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\begin{document}

\title{Ketamine in Pediatric Oncology: a drug review}



\author[1]{Satya Prakash}%
\author[1]{Aditya Gupta}%
\author[1]{J Meena}%
\affil[1]{All India Institute of Medical Sciences}%


\vspace{-1em}



  
  \date{June 06, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Ketamine is a dissociative anesthetic agent, with excellent analgesic
properties and a favorable safety profile. Although it acts
predominantly through NMDA receptor antagonism, numerous other molecular
targets have been characterized, rendering anti-inflammatory,
anti-depressant, and thus expanding its scope for new clinical
applications. The noticeable safety of ketamine in children enables its
widespread use in pediatric oncology, chiefly for procedural sedation.
Its value for chronic pain management in children with cancer is being
increasingly recognized but requires more evidence. The topical use of
ketamine is largely in investigational stages.. Rational medical use of
ketamine is largely free from significant long-term neurological side
effects but may have some troublesome short-term effects such as
vomiting, palpitations, urinary retention, and hallucinations. This
review will provide a brief account of the pharmacology of ketamine and
primarily focus on the relevant aspects of ketamine in pediatric
oncology.%
\end{abstract}%



\sloppy


\textbf{Abstract:}

Ketamine is a dissociative anesthetic agent, with excellent analgesic
properties and a favorable safety profile. Although it acts
predominantly through NMDA receptor antagonism, numerous other molecular
targets have been characterized, rendering anti-inflammatory,
anti-depressant, and thus expanding its scope for new clinical
applications. The noticeable safety of ketamine in children enables its
widespread use in pediatric oncology, chiefly for procedural sedation.
Its value for chronic pain management in children with cancer is being
increasingly recognized but requires more evidence. The topical use of
ketamine is largely in investigational stages.. Rational medical use of
ketamine is largely free from significant long-term neurological side
effects but may have some troublesome short-term effects such as
vomiting, palpitations, urinary retention, and hallucinations. This
review will provide a brief account of the pharmacology of ketamine and
primarily focus on the relevant aspects of ketamine in pediatric
oncology.

\textbf{Keywords:} Ketamine; Oncology; Chronic pain; Sedation;
Mucositis; Children

\textbf{INTRODUCTION}

The history of ketamine began almost seven decades back when the search
for an ideal anesthetic and analgesic agent in the 1950s led to the
discovery of a cyclohexylamine called Phencyclidine (PCP), also marketed
as Sernyl.\textsuperscript{1} The advantages of PCP over other sedatives
such as opioids were that it did not depress the cardiovascular and
respiratory functions, nor did it impair the laryngeal and pharyngeal
reflexes. These advantages, together with its potent anesthesia without
a total loss of consciousness (later termed dissociative anesthesia)
seemed promising. However, a major limiting adverse effect was the
occurrence of psychotic reactions, including hallucinations lasting
several hours, even after a single dose.\textsuperscript{2}Additionally,
the abuse potential of PCP was increasingly recognized. Thus, the
initial excitement for PCP as a human anesthetic waned. Further research
into similar compounds entailed the development of a compound in 1962
with a ketone bond together with an amine, hence named ketamine. This
chemical had similar advantages as PCP, such as excellent anesthesia,
hemodynamic stability, and preservation of protective reflexes, but with
a shorter duration of action and lesser neuropsychiatric adverse
effects.\textsuperscript{3} By 1970, ketamine was approved for human
use. It was not until a decade later that the principal sites of its
action, the NMDA receptors, were discovered.\textsuperscript{4} Another
crucial observation was that ketamine, in sub-anesthetic doses, produces
excellent analgesia, and was largely devoid of the troublesome
psycho-behavioral adverse effects seen at higher doses. Since then,
ketamine has been extensively studied, and a wide variety of therapeutic
effects (anesthetic, analgesic, anti-inflammatory, anti-depressant) have
been explored and their mechanisms characterized. Even though its role
as an anesthetic has dwindled in the last three decades, its benefits in
other domains remain of utmost utility, especially concerning analgesia
in children, a population in which ketamine has proved to be noticeably
safe and effective. The role of ketamine in acute severe asthma and
refractory status epilepticus is also well-described. This review will
provide a brief account of the pharmacology of ketamine and primarily
focus on the relevant aspects of ketamine in pediatric oncology.

\textbf{PHARMACOLOGY (Mechanisms of action, pharmacokinetics, routes of
administration)}

2.1 Mechanisms of action (MOA)

Ketamine has a use-dependent non-competitive NMDA receptor-channel
blocking activity, wherein it binds the PCP site of the channel in the
open activated state and reduces mean channel opening time. It has also
been shown to bind to a second site on the membrane which, through an
allosteric mechanism, causes a decrease in the frequency of the channel
opening.\textsuperscript{5} The principal site of action of ketamine
administered in anesthetic doses is the limbic system, manifesting as an
increased uptake seen in nuclear studies. However, in sub-anesthetic
doses, the activity in these regions is interestingly
decreased.\textsuperscript{6,7} This coupled with the observation that
low concentrations of ketamine act predominantly by the allosteric
mechanism rather than by blocking the open NMDA channel, likely explain
the differential effects of ketamine at different doses (anesthesia vs
analgesia).\textsuperscript{8}

Besides being effective at a dose much lower than that used for
anesthetic effect, the efficacy of ketamine as an analgesic has also
been noted to last even after the drug has cleared from the system. This
is thought to be mediated by its sustained action on the glutaminergic
neurons, which in turn causes an increase in structural synaptic
connectivity.\textsuperscript{9} An interesting mechanism for relief in
chronic pain is its desirable effect on pain memory and the
desensitization of central pain pathways, as well as that on the
motivational affective aspects of pain.\textsuperscript{10}

Several other mechanisms of action have been proposed for the analgesic
effect of ketamine based mostly on in-vitro studies, including dopamine
D2 antagonism, 5-HT2 serotonin receptor agonism, HCN1 channels, calcium
and sodium channels, and cholinergic
transmission.\textsuperscript{11,12,13,14} These findings suggest that
instead of a specific NMDA action, ketamine possibly has a multipronged
role in modulating neural functions like pain, wakefulness, and mood.

\textbf{Anti-inflammatory actions:} Emerging evidence shows that
ketamine also exerts an anti-inflammatory effect. Several studies,
including both in vitro and in vivo, have demonstrated a reduction in
blood levels of TNF-alpha, iNOS, IL-6, and C-reactive protein (CRP).
This effect is likely mediated by inhibition of the NF-\selectlanguage{polish}ĸ\selectlanguage{english}B pathway,
thereby impeding the pro-inflammatory cytokine
response.\textsuperscript{15,16,17} Another possible mechanism could be
the inhibition of inflammation-induced nitric oxide
production.\textsuperscript{18,19} These effects may partly be
responsible for the beneficial effects of ketamine in inflammatory and
traumatic pain, such as that seen
post-operatively.\textsuperscript{20}However, a concrete clinical
benefit of ketamine based on its anti-inflammatory actions is yet to be
demonstrated, and this effect is likely at best a minor contributor to
the overall benefit of ketamine as an analgesic. Additionally, a few
animal model studies suggest a neuroprotective action owing to its NMDA
antagonistic effects, but this has not been definitively replicated in
humans yet.\textsuperscript{21,22}

\textbf{Local effects:} NMDA receptors are present not only in the
central nervous system (CNS) but also in peripheral sensory pathways.
All motor and sensory axons are equipped with NMDA receptors. NMDA,
\selectlanguage{greek}α-\selectlanguage{english}amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate
receptors are up-regulated on the axons as a reaction to
inflammation.\textsuperscript{23} These findings support the rationale
for treating neuropathic and inflammatory pain with topical ketamine to
modulate NMDA, AMPA, and kainate receptors and subsequently
downregulating the peripheral mechanisms contributing to neuropathic and
inflammatory pain. Some other actions, particularly blockade of sodium
channels, could contribute to its efficacy following local peripheral
administration where tissue levels are likely to be higher than are
attained with systemic administration.\textsuperscript{24} Ketamine has
local anesthetic properties at high doses which have been compared with
lignocaine and procaine, although with lesser
potency.\textsuperscript{25} Indeed, ketamine has been widely studied as
a topical agent for reducing post-tonsillectomy pain in children,
including nebulized and oral rinse forms.\textsuperscript{26}

\textbf{2.2 Pharmacokinetics}

Systemically administered ketamine is chiefly metabolized by the
cytochrome P450 liver enzymes, initially to a much less potent
norketamine, and further to inactive hydroxynorketamines,
dehydronorketamines, and other
metabolites.\textsuperscript{27,28}Ketamine has a relatively low plasma
protein binding (10-50\%) and is rapidly accumulated in the brain. It
has a high clearance rate, with a half-life of 2-4
hours.\textsuperscript{29,30} The excretion is predominantly in urine,
with minimal amounts (\textless{}5\%) in feces. The rate of elimination
of ketamine is twice as rapid in children when compared to adults,
likely due to faster enzymatic metabolism in
children.\textsuperscript{31} This information plays a role in
determining the ketamine dosing frequency in children. Ketamine is
commonly available as a mixture of (S)- and (R)- enantiomers.
(S)-enantiomer is more potent as compared to (R)-enantiomer, with some
evidence of a more favorable safety profile.\textsuperscript{32}

Due to its metabolism by cytochrome P450 enzymes, there is a potential
for drug interactions when used along with enzyme-inducer and
enzyme-inhibitor drugs. Drugs like metoclopramide and fosaprepitant,
which may at times be used in cancer patients as antiemetics, may have
drug interactions with ketamine, and caution must be exercised during
their concomitant use. Similarly, other CYP3A4 inhibitors like
clarithromycin, azole antifungals, verapamil, and inducers like
phenytoin, rifampicin, and steroids can alter ketamine
levels.\textsuperscript{33}

\textbf{2.3 Routes of administration}

The most common route of administration is intravenous. Other routes
often employed include intramuscular and oral routes. Increasingly,
several other routes are being explored such as subcutaneous,
intranasal, epidural, rectal, topical, nebulization, and
transdermal.\textsuperscript{34,35,36} Studies to evaluate the plasma
levels of ketamine after nasal and rectal administration as compared to
intravenous administration in children have found acceptable levels for
analgesia.\textsuperscript{37} The transdermal route has also been shown
to be effective for postoperative
analgesia.\textsuperscript{38}Pharmacokinetic details of major routes of
administration have been depicted in table 1. The bioavailability of
oral ketamine is low because of the extensive first-pass
metabolism.\textsuperscript{39} There is a paucity of data on the
pharmacological aspects of the lesser-known routes.

\textbf{Uses}

The primary purpose for the development of ketamine was anesthesia, due
to its aforementioned unique advantages over opioids. Its safety profile
also allowed its use in non-OT settings including wars and mass
casualties.\textsuperscript{43} However, with the advent of newer
anesthetic agents and the propensity for neurocognitive effects of
ketamine, its use declined significantly, especially in the developed
world. Nevertheless, its utility continued to be evaluated, and lately,
it is gaining renewed interest as an adjunct to opioid-based anesthesia,
to overcome issues like post-anesthesia
delirium.\textsuperscript{44}Ketamine is also considered a particularly
useful agent for pediatric anesthesia because of its safety profile.
Ketamine has been adjudged as an excellent drug for short-term medical
procedures, due to its potent analgesic and sedative effect, favorable
hemodynamic profile, and short duration of action.

The excellent analgesic effect of ketamine has been known for almost
five decades, with the added benefit of much lesser neuropsychiatric
adverse effects noted with the doses sufficient for analgesia. Although
several reports have found it to be remarkably effective for neuropathic
pain, including chronic cancer-related pain, systematic evidence for the
same from large-scale randomized controlled trials is
lacking.\textsuperscript{45,46,47,48} The analgesic efficacy of ketamine
has also been replicated in children of various ages and disease
profiles.\textsuperscript{49,50,51}

Systemic ketamine has been used in acute severe asthma owing to its
bronchodilatory effect, although clear evidence of benefit is
lacking.\textsuperscript{52,53,54} Similarly, the role of ketamine in
refractory and super-refractory status epilepticus is being increasingly
recognized wherein it acts chiefly through its antagonistic effect on
excitatory glutaminergic action.\textsuperscript{55} However, no
standard protocols are available for either of these uses. Another
well-described use of ketamine is in treatment-resistant depression in
adults, wherein it has been thoroughly investigated. A recent systematic
review of the efficacy of ketamine for treatment-resistant mood
disorders in children found an overall beneficial effect in terms of
depressive symptoms, suicidality and mood lability, but emphasized on
the need for further systematic evaluation in
children.\textsuperscript{56} Intranasal ketamine is useful in migraine
by reducing the severity of aura.\textsuperscript{57}

\textbf{Scope in Pediatric Oncology}

\textbf{4.1 Cancer-related pain}

Cancer-related pain can be severely debilitating. Opioids have
traditionally been the mainstay of pain management in such patients.
However, the somnolence induced by these drugs may sometimes be
unacceptable, with impairment in the child's quality of life and ability
to communicate. Moreover, tolerance to opioids is a common concern, with
requirements of increasingly higher doses. Ketamine, due to its low
sedation potential and safe hemodynamic profile, has been used as an
adjunct to opioids and is often regarded as second-line therapy after
opioids for intractable neuropathic pain in pediatric oncology practice,
with usual doses ranging from 0.025-0.3
mg/kg/hour.\textsuperscript{58}In pediatric end-of-life care, the role
of ketamine patient-controlled analgesia (PCA) has also been
mentioned.\textsuperscript{59} Low dose ketamine infusion for refractory
pain in children with cancer has been shown to significantly reduce pain
as well as the requirement of opioid dose.\textsuperscript{60,61,62} In
this regard, the anti-hyperalgesic and anti-allodynic effect of ketamine
has been well-described.\textsuperscript{63,64} However, a recent
systematic review found no post-operative opioid-sparing effect of
ketamine in children.\textsuperscript{65} Epidural ketamine in
combination with morphine has been found to increase the duration of
analgesia.\textsuperscript{66} Oral ketamine doses ranging from 0.25-1
mg/kg/dose are safe and effective in children with chronic
pain.\textsuperscript{67} Oral ketamine offers the distinct advantage of
the ease of administration combined with potent analgesic, something
which has so far been achieved satisfactorily only with a handful of
agents. Despite the emerging evidence for ketamine for cancer pain, its
use currently remains largely off-label. World Health Organization (WHO)
has discontinued its guidelines on the pharmacological treatment of
persisting pain in children with medical illnesses (2012) in light of
new evidence and is revising it, but perhaps it would be premature to
list ketamine as an upfront analgesic after opioids for children with
cancer.\textsuperscript{68} Moreover, ketamine doesn't find a mention in
WHO guidelines for the pharmacological and radiotherapeutic management
of cancer pain in adults and adolescents (2018), in the absence of
concrete evidence from high-quality studies.\textsuperscript{69}Table 2
provides a summary of the prospective studies of ketamine for cancer
pain in children.

\textbf{4.2 Sedation and procedural pain}

Parenteral ketamine (intravenous/ intramuscular) is often used for
sedation during outpatient as well as inpatient procedures, including
lumbar puncture, bone marrow aspiration, and biopsies, with good
efficacy and tolerable adverse effects.\textsuperscript{74}Intramuscular
administration has the advantage of not requiring intravenous access but
has been associated with a slightly higher incidence of adverse
events.\textsuperscript{75} For sedation, ketamine is also frequently
combined with other agents like midazolam, propofol, and
dexmedetomidine.\textsuperscript{76,77,78,79} Pellier et al
prospectively evaluated a combination of midazolam (IV, 25 mcg/kg) and
ketamine (IV, 0.5-2 mg/kg) for procedural sedation in children with
cancer, and found it to be safe and effective.\textsuperscript{80} Some
of the undesirable adverse effects of intravenous ketamine used for
sedation such as hypersalivation and tachycardia may be alleviated by
using atropine.\textsuperscript{81} An oral mixture of ketamine,
midazolam, and atropine was found to be equivalent to intramuscular
administration of these drugs for procedural sedation during minor
oncological procedures in children.\textsuperscript{82} However, a trial
evaluating the analgesic effect of oral ketamine (1 mg/kg) for
procedural analgesia before bone marrow examination did not find any
significant benefit over placebo.\textsuperscript{83} Similarly, oral
ketamine sedation (8-15 mg/kg) was found to be insufficient in children
with cancer undergoing radiotherapy.\textsuperscript{84} Thus, while
intravenous ketamine has gained widespread popularity as a procedural
agent, the role of oral ketamine is yet to be established. Intranasal
ketamine has also been used for sedation in children. Yang et al
described the use of intranasal ketamine and dexmedetomidine in 17948
children for procedural sedation and concluded it to be satisfactorily
effective with fewer adverse events.\textsuperscript{85} Table 3
provides a summary of the prospective trials of ketamine (sample size [?]
10) for procedural pain or sedation in children with cancer.

\textbf{4.3 Topical ketamine}

The evaluation of topical ketamine preparations for chemotherapy-induced
peripheral neuropathic pain has yielded variable results, with some
suggesting a promising role but many studies indicating no significant
benefit.\textsuperscript{91,92,93} Topical ketamine is a safe and
effective analgesic for decreasing post-tonsillectomy pain in children,
and has been used as a skin preparation for non-cancer
pain.\textsuperscript{26,94,95} Preliminary evidence for ketamine
mouthwash for oral mucositis pain had suggested a beneficial role in
adults, but a recent RCT evaluating the role of ketamine mouthwash for
oral mucositis pain relief in children (N=44; 8-18 years) found ketamine
to be ineffective at a dose of 1 mg/kg.\textsuperscript{96,97,98,99} The
summary of various studies of ketamine mouthwash in oral mucositis (OM)
pain in cancer patients has been provided in Table 4.

There are several potential advantages of using topical agents over
systemic, such as higher analgesic concentration at the site of pain,
faster onset of action, low or no systemic drug levels and side effects,
decreased risk of drug interactions, better drug compliance, and
decreased risk of abuse or dependence.\textsuperscript{100} Considering
these benefits and the fact the patients with cancer are already on a
concoction of systemic agents, discovering effective topical agents
could prove to be very useful in this group in providing desired
therapeutic effects while minimizing adverse effects and harmful drug
interactions. Hence, further studies investigating the topical delivery
of ketamine for analgesic and anti-inflammatory effects are the need of
the hour.

\textbf{Adverse effects}

Commonly seen adverse effects include sedation, nausea, vomiting,
hallucinations, anorexia, urinary retention, hypertension, tachycardia,
muscle stiffness, increased respiratory secretions, vertigo, and
ataxia.\textsuperscript{101,102} Nystagmus, diplopia, laryngospasm,
reversible cystitis, and central diabetes insipidus have been noted on
rare occasions.\textsuperscript{103,104} Abrupt discontinuation of
ketamine infusion may lead to anxiety, tremors, sweating, and emergence
reactions.\textsuperscript{105} These reactions manifest as
hallucinations, vivid dreams, and delirium. There is also evidence to
believe that the emergence reactions are seen less commonly in children
as compared to adults.\textsuperscript{106,107} As noted previously, the
notorious psychomimetic effects of ketamine have been seen to be much
less frequent at analgesic doses. The emergence of reactions can be
minimized by concomitantly using a benzodiazepine with
ketamine.\textsuperscript{108} All the aforementioned adverse effects
are rare with topical preparations.\textsuperscript{96,97,98,99}

The conventional contra-indications to the use of ketamine include
conditions in which a sudden increase in systemic blood pressure might
be dangerous (cerebrovascular accidents, myocardial infarction, aortic
dissection, aneurysm), known or suspected schizophrenia spectrum
disorder and documented hypersensitivity. The American College of
Emergency Physicians has also listed age less than three months as an
absolute contraindication to the use of ketamine, due to a high risk of
airway complications, although ketamine is still occasionally used in
this age group.\textsuperscript{101} Ketamine is to be avoided in
patients with glaucoma due to its propensity to cause intraocular
pressure. A few other relative contraindications include a history of
airway instability, known cardiovascular disease, porphyrias, and
hyperthyroidism (increased sympathomimetic activity). Additionally, in
the absence of sufficient safety data available for ketamine levels in
breastmilk, it is recommended that alternate agents be preferred when
feasible.\textsuperscript{109}

Early reports about ketamine dating as far back as the 1970s suggested a
propensity of ketamine to cause intracranial
hypertension.\textsuperscript{110,111} However, since then ample
evidence has questioned this notion. Ketamine has been shown not to
cause intracranial hypertension in patients, including in those with
traumatic brain injury in children.\textsuperscript{112,113,114} In
fact, ketamine by maintaining cerebral perfusion pressure may have a
neuroprotective effect, especially under conditions of controlled
ventilation.

\textbf{Concerns in children}

Long term use of high dose ketamine has been linked to adverse
neurodevelopmental outcomes, including those related to memory,
cognition and executive function.\textsuperscript{115} However, most of
such information has been derived from studies done on recreational
abusers of ketamine and is unlikely to have much basis in the clinical
use of controlled doses of ketamine. Nevertheless, the abuse potential
of ketamine is well-documented and has to be kept in mind. Moreover,
even sub-anesthetic doses of ketamine have been shown to cause some
impairment in memory and attention.\textsuperscript{116} It is therefore
imperative for clinicians to monitor for any such effects during the
administration of ketamine to children.

In the developing brain of some animal models, ketamine has been noted
to induce altered development of Neural Stem Progenitor Cells, with the
potential to cause long-lasting cognitive
damage.\textsuperscript{117,118} The extrapolation of such evidence into
clinical practice is debatable, and further evidence is needed to make a
final statement on the developmental neurotoxicity of
ketamine.\textsuperscript{119} In fact, in the presence of harmful
stimuli such as pain and inflammation, ketamine, by its analgesic and
anti-inflammatory action, may even have a neuroprotective
role.\textsuperscript{120} Nonetheless, it would be prudent to practice
caution while administering ketamine to neonates, young infants, and
pregnant and lactating women, and prefer alternative agents.

\textbf{Prospects for future research}

There is ample evidence for ketamine as a good agent for procedural
sedation in children with cancer. However, regarding its role as an
analgesic, despite numerous reports from small studies and case reports,
there is a paucity of quality evidence. There is a clear need for
systematic well-designed studies to evaluate the efficacy and safety of
ketamine as an analgesic agent, including that of oral and local routes
of administration. Understandably, there are ethical concerns regarding
the conduction of a drug trial for end-of-life cancer pain. In such
circumstances, the clinician and parental tolerance for adverse effects
are much higher, allowing the use of a wider gamut of analgesic agents
and at higher doses. Ketamine has been successfully used in this setting
in children with terminal cancer.\textsuperscript{70,71} However, the
role of ketamine for the treatment of neuropathic pain in children with
cancer in non-terminal stages is still not convincing. There are
concerns regarding sustained efficacy as well as the potential for
neuropsychiatric adverse effects. This aspect requires further research,
preferably as a randomized controlled trial, to enable confident
prescription of ketamine by pediatric oncologists.

\textbf{Conclusion}

Ketamine is a dissociative anesthetic with an excellent analgesic action
at low doses. Due to its desirable effect on hemodynamics and protective
airway reflexes, it is commonly used for short term procedural sedation
as an intravenous drug. Other forms of systemic administration like oral
or intranasal routes have been proven to be safe and effective and have
the advantage of easy administration. Moreover, topical delivery of
ketamine has also shown encouraging results but still requires further
investigations, especially in children. Ketamine is a commonly used drug
in pediatric oncology practice, mostly for sedation, but its efficacy as
an analgesic is largely underutilized. Pediatric oncologists need to
familiarize themselves with the pharmacological aspects of the drug to
prescribe it more rationally and effectively, while keeping in mind the
possible, albeit rare, serious adverse effects.

\textbf{FUNDING SUPPORT}

None

\textbf{CONFLICT OF INTEREST}

The authors have no conflicts of interest relevant to this article to
disclose.

\textbf{AUTHOR CONTRIBUTIONS}

\textbf{Satya Prakash:} Design the study and drafting of
manuscript.\textbf{Aditya Kumar Gupta:} Critical inputs and drafting of
manuscript.\textbf{Jagdish Prasad Meena:} Supervision, critical inputs
and drafting of manuscript.

\textbf{ORCID}

Jagdish Prasad Meena:https://orcid.org/0000-0001-6024-9762

Satya Prakash: https://orcid.org/0000-0003-4248-9855

Aditya Kumar Gupta https://orcid.org/0000-0002-3730-8944

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