Ketamine Administration Routes at a Glance: A Quick Comparison for Clinicians on the Go

Ketamine repurposing has drawn a lot of scientific interest in recent years. Consequently, its expanding applications—ranging from emergencies to self-administration at home—have made it imperative to explore different routes and dosing options.

We all want a drug that patients can take hassle-free, fix them up in a snap, have no side effects, and get rid of symptoms for good. Currently, something like that doesn’t exist.

Currently, we are short of high-quality comparative data for various ketamine administration routes (Xiong et al., 2021; Glue et al., 2020). The hunt for new ketamine indications has intensified in the last few decades, but some practitioners still want to know if they are giving the medication efficaciously when using non-IV routes of administration. This article aims to enlighten you on what experts have found so far.

Why Do We Need to Probe into Other Ketamine Delivery Methods?

The intravenous route is currently the most widely used for dispensing ketamine, but it is not necessarily the most optimal route for every clinical scenario.

Subanesthetic intravenous ketamine infusions are useful for treating chronic and acute pain, depression, and many other conditions (Gao et al., 2016; Gaspard et al., 2013; Tiwari et al., 2016). However, creating a single highly efficacious, rapid-acting formulation that is cost-effective and convenient to administer for every clinical indication and in all healthcare settings is unlikely, which is why it is so important to understand how various routes of administration could be utilized for various clinical situations.

Ketamine Pharmacokinetics: Does Metabolism Affect Efficacy?

Ketamine is a highly lipophilic molecule. It is only 10-30% protein-bound in plasma, but its distribution volume is high at 2.3 L/kg (Mion & Villevieille, 2013).

Its most important metabolic site is the liver, where 80% is N-demethylated to norketamine by microsomal enzymes. This metabolite is more slowly transformed into 6-hydroxy-norketamine before it is glucuronidated and excreted in bile and urine (Mion & Villevieille, 2013).

Ketamine’s elimination clearance is high at 1000-1600 ml/min, which almost equals the liver blood flow rate. However, its effects may linger with the accumulation of norketamine, which has 20-30% of its parent molecule’s activity (Mion & Villevieille, 2013)

About 5% of the drug is metabolized into other forms outside the liver, particularly the kidneys, intestines, and lungs. Ketamine is also a cytochrome inhibitor, which is thought to be responsible for the occurrence of tachyphylaxis in some users (Mion & Villevieille, 2013).

Glue and colleagues reported that the plasma norketamine-ketamine ratio correlated with the parent drug’s efficacy in patients with treatment-resistant depression or anxiety. Their findings suggest that oral ketamine’s efficacy and tolerability may be due to the parent molecule’s blunted plasma level rise coupled with its active metabolite’s increasing effect over time (Glue et al., 2020).

So when you think about it, ketamine’s unique metabolism may be the key to finding its optimum formulation.

Ketamine Metabolism in the Human Body. Norketamine production is the main pathway and occurs in the liver (Mion & Villevieille, 2013).

How Do the Different Ketamine Dosing Routes Compare?

Here, we rounded up the various ketamine delivery approaches, so you will know what works well and what doesn’t.

Intravenous Ketamine

With this formulation, the drug is injected into the vein, travels through the bloodstream, and reaches its CNS targets without the first-pass effect. IV ketamine, by definition, has 100% bioavailability. When used for procedural sedation or analgesia, the starting dose by this route is 0.25-1 mg/kg for adults and 0.25-2 mg/kg for children. Anesthetic doses are typically higher (Gao et al., 2016).

The onset of analgesic action is 30 seconds (Pai & Heining, 2007), with a duration that can last up to 10 minutes after a bolus (Cohen et al., 2018).

Depressive symptoms respond to as low as 0.1-0.75 mg/kg, given as a 40-45-minute infusion. Two treatments every week are needed for longer-lasting relief. Some patients achieve remission after 6 sessions (Andrade, 2017; Cusin et al., 2016; Loo et al, 2016).

Intravenous ketamine treats various conditions effectively and rapidly, so it is appropriate for life-threatening, time-sensitive conditions like status epilepticus (Gaspard et al., 2013) and suicidal ideation (Bahji et al., 2021). Its analgesic efficacy is similar to that of IV morphine (Balzer et al., 2020). Direct intravascular infusion produces rapid plasma peaking, poses the largest risk for unwanted side effects (Loo et al., 2016)., but also for rapid titration and discontinuation.

Intranasal Ketamine

Intranasal ketamine takes advantage of the rich vascularity inside the nose and its unimpeded access to the blood-brain barrier (Fantacci et al., 2018; Musumeci et al., 2019). Bioavailability is about 45-50% (Schoevers et al., 2016; Mion & Villevieille, 2013), though it can be much higher as long as the drug does not escape into the pharynx or down to the lips (Andrade, 2017).

Subanesthetic doses are within the 0.25-4 mg/kg range (Gao et al., 2016) and may be given for pain management and non-anesthetic applications. Analgesic effects manifest 5-15 minutes after intake (Cohen et al., 2018; Shimonovich et al., 2016) and last up to 3 hours (Andolfatto et al., 2019).

Intranasal racemic ketamine may be used as an analgesic or anesthetic agent (Fantacci et al., 2018). For depression, the esketamine nasal spray, Spravato, is the one with FDA approval. Its dosing schedule is 56-84 mg twice weekly for four weeks, then tapered afterward (Ionescu et al., 2021). Racemic ketamine given intranasally at 50 mg has also shown promise in the treatment of depression (Lapidus et al., 2014).

Oral Ketamine

Using this formulation, drug absorption takes place in the gut capillaries. Then it undergoes extensive first-pass metabolism before systemic distribution. It has the lowest bioavailability—only between 20 and 30%—although increased norketamine formation appears to improve its antidepressant effect (Schoevers et al., 2016; Glue et al., 2020).

For analgesia and sedation, the oral ketamine dose is 3-15 mg/kg in children and up to 500 mg in adults (Gao et al., 2016). Antidepressant dosing is generally lower and has less abuse potential (Schoevers et al., 2016). An oral dose of 1 mg/kg three times a week has been found to be an effective adjunct in treatment-resistant depression (Domany et al., 2019), though it still doesn’t beat IV ketamine treatment (Al Shirawi et al., 2017).

The onset of analgesia for regular oral preparations is 30 minutes, with a duration of about 4-6 hours (Quibell et al., 2011). Meanwhile, the antidepressant effect of extended-release oral ketamine, though delayed, is comparable to that of the subcutaneous drug. But this preparation is more tolerable than the parenteral form (Glue et al., 2020).

Intramuscular Ketamine

Bulky muscles have good vascularity (Nakajima et al., 2020), making them a suitable option for ketamine delivery. IM ketamine injection has a 93% bioavailability (Mion & Villevieille, 2013), 5-minute analgesic onset and 0.5-2-hour effect duration (Quibell et al., 2011). The starting dose for pain management is 4-5 mg/kg (Gao et al., 2016).

For treating depression IM dosing has been studied much less and therefore is not utilized as often clinically. However, a small, open-label, randomized trial showed that the intramuscular injection of 0.25-0.5 mg/kg ketamine was as effective and safe as 0.5 mg/kg intravenous infusion in treating depression (Chilukuri et al., 2014). Another study found that an IM dose of 0.1 mg/kg could be enough to exhibit some antidepressant action (Loo et al., 2016). IM administration in larger doses often needs to be divided into two separate doses administered 15-20 minutes apart due to the rapid onset and higher level of dissociation and other unpleasant side effects. One study showed that repeated IM ketamine treatment may lead to remission (Zanicotti et al., 2012).

Subcutaneous Injection

The subcutaneous route uses the hypodermal capillaries for drug absorption (Usach et al.,

2019). Like its intramuscular version, SC ketamine also has nearly complete bioavailability (Andrade, 2017), although the onset of analgesia may take up to 30 minutes (Cohen et al., 2018; Quibell et al., 2011). Effect duration is also similar to that of IM ketamine (Quibell et al., 2011).

The effective dose of SC ketamine for pain management has not been established. However, subcutaneous infusions of 0.1-1.2 mg/kg/hour have been used for chronic pain (Cohen et al., 2018).

There are even fewer studies exploring the potential of SC ketamine in the treatment of depression. However, Loo and colleagues demonstrated that as low as 0.1 mg/kg injected subcutaneously can treat depressive symptoms effectively and is better tolerated than the IV and IM forms (Loo et al., 2016).

Other Approaches

Other methods of ketamine administration have also been tried for various conditions, but reliable data on these methods are wanting. They include the rectal (Mion & Villevieille, 2013), sublingual (Andrade, 2017), transdermal (Sawynok, 2014), intraosseous (Gao et al., 2016), nebulized inhalation, and spinal routes (Yaksh et al., 2017). Further studies can help determine the optimum doses for these methods in various clinical settings.

Here is a table summarizing the critical differences between various ketamine administration routes:

This quick guide should help you figure out the best ketamine dosing strategies in various clinical situations.

Summing It Up

The discovery of ketamine’s new indications has sparked interest in the reliability and safety of its dosing and various routes of administration. Intravenous infusion is currently the route that is most widely used. However, it may not be ideal for every clinical setting. Clinicians need a thorough understanding of various routes and dosing as well as the ability to exercise sound clinical decision-making.

Here, we just discussed the various approaches to ketamine administration. The information on this subject is still evolving, but you may use this article as a rough but quick guide for your practice.


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