Feasibility and pharmacokinetics of nebulized S-ketamine inhalation in healthy adults

Traditionally, ketamine is dissolved in saline and administered intravenously
or intramuscularly. However, a dozen alternative routes, such as oral, nasal
and rectal administration, have been described in the need of a less
resource-consuming and painless administration [5]. Intranasal ketamine is
frequently used in clinic and is known to result in rapid (within 2 minutes)
detectable blood concentrations with peak ketamine plasma concentrations 20-30
minutes after intranasal administration [3,4]. Ketamine-induced analgesia after
intranasal application is known to correlate with plasma concentrations of both
ketamine and its metabolite norketamine [4]. Intranasal ketamine administration
is without overt side effects. Described adverse events are transient and
similar as observed with other routes of administration. These include
dizziness, nausea, feeling of unreality, sedation, and are dose-related
[2,4,7]. No adverse events have been described after intranasal ketamine use
that affect vital signs (such as oxygen saturation and blood pressure).
Surprisingly, so far there have been no reports of ongoing
(www.clinicaltrials.gov, www.clinicaltrialsregister.eu,
www.umin.ac.jp/ctr/index.htm, http://www.anzctr.org.au,
http://www.trialregister.nl (last checked: March 2015)) or published (Pubmed,
EMbase (last checked: March 2015)) human studies that tested ketamine
administration by inhalation, with the exception of one publication. In this
publication, nebulized ketamine (50 mg) was administered to postoperative
patients to assess reduction of post-operative sore throat [1]. The authors
describe that nebulized ketamine was tasteless, and they observed reduced
post-operative sore throat in ketamine-treated patients, compared to
placebo-treated patients. What is of importance is that patients in both groups
remained hemodynamically stable with no nausea, vomiting, stridor,
laryngospasm, cough, dry mouth, hoarseness, dissociative symptoms or any other
adverse effect during the entire study period [1]. However, their primary aim
was to assess topical analgesia in the throat, and they did not study systemic
analgesia and/or blood pharmacokinetics. Canine data showed effective plasma
levels after inhalation of nebulized ketamine (unpublished observations). For
humans no pharmacological data on administration of nebulized ketamine is
available. Nebulization would be a novel route for ketamine administration that
is an easy and safe alternative in the treatment of acute and chronic pain and
clinical depression. This would allow painless and easy administration in a
huge population of patients. In the future, even at home self-application might
be feasible for depressive or chronic pain patients.

Hypothesis #1 efficacy
We hypothesize that a quick onset and a good adjustability of analgesia can be
achieved with inhaled ketamine.

Hypothesis #2 safety
Inhalation of nebulized ketamine might lead to a fast onset of analgesia, with
limited adverse events.

To this end, nebulized ketamine will be administered to healthy volunteers and
pharmacokinetic and pharmacodynamic parameters will be measured.

Open label

Mild to moderate: psychomimetic side effects during expsoure to ketamine