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Review Article
Role of Ketamine in Acute Postoperative Pain Management:
A Narrative Review
Brian M. Radvansky, Khushbu Shah, Anant Parikh, Anthony N. Sifonios,
Vanny Le, and Jean D. Eloy
Department of Anesthesiology and Peri-Operative Medicine, Rutgers-New Jersey Medical School, 185 South Orange Avenue,
SouthOrange,Newark,NJ07103,USA
Correspondence should be addressed to Jean D. Eloy; eloyje@njms.rutgers.edu
Received December ; Accepted March
Academic Editor: Kok Eng Khor
Copyright © Brian M. Radvansky et al. is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Objectives. e objective of this narrative review was to examine the usage of ketamine as a postoperative analgesic agent across
a wide variety of surgeries. Design. A literature search was performed using the phrases “ketamine” and “postoperative pain.”
e authors analyzed the studies that involved testing ketamine’s eectiveness at controlling postoperative pain. Eectiveness was
assessed through various outcomes such as the amount of opiate consumption, visual analog scale (VAS) pain scores, and persistent
postoperative pain at long-term follow-up. Results. While many dierent administration protocols were evaluated, delivering
ketamine both as a pre- or perioperative bolus and postoperative infusion for up to hours appeared to be the most eective.
ese eects are dose-dependent. However, a number of studies analyzed showed no benet in using ketamine versus placebo for
controlling postoperative pain. While ketamine is asafe and well-tolerated drug, it does have adverse eects, and there are concerns
for possible neurotoxicity and eects on memory. Conclusions. In a number of limited situations, ketamine has shown some
ecacy in controlling postoperative pain and decreasing opioid consumption. More randomized controlled trials are necessary
to determine the surgical procedures and administrations (i.e., intravenous, epidural) that ketamine is best suited for.
1. Introduction
Postoperative pain is one of the most undesirable experiences
for a patient undergoing surgery. Deliberate action should be
taken to prophylactically treat the pain. If postoperative pain
does develop, it should be managed early and aggressively,
becauseseverepainnotonlyinducesadelayindischargeand
poorer patient satisfaction, but also can create a hyperalgesic
condition known as persistent postoperative pain (PPP). is
strainsnotonlythepatient,butalsothehealthcaresystem
as a whole. Recent studies show that PPP has an incidence
as high as %. Furthermore, .% of patients report that
this pain is moderate to severe []. erefore, it is in the
anesthesiologist’s best interest to be aware of the severity of
this problem and of all the pharmacological agents used to
prevent and treat postoperative pain. To date, the mainstay of
treatment has been the administration of exogenous opioids
such as morphine or fentanyl. However, pain is not always
fullyrelievedbysuchagents,andoenpatientsdevelop
tolerance to them. e ever-increasing doses of opioids are
clearly not without their adverse eects. In addition to that,
many patients and even some clinicians wrongly believe that
addiction can be inevitable aer administration of opioids
[].
Recently, interest has focused on the use of N-methyl-D-
aspartate (NMDA) receptor antagonists for the management
of postoperative pain. In particular, ketamine has been thrust
into the limelight both as a standalone drug and as an
adjuvant to other analgesics (e.g., morphine, fentanyl, and
tramadol) []. Ketamine exerts its main analgesic eect by
antagonism of NMDA receptors []. In doing so, ketamine
modulatescentralsensoryprocessingofpain.Inbothanimal
and human studies, ketamine has shown itself to be a potent
antihyperalgesic agent. It can counteract opioid-induced
hyperalgesia and prevent the development of opioid tolerance
[].
Ketamine was rst described in the literature in
[]andFDA-approvedin[]. e drug was originally
Hindawi Publishing Corporation
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Volume 2015, Article ID 749837, 10 pages
http://dx.doi.org/10.1155/2015/749837
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noticed to have anesthetic eects, much like its close relative,
phencyclidine, and only later, its analgesic properties did
become coveted []. Various studies mentioned throughout
this review speak of its use for postoperative analgesia.
Ketaminehasalsobeenusedtotreatdepression[,],
complex regional pain syndrome [], cancer pain [,],
alcohol addiction [], heroin addiction [,], asthma
exacerbations [], wheezing [], and pain during propofol
injection []. Adverse eects can include irritability, night-
mares, dissociation, headaches, impaired memory, transient
elevations in blood pressure and heart rate, urinary tract
symptoms, and hepatotoxicity [].
isreviewwilldescribethepharmacologyofketamine,
examine its usage as a postoperative analgesic, and discuss its
adverse eects and safety prole.
2. Chemical and Structural Characteristics
e word “ketamine” is a portmanteau of the words “ketone”
and “amine,” speaking of its chemical structure. It is a
hydrochloride salt, available in both powdered and aque-
ous forms, with the molecular formula C13H16ClNO and
a molecular mass of . g/mol. It is composed of a
chlorophenyl ring structure that is bonded to a cyclohex-
anone ring. Ketamine has a chiral center at the carbon-
atom of its cyclohexanone ring and therefore it exists as the
optical stereoisomers S(+) and R(−)ketamine. Ketamine was
previously only available as a racemic mixture but now comes
in its two stereoisomer varieties. S(+)ketamine binds NMDA
receptors with anity that is four times greater than that of
R(−)ketamine. While the duration of S(+)ketamine is shorter
than that of R(−)ketamine, S(+)ketamine has been shown
to have an analgesic potency twice as great as the racemic
mixture and four times as great as R(−)ketamine [].
3. Pharmacodynamics
e diverse eects and multifaceted mechanisms of action of
ketamine have given it the title “nightmare of the pharmacol-
ogist” []. As there are many high-quality reviews that focus
solelyonthepharmacologyofketamine[,–], we will
only touch upon the most salient and novel points. Ketamine’s
predominant eect is NMDA receptor antagonism. It binds
noncompetitively to the phencyclidine binding site of NMDA
receptors and modies receptors via allosteric mechanisms.
e NMDA receptor is noteworthy in anesthesia because of
its role in central sensitization. is complex process involves
a nociceptive signal that is potentiated in the peripheral
nervous system, causing hyperexcitability in the spinal cord.
It can evoke chronic pain and allodynia at surgical incision
sites, as well as at sites surrounding incisions. e blunting
of central sensitization has played an important role in
the prevention and treatment of both postoperative pain
and chronic pain []. Ketamine has also been used in
IV regional anesthesia, further speaking of its peripheral
analgesic eects. However, when used as an eective IV re-
gional agent, the concentrations of ketamine were more
than -fold greater than when used systemically, decreasing
the likelihood that systemic administration provides a strong
eect on peripheral receptors [].
Ketamine causes the central eect of anesthesia when it
interacts with NMDA receptors in the brain. Brain concen-
trations of ketamine were directly related to analgesia using
an ischemic pain model. Pain activation in the secondary
somatosensory cortex, insula, thalamus, and anterior cin-
gulate cortex was all decreased. Functional magnetic reso-
nance imaging (fMRI) studies demonstrated that both pain
and ketamine changed brain connectivity in areas involved
in endogenous pain modulation. e studies showed that
ketamine was responsible for a decrease in connectivity in
the brain regions responsible for pain sensing and aective
processing [,].
e analgesic eects of ketamine do not end with NMDA
receptors. It has been shown to interact with opioid receptors
𝜇preferentially in rats []. Studies in guinea pig ileum
pointed to possible activation of the 𝜅-opioid receptor as the
site of analgesia []. However, subsequent tests performed
with naloxone failed to aect the analgesia attributed to
the ketamine, and interaction with any opiate receptor was
questioned []. Other studies showed the reduction in e-
cacy of ketamine as an anesthetic induction agent in the
presence of naloxone, again implying an interaction with the
opiate receptor []. A study by Pacheco et al. which
used specic opioid receptor blocking agents suggests that
interaction with 𝜇-and𝛿-opioid receptors is responsible for
the central antinociceptive eects of ketamine [].
Studies show that prevention of opioid tolerance may
be another mechanism of pain prevention by ketamine. It
has been reported that 𝜇-receptor activation by opioids leads
to a sustained increase in glutamate synaptic eectiveness
at the level of NMDA receptors. Although the mechanisms
that allow ketamine to be an analgesic and opiate-sparing
agent aer opiate exposure remain poorly understood; an
important concept that is worth mentioning is being studied
in rat models. Rat studies in brain ischemia have found a
role of postsynaptic density (PSD), proteins, specically PSD-
, in potentiating NMDA function and signaling to nitric
oxide synthase resulting in chronic and neuropathic pain.
Studies show that ketamine may decrease injury-triggered
increases in interactions between the NMDA receptor, post-
synaptic density protein (PSD), and protein kinases,
thereby reducing nitric oxide-related neuronal injury [].
is concept may represent a mechanism underlying reduced
pain sensitization and opiate tolerance phenomena. Cancer
patients who receive chronic opioids oen have developed a
high level of tolerance, and, in this situation, ketamine can be
a useful adjuvant in analgesia [,].
Many other receptors have been shown to play role in ket-
amine analgesia; however, their mechanisms remain unclear.
Once thought to be an opioid receptor, the sigma-receptor
hasbeenimplicatedasabindingsiteforketamine.erole
of sigma receptors is uncertain; they may modify other recep-
tors such as NMDA receptors.
Needless to say, the eects of ketamine on the human
body, both within the realm of analgesia and without, are
incredibly complex. Further study is encouraged to fully
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elucidate the eects of this multifaceted drug on the body’s
various receptors.
4. Applications in Acute Pain Management
4.1. Otolaryngologic Surgery. AstudybyJhaetal.[]
(Table ) evaluated the ecacy of ketamine in postoperative
analgesia aer surgical site inltration for pediatric patients
undergoing cle palate surgery. Surgical sites were inltrated
with either mg/kg of bupivacaine or .mg/kg of ketamine.
Although pain scores were similar between groups at the
h mark, pain scores were lower with ketamine at the h
mark. Only % of children in the ketamine group required
rescue analgesia, compared to % in the bupivacaine group.
Administration of ketamine also led to statistically signicant
decreases in sleep disturbances and dysphagia when com-
pared to the bupivacaine group. is allowed for an earlier
resumption of feeding with ketamine inltration.
Eghbal et al. [] examined the eects of ketamine
on postoperative pain and emergence agitation in children
undergoing adenotonsillectomy. is randomized clinical
trial (RCT) divided children into a placebo (normal saline)
group and a ketamine (. mg/kg IV) group. Emergence agi-
tation scores, acetaminophen requirements, and pain scores
at all hours were signicantly lower in the ketamine group.
A meta-analysis by Cho et al. []reportsthat,
in tonsillectomy in children, preoperative administration of
ketamine, either systemically or locally, resulted in signi-
cantly decreased pain at hours and decreased analgesic need
over hours.
4.2. Spinal Surgery. Nitta et al. [] tested the ecacy of mor-
phine alone, morphine and ketamine, morphine and clon-
idine, and morphine/ketamine/clonidine in reducing the
need for patient-controlled analgesia (PCA) following cer-
vical and lumbar spinal surgery. When used, ketamine was
delivered as a high-dose infusion at . mg/kg/hour. e
study demonstrated that oral premedication with clonidine
combined with intraoperative administration of ketamine
potentiated the analgesic eect of postoperative IV morphine.
ere was a signicant reduction in the amount of PCA
requests and in the amount of cumulative morphine delivered
viaPCAat,,,andhours.isdemonstrates
ketamine’s adjunctive eect when added to other analgesics,
synergistically decreasing overall administration of opioids.
Hadi et al. []usedlow-doseIVketamineasanadjunct
to therapy during and aer lumbar microdiscectomy surgery.
Patients were divided into a control group, a group receiv-
ing 𝜇g/kg/min perioperatively and a group receiving both
𝜇g/kg/min perioperatively and 𝜇g/kg/min postoperatively.
e patients in the control group required rst analgesic
demand dose earlier than the ketamine groups. Total mor-
phine consumption, visual analog scale (VAS) pain scores,
and rates of nausea and vomiting were signicantly lower in
the group receiving both peri- and postoperative ketamine
versus the control group.
Kimetal.[] report similar results in lumbar spinal
fusion patients: a ketamine 𝜇g/kg/min infusion following
a bolus dose of . mg/kg resulted in patients requiring
signicantly less fentanyl in the postoperative period with no
increase in adverse eects [].
Pestieau et al. [] evaluated a low-dose perioperative
infusion of ketamine in pediatric patients undergoing scol-
iosis surgery, a procedure in which opioid analgesic require-
ments are routinely high. e study was a double-blinded
controlled trial with one group receiving ketamine and
the other receiving a placebo. Patients were given a bolus
of . mg/kg ketamine prior to incision, an intraoperative
infusion of . mg/kg/h, and a postoperative infusion of
. mg/kg/h. Postoperative opioid usage was similar between
thetwogroupsaswerethereportedpainscores.
4.3. Orthopedic Surgery. Cengiz et al. []performeda
randomized double-blinded study to evaluate the eect
of low-dose ( 𝜇g/kg/minute) intraoperative ketamine on
postoperative pain aer total knee replacement surgery. e
control group received a placebo. ere was a prolonged
time to rst analgesic request in the ketamine group and a
reductionincumulativemorphineconsumptionat,,,,
and hours aer surgery. VAS scores were also signicantly
lowerinthegroupreceivingketamineinsteadofplacebo.
AstudyperformedbyGuar
´
aSobrinhoetal.[]assessed
ketamine’s eectiveness as an analgesic agent when deliv-
ered intra-articularly during total knee replacement surgery.
Authors did not nd a signicant dierence between groups
using . mg/kg S(+)ketamine, .mg/kg S(+)ketamine and
control groups in terms of postoperative pain scores.
4.4. oracic Surgery. D’Alonzo et al. []testedasingle
. mg/kg bolus of ketamine delivered intravenously prior
to chest wall incision versus placebo. Levels of IL- and
C-reactive protein (CRP) were compared before and aer
surgery between the two groups and reported pain scores
at and hours postoperatively. IL- levels, CRP levels,
and postoperative pain scores at both of these times did not
vary signicantly between the two groups, suggesting that
this dosing schedule of ketamine does not have a measurable
eect on postoperative pain in thoracic surgery.
Nesher et al.’s study [] examined thoracic surgery
patients who received PCA boluses of morphine combined
with ketamine versus morphine alone. Fiy-eight patients
were divided into two groups, one group receiving .mg
IV bolus morphine upon request and the other receiving
. mg morphine and mg ketamine IV bolus upon request.
e group receiving the ketamine/morphine combination
required only half the amount of morphine as the morphine-
only group. At the -hour time-point, of the morphine-
only patients still required PCA compared to patients in
the morphine/ketamine group. Pain scores and postoperative
nausea and vomiting (PONV) were also decreased in the
ketamine/morphine group.
4.5. Ophthalmological Surgery. Abdolahi et al. [] utilized
low-dose ketamine (. mg/kg) during painful ophthalmo-
logic surgeries (i.e., retinal detachments, strabismus, and
keratoplasty). Ketamine was administered during anesthetic
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T : Studies in which ketamine usage has signicant benet.
Author Year Surgical setting Dosing Timing Outcomes
Single studies
Jha et al. []
Cle palette repair . mg/kg inltration of surgical site Lower pain score than bupivacaine ( mg/kg)
at h, less rescue analgesia required
Eghbal et al. []
Adenot onsillec tomy . m g/kg IV bolus Decreased emergence agitation,
acetaminophen requirements, and pain scores
Nitta et al. []
Cervical and lumbar spinal surger y . mg/kg/h IV Bolus given for h periop. (total of
mg/kg total)
Reduction in PCA requests and total morphine
distributedat,,,andhours
Hadi et al. []
Lumbar microdiscectomy 𝜇g/kg/min IV Peri- and pos top. for a tot al of h Decreased total morphine consumption, pain
scores, and PONV
Kim et al. []
Lumbar spinal fusion . mg/kg bolus, 𝜇g/kg/min IV
infusion Infusion for h postop. Less fentanyl requirement postop.
Cengiz et al. []
Tot al k nee r e p l a c e m e n t 𝜇g/kg/min IV Periop. only Reduction in morphine consumption at , , ,
, and h, lower pain scores
Nesher et al. []
oracic surgery mg morphine and mg ketamine
IV-PCA
Morphine consumption and patients requiring
PCA at h reduced by %; decreased pain
scores and PONV
Suppa et al. []
Cesarean section . mg/kg bolus, 𝜇g/kg/min IV
infusion
Bolus @ min p ostop. then infusion for
h Reduced pain sensitivity at T- dermatome
Zakine et al. []
Major abdominal surgery . mg/kg bolus, 𝜇g/kg/min IV
infusion Periop. bolus, infusion for h Decreased morphine consumption, pain
scores, and PONV
de Kock et al. []
Rectal adenocarcinoma resection . mg/kg bolus, . mg/kg/h IV
infusion Periop. infusion only
Lower morphine requirements, smaller
hyperalgesic areas, and less pain at months of
follow-up
Systematic reviews and meta-analyses
Cho et al. []
Tonsillectomy Various Preop. dosing Decreased pain at h, decreased analgesic
need at h
Laskowski et al. []
Var io u s Va r i o u s Var i o u s % of ketamine groups required less postop.
opioids, % reported less postop. pain
Elia and Tram`
er []
Var io u s Va r i o u s Var i o u s
Decrease in morphine consumption, longer
time to rst analgesic request, less pain at
months offollow-up
Subramaniam et al. [] Var i o u s Va r i o u s Var i o u s
Single bolus-less opioid consumption in %
of trials; continuous infusion-less opioid
consumption in % of trials; epidural
infusion-benecial in % of trials
McCartney et al. []
Various .–. mg/kg, various routes Various Decreased postop. pain and/or decreased
analgesic consumption in % of trials’
PONV: postoperative nausea and vomiting.
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induction. Recovery time, postoperative pain scores, anes-
thetic consumption, analgesic requirements, and perioper-
ative additional analgesic were measured across the two
groups. ere were no dierences in any of these variables
between the two groups.
4.6. Gynecological Surgery. omas et al. []studiedthe
usage of a single preoperative dose of ketamine before elect-
ive gynecological procedures. is prospective study divided
patients into a control group, which received normal saline
andaketaminegroup,whichreceived.mg/kgofketamine
just before anesthetic induction. Although the ketamine
group required slightly less cumulative morphine for post-
operative analgesia, this result was not signicant. ere was
also no signicant dierence in the reporting of pain on
the VAS between the two groups. Although there was no
dierence in the length of postoperative stays, the group
receiving ketamine reported signicantly greater satisfaction
with their pain management.
Bilgen et al.’s study [] utilized three dierent doses
of ketamine (., ., and mg/kg) and a placebo to test the
eects on postoperative morphine requirements and pain in
women undergoing elective Cesarean sections. e primary
outcome assessed was cumulative postoperative morphine
consumption at hours. is variable, acute pain score and
prolonged postoperative pain measured at weeks, month,
months, and year were all similar between all groups.
Ketamine did not have a signicant eect on any of these
outcomes.
Suppa et al. [] performed a similar study in women
undergoing elective Cesarean sections, using a . mg/kg
ketamine bolus minutes aer birth in addition to a
𝜇g/kg/min IV ketamine infusion for hours thereaer.
Usage of ketamine reduced morphine requirements at the
–, –, and –-hour time points. e patients in
the ketamine group showed reduced pain sensitivity at the
T- dermatome, suggesting an antihyperalgesic eect. At
three years aer surgery, patients reported no dierences in
residual pain or dysesthetic symptoms.
4.7. Major Abdominal Surgery. Zakine et al. []performed
a double-blinded study comparing the eectiveness of keta-
mine administration in two dierent settings with one control
group which received placebo. e rst ketamine group
received a . mg/kg bolus perioperatively and a 𝜇g/kg/min
infusion thereaer for hours; the second ketamine group
received a . mg/kg bolus perioperatively and a 𝜇g/kg/min
infusion only for the duration of the surgical procedure. All
of the patients were given morphine PCA. e authors found
that cumulative morphine consumption was signicantly
lower in the group receiving the -hour infusion when
comparedtotheshorterinfusionandcontrolgroups.VAS
scores were measured postoperatively and were signicantly
lower in the ketamine groups when compared to the control
group. As an added eect, while all patients in the study
received hydroxyzine preoperatively, the -hour infusion
group experienced signicantly less nausea than the control
group (% versus %, 𝑃 = 0.005). It is worth nothing that
there were no side eects of the ketamine, psychotomimetic,
or otherwise.
Katz et al. [] analyzed ketamine as a postoperative anal-
gesic in men undergoing radical prostatectomy. Men were
double-blinded into dierent groups, all of which received
fentanyl. In addition, group received a preincisional intra-
venous bolus (. mg/kg) and infusion (. mL/kg/min)
of ketamine, group received the same dosages minutes
aer incision, and group received no ketamine. e authors
found that pain scores did not dier signicantly among the
groups and follow-up at two weeks and again at six months
they showed no signicant dierences in pain incidence or
intensity.
de Kock et al. [] studied ketamine given both systemi-
cally and epidurally to patients undergoing rectal adenocar-
cinoma resection. All patients received a preoperative epidu-
ral bolus and continuous infusion of bupivacaine/ sufen-
tanil/clonidine. A control group received no ketamine, and
other groups received ketamine at dierent dosages, admin-
isteredeitherepidurallyorintravenously.egroupthat
received a ketamine bolus of .mg/kg and continuous infu-
sion of . mg/kg/h had signicantly lower PCA require-
ments, smaller hyperalgesic areas, and less residual pain
through six months of follow-up.
4.8. Systematic Reviews. AreviewbyLaskowskietal.
[] found a reduction in total opioid consumption and
an increase in time to rst analgesic request in groups
receiving ketamine. % of the ketamine treatment groups
required less postoperative opioid analgesia and reported less
postoperative pain.
AsecondreviewbyEliaandTram
`
er [] shows signif-
icant decreases in pain intensity at rest when ketamine is
comparedwithacontrolath,h,h,andhours
postoperatively. All trials except one within the review
report a signicant decrease in morphine consumption when
ketamine is used intraoperatively. Average time to rst
analgesic request had an average improvement of minutes.
Regarding long-term follow-up, signicantly fewer patients
who had received high-dose IV ketamine (bolus . mg/kg,
infusion . mg/kg/h during surgery) suered from residual
pain at the -month mark.
Subramaniam et al.’s systematic review [], includ-
ing studies and patients, addressed ketamine’s eec-
tiveness in reducing opioid consumption for postoperative
analgesia. ey divided subjects into subgroups based on
therouteandmethodofketamineadministration:ketamine
as single dose, continuous infusion, PCA, and epidural
ketamine with opioids. Low-dose ketamine was found to be
safe, and no increase in side eects was suggested. A single
bolus dose of ketamine decreased opioid requirements in
of studies. Continuous infusion of ketamine decreased
IV and epidural opioid requirements in out of studies.
Adding ketamine to PCA morphine was not found to be
useful. Epidural ketamine showed benecial eects in out of
studies. Among the various methods of IV ketamine admin-
istration, continuous IV infusion of ketamine was the most
helpful in major surgeries requiring increased postoperative
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opiate use such as major abdominal surgical procedures and
thoracic procedures.
McCartney et al. []performedasystematicreviewthat
looked at the eects of various NMDA receptor antagonists,
including ketamine, on postoperative pain and analgesic
consumption. Twenty-four ketamine-based studies met their
inclusion criteria; of (%) demonstrated a positive
eect in lowering postoperative pain and/or decreasing anal-
gesic consumption. Dosages used in the analyzed studies
ranged from . to mg/kg.
5. Adverse Effects
Ketaminehasbeenreportedtobeasafeandwell-tolerated
drug [,]. Despite the benets and the increase in pop-
ularity of using ketamine as both an anesthetic and an anal-
gesic, there are some troubling adverse eects associated with
its use. ese eects are usually temporary; however, they
can be signicantly distressing for patients. erefore, it is
paramount to discuss these eects. Common adverse eects
include feelings of inebriation, nausea, psychotomimetic
eects, and headaches with long-term use, possibly resulting
in impaired cognition, memory, and mood [].
e most common concerns about ketamine as an anal-
gesic agent are related to its mind-altering eects. Katalinic’s
team addressed these concerns and their review showed that
most of the research conducted using subanesthetic doses
of ketamine has shown transient increases in the following
psychiatric symptoms: positive and negative symptoms of
schizophrenia, dissociative symptoms, and manic symptoms.
Fortuitously, these symptoms are only present at times of
administration and usually disappear within minutes of
administration []. Quiet, relaxed surroundings contribute
to a reduced incidence of these side eects and when
ketamine is administered alone, the prophylactic use of
asedativeagentsuchas.–.mgoralmidazolamhas
generally decreased their incidence and severity [].
Other psychotomimetic eects of ketamine use include
feelings of intoxication, increased confusion, lowered inhibi-
tion, and perceptual disturbances. In addition, research
shows that chronic use of ketamine may impair several mem-
ory systems including episodic and working memory. None-
theless, these eects have been restricted to time of adminis-
tration and are transient in nature. Additionally, implications
of these eects have not been found to be dependent on dose
or route of administration [].
No severe physical symptoms have been reported with
the use of low-dose ketamine; however, studies have reported
benign eects of lightheadedness, headache, nausea, diplopia,
drowsiness, and dizziness. ese eects, unlike the psychot-
omimetic eects, tend to be dose-dependent. ey are also
limited to time of administration and a short time thereaer
[].
Ketamine can also induce various CNS side eects (e.g.,
dizziness, diplopia, dysphoria, dreams, hallucinations, disori-
entation, strange sensations, lightheadedness, sleep dicul-
ties, and confusion). One systematic review found incidences
of these CNS eects were %, %, %, and .% with
IV PCA, IV infusion, IV single dose, and epidural groups,
respectively. No signicant increase in these eects was seen
compared to patients who did not receive ketamine [].
Almost cases of ketamine-induced uropathy have
been reported in the literature, mostly in the context of
chronic abuse, but ve within medical analgesic use [].
Case series demonstrate a temporal link between ketamine
abuse and urological symptoms, urinary tract damage, and
renalimpairment,withsomebutnotallsymptomsimproving
upon cessation of ketamine. Chu et al. reported lower uri-
nary tract symptoms of ketamine-induced cystitis, dysuria,
urgency, frequency, incontinence, macroscopic hematuria,
and suprapubic pain. Investigations showed negative urine
cultures in % and cystoscopy showed epithelial damage in
% [].
Hepatotoxicity has been reported at anesthetic doses
(≥ mg/kg) and patients receiving low-dose continuous infu-
sion. Noppers et al. present data on the occurrence of
ketamine-induced liver injury during repeated administra-
tions of S(+)ketamine for the treatment of chronic pain.
Six patients received continuous intravenous -hour
S(+)ketamine infusions, – mg/h, separated by days.
ree of these patients developed hepatotoxicity evident
through elevated transaminases. Ketamine infusion was
promptly terminated and the liver enzymes slowly returned
to reference values within months, suggesting an increased
risk for development of ketamine-induced liver injury when
theinfusionisprolongedand/orrepeatedwithinashorttime
frame []. Trials using single doses of ketamine < mg/kg
report no changes in liver function tests [].
It has been described in the literature that ketamine
use can lead to neuronal cell apoptosis. is is triggered
by the direct blockade of NMDA receptors. e eect was
demonstrated in rats at repeated doses of mg/kg [].
However, an eect was not seen aer a single bolus at this
dose [].isisespeciallyconcerninginthedeveloping
brain, where ketamine can interfere with both neuronal
proliferation and dierentiation []. Recent studies have
already indicated that ketamine can result in long-lasting
cognitive decits in a primate model. Paule et al. tested this
eect with rhesus monkeys who received enough ketamine
to maintain anesthesia for a hour surgery during their
rst week of life. At approximately months of age, control
monkeys began to outperform the ketamine-dosed monkeys
at a battery of tests. At three-and-one-half years of age, the
ketamine monkeys still performed worse than the controls
[].
Chang et al. [] reported a marked and sudden
increase in intracranial pressure (ICP) during induction
with ketamine in a patient with traumatic brain injury. It
should be noted, however, that this patient’s ICP was quite
elevated even before induction. e ICP fell rapidly when
mechanical ventilation began. Administration of ketamine
for sedations has been shown to result in higher opening
pressures during lumbar puncture in children, but this eect,
like the psychotomimetic eects, can be tempered with
midazolam [].
In a study conducted to evaluate the safety and ecacy
of ketamine for the treatment of refractory status epilepticus,
BioMed Research International
it was found that the drug’s administration caused possible
adverse events in out of study patients. ese included
a life-threatening severe acidosis, a syndrome similar to
propofol-related infusion syndrome, supraventricular tachy-
cardia, and atrial brillation [].
Ketamine is not FDA-approved for epidural use as it car-
ries a risk of neurotoxicity. Furthermore, there is no safety
or ecacy data on the neuraxial administration of ketamine.
Becauseofthis,theepiduraland/orintrathecaladminis-
tration of ketamine are discouraged outside of the preclin-
ical research setting. Spinal neurotoxicity aer continuous
intrathecal ketamine infusion of mg/day over weeks
has been reported [].However,thedrugusedinthis
case was not preservative-free, and chemical cytotoxicity
has oen implicated the preservatives used rather than the
active compound. erefore, only preservative-free ketamine
should be used for intrathecal infusion. is eect was also
described aer a -week continuous infusion, a situation that
we are unlikely to see in patients that are given ketamine with
the short-term goal of postoperative analgesia.
Potential dependence through chronic or repetitive keta-
mine use is concerning. Studies of recreation ketamine-
using populations report cravings for the drug, physiolog-
ical tolerance, and possible withdrawal symptoms on drug
cessation. Physiological tolerance is of particular relevance
as it has been suggested for individuals having undergone
repeated procedures requiring anesthesia with ketamine [].
Tolerance development with ketamine used as analgesia is
less certain. Perry et al. []followedhealthysubjectsgiven
subanesthetic doses of ketamine for up to months. Results
showed no reports of cravings or abuse outside of the study,
suggesting that ketamine in low doses is less likely to produce
dependence.
6. Conclusion
Although it was rst used purely as an anesthetic, ketamine is
making a certain resurgence in the management of postoper-
ative pain. Many of the aforementioned studies have demon-
strated signicant eectiveness in controlling postoperative
pain, increasing time to rst analgesic request, and decreasing
overall opioids required, as well as demonstrating fewer of the
opioid-related side eects like PONV. ese eects have been
demonstrated across many realms of surgery, including oto-
laryngology, abdominal surgery, orthopedic surgery, spinal
surgery, and gynecological surgery. While all of the exact
mechanisms have not been entirely agreed upon, the primary
eect of the drug is related to its NMDA receptor antagonism.
An intravenous bolus given prior to incision followed by a
continuous infusion appears to be the most eective modal-
ity for postoperative pain control. If the infusion is given
over a protracted time course ( h) for more invasive and
routinely painful procedures, patients can have a decreased
risk of developing persistent postoperative pain in months
thatfollow.isinfusioncanalsobecombinedwithPCA
for excellent control of acute postoperative pain. Ketamine
may not provide a clear benet for patients undergoing
smaller procedures, as analgesia with low dosages of opioids,
NSAIDs, and local anesthetic inltration can usually provide
adequate pain relief. e oen feared psychotomimetic eects
can be blunted by administering general anesthesia or the
less eective benzodiazepine. While animal models show
some degree of neurotoxicity in high-dose applications and
possible induction of neuronal apoptosis, these eects have
not been demonstrated and are not of concern at the dosages
and durations employed for postoperative analgesia. e
other conclusion that can be drawn from the aforementioned
studies is that although ketamine was eective in many of
thetrials,othertrialsshowedthatitprovidednobenet
when compared to a placebo. While ketamine holds a place
in the prevention and treatment of postoperative pain, more
large, high-quality controlled studies are necessary in order to
determine which procedures it is best suited for and at what
dosages and frequencies it should be administered.
Conflict of Interests
e authors declare no competing nancial interests.
Acknowledgment
All research performed by Department of Anesthesiology,
Rutgers New Jersey Medical School.
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