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Citation: Sabia M, Kudur V and Reddy A. Ketamine: Variable Uses
in Medicine. Austin J Anesthesia and Analgesia. 2017; 5(3):
1063.
Austin J Anesthesia and Analgesia - Volume 5 Issue 3 - 2017ISSN
: 2381-893X | www.austinpublishinggroup.com Sabia et al. © All
rights are reserved
Austin Journal of Anesthesia and AnalgesiaOpen Access
Abstract
Ketamine over the years has found its primary use in the setting
of analgesia but recently studies have shown a spectrum of
applications that range in a variety of specialties. The most
profound utility is demonstrated in its application in acute and
chronic pain, both of which has been addressed previously with
opioids over the years. A more novel approach has been in the area
of psychiatry where ketamine has found application in a variety of
pathologies from depression to PTSD. The benefit is not only found
in the efficacy of the intervention but the possible reduction of
the side effect profile versus the standard of care. Further
exploration of ketamine’s use in medicine will only build upon what
we know and drive future application.
Keywords: Ketamine; Pain; Psychiatry; Depression; Acute;
Chronic
SummaryKetamine has a variety of uses in both acute and chronic
pain,
as well as sedation. In addition to its known effect on pain,
recent studies are showing its use in psychiatric conditions as
well. Despite ketamine’s benefits in clinical use, its precise
mechanism still remains unknown. It is believed to act as NMDA and
HCN1 receptors antagonist and possesses positive and negative
modulatory role on analgesia and sedation. Chronic pain is often
managed with ketamine for its hyper-glutamatergic properties in
which the effects of the drug outlast the levels of the drug itself
[1].
IntroductionKetamine has been in use for nearly half a century
as it produces
a multitude of effects with dissociative anesthesia properties.
The spectrum of effects includes hypnosis, anti-nociception,
increased sympathetic activity, and maintenance of the airway
[2].
Ketamine causes dependent blockade of the NMDA receptor which
creates a blockade of the excitatory synaptic activity. This in
turn creates a loss of responsiveness that allows it to aid in
several clinical scenarios from acute and chronic pain to the most
recent- as an antidepressant [1].
It has been shown that the effects of ketamine remain long after
the drug has been excreted from the body, which makes it necessary
to create a dose-response curve. This dose-response curve can be
affected by a variety of factors. For instance, if the drug has a
specific response in its molecular state in the lab, there must be
a reason that same effect is not occurring in living organisms. One
of the theories includes ketamine’s inability to penetrate the
blood-brain barrier, or the presence of enzymes causing metabolism
of the drug itself.
Molecular Actions of KetamineAt concentrations within the
clinical dose range, ketamine is now
known to directly affect a wide range of cellular processes -
including blockade of NMDA channels, nicotinic ACh channels, delta
and mu-opioid and the nitric-oxide (NO)- cyclic
guanosine-mono-phosphate (cGMP) system (Figure 1) [3].
Mini Review
Ketamine: Variable Uses in MedicineSabia M1*, Kudur V1 and Reddy
A21Department of Anesthesiology, Cooper University Hospital, USA
2Department of Emergency Medicine, Cooper University Hospital,
USA
*Corresponding author: Sabia M, Department of Anesthesiology,
Cooper University Hospital, USA
Received: November 06, 2017; Accepted: November 28, 2017;
Published: December 05, 2017
Ketamine disrupts large number cellular processes, such as
altered gene expression and protein regulation. NMDA control of
calcium entry into the cell and the intracellular effects of
calcium ions on protein and mitochondrial function can affect this
[4].
Ketamine has been shown to result in suppression of immediate
early gene expression at the site of mechanical injury. This alters
the regulation of NMDA receptor phosphorylation and NMDA receptor
mRNA expression that would result in a reduction in neuropathic
pain [3].
NMDA action is influenced by competitive antagonists, open
channel blocks, and non-competitive antagonists. Each compound has
a different NMDA subtype which also results in a different spectrum
of action [1]. For instance GLuN2b and GluN2a are both found within
the brain however the GluN2B affects more of the limbic system,
spinal cord and thalamus, while GluN2C is specific to the thalamus
and cerebellum, and GluN2D to the brainstem, diencephalon, and
spinal cord [2]. This allows ketamine to affect several parts of
the brain through different channels and produce a variety of
responses, each pertaining to different physiologic processes
[1].
PharmacologyKetamine is metabolized into two major metabolites
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norketamine and dehydronorketamine of the two, norketamine is
the predominant metabolite and the non-competitive antagonist of
the NMDA receptor, which contributes to ketamine analgesia. The
half-life of ketamine varies between two and two and half hours
(Figure 2) [5].
Administration routes for ketamine include IV, intramuscular,
intranasal, epidural, subcutaneous, transdermal, intra-articular,
sublingual and oral. Oral ketamine undergoes extensive first-pass
liver metabolism resulting in a bioavailability of approximately
16%. The IM administration results in a bioavailability of
approximately 93% [5].
When comparing IV and oral levels of ketamine, oral
administration results in a higher level of drug than via IV
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administration. After IV administration, the plasma norketamine
level rises but remains below the plasma ketamine level for about 2
hours. After administration, ketamine is rapidly metabolized into
norketamine via cytochrome P450 enzymes in the liver, and
norketamine is further metabolized into hydroxynorketamine.
Ketamine and norketamine are both centrally acting NMDA receptor
antagonists, while hydroxynorketamine has no pharmacological
activity [6].
Once ketamine is metabolized to norketamine in the liver via
cytochrome P450, the next step is to determine its effect compared
to ketamine. Many studies measure the plasma concentration of
ketamine and norketamine by using rifampicin, which is a CYP450
inducer. Using this method, the effectiveness of the metabolite and
its actions are measured. When compared, it is said that
norketamine is approximately 20-60% as potent as its
pre-metabolized form, ketamine [6].
Ketamine Use in PainUntil recently, IV ketamine was widely used
as an acute analgesic.
In recent years, several long terms trials have been developed
about the uses of ketamine on chronic pain varying from days to
weeks to months of pain relief. Although the studies show the
positive effect of pain control, they have not completely addressed
the safety concerns of the long term use. Ketamine has also been
utilized in the treatment of patients with chronic refractory pain
due to cancer and to reduce nonresponsive pain in patients with
complex regional pain syndrome, and phantom limb pain [7].
Ketamine is structurally related to phencyclidine (PCP) and can
be absorbed via IM, IV, oral, topical routes. It is metabolized by
the hepatic microsomal enzymes specifically by cytochrome P450
enzymes including CYP3A4, CYP2B6, and CYP2C9. When ketamine is
administered orally the first pass metabolism by CYP450 enzymes
produces a variety of metabolites with the most active being
norketamine [8]. Norketamine is metabolized to levels three times
higher than the original ketamine agent but its drop in efficacy as
a centrally acting NMDA receptor antagonist is notable.
Norketamine
acts as a non-competitive NMDA receptor antagonist which allows
for a break in the activation of the neuronal pain cascade found in
chronic pain. Norketamine is transformed into dehydronorketamine
via hydroxylation with the help of CYP2B6 and CYP2A6. After further
hydroxylation, these metabolites are able to be excreted in the
bile and kidney [9].
Another metabolite of ketamine that is being explored for its
efficacy in a clinical role is hydroxynorketamine.
Hydroxynorketamine differs from its counterpart norketamine because
of its indirect action on the NMDA receptor rather than direct.
Hydroxynorketamine reduces the serum levels of D-serine, a
coagonist of NMDA, and thus reducing NMDA excitation. In states of
neuropathic pain, depression, chronic pain, and emotional stress
D-serine may have the potential to be used as a biomarker for
pre-and/or post response to ketamine [10].
Uses in Psychiatric ConditionsOne of the newer uses for ketamine
in addition to acute and
chronic pain is for psychiatric conditions. These new uses for
ketamine are still in the early stages and have yet to be
established via long term meta-analysis. As of recent, there are no
randomized, adequately controlled trials of repeated-dose ketamine
for depression has been published. Evidence in support of repeated
ketamine administration has been limited and ketamine therapy
remains a highly experimental treatment approach. Due to
similarities in brain network activity in depression and anxiety
disorders, there is the possibility that ketamine might also be
active in other refractory anxiety disorders. Ketamine may be a
potential therapeutic alternative for patients with refractory
generalized anxiety disorder/social anxiety disorder as well as
post traumatic stress disorder [11-12].
One of the uses of ketamine for psychiatric conditions was
described in the Trauma Interventions using Mindfulness Based
Extinction and Reconsolidation (TIMBER) trial (2017) which analyzes
the use of ketamine in PTSD patients along with specified
psychotherapy. The goal of the trial was to establish the efficacy
of combining dose related ketamine to patients with refractory
trauma memories [12]. This works because ketamine is known to be a
dissociative anesthetic agent and administration of ketamine
Figure 1: Ketamine disrupts multiple cellular processes on the
extracellular side of the NMDA receptor through itself and its
metabolites. Interaction with each subtype results in a different
downstream result leading to a therapeutic treatment.
Figure 2: The breakdown of ketamine into two bioactive
metabolites, Norketamine and Hydroxynorketamine. Norketamine can be
metabolized down further into hydroxylnorketamine in the liver.
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(approx 0.5mg/kg body weight) augments the mindfulness state in
the subject and causes a relaxed and dissociated mental state. This
in turn allows the subject not to respond to the traumatic memories
and accept them passively as they cross their mind. Throughout the
peri-infusion period, the arousal response is kept under control to
avoid risk of retraumatization. This combined targeted approach
integrates the strengths of both psychotherapy and ketamine and
prevents restoration of traumatic experiences and the associated
reactivity [13].
Another use for ketamine within psychiatry presents in the
treatment of refractory bipolar disorder (BPD) as a rapid
antidepressant rescue during acute depressive episodes. The basis
for its efficacy lies in the presence of N-methyl-D-Aspartate
(NMDA) receptor modulation in patients with symptomatic BPD. A
randomized controlled trial conducted between 2006-2009 showed
statistically significant improvements in depression within 40
minutes of receiving ketamine versus placebo. The intervention had
this significant therapeutic result for 3 days with its peak
benefit on day 2. Ketamine was administered by a single intravenous
infusions dose 0.5mg/kg on 2 test days two weeks apart and the
Montgomery As berg Depression Rating Scale was used to assess
response. The evidence provided in this study opens the doors to
ketamine as a rescue and potentially long term maintenance
[14].
DosingTypically, 1-3 mg/kg of ketamine IV post surgery
produce
characteristic changes caused by ketamine. These changes
include: normal pharyngeal-laryngeal reflexes, slightly enhanced
skeletal muscle tone, and cardiovascular and respiratory
stimulation, with minimal respiratory depression [6]. Depending on
the dosage given, the clinical action of ketamine lasts between
thirty minutes to two hours if administered intramuscularly, or
four to six hours if administered orally [12]. Norketamine may also
exhibit enantioselective pharmacological activity e.g.
(S)-norketamine has an 8-fold higher affinity than (R)-norketamine
in a rat cortical wedge separation. In a recent study, ketamine
infusion was titrated for a 5 day infusion for 10-40mg/hour, and
the plasma and urine concentrations of (S)-ketamine, (R)-ketamine,
and their metabolites were obtained on day 3 of the infusion which
revealed that the plasma concentrations of (R)-ketamine was greater
than that of (S)-ketamine [15].
Adverse reactionsKetamine causes many side effects including
nausea/vomiting,
hypertension, psychotropic effects, nightmares, and cognitive
impairment. Several studies performed compare the norketamine
plasma concentrations and how much analgesia is produced while
monitoring side effects. Study analysis indicated that ketamine
produced greater analgesia, psychotropic effects (drug high) and
impairment of cognition than placebo medications [11].
ConclusionOriginally the uses for ketamine were limited to those
related
to analgesia. Over the past several years, it use has been
extended into sedation, and more recently, psychiatric related
uses. Its use in
depression and anxiety is becoming more and more widely studied.
Adequate trials have not yet been accomplished to determine the
best dose range and long term side effects of ketamine with
prolonged use in psychiatric patients.
Research does show that the role of ketamine pharmacology and
metabolism are important factors in expanding the use for ketamine
as many receptors and circuits for anxiety and depression are
similar to those used in analgesia.
References1. Olofsen E, Noppers I, Niesters M, Kharasch E, Aarts
L, Sarton E, and
Dahan A. Estimation of the contribution of norketamine to
ketamine-induced acute pain relief and neurocognitive impairment in
healthy volunteers. Anesthesiology. 2012; 117: 353-364.
2. Mion G and Villevieille T. Ketamine pharmacology: an update
(pharmacodynamics and molecular aspects, recent findings). CNS
neuroscience & therapeutics. 2013; 19: 370-380.
3. Leung LY and Baillie TA. Comparative pharmacology in the rat
of ketamine and its two principal metabolites, norketamine and
(Z)-6-hydroxynorketamine. Journal of medicinal chemistry. 1986; 29:
2396-2399.
4. Domino Edward F. Taming the ketamine tiger. 1965. The Journal
of the American Society of Anesthesiologists. 2010; 113:
678-684.
5. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T,
Reichenberger E, and Perreault M. Outpatient intravenous ketamine
for the treatment of complex regional pain syndrome: A double-blind
placebo controlled study. Pain. 2009; 147: 107-115.
6. Cvrček Petr. Side Effects of Ketamine in the Long-Term
Treatment of Neuropathic Pain. Pain Med. 2008; 9: 253-257.
7. Grant IS, Nimmo WS, and Clements JA. Pharmacokinetics and
analgesic effects of i.m. and oral ketamine. British Journal of
Anaesthesia. 1981; 53: 805-810.
8. Goldberg ME, Torjman MC, Schwartzman RJ, Mager DE, Wainer IW.
Enantioselective pharmacokinetics of (R)-and (S)-ketamine after a
5-day infusion in patients with complex regional pain syndrome.
Chirality. 2011; 23: 138-143.
9. Morgan CJ, Curran HV. Ketamine use: A review. Addiction.
2012; 107: 27-38.
10. Grant IS, Nimmo WS, and Clements JA. Pharmacokinetics and
analgesic effects of i.m. and oral ketamine. British Journal of
Anaesthesia. 1981; 53: 805-810.
11. Kiefer RT, Rohr P, Ploppa A, Nohé B, Dieterich HJ, Grothusen
J, et al. A Pilot Open Isomeric S (+)-Ketamine in Refractory CRPS
Patients. Pain Med Pain Medicine. 2008; 9: 44-54.
12. Kiefer RT, Rohr P, Ploppa A, Dieterich HJ, Grothusen J,
Koffler S, et al. Efficacy of Ketamine in Anesthetic Dosage for the
Treatment of Refractory Complex Regional Pain Syndrome: An
Open-Label Phase II Study. Pain Medicine. 2008; 9: 1173-1201.
13. Cvrček P. Side Effects of Ketamine in the Long-Term
Treatment of Neuropathic Pain. Pain Med Pain Medicine. 2008; 9:
253-257.
14. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein
P, Khalife S. A Randomized Add-on Trial of an N-methyl-D-Aspartate
Antagonist in Treatment-Resistant Bipolar Depression. Arch Gen
Psychiatry. 2010; 67: 793-802.
15. Goldberg ME, Torjman MC, Schwartzman RJ, Mager DE, Wainer I.
Pharmacodynamic profiles of Ketamine (R-) and (S+) with five day
inpatient infusion for the treatment of complex regional pain
syndrome. Pain physician. 2010; 13: 379-387.
https://www.ncbi.nlm.nih.gov/pubmed/22692377https://www.ncbi.nlm.nih.gov/pubmed/22692377https://www.ncbi.nlm.nih.gov/pubmed/22692377https://www.ncbi.nlm.nih.gov/pubmed/22692377https://www.ncbi.nlm.nih.gov/pubmed/23575437https://www.ncbi.nlm.nih.gov/pubmed/23575437https://www.ncbi.nlm.nih.gov/pubmed/23575437https://www.ncbi.nlm.nih.gov/pubmed/3783598https://www.ncbi.nlm.nih.gov/pubmed/3783598https://www.ncbi.nlm.nih.gov/pubmed/3783598https://www.ncbi.nlm.nih.gov/pubmed/20693870https://www.ncbi.nlm.nih.gov/pubmed/20693870https://www.ncbi.nlm.nih.gov/pubmed/19783371https://www.ncbi.nlm.nih.gov/pubmed/19783371https://www.ncbi.nlm.nih.gov/pubmed/19783371https://www.ncbi.nlm.nih.gov/pubmed/19783371https://www.ncbi.nlm.nih.gov/pubmed/18298710https://www.ncbi.nlm.nih.gov/pubmed/18298710https://www.ncbi.nlm.nih.gov/pubmed/7272143https://www.ncbi.nlm.nih.gov/pubmed/7272143https://www.ncbi.nlm.nih.gov/pubmed/7272143https://www.ncbi.nlm.nih.gov/pubmed/20803495https://www.ncbi.nlm.nih.gov/pubmed/20803495https://www.ncbi.nlm.nih.gov/pubmed/20803495https://www.ncbi.nlm.nih.gov/pubmed/20803495https://www.ncbi.nlm.nih.gov/pubmed/21777321https://www.ncbi.nlm.nih.gov/pubmed/7272143https://www.ncbi.nlm.nih.gov/pubmed/7272143https://www.ncbi.nlm.nih.gov/pubmed/7272143https://www.ncbi.nlm.nih.gov/pubmed/18254766https://www.ncbi.nlm.nih.gov/pubmed/18254766https://www.ncbi.nlm.nih.gov/pubmed/18254766https://www.ncbi.nlm.nih.gov/pubmed/18266808https://www.ncbi.nlm.nih.gov/pubmed/18266808https://www.ncbi.nlm.nih.gov/pubmed/18266808https://www.ncbi.nlm.nih.gov/pubmed/18266808https://www.ncbi.nlm.nih.gov/pubmed/18298710https://www.ncbi.nlm.nih.gov/pubmed/18298710https://www.ncbi.nlm.nih.gov/pubmed/20679587https://www.ncbi.nlm.nih.gov/pubmed/20679587https://www.ncbi.nlm.nih.gov/pubmed/20679587https://www.ncbi.nlm.nih.gov/pubmed/20679587https://www.ncbi.nlm.nih.gov/pubmed/20648207https://www.ncbi.nlm.nih.gov/pubmed/20648207https://www.ncbi.nlm.nih.gov/pubmed/20648207https://www.ncbi.nlm.nih.gov/pubmed/20648207
TitleAbstractSummaryIntroductionMolecular Actions of
KetaminePharmacologyKetamine Use in PainUses in Psychiatric
ConditionsDosingAdverse reactions
ConclusionReferencesFigure 1Figure 2
