Updated: Aug 11, 2021
When you read about ketamine’s non-anesthetic applications, you will inevitably come across a related term, “esketamine.” Ketamine’s off-label uses emerged from the exploration of the systemic effects of its intravenous racemic form. But decades later, it was intranasal esketamine that got the FDA’s nod for the treatment of depression.
Healthcare providers are trained and licensed to use both forms of the medication. As a clinician, it falls on you to decide which one to use when the need arises. That’s why we wrote this quick guide for you.
Here, we explain the chemical, clinical and pharmacological differences between intravenous racemic ketamine and intranasal esketamine.
Flip, Flop or Neutral: Are All Ketamines Created Equal?
Ketamine exists in two enantiomeric forms:
R-ketamine, otherwise called “arketamine”
and S-ketamine, also known as “esketamine”
The two molecules have the same atoms in similar locations, but their orientation differs so that they are mirror images of each other. Arketamine rotates polarized light clockwise, while esketamine spins it in the opposite direction. Their optical differences diminish when combined in a racemic mixture (Andrade, 2017).
Ketamine Enantiomerism (Yang et al., 2018)
Clinically, the most commonly used form of ketamine is the intravenous racemate. It was the first ketamine type investigated for treating depression. NMDA antagonism was thought to be primarily responsible for its antidepressant effects.
Years later, esketamine was found to bind more strongly to the NMDA receptor than racemic ketamine, making it the more potent form. This discovery ignited hopes of safer dosing levels, better pricing, and ease of administration. Intranasal esketamine was then conceived and born (Wei et al., 2021).
Intravenous vs. Intranasal: Which Route Is More Beneficial?
We know from practice that the intravenous route is the most efficient method of drug delivery, but it is not the ideal one.
Cannulation of cancer patients and those in shock can easily turn into a fishing expedition. IV start kits are not always available when you need them, as in mass casualties.
And who never wishes for a mimosa after sticking a fussy, chubby-handed patient?
On the other hand, intranasal dosing offers several advantages over intravenous infusion (Musumeci et al., 2019; Hanson & Frey, 2008).
Intranasal delivery is non-invasive, minimizing tissue trauma and infection risk.
It is convenient, both for the patient and the care provider.
Rapid drug distribution is possible even without tissue injury because of the nasal cavity’s vascularity and avoidance of the first-pass effect.
It can reduce the systemic side effects of a drug.
It is quick for CNS medications like esketamine, as it bypasses the blood-brain barrier.
It is more affordable because it uses cheaper packaging, fewer consumables, and less manpower.
It produces less medical waste.
However, drug formulators have to keep the following in mind when making a medicated nasal spray:
Mucociliary clearance can speed up drug elimination.
Nasal congestion or injury can compromise drug delivery.
The nasal cavity has limited room, so only potent medications can be given through this route.
Nasal mucosal irritation is a risk with repeated use, which may also predispose patients to infection.
Drug losses can occur if the patient uses the wrong application technique.
Titrating an intranasal medication is not that easy.
Johnson and Johnson market Spravato, the first esketamine nasal spray brand that the FDA approved for refractory depression treatment. Various studies show that it is better than a placebo in reducing depressive symptoms and suicidal ideation (US Food and Drug Administration, 2019). However, no randomized controlled trial has ever compared it directly with ketamine infusion for any clinical condition.
Racemate vs. Pure S-Enantiomer: From Evidence of Late, What Do Ketamine Experts Conjecture?
Here’s what we know so far about the performance of these two ketamine treatment forms:
Both IV ketamine and IN esketamine are more effective than placebo in treating acute suicidal ideation and depressive symptoms (Xiong et al., 2021). They also work much faster and are more likely to produce stable remission (Zarate et al., 2006; Wang et al., 2021).
When used preoperatively, both the pure enantiomer and racemic mixture provide satisfactory levels of sedation compared to placebo (Poonai et al., 2017).
Both forms have comparative efficacy to opioids in managing acute (Balzer et al., 2020; Shimonovich et al., 2016) and chronic pain (Rigo et al., 2017; Page & Nirabhawane, 2018).
Both ketamine versions show potential in treating migraine (Afridi et al., 2013; Lauritsen et al., 2016; Pomeroy et al., 2017; Turner et al., 2019), although further studies are needed to standardize dosing levels and patient classification strategies.
No large, double-blind, randomized clinical trial has ever compared IV ketamine treatment directly with intranasally delivered esketamine. But recent studies suggest that the IV racemate could be better.
Among patients with treatment-resistant depression and bipolar depression, racemic ketamine produces a better overall response, greater remission rates, and fewer adverse event-related drop-outs than esketamine. Moreover, subanesthetic racemic ketamine infusion is less likely to cause dissociation than intranasal esketamine (Bahji et al., 2021).
IV ketamine infusion is superior to intranasal esketamine treatment in improving the depressive symptoms of patients with baseline suicidality (Siegel et al., 2021).
IV morphine is slightly better than esketamine nasal spray in terms of pain reduction speed and side effect profile (Li et al., 2021). In contrast, IV ketamine has been more consistent in mimicking IV morphine’s analgesia but not its undesirable actions (Balzer et al., 2020).
These newer findings may look counterintuitive on the surface, but investigators believe that the drug’s enantiomerism can solve this mystery.
Mirror, Mirror on the Wall, Which Ketamine Enantiomer Is the Best of All?
Drug isomers differ in their affinity for their biological targets, and consequently, their pharmacological effects. It’s easy to fall into the trap of assuming that esketamine alone is better than the racemate when you think of it only as an NMDA receptor inhibitor.
However, animal studies show that ketamine’s antidepressant effect involves other signaling pathways. Additionally, the pharmacological differences between its enantiomers could be responsible for the racemic mixture’s apparent benefits.
Arketamine inhibits NMDA weakly, but its antidepressant action is more lingering. It creates more neuroplastic changes, though esketamine-induced synaptic rewiring lasts longer (Andrade, 2017). These findings may be explained by the enantiomers’ contrasting effects on NMDA-independent pathways. The neurotrophin BDNF mediates neuroplasticity, and NMDA inhibition is only one of its many stimuli (Yang et al., 2018).
Esketamine, but not arketamine, enhances dopamine release in the striatum, which may contribute to the drug’s dissociative side effects and abuse potential (Wei et al., 2021). Esketamine’s pharmacological effects are thought to diminish in the racemic mix.
The enantiomers’ metabolites also behave differently from each other. S-norketamine exhibits antidepressant actions similar to those of esketamine but none of its side effects. The changes are mediated by BDNF but occur independently of NMDA and AMPA blockade. By comparison, R-norketamine has demonstrated weaker antidepressant effects under the same experimental conditions (Yang et al., 2018).
Human signaling systems are much more complicated than those of animals, making the enantiomers’ clinical effects even harder to predict. Nevertheless, what’s important is that we have peace of mind knowing that these two lifesaving treatments are in our arsenal. They may be heavily regulated, but that is still much better than having nothing at all.
So Here’s the Clincher: Which Isomer and How to Deliver?
IV ketamine and IN esketamine are chemically distinct drugs with different pharmacodynamics and pharmacokinetics. Both are proven effective for various conditions, though one may have more advantages than the other, depending on the clinical setting. Clinicians must consider resource availability and patient factors when deciding which one to administer. In the ketamine clinic setting, IV racemic ketamine remains the pharmaceutical of choice for the overwhelming majority of clinicians due to several factoring including its much lower cost, predictable uptake, ability to instantly titrate, and its higher efficacy.
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
Andrade, C. (2017). Ketamine for Depression, 3: Does Chirality Matter? Clinical and Practical Psychopharmacology, 78(6), e674-e677. https://doi.org/10.4088/jcp.17f11681
Bahji, A., Vazquez, G. H. & Zarate, C. A. J. (2021). Comparative Efficacy of Racemic Ketamine and Esketamine for Depression: A Systematic Review and Meta-Analysis. Journal of Affective Disorders, 278, 542-555. https://doi.org/10.1016/j.jad.2020.09.071
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
Hanson, L. R. & Frey, W. H. II. (2008). Intranasal Delivery Bypasses the Blood-Brain Barrier to Target Therapeutic Agents to the Central Nervous System and Treat Neurodegenerative Disease. BMC Neuroscience, 9, 1-4. https://dx.doi.org/10.1186%2F1471-2202-9-S3-S5
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
Li, X., Hua, G. & Peng, F. (2021). Efficacy of Intranasal Ketamine for Acute Pain Management in Adults: A Systematic Review and Meta-Analysis. European Review for Medical and Pharmacological Sciences, 25(8), 3286-3295. https://doi.org/10.26355/eurrev_202104_25738
Musumeci, T., Bonaccorso, A. & Puglisi, G. (2019). Epilepsy Disease and Nose-to-Brain Delivery of Polymeric Nanoparticles: An Overview. Pharmaceutics, 11(3), 1-21. https://doi.org/10.3390/pharmaceutics11030118
Page, N. & Nirabhawane, V. (2018). Intranasal Ketamine for the Management of Incidental Pain during Wound Dressing in Cancer Patients: A Pilot Study. Indian Journal of Palliative Care, 24(1), 58-60. https://dx.doi.org/10.4103%2FIJPC.IJPC_143_17
Pomeroy, J. L., Marmura, M. J., Nahas, S. J. & Viscusi, E. R. (2017). Ketamine Infusions for Treatment Refractory Headache. Headache, 57(2), 276-282. https://doi.org/10.1111/head.13013
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
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.
Shimonovich, S., Gigi, R., Shapira, A., Sarig-Meth, T., Nadav, D., Rozenek, M., West, D. & Halpern, P. (2016). Intranasal Ketamine for Acute Traumatic Pain in the Emergency Department: A Prospective, Randomized Clinical Trial of Efficacy and Safety. BMC Emergency Medicine, 16(1), 1-9. https://doi.org/10.1186/s12873-016-0107-0
Siegel, A. N., Di Vincenzo, J. D., Brietzke, E., Gill, H., Rodrigues, N. B., Lui, L. M. W., Teopiz, K. M., Ng, J., Ho, R., McIntyre, R. S. & Rosenblat, J. D. (2021). Antisuicidal and Antidepressant Effects of Ketamine and Esketamine in Patients with Baseline Suicidality: A Systematic Review. Journal of Psychiatric Research, 137, 426-436. https://doi.org/10.1016/j.jpsychires.2021.03.009
Turner, A. L., Shandley, S., Miller, E., Perry, M. S. & Ryals, B. (2019). Intranasal Ketamine for Abortive Migraine Therapy in Pediatric Patients: A Single-Center Review. Pediatric Neurology, 104, 46-53. https://doi.org/10.1016/j.pediatrneurol.2019.10.007
US Food and Drug Administration (2019, February 12). Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting. https://www.fda.gov/media/121376/download
Wang, S., Kim, N., Na, H., Lim, H. K., Woo, Y. S., Pae, C. & Bahk, W. (2021). Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis. Clinical Psychopharmacology and Neuroscience, 19(2), 341-354. https://doi.org/10.9758/cpn.2021.19.2.341
Wei, Y., Chang, L. & Hashimoto, K. (2021). Molecular Mechanisms Underlying the Antidepressant Actions of Arketamine: Beyond the NMDA Receptor. Molecular Psychiatry. Advance online publication. https://doi.org/10.1038/s41380-021-01121-1
Xiong, J., Lipsitz, O., Chen-Li, D., Rosenblat, J. D., Rodrigues, N. B., Carvalho, I., Lui, L. M. W., Gill, H., Narsi, F., Mansur, R. B., Lee, Y. & McIntyre, R. S. (2021). The Acute Antisuicidal Effects of Single-Dose Intravenous Ketamine and Intranasal Esketamine in Individuals with Major Depression and Bipolar Disorders: A Systematic Review and Meta-Analysis. Journal of Psychiatric Research, 134, 57-68. https://doi.org/10.1016/j.jpsychires.2020.12.038
Yang, C., Kobayashi, S., Nakao, K., Dong, C., Han, M., Qu, Y., Ren, Q., Zhang, J., Ma, M., Toki, H., Yamaguchi, J., Chaki, S., Shirayama, Y., Nakazawa, K., Manabe, T. & Hashimoto, K. (2018). AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine. Biological Psychiatry, 84(8), 591-600. https://doi.org/10.1016/j.biopsych.2018.05.007
Zarate, C. A. J., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S. & Manji, H. K. (2006). A Randomized Trial of an N-Methyl-D-Aspartate Antagonist in Treatment-Resistant Major Depression. Archives of General Psychiatry, 63(8), 856-864. https://doi.org/10.1001/archpsyc.63.8.856