British Journal of Anaesthesia 107 (2): 1236 (2011)

doi:10.1093/bja/aer221
EDITORIAL II
Ketamine: new uses for an old drug?
K. Hirota
1
*
and D. G. Lambert
2
1
Department of Anesthesiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
2
Division of Anaesthesia, Critical Care and Pain Management, University Department of Cardiovascular Sciences, Leicester Royal Inrmary,
Leicester LE1 5WW, UK
* E-mail: hirotak@cc.hirosaki-u.ac.jp
In1996, wepublishedaneditorial Ketamine, mechanism(s) of
action and unusual clinical uses in the British Journal of
Anaesthesia.
1
In that editorial, we described the pharma-
cology of ketamine including bronchodilator, anti-shock, and
neuroprotective actions along with some unusual clinical
applications. The editorial has been cited more than
130 times in total with around 10 citations every year, which
implies that ketamine is still of interest to a wide audience.
However, as ketamine anaesthesia is associated with cardio-
vascular hyperdynamics and disturbing emergence reactions,
this agent is often avoided, despite the ease with which these
adverse reactions can be prevented by pre-administration,
co-administration of sedatives, or both such as benzo-
diazepines, propofol, dexmedetomidine, or droperidol.
In the past 15 yr, ketamine has been reported to possess
several new clinically benecial properties such as poten-
tiation of opioid analgesia, prevention of opioid-induced
acute tolerance and spinal ischaemia, anti-inammatory
actions, preventive effects on recall and awareness during
general anaesthesia, and anti-tumour actions. In this
update editorial, we have focused on these potential clinical
advantages of ketamine.
Antinociception
Ketamine per se produces antinociceptive actions via inhi-
bition of N-methyl-D-aspartate (NMDA) receptors
1
and acti-
vation of descending inhibitory monoaminergic pain
pathways. NMDA receptor-mediated spinal reexes are inti-
mately involved as the pharmacological basis for wind-up,
which contributes to neuropathic pain. Ketamine prevents
pain associated with wind-up.
2
However, ketamine is rarely
used as a sole analgesic agent for postoperative pain
control as it produces psychotomimetic adverse reactions.
Low-dose ketamine is often used as an adjuvant to
opioid-induced analgesia.
Potentiation of opioid analgesia
Ketamine even at non-analgesic doses has been reported to
potentiateopioidanalgesiainrodents. Aninvestigationof sub-
analgesic doses of ketamine (30 mg kg
21
i.p.) on analgesia
induced by morphine (2.5, 5.0, and 7.5 mg kg
21
, s.c.) using
the tail-ick test in rats found that the combination of mor-
phine and ketamine resulted in a dose-related increase in
both intensity and duration of morphine antinociception.
3
This potentiation has also been reported clinically. A systema-
tic review of randomized, controlled clinical trials of ketamine
addition showed that ketamine reduced 24 h patient-
controlled analgesia (PCA) morphine consumption and post-
operative nausea or vomiting.
4
In addition, they described
that adverse effects were mild or absent. A recent review of
randomized, double-blinded clinical trials of ketamine added
to opioid in i.v. PCA for postoperative pain found that the keta-
mineopioid combination could signicantly reduce pain
scores, cumulative morphine consumption, and postoperative
desaturation in patients undergoing thoracic surgery,
although this is less clear in orthopaedic or abdominal
surgery.
5
Ketamine may be useful as an efcient adjuvant
analgesic in chronic pain or palliative care patients. Patients
with uncontrolled severe pain receiving i.v. or epidural PCA
obtained analgesia with ketamine.
6
In a group of patients
with intractable cancer pain, ketamine reduced the total
daily dose of morphine required by 50% in 12 patients; eight
patients were able togohomewitha portable pumpdelivering
morphine and ketamine.
7
The mechanism of opioid acute tolerance and
preventive effects of ketamine
Although opioids are often used as sole analgesics during
anaesthesia and for postoperative pain control, opioids
have been reported to produce hyperalgesia and tolerance.
8
These effects are particularly important in patients suffering
from intractable severe pain caused by malignancy, trauma,
or neuropathy. Tolerance and dependence result from long-
term exposure, high-dose exposure, or both to opioids.
Basic research suggests that receptor desensitization com-
prising loss of receptor function and internalization is
involved.
8 9
Changes in opioid receptor conformation
caused by agonist-induced receptor phosphorylation
increase opioid receptor afnity for cytosolic b-arrestins.
Interaction of b-arrestins with opioid receptors results in
redistribution of opioid receptors from the plasma membrane
to intracellular vesicles. This process has been dened as
Editorial II BJA
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opioid receptor internalization.
8 9
b-Arrestin also desensitizes
cells to opioid by functional uncoupling m-opioid receptors.
8 9
It is important, however, to remember that these general
processes are opioid-dependent. Noxious stimuli such as
surgery may also produce opioid receptor internalization
via NMDA receptor-mediated opioid release. Pretreatment
with NMDA receptor antagonists (MK801, AP5, MRZ2/576,
and MRZ2/596) signicantly inhibited m-opioid receptor
internalization in neurones caused by laparotomy in guinea
pigs.
10
In this context, ketamine is a non-competitive antag-
onist of the NMDA receptor.
1
In addition, at clinically relevant
concentrations, ketamine interacts with the phencyclidine
(PCP)-binding site leading to a signicant inhibition of
NMDA receptor activity.
1
This interaction with the
PCP-binding site appears to be stereoselective with afnity
(K
i
) values of 3.2 and 1.1 mM for S(+)- and R(2)-ketamine,
respectively, implying that subanaesthetic concentrations
of ketamine inhibit the NMDA receptor via the PCP-binding
site.
1
It could therefore be predicted that ketamine could
inhibit opioid receptor internalization. Indeed, ketamine pre-
vents opioid-induced hyperalgesia and acute tolerance. In
rats, fentanyl produced analgesia but also induced early
(hours) and long-lasting hyperalgesia (days) and acute toler-
ance to the analgesic effects of morphine, but ketamine pre-
treatment completely prevented both hyperalgesia and
tolerance.
11
After systemic administration, ketamine is
rapidly metabolized in the liver and lung to norketamine.
Norketamine has been reported to have antinociceptive
actions and to enhance morphines antinociceptive action
to thermal nociception, peripheral neuropathy, and tonic
inammatory pain and blocked tolerance.
12
Therefore, we
believe that norketamine could maintain (parent) poten-
tiation of opioid analgesia and prevention of both hyperalge-
sia and tolerance.
Interaction of ketamine with opioid receptors
Subanaesthetic doses of ketamine potentiate opioid-
analgesia via NMDA receptor block, but what about anaes-
thetic doses? Ketamine has been reported to interact with
MOP(m)-, DOP(d)-, and KOP(k)-opioid receptors.
1
Clinical
studies show that S(+)-ketamine produces two to three
times more potent antinociception than R(2)-ketamine,
1
and in agreement with these clinical observations,
S(+)-ketamine produces a two- to three-fold stereoselec-
tivity (for binding not function) at m- and k- but not
d-receptor.
1 13
Morphine, but not ketamine, analgesia
can be reversed by microinjection of naloxone into the
periaqueductal gray (PAG) region of the rat brain, which
contains m- but not k-receptor.
1
Moreover, microinjection
of ketamine into the PAG did not produce analgesia but
antagonized the effects of morphine. We previously
found that anaesthetic concentrations of ketamine
reversed both m- and k-opioid inhibition of the formation
of cyclic adenosine monophosphate (as a marker of
receptor activation) in Chinese hamster ovary cells expres-
sing recombinant m- and k-opioid receptors, similar to
naloxone.
13
These data suggest that anaesthetic concen-
trations of ketamine could exert antagonistic actions at
both m- and k-opioid receptors. Therefore, high-dose keta-
mine may not be an appropriate addition to opioids.
Anti-inammatory effects
We have previously reported that i.v. ketamine
14
inhibits
albumin extravasation in a rat model of chemical peritonitis.
Recently, the immunoinhibitory effects of ketamine were
found to be partly due to inhibition of transcription factor
activator protein-1 and nuclear factor-kB (NF-kB), which
regulate the production of proinammatory mediators.
15
In vivo, a subanaesthetic dose of ketamine produced a dose-
dependent decrease in mortality with a signicant reduction
in the production of tumour necrosis factor-a and interleukin
(IL)-6 in septic rats.
16
An anaesthetic dose of ketamine atte-
nuated lipopolysaccharide-induced liver injury with a
reduction in cyclooxygenase-2, inducible nitric oxide
synthase protein, and NF-kB-binding activity.
17
These data
clearly indicate that ketamine may exert anti-inammatory
actions in vivo. These anti-inammatory effects of ketamine
have also been found in clinical settings. A low dose of keta-
mine (0.25 mg kg
21
) signicantly suppressed intraoperative
and postoperative increases in serum IL-6 in patients under-
going coronary artery bypass surgery (CABG) with cardiopul-
monary bypass (CPB)
18
and signicantly decreased
superoxide production after on-pump CABG.
19
Similarly,
low-dose ketamine (0.5 mg kg
21
) attenuated the increases
in serum C-reactive protein, IL-6, and IL-10 after cardiac
surgery with CPB.
20
However, low-dose ketamine was not
shown to have any anti-inammatory effects in low-risk
patients undergoing off-pump coronary artery bypass graft
surgery.
21
The link remains controversial.
Prevention of awareness, recall, or both
during general anaesthesia
Errando and colleagues
22
reported that the incidence of
awareness with recall and dreaming during general anaes-
thesia were relatively high, 1.1% with propofol total intrave-
nous anaesthesia and 0.59% with balanced anaesthesia
(i.v. agent induction with halogenated maintenance). Long-
term potentiation (LTP or increased amplitude of excitatory
post-synaptic potentials after high-frequency stimulation)
of synaptic transmission in the hippocampal CA1 region con-
tributes to learning and memory processes.
23
As memories
are thought to be encoded by synaptic modication in the
hippocampus, LTP is considered as one of the major cellular
mechanisms of learning and memory.
23
A study of recall
during spinal anaesthesia under propofol sedation (mean
4.2 mg kg
21
h
21
) sufcient to maintain bispectral index 70
found that 56% of patients had recall.
24
In contrast,
several reports suggest that subanaesthetic doses of keta-
mine may inhibit LTP via NMDA receptor block.
25
Indeed,
clinical investigations
26
clearly show that subanaesthetic
doses of ketamine impair memory and recall. A comparison
of sedation quality during bronchoscopy between propofol
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alfentanil (Group PA, n138)- and propofol ketamine (Group
PK, n138)-treated groups showed that recall was signi-
cantly lower in the PK group.
27
Although these reports
support our hypothesis that the preventive effects of propofol
on recall might be weak, further clinical studies are required.
Anti-tumour effects
Although a variety of surgical procedures for malignancy are
performed under general anaesthesia, it is unclear how
anaesthetics affect the behaviour of malignant tumours.
Uncontrolled cell proliferation, local invasion, and metastasis
are responsible for the progression of malignant tumours. It
has been reported that glutamate receptor subunits are
expressed in a variety of tumour cells such as glioma, colo-
rectal and gastric cancer, oral squamous cell carcinoma,
prostate cancer, melanoma, and osteosarcoma.
28
In
addition, glutamate and its receptors may regulate tumour
growth as glutamate receptor antagonists limit prolifer-
ation.
29
NMDA receptor block has been reported to inhibit
several tumour-related actions. The NMDA receptor antagon-
ist MK801 inhibited extracellular signal-regulated kinase 1/2
pathway, an intracellular signalling cascade, and the prolifer-
ation of lung carcinoma cells.
30
MK801 also improved the
survival of mice with metastatic lung adenocarcinoma and
slowed the growth of neuroblastoma and rhabdomyosar-
coma in mice. The NMDA receptor antagonist AP5, or silen-
cing the NMDA receptor NR2A subunit, suppresses cell
proliferation due to cell cycle arrest at G1 phase in MKN45
gastric cancer cells.
31
It has been reported that most
breast cancer cells expressed functional NMDA1 and
NMDA2 receptors which play important roles in human
breast cancer xenografts (e.g. Mc-f in mice).
32
Moreover,
daily administration of MK801 completely arrested the
growth of the Mc-f-human mouse-xenograft. Accordingly,
NMDA receptor antagonism with ketamine (which binds to
the same site as MK801) should exert anti-tumour actions.
Indeed, ketamine suppressed the proliferation of rat glioma
(but not normal brain) cells and induced apoptosis (Niwa
and colleagues, unpublished data). Clinical investigations
are required to evaluate the anti-tumour effects of ketamine
on postoperative outcome such as survival rate in patients
undergoing tumour resection.
Neuroprotective effects of ketamine
Cerebral ischaemia
As activation of NMDA receptors induces cerebral ischaemic
damage, ketamine clearly has a neuroprotective potential.
Indeed, experimental reports suggest neuroprotective
effects of ketamine. Ketamine improved neuronal outcome
from incomplete cerebral ischaemia in rats by a mechanism
related to a decrease in plasma catecholamine levels,
improved neurological outcome with a reduction in volume
of haemorrhagic necrosis in head trauma rats, and attenu-
ated damage in the caudoputamen of hypocapnic rats with
chronic cerebral hypoperfusion.
1
In the clinical setting,
ketamine may also produce neuroprotective actions as
several reports show that ketamine attenuated postoperative
delirium and cognitive dysfunction in patients undergoing
cardiac surgery.
33
However, it remains unclear whether keta-
mine could exert neuroprotective effects in other surgical
groups who are not subjected to the stress of CPB.
Opioid-induced spinal ischaemia
Several articles
34 35
suggest that opioids worsen spinal
ischaemia. Intrathecal administration of m- and d-, but not
k-opioid, receptor agonists increased spasticity in a dose-
dependent manner after a short period of spinal cord ischae-
mia in rats.
34
Although opioids such as morphine, fentanyl,
and remifentanil are often used as analgesics for thoracoab-
dominal aortic aneurysm repair surgery, opioids may be
involved in neuronal injury in the spinal cord after aortic
cross-clamping as naloxone could attenuate neurological
consequences of spinal injury in rats. NMDA receptor acti-
vation could contribute to this opioid-induced neurotoxi-
city.
35
Ketamine might therefore attenuate opioid-induced
degeneration of spinal motor neurones.
We have introduced what we believe to be clinically
important benecial effects of ketamine. However, as most
published clinical trials were of limited size, the data from
these trials used to determine optimal dose and timing of
administration are questionable. In addition, long-term
follow-up data are lacking. Therefore, large clinical trials
are required to address these issues.
Conict of interest
K.H. organized the 17th Japanese Society of Intravenous
Anesthesia Meeting in 2010 that was partly supported by
several Pharmaceutical companies including Daiichi Sankyo
Co. Ltd who provides ketamine in Japan. The support was
used for meeting running costs. In addition, K.H. has received
a lecture fee from this company in the past 5 yr. D.G.L. is a
Director on the Board of the British Journal of Anaesthesia.
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