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.
Keywords: Ketamine; Oncology; Chronic pain; Sedation;
Mucositis; Children
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.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.2Additionally, 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.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.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.
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.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.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).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.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.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.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.
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-ĸB pathway,
thereby impeding the pro-inflammatory cytokine
response.15,16,17 Another possible mechanism could be
the inhibition of inflammation-induced nitric oxide
production.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.20However, 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.21,22
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,
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate
receptors are up-regulated on the axons as a reaction to
inflammation.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.24 Ketamine has
local anesthetic properties at high doses which have been compared with
lignocaine and procaine, although with lesser
potency.25 Indeed, ketamine has been widely studied as
a topical agent for reducing post-tonsillectomy pain in children,
including nebulized and oral rinse forms.26