MC Rajesh
Baby Memorial Hospital, Kozhikode,
Kerala, India. PIN: 673004
Address for Correspondence: Dr. MC Rajesh MD, MBA,
Senior Consultant Anaesthesiologist, Baby Memorial Hospital,
Kozhikode, Kerala, India. PIN: 673004. E- mail:
rithraj2@yahoo.co.in
Abstract
In the present day anaesthesia practice, ketamine is not
routinely used as an induction agent. But it is a popular
pharmacological agent in variety of pain conditions from
nociceptive to neuropathic pains and for paediatric procedural
sedation outside operation theatre complex. Of late, there is
a renewed enthusiasm with regard to use of Ketamine for
variety of indications like pain relief in pre hospital trauma
victims, as an antidepressant, anticonvulsant, to prevent post
operative sore throat and even in renal colic.
Following text is a narrative review on the recent evidences
with regard to pharmacology of the agent for its extended
indications other than in day to day anaesthesia practice.
Keywords: Ketamine, Neuropathic pain, Trauma pain,
Burns dressings
Introduction
Since its introduction into clinical practice, prescription of
ketamine for more than half a century was entirely in the
domain of anaesthesiologists. It binds to the phencyclidine
receptor of the N-methyl D-aspartate (NMDA) channel
noncompetitively and inhibits activation of receptors by
glutamate. Ketamine was once a popular agent for induction of
anaesthesia in patients with relative hypovolaemia or for
short surgical procedures. In most of the so called emerging
pharmacological indications of ketamine, it is used in
subanaesthetic doses. The perceived advantage at this
therapeutic range is that it causes little or no respiratory
depression but at the same time maintaining airway tone and
reflexes unlike other induction agents. When used in sub
anaesthetic doses there is no or mild psychotomimetic effects
with good patient acceptance. But it must be recognized that
ketamine is an anaesthetic agent and the user should have the
competence and confidence in handling airway compromise if
need arises.
The commercial preparation of ketamine which is commonly
available consists of two enatiomers in equimolar amounts [1].
Out of this, the S(+) ketamine has four fold greater
affinities to N methyl D aspartate receptors (NMDA) than R(-)
ketamine, but with shorter duration of action [1]. The S(+)
ketamine is now available as a preparation for clinical use.
Procedural sedation
Routine use of ketamine as an induction agent is limited due
to unpleasant psychomimetic effects. But because of its
ability to maintain airway reflexes even while providing
adequate levels of sedation makes it an attractive option for
procedural sedation, especially in paediatric practice. Its
relative safety makes it a practical option in situations
which lack sophisticated equipments and monitors as in
military practice, emergency department and in procedural
sedation outside the operation theatre. Ketamine is used alone
or in combination of other agents like Propofol for this
purpose.
In our present day practice, use of ketamine is common in
cardiac catheterization, gastrointestinal endoscopy,
paediatric radiological investigations and radiotherapy.
Though it can be administered by different routes, intravenous
one is considered superior [2] because of more predictable
effects. Most anaesthesiologists prefer to have an IV access
in situ as a precautionary measure and with the advantage of
giving top up doses, if the need arises.
Trauma victims
Ketamine produces predictable and profound analgesia with both
intramuscular and intravenous administrations. It is an
attractive option as an analgesic in trauma patients [3].
Especially in subanaesthetic dosage it is a safe alternative
to opioids in prehospital care of polytrauma victims [4]. It
avoids the potential drop in blood pressure and respiratory
depression that is sometimes associated with the use of
opioids. Airway related problems are also less compared to
opioids, but there is risk of hallucinations and agitations
with ketamine compared to opioids [5].
In low resource rural trauma situations, ketamine proved to be
safer alternative to opioids as was evident from a ten year
cohort study from Iraq [6]. Jennings PA et al in a out of
hospital, randomized, controlled study established the
superiority of intravenous morphine plus ketamine combination
over intravenous morphine alone in out of hospital adult
trauma patients. But the combination is also associated with
some increase in the rate of minor adverse effects [7]. A
recent meta analysis of six trials indicates the favourable
effects of ketamine over opioids, establishing itself as a key
agent for pain control in trauma patients [8].
Post operative pain
It was Sadove et al who first suggested the use of ketamine as
an analgesic in sub anaesthetic doses [9]. Since then there is
growing literature evidence to support the efficacy of
ketamine in variety of pain conditions. Parikh B et al in
sixty American Society of Anaesthesiologists (ASA) I and II
patients for elective renal surgeries found that small dose of
ketamine before skin incision (0.15mg/kg) and continued as
infusion (2microgram/kg/minute) during procedure is effective
in reducing post operative morphine requirements [10]. The
analgesic potency of ketamine at this subanaesthetic dose is
explained by the inhibiting action on the NMDA receptor
mediated pain facilitation [11]. Bell RF et al in a meta
analysis involving 37 trials found ketamine to be effective in
reducing morphine requirements in the first 24 hours after
surgery [12]. Incidentally there is also reduction in post
operative nausea and vomiting with fewer adverse effects
reported [12]. Ketamine was also found to be a useful adjuvant
when used along with local anaesthetics in both central
neuraxial blocks and peripheral plexus blocks [13]. However
only preservative free ketamine should be used in central
neuraxial blocks. Marc De Kock described perioperative use of
intravenous ketamine (0.5mg/kg bolus) followed by 0.25mg/kg/hr
to reduce wound hyperalgesia and can be used as a useful
adjuvant in balanced analgesia [14].
Neuropathic chronic pain
The rationale in prescribing ketamine for neuropathic pain is
the concept that hypersensitivity of NMDA receptors is
responsible for the genesis of neuropathic pain and ketamine
is a potent NMDA receptor anatagonist [15]. At subanaesthetic
dose, the analgesic efficacy parallels with its inhibitory
action on the NMDA receptor mediated pain facilitation.
Ketamine was tried through different routes (intravenous,
subcutaneous, oral, topical, intranasal) and proved to be
efficient in different neuropathic pain conditions [15].
Bioavailability with oral and sublingual preparations is
around 25%. There is even a gel based oral preparation for
topical application [16].
There are case reports wherein ketamine infusion is associated
with significant pain relief in complex regional pain syndrome
type-1(CRPS-1) [17] and is investigated as a modality of
treatment [18]. It has proved its worth not only in CRPS-1,
but also in other chronic neuropathic conditions such as
central pain, fibromyalgia and in post ischaemic pain
[19]. A recent randomized controlled trial showed that a
ketamine regimen is superior to methadone or ketamine combined
with methadone in alleviating neuropathic pain [20]. Another
indication for ketamine is in pain relief for chronic
opioids-tolerant patient when all other options have exhausted
[21]. Allodynia, resulting from nerve injury responds poorly
to opioids and ketamine has been reported to reduce this
discomforting problem [22]. Ketamine though can't be
prescribed on long term basis, is found to be useful as a
short term therapy in central post-stroke pain [23].
Burns dressings
Ketamine is used extensively in burns ICUs and in operation
theatres for burns dressings and for minor tangential
excisions and skin grafting. It is especially useful in
paediatric patients who are anxious about the repeated
procedure and pain. With sub-anaesthetic ketamine, both
primary and secondary hyperalgesia is also found to be less.
To minimise emergence phenomenon, pre-treatment with
benzodiazepine is ideal. A prospective study conducted by Mac
Pherson RD, et al concluded that a patient controlled
analgesia technique by a combination of ketamine/midazolam
provided adequate and effective analgesia for burns dressings
[24]. Recovery time after a continuous administration may be
prolonged. Patients who require repeated administration may
develop tolerance, i.e., they require increasing subsequent
doses. In a randomized double blind cross over study, Pankaj
Kundra et al clearly showed the superiority of oral ketamine
as an analgesic compared to dexmedetomidine in adult burn
dressings [25.] But the use of ketamine was associated with
delirium and excessive salivation [25].
Phantom limb pain
Hyperactivity of NMDA receptors is believed to be one of the
mechanisms for the maintenance of phantom limb pain (PLP).
Hence ketamine may have a role in the treatment of PLP.
Successful use of oral ketamine to reduce the intensity of
phantom limb pain has come in literature [26, 27].
Anticonvulsant!
An interesting case report appeared in Annals of Pharmacology
by Diane et al in 2013 where ketamine infusion was used to
control refractory status epilepticus in a patient with
anticonvulsant hypersensitivity syndrome [28]. There are
animal studies and literature evidence to say that ketamine
indeed has antiepileptic properties. But it is difficult to
conclude and analyse from the many reported cases as patients
were on multiple antiepileptic medications [29].
Antidepressant!
Present therapeutic options for major depressive disorder
takes weeks to achieve the desired effects. On the other hand,
patients given ketamine found to have antidepressant effects
within few hours. This made researchers to think of new
generation fast acting antidepressants by modulating NMDA
receptors. Interestingly when other NMDA receptor antagonists
where tested clinically, they have only modest antidepressant
effects compared to ketamine but with less dissociative
effects [30]. Zhang JC et al in animal studies demonstrated
R(-) ketamine to have greater potency and long lasting
antidepressant effect than the S(+) enantiomer [31].
Interestingly ketamine also was shown to rapidly reduce
suicidal thinking [32]!
Renal colic pain
Renal colic pain is usually very intense and require very
strong analgesics. In a recently published randomized double
blind controlled trial performed in 53 patients with renal
colic, Farnia MR et al demonstrated the effectiveness of
intranasal ketamine in relieving renal colic pain [33].
However ketamine is not yet a popular agent as the first line
therapy for renal colic pain and there is paucity of studies
on the topic.
Prevention of Post operative sore throat
Post-operative sore throat is a vexing problem for
anaesthesiologists. Different pharmacological agents are being
tried to prevent occurrence of sore throat in the
post-operative period. O Canbay et al in a randomized,
placebo-controlled, single blind study observed that
preoperative ketamine gargling significantly lowered the
incidence and severity of post-operative sore throat [34].
However such beneficial effect is not observed with
intravenous ketamine [35].
Neuroprotective action
Neuroprotective role of ketamine contradicts the conventional
teaching of anaesthesiologist, wherein it is relatively
contraindicated as it increases intracranial pressure. Recent
enthusiasm to apply the drug as a neuroprotective agent stems
from two basic understandings: (1) Mechanism of action of
ketamine i.e. non-competative antagonism at NMDA receptors,
(2) Increase in intracranial pressure it produces may not be
relevant in the presence of normocapnia and stable blood
pressure. In animal experiments, ketamine has been shown to
attenuate the damage in the caudoputamen of hypocapnic rats
[36]. But at present, evidence is inconclusive to recommend
the use of ketamine as a neuroprotective agent.
Summary
Ketamine was introduced into clinical practice in 1960s. But
with the advent of new pharmacological agents and because of
undesired psychic actions, ketamine is slowly taken off from
the drug cart of anaesthesiologist in the operation theatre.
Outside operation theatre its role as an analgesic for the pre
hospital trauma victims as well as in emergency minor
procedures in casuality environment, chronic neuropathic pain,
burns dressings and for paediatric procedure sedation are all
established. But what is interesting is clinical and
experimental evidence of its role in new frontiers like
anticonvulsants, antidepressants, neural protection and even
to blunt post operative sore throat. For the time being
ketamine is not the first choice drug in these scenarios. We
need more data to clearly recommend its use for these emerging
indications.
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