), 1084-1090. https://doi.org/10.1038/npp.2014.298
Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K. Green, C. E., Perez, A. M., Iqbal, S., Pillemer, S., Foulkes, A., Shah, A., Charney, D. S. & Mathew, S. J. (2013). Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. The American Journal of Psychiatry, 170(10), 1134-1142. https://doi.org/10.1176/appi.ajp.2013.13030392
Nielsen, R. V., Fomsgaard, J. S., Nikolajsen, L., Dahl, J. B. & Mathiesen, O. (2018). Intraoperative S-Ketamine for the Reduction of Opioid Consumption and Pain One Year after Spine Surgery: A Randomized Clinical Trial of Opioid-Dependent Patients. European Journal of Pain, 23(3), 455-460. https://doi.org/10.1002/ejp.1317
O’Brien, B., Green, C. E., Al-Jurdi, R., Chang, L., Lijffijt, M., Iqbal, S., Iqbal, T., Swann, A. C. & Mathew, S. J. (2019). Bayesian Adaptive Randomization Trial of Intravenous Ketamine for Veterans with Late-Life Treatment-Resistant Depression. Contemporary Clinical Trials Communications, 16, 1-6. https://doi.org/10.1016/j.conctc.2019.100432
Oh, S. & Kingsley, K. (2018). Efficacy of Ketamine in Pediatric Sedation Dentistry: A Systematic Review. Compendium of Continuing Education in Dentistry, 39(5), e1-e4.
Phillips, J. L., Norris, S., Talbot, J., Birmingham, M., Hatchard, T., Ortiz, A., Owoeye, O., Batten, L. A. & Blier, P. (2019). Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. The American Journal of Psychiatry, 176(5), 401-409. https://doi.org/10.1176/appi.ajp.2018.18070834
Poonai, N., Canton, K., Ali, S., Hendrikx, S., Shah, A., Miller, M., Joubert, G., Rieder, M. & Hartling, L. (2017). Intranasal Ketamine for Procedural Sedation and Analgesia in Children: A Systematic Review. PLOS One, 12(3), 1-15. https://doi.org/10.1371/journal.pone.0173253
Riddell, J. M., Trummel, J. M. & Onakpoya, I. J. (2019). Low-Dose Ketamine in Painful Orthopaedic Surgery: A Systematic Review and Meta-Analysis. British Journal of Anesthesia, 123(3), 325-334. https://doi.org/10.1016/j.bja.2019.05.043
Rigo, F. K., Trevisan, G., Godoy, M. C., Rossato, M. F., Dalmolin, G. D., Silva, M. A., Menezes, M. S., Caumo, W. & Ferreira, J. (2017). Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial. Pain Physician, 20, 207-215.
Rosati, A., De Masi, S. & Guerrini, R. (2018). Ketamine for Refractory Status Epilepticus: A Systematic Review. CNS Drugs, 32(11), 997-1009. https://doi.org/10.1007/s40263-018-0569-6
Tiwari, A., Guglani, V. & Jat, K. R. (2016). Ketamine versus Aminophylline for Acute Asthma in Children: A Randomized, Controlled Trial. Annals of Thoracic Medicine, 11(4), 283-288. https://dx.doi.org/10.4103%2F1817-1737.191874
Tran, K. P., Nguyen, Q., Truong, X. N., Le, V., Le, V. P., Mai, N., Husum, H. & Losvik, O. K. (2014). A Comparison of Ketamine and Morphine Analgesia in Prehospital Trauma Care: A Cluster Randomized Clinical Trial in Rural Quang Tri Province, Vietnam. Prehospital Emergency Care, 18(2), 257-264. https://doi.org/10.3109/10903127.2013.851307
US Food and Drug Administration (2019, March 5). FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression; Available Only at a Certified Doctor’s Office or Clinic. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified
Wang, M., Zhang, B., Zhou, Y., Wang, C., Zheng, W., Liu, W., Zhan, Y., Lan, X. & Ning, Y. (2021). Sleep Improvement is Associated with the Antidepressant Efficacy of Repeated-Dose Ketamine and Serum BDNF Levels: A Post-Hoc Analysis. Pharmacological Reports, 73(2), 594-603. https://doi.org/10.1007/s43440-020-00203-1
Zhao, J., Wang, Y. & Wang, D. (2018). The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis. Current Pain and Headache Reports, 22(2), 1-8. https://doi.org/10.1007/s11916-018-0664-x