Prof. Mridul Panditrao, dwells upon, the newer applications of Ketamine, good old friend of anaesthesiologists, a trusted weapon! Now is making a strong comeback for diverse indications like chronic/ neuropathic pain and major depressive disorders, in addition to its traditional applications of peri-operative analgesia.

1. KETAMINE
IS IT REALLY A WONDER DRUG?
IT APPEARS SO!!

2. KETAMINE: OLD WINE IN NEW BOTTLE
ROLE IN
CHRONIC/NEUROPATHIC PAIN CONDITIONS
&
MAJOR DEPRESSIVE DISORDERS!

3. Prof. Mridul M. Panditrao
Professor, Head & In-Charge of ICU
Department of Anaesthesiology & Intensive Care
Adesh Institute of Medical Sciences & Research
Dean Academic Affairs
Adesh University
Bathinda
Punjab
3

4. Introduction :
• Good Old Ketamine- reliable, dependable and effective!
• Amazing track record of a drug, which was introduced more than
55 years back,
• One of the most commonly used drugs, at least in India
• Be it a novice under supervision or an experienced one
• As a: premedication, sedative, intra-op/post-op analgesia, opioid
sparing, adjuvant to LAAs, emergency, ICU, Dark Room, IVF, ……..!
• Feeling reassured, confident and comfortable about its action!!!

5. Introduction : Historical
• In 1926, Phencyclidine Hydrochloride—called PCP or angel
dust on the street—was developed
• With the hope of finding a safe/effective anesthetic
• As an N methyl D aspartate Receptor (NMDAR) antagonist
• Found to produce convulsions at high doses
• Long-lasting psychoactive side effects during emergence
• Habit forming tendencies
• Banned & Obsolete!
5

6. Introduction : Historical
• 1962 – American scientist Calvin Stevens (CI-581) at Parke Davis
Laboratories
• Even after more than 55 years since its introduction
• Still remains an Enigma in terms of its wide variety of
pharmacological actions

7. “Dissociative State”• By 1965, the first report of
ketamine’s recreational use
(Professor Edward Domino)
• Where he described it as a
potent psychedelic drug and for
which he termed it as a
“dissociative anesthetic”
• at low concentrations: analgesic
• at higher concentrations,
“Dissociative State”
• Has a true anatomic basis
Depression in
certain areas &
Stimulation in
others
It is the functional dissociation between
the cortical and limbic systems

8. Pharmacology:
• Ketamine is a classic example of ‘stereoisomerism’
• The stereoisomers have same number of atoms, bound to each
other by same number of bonds, single as well as double (triple)
• If they form mirror images, which cannot be superimposed, they
are called ‘enantiomers’
• Only their ‘orientation’ or ‘handedness’ is different
• This handedness is called as ‘chirality’
• ketamine molecule has a chiral center, so two enantiomers
• R (-), the right handed one, while S (+), the left handed one

10. S (+) Ketamine
S(+) ketamine, has obvious advantages of :
• better clearance,
• 3-4 times more potency as an analgesic, as compared to either
the racemate or R ketamine.
• induces less drowsiness, less lethargy and less cognitive
impairment
• Less dose required, reduced drug load, with more rapid recovery,
• fewer psychotic emergent reactions, less agitated behavior, &
better intraoperative amnesia/analgesia than R(–) enantiomer

11. Mechanism/s of Action:
• Ketamine: racemate or its enantiomers, primarily are NMDAR antagonists
• NMDAR hyperactivity, also called as ‘excitotoxicity’!
• Excitotoxicity has been postulated to be the main contributor for the
central sensitization to the noxious stimuli
• By inhibiting NMDARs
• Ketamine has been producing Analgesia.

12. NMDARs:?!?
• NMDAR is a ion channel protein belonging to a subclass of
ionotropic glutamate Receptor (iGluR) family
• These mediate most of the excitatory glutamatergic transmission
in the CNS.
• The NMDAR is one of three types of iGluRs, other two being the
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid or quisqualate) and Kainate receptors.
• The NMDAR, is so named because the agonist molecule N-
methyl-D-aspartate (NMDA) binds selectively to it, and not to
other glutamate receptors.

13. • activated when glutamate and glycine (or D-serine) bind to it
• Ca2þ channel pore gated by a Mg2+, opens briefly to allow the
influx of cations, especially, Na+/ Ca2+
• Calcium activates second-messenger systems,  neuronal
hyperactivity  generation of excitatory post-synaptic current,
• Thus regulating the transductional mechanisms, important for cell
survival/ apoptosis, learning and memory.
• Ketamine neither binds to the agonist; i.e. glutamate binding site
nor to the glycine one,
• rather to an adjacent site, which is called, allosteric binding site.
• That is the reason why, it is called as noncompetitive antagonist
at NMDAR.
• Once bound it does not allow the displacement of Mg2+ ion,
preventing the entry of Na+ and Ca2+ inside the cell.

14. NMDARs:!!!!
• Play an important role in the health and function of neurons : can affect
both cell survival and cell death
• Control synaptic plasticity, memory function, also synapse formation
underlying memory, learning and formation of neural networks during
development in CNS
• Over activation of the receptor, causing excessive influx of Ca2+ can lead to
‘excitotoxicity’
• which is hypothesized to be involved in, chronicity of Pain, & some
neurodegenerative disorders.
• Blocking of NMDARs could therefore, in theory, be useful in treating such
diseases.
• Abnormal NMDAR function may cause neurologic disorders : Alzheimer’s
disease, amyotrophic lateral sclerosis, depression, epilepsy, multiple
sclerosis, Parkinson’s disease, and schizophrenia.

15. NMDARs:!!!!
extra-synaptic
• overstimulation of “extra synaptic”
NMDARs responsible for
excitotoxicity
• stimulation of extra synaptic NMDARs
appear to contribute to cell death
synaptic
• stimulation of synaptic: no
excitotoxicity
• stimulation of synaptic NMDARs
contributes to the health and
longevity of the cell
Two subspecies of NMDARs, as per their location
• Ample evidence to support the dual nature of NMDARs based on location
• Hypothesis explaining the two differing mechanisms is : “localization hypothesis”

16. NMDARs, KETAMINE & CHRONIC PAIN:
• Pain signals peripheral nerves spinothalamic tract to the cerebral
cortex  where it is perceived, localized, and interpreted.
• The anti-nociceptive system balances out the pain-sensing system
• The transmitted pain signals activate neurons in the Peri Aqueductal Gray
(PAG) & Nucleus Raphe Magnus of the brainstem which release
endorphins and enkephalins, inhibition of further nociception &
analgesia.
• This entire process of central inhibition is termed neuromodulation

17. Inhibition of
neuromodulation
Immune
cell
activation Release of
inflammatory
cytokines
Death of inhibitory
neurons,
compounds the
excitatory state
Upregulation of
NMDARs
expression &
neuroplasticity
spinal cord
primary afferent
neurons hyper
activated
INTRACTABLE CHRONIC PAIN
UNRESPONSIVE TO ANALGESICS

18. CHRONIC PAIN is
• a provoked &/or
irreversible
• progressive or stable
• dysfunctional &/or
neurodegenerative
disease of the CNS
CENTRAL
NEUROPATHIC
PAIN
Whatever
is the initial
pain
mechanism
All types of
unrelieved
pain end as

19. Ketamine & Substance P
• Extra-synaptic NMDARs  modulate the vesicular release of substance P.
• In addition Substance P receptors also found in afferent neurons (C-fibers),
• Substance P implicated in both physiological & chronic/pathological
sensitization of pain.
• Ketamine causes indirect decrease in release of substance P
• As well as direct inhibition of the substance P receptors

20. Additional Mechanisms: Ketamine:
• Inhibits Serotonergic pathways, especially in the presence of mechanical
injury.
• Potentiates impaired dopamine signaling in Dopaminergic pathways
• Direct inhibition of Muscarinic Acetyl Choline receptors (mAChR) are
known to have nociceptive potential.
• acts at multiple sites, AMPA receptor, GABAA receptors,
• Monoaminergic receptors: (Dopaminergic, noradrenergic and adrenergic)
• HCN1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-
gated channel 1
• Cholinergic & muscarinic receptors, indeed, produces anticholinergic
symptoms (e.g. tachycardia and bronchodilation)
• At high doses has local anaesthetic properties these may be through its
ability to inhibit neuronal sodium channels.

21. Chronic Pain: Clinical Indications
• Sub-anaesthetic doses of 0.5 to 1mg/ kg both intravenous
infusion as well as orally
• Used in
• Central neuropathic pain
• Complex regional pain syndrome (CRPS)
• Fibromyalgia
• Postherpetic neuralgia
• Migraines
• Ischemic pain
• Acute on Chronic and Nonspecific Neuropathic pain
• Orofacial pain
• Phantom limb pain
• Spinal cord injury
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24. Pain Physician 2010;13:278-287

25. Anaesth Analg 2003; 97: 1730-9
An excellent Evidence based
review
• Has brought out some
very significant facts
• About the evidence
regarding the efficacy of
ketamine
• As a drug of choice in
various Chronic pain
conditions

26. Hocking G, Cousins M. Anaesth Analg 2003; 97: 1730-9
• The authors have done a metanalysis of multiples of studies level II to
Level IV
• Obvious conclusion was, that there is no definitive (level I) evidence
available,
• Evidence ranges from Level II to Level IV, suggesting the efficacy ranging
between Moderate to weak
• Whatever Level II was there was offset by the limitations like, case
reports, case series, in trials: small number of patients.
• In cases with phantom limb and post herpetic neuralgias, there was
significant reduction in incidence of hyperpathia and analgesia.

28. Suggested protocol for a RCT!
• Ensure that there are no contraindications to the use of ketamine
• Educate the patient regarding the potential side effects and obtain fully informed consent (level IV)
• Perform a fully monitored, placebo controlled IV trial of ketamine to assess therapeutic benefit
• Available data suggest this should be a dose of 0.25–0.5 mg/kg given slowly over 30 min with pain
assessments before and after administration (level II)
• Poor responders or non-responders are unlikely to benefit from oral ketamine
• A good therapeutic response from systemic administration suggests a greater likelihood of benefit from oral
dosing (level IV)
• Commence oral ketamine 0.5 mg/kg taken immediately before going to bed to minimize the likelihood of
side effects (level IV)
• Increase the dose by 0.5 mg/kg as tolerated until pain relief is obtained or intolerable side effects occur
(level IV)
• The mean effective dose from the literature is 200 mg/day (level II) although there is a wide variation.
• For severe acute on chronic episodes of neuropathic pain, administer ketamine by continuous infusion (IV) at
a rate of 0.14– 0.4 mg/kg/h (level IV).
•

29. Oral Ketamine :
Liquid Preparation Vs. Placebo
• 5 mL ketamine injection 100 mg/m
• 1.25 mL conc. peppermint water BP.
• 0.1 mL conc. anise water BP.
• 1.25 mL conc. chloroform water BPC.
• 20 mL syrup (preserved) BP.
• Water to make total of 50 mL.
Placebo Liquid
2 mL conc. peppermint water BP
0.2 mL conc. anise water BP
1.25 mL conc. chloroform water BPC.
5 mL syrup (preserved) BP
Water to make 50 mL.

30. Major Depressive Disorder (MDD)
• Is a debilitating mental illness that affects millions of people worldwide
leading to severe health and socioeconomic consequences
• Although many antidepressant treatments are available, there is a need for
more effective treatments, especially for treatment-resistant depression
(TRD) and depression with suicidal ideation.
• Most conventional antidepressants act through monoaminergic
mechanisms.
• The concept is that depression is related to some imbalance in
neurotransmitters such as serotonin, dopamine and norepinephrine
• However, there is evidence that other neurotransmitters also play a role.
• Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Nor-
epinephrine Reuptake Inhibitors (SNRIs) require a period of several weeks
before improvements in mood are experienced.

31. Ketamine as a novel antidepressant
• Till 2000, ketamine only for modalities of pain and its management
• However, Burman and his team, first reported its rapid antidepressant
effects by their action again as NMDAR antagonist
• It simply opened a new dimension to the already burgeoning
reputation of ketamine
• Various trials provided growing evidence for ketamine’s potential
rapid and sustained anti-depressant effects
• Especially in treatment resistant cases of depression (TRD), bipolar
disorders as well as in ECT.

32. R (-) Ketamine!!
• Recent studies: R(-) Ketamine more promising anti-depressant
activity, than S(+)
• Reason postulated: R(-) form may be devoid of the psychomimetic
and dissociative symptoms
• Apparently mediated by the action of R(-) form on AMPA receptors
• Increase in glutamate leads to stimulation/depolarization of AMPA
• Induces release of Brain Derived Neurotropic factor (BDNF)
• Activation of mammalian target of Rapamycin Complex1 ( mTORC1)
signaling pathway.
• R(-) ketamine directly acts at AMPA site antagonizing them and thus
causing improvement in symptomatology

33. Ketamine and ECT:
• Two different scenarios where Ketamine has been correlated with ECT
• The first was when a group of major depression patients received 3
successive ECT sessions under a standard protocol (atropine,0.5mg,
Thiopentone, 2-3 mg/kg, succinyl choline,0.5mg/kg, every 48 hourly)
versus
• 3 successive infusions of I.V. ketamine 0.5mg/kg over 45 minutes, every 48
hourly
• With proper Psychiatric assessment, ketamine was found to be much rapid
acting with better scores in early treatment of major depression, as
compared to ECT
• The second scenario: ketamine was compared with propofol for IV use
during ECT & was found to be better in improving the recovery,
symptomatology!

34. Recent Advances: Newer Ketamine like drugs!
• By the action on NMDARs, a drug called Memantine, for
• Dementia of Alzheimer’s
• Parkinson’s Disease
• Stroke
• Epilepsy
• Cerebral trauma
• Amyotrophic Lateral Sclerosis (AMS)
• drug dependence and Chronic Pain
• The action is mediated by uncompetitive antagonism of NMDARs, by
reducing ‘glutamate excitotoxicity’, thus providing ‘neuroprotection
• Ephenidine : especially for the recreational uses
• because of increasing legislation against free use of Ketamine

35. Conclusion
• Our Good Old Ketamine, has rejuvenated itself in to newer applicabilities
• Transcended beyond the conventional peri-operative analgesia/
anaesthesia, procedural sedation, adjuvant to GA/ LA.
• Research is opening newer dimensions, identifying myriads of binding
sites, understanding the multiples of mechanisms of actions
• We need to get up and take cognizance of yet unexplored areas of
Ketamine’s therapeutic possibilities

36. Conclusion
• The areas like
• Management of chronic pain
• As a Novel antidepressant
• For Electro Convulsive Therapy (ECT)
• For understanding many Neurological Disorders
• In the normal developmental process of learning & memory
are some of the promising possibilities
• Newer drugs like, ephenidine, memantine, for treatment of the
neuro-degenerative disorders, with promising results.

37. Thank you!