Oral ketamine for the treatment of pain and treatment-resistant depression

The meta-analysis (2016) examined the antidepressant effects of ketamine in specific regard to its oral administration route. In terms of safety, oral ketamine administration over longer time periods appears to be well-tolerated, but its long-term negative side-effects and the strength of its antidepressant efficacy remain understudied.

Abstract

“Background: Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications.

Aims: To review the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for treatment-resistant depression and pain.

Method: Searches in PubMed with the terms ‘oral ketamine’, ‘depression’, ‘chronic pain’, ‘neuropathic pain’, ‘intravenous ketamine’, ‘intranasal ketamine’ and ‘subcutaneous ketamine’ yielded 88 articles. We reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality.

Results: Overall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for treatment-resistant depression in terms of tolerability and side-effects.

Conclusions: Oral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer-term negative consequences. The short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomised controlled trials.”

Authors: Robert A. Schoevers , Tharcila V. Chaves , Sonya M. Balukova , Marije aan Het Rot & Rudie Kortekaas

Summary

Researchers, clinicians and patients are interested in the rapid antidepressant action of the glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, which occurs within hours of intravenous (i.v.) infusion with ketamine. Ketamine increases the presynaptic release of glutamate, resulting in higher extracellular levels of glutamate.

Ketamine has been studied for treatment-resistant unipolar or bipolar depression. Six double-blind, crossover RCTs have been published that compared a single dose of i.v. ketamine with placebo, but overall the difference between ketamine and placebo (inactive or active) was no longer statistically significant at 7 days post-infusion.

To date, psychiatry has paid little attention to the use of ketamine for chronic pain. Ketamine is a well-known anaesthetic with analgesic effects.

Method

We searched PubMed for studies on ketamine and depression and pain, and extracted information about study type, size, dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects. We designed two graphs with the information provided by the tables.

For depression, 4 studies used oral ketamine, 43 studies used intravenous ketamine, 2 studies used intranasal ketamine, 1 study used sublingual ketamine, and 2 case reports concerned intramuscular ketamine. We found no studies using subcutaneous ketamine for depression.

We calculated the daily oral racemate equivalent dose for intranasal, intramuscular, and sublingual dosing regimens by multiplying the i.v. dose by five, the (S)-ketamine dose by two, and the sublingual dose by 1.5.

Oral ketamine for depression

Five uncontrolled, open-label studies were found that investigated the antidepressant properties of oral ketamine. One study found that patients with treatment-resistant unipolar or bipolar depression were given up to 1.25 mg/kg oral (S)-ketamine for 2 weeks, and another study found that patients with chronic suicidal ideation were treated with ketamine.

Lara etal reported that 10 mg sublingual ketamine improved mood in 20 out of 26 patients with treatment-resistant unipolar or bipolar depression.

Dosing regimen and treatment duration of ketamine in chronic pain

The majority of studies using ketamine for pain used the i.v. route of administration, and administered ketamine once or for as long as 660 days. The doses used in the pain studies differed from 0.1 daily oral racemate equivalent dose via oral administration to 62.5 mg/kg/day intravenously.

Some studies on patients with chronic pain showed that they required higher doses over time. This is in line with preclinical and clinical studies on anaesthesia and studies on ketamine misuse.

The bioavailability of ketamine is low after oral administration, because of extensive first-pass metabolism. Other factors underlying the variability after oral administration include the formulation, state of the stomach, dietary enzyme induction, and individual differences in cytochrome phenotype.

Safety and abuse potential

Ketamine side-effects include psychotomimetic effects, dissociative symptoms, confusion, dizziness, euphoria, elevated blood pressure and increased libido.

Ketamine neurotoxicity has been described in preclinical studies, but the presence of the preservative chlorobutanol may be more important than the ketamine itself. Injecting ketamine in high doses into the subarachnoid space can cause neurotoxicity. Currently available clinical studies with i.v. ketamine used only one or few applications, and prolonged misuse has been associated with white matter changes, memory changes, neurocognitive impairment, reduced well-being, and inflammation and damage to the ureter and bladder.

The majority of studies using oral ketamine for pain and depression did not report side-effects as a major burden in treatment maintenance. Some studies reported increased blood pressure when a benzodiazepine was administered concomitantly, but these side-effects were usually limited to the treatment phase and did not persist after ketamine discontinuation.

Ketamine has been used as a street drug since the 1960s and has been shown to produce hallucinatory and dissociative effects as well as ‘giggliness’. Its misuse potential is higher with i.v. administration or inhalation that produces much more rapid and intensive effects compared to oral administration.

Discussion

Ketamine may be well tolerated in the described doses, but further research is needed to assess its possible longer-term consequences. This includes basic science, acceptability and feasibility studies, ethical perspectives, and ultimately building to randomised trial designs.

The side-effect profile of oral ketamine seems milder than that reported in i.v. studies and in severe drug misusers, but further studies are needed to determine the benefits as well as possible unsolicited consequences of oral ketamine for patients with treatment-resistant depression.