Why is Intravenous (IV) racemic ketamine better than other administration routes, such as intranasal sprays or oral lozenges?
Ketamine is becoming the standard of care to treat mood disorders such as Suicidal Ideations, Depression, and Generalized Anxiety Disorder. Therefore, it is essential to understand the significant clinical differences amongst routes of administration, essentially how the ketamine gets into the body and is available to affect the nerve cells in the emotional centers of the patient’s brain. While the medication is chemically identical, the way it is administered determines how much medication and when it actually gets to the nerve cell membranes to do the “work.” In medical terms, this is referred to as bioavailability. With Ketamine, bioavailability is one of the primary factors that directly affect the patient’s clinical outcomes.
The route that gives the most bioavailability is intravenous (IV), with nearly 100% of the medication administered going directly to the neurons in the brain. In technical terms, this is where the medication blocks the N-methyl-D-aspartate (NDMA) receptor and activates the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor
(AMPA) and Tyrosine Kinase receptors. Intravenous administration allows the physician and treatment team to give you the smallest medication dosage possible while getting the best possible result. It also allows for stopping of the medication infusion if a patient experiences any unpleasant side effects. Intravenous administration is the method that has been studied most and has shown Ketamine to rapidly relieve the symptoms of Suicidal Ideation, Depression, and Generalized Anxiety Disorder. One of the most significant studies using IV ketamine infusions showed up to 85% resolution of Suicidal Ideation after 15 infusions, a 72% response rate of symptoms, and up to 38% remission of all symptoms for depression after 10 infusions.
The next best route of medication administration is intramuscular (IM), which yields about 93% bioavailability, but the absorption may be more erratic as it does not allow for steady controlled and constant administration of the medication over 40 minutes like the IV route of administration. A small study of 27 patients was conducted in Southern India comparing 0.5mg/kg over 40 minutes IV verse 0.5mg/kg IM once and 0.25mg/kg IM once. The results were similar, with 58.86%, 60.29%, and 57.36%, respectively. It should be noted that this was only a one-administration study, and the patients were only followed for four days. Additionally, these numbers are approximately 15% points lower than the IV versions of administration when done in a series of six to ten infusions.
The intranasal route is how Esketamine (Spravato), the S enantiomer or mirror image of racemic Ketamine, is administered. When administered as a nasal spray, the issue is that the absorption via the mucous membranes in the nose is approximately 48%, but may be less if a patient is congested, swallows the medication or sneezes during the administration. The route avoids the first-pass metabolism, which reduces bioavailability with oral ketamine tablets and when other Ketamine is swallowed. Esketamine (Spravato) Nasal Spray requires the patient to be present for two and a half hours, 40 minutes longer per treatment versus IV. Also, the Spravato regimen is 16 infusions over three months instead of six to ten infusions over three weeks because of the reduced bioavailability. The response rate evaluated on day 74 showed 65% of participants responding to the treatment and a decrease of 50% or more in their depression, and 32% of the patients had no-to-mild depression on day 74. IV administration of ketamine is, therefore, less time-intensive, works faster, and the positive effects are greater and longer lasting than a nasal spray of the same medication. Additionally, while Spravato is covered by several insurance companies after a Prior Authorization has been obtained, the cost is approximately three times per session as IV ketamine is, and it isn’t as efficacious.
Ketamine is also available in sublingual and oral formulations in Rapidly Dissolving Tablets (RDTs). The results of some of these patients were studied and published in the Journal of Affective Disorders on the 1st of October, 2022. The results were remission, defined as a 50% improvement of symptoms from depression of 62.9% from the PHQ-9 (Patient and Health Questionnaire – 9) and 62.9% for the symptoms of Generalized Anxiety Disorder based on the GAD-7(General Anxiety Disorder – 7). This paper reported the results for less than half of the eligible patients (43.8%). This makes it difficult to fully assess if the success rates for all or most of the patients were similar or if they excluded multiple patients for unknown reasons.
In summary, Ketamine is an effective therapeutic for treating mood disorders. However, the route of administration does affect the clinical outcome. Studies have shown that Ketamine given intravenously has the most bioavailability, providing the highest standard of care. The most comprehensive studies published use intravenous as the treatment regimen. In one of the most extensive studies, depression had a 72% response rate and 38% remission rate of symptoms of depression. Additionally, this data has shown a rapid resolution of suicidal ideations and thoughts with up to an 85% resolution of symptoms after 15 infusions.
If you are interested in learning more about IV Ketamine treatment, contact us today!