KETAMINE

The line-up
 What is ketamine?
 Pharmacology of ketamine
 A brief history
 Article highlights: Use of ketamine for analgesia
 Clinical applications
 Analgesia
 Anaesthesia
 Contraindications/Adverse effects
 The future of ketamine
 INTRODUCING…VITAMIN K
 The only anaesthetic which has analgesic, sedative and amnesic effects

 Highly lipid soluble

 rapid breakdown and redistribution

 NMDA receptor antagonist

 binds to phenycyclidine site non-competitively

 Common routes: IV, IM, oral

 IV has faster recovery and less emesis than IM

 Metabolised by liver to norketamine

 main metabolite
 30% analgesic activity of parent compound

 Excreted in bile and urine

 Pharmacology
 Onset
 30 sec (IV)
 3-4 min (IM)

 Duration
 5-10 min (IV)
 2-25 min (IM)
 Dissociative state may last > 20 min

 Elimination half life: 2-3 hours

Reference: Medscape
Table from journal article Ketamine: an old drug revitalised in pain medicine PY Tsui et al. BJA Education, March 2017
Effects of Ketamine
 Stimulates the CVS
 increase in heart rate, blood pressure
and cardiac output
 mediated principally through
sympathetic nervous system

 Reaches a maximum about 2 mins after

injection and settles over 15 – 20 mins

 Wide variation in individual response

 Can occasionally see a large rise in

blood pressure - not related to a
preoperative history of hypertension1
1 Rachel Craven. Ketamine in anaesthestic practice, 2006
 Airway is usually well maintained

 Preserves the laryngeal and

pharyngeal reflexes

 Has minimal effects on central

respiratory drive

 Rapid IV injection can cause apnea for

a short while but usually restarts
within a minute

 Effective bronchodilator
 Increase salivation -> laryngeal spasm
or obstruction

 Atropine can be given either as a

premed 30 minutes preoperatively, or
at the time of induction
 Increases skeletal muscle tone - most
prominent after the initial iv bolus and
gradually decreases

 Improved by administration of
benzodiazepines
CNS Effects

Dissociation threshold
1-1.5 mg/kg (IV)
3-4 mg/kg (IM)
The history of ketamine
 1962 - Discovered by American scientist Calvin Stevens
who was looking for short acting anaesthetic agent to
replace phencyclidine (PCP)

 1970 – approved for use in humans –

 battlefield anaesthetic for US soldiers
in Vietnam War

 1970-1980 recreational drug use

1980s – became unpopular in medicine due

to emergence phenomena
1990s
 Renewed interest in ketamine as an adjunct
analgesic after discovery of anti-tolerant and anti-
hyperalgesic effects
How does ketamine help?
 NMDA receptors

 Sustained nociceptive transmission

 Opioid induced hyperalgesia

 Since ketamine antagonises the NMDA receptor ->

anti-hyperalgesic and anti-allodynic properties
Studies have found ketamine to be
useful in…
 Acute pain
 Preventive analgesia
 Cancer pain
 Chronic non-cancer pain
 OIH and opioid tolerance
 Regional/Local use
Acute pain – Ketamine as analgesia
 Reduce opioid consumption and time-to-first-analgesic
request 1

 Analgesic benefit observed in painful procedures

 upper abdominal, thoracic, major ortho surgeries

 Analgesic effect apparent with subanaesthetic doses,

independent of type of intraop opioid used

 Less post op nausea and vomiting

 Safe and effective analgesia for trauma patients

1 Laskowski K et al. A systematic review of intravenous ketamine for postoperative analgesia. 2011
 Acute pain – Ketamine as an additive
 Pre-treatment reduces pain during propofol injection

 Ketamine
 + opioid PCA after thoracic surgeries 1

 + opioid analgesics during burns care 2

 + propofol in A&E3

 Low dose IV 0.5 mg/kg at end of surgery is safe and

effective for post-tonsillectomy pain control 4

1 Matthews TJ et al. Does adding ketamine to morphine patient-controlled analgesia safely improve post-thoracotomy pain? 2012
2 Gregoretti C et al. Analgo-sedation of patients with burns outside the operating room. 2008
3 Schug SA et al. Acute pain management: scientific evidence. 2015
4 Javid MJ et al. Evaluation of a low dose ketamine in post tonsillectomy pain relief: A randomized trial comparing intravenous and subcutaneous ketamine in
pediatrics.Anesth Pain Med. 2012
 Acute pain –
Ketamine in chronic opioid users

 Opioid tolerant patients: post op continuous

ketamine infusion reduces pain score but NOT
opioid consumption post op 1

1 Barreveld AM et al. Ketamine decreases post-operative pain scores in patients taking opioids for chronic pain: results of a prospective, randomised,
double blind study. 2013
 Preventive analgesia

 Perioperative ketamine use > 24hrs reduces incidence of

persistent post-surgical pain at 3 months post op

 Beneficial effects also observed at 6 months but not at 12

months 1

1 McNicol ED et al. A systemic review and meta-analysis of ketamine for the prevention of persistent post surgical pain. 2014
 Cancer pain
 Used in refractory cancer pain1

 Available routes: IV, SC injection/infusion, IM, sublingual,

intranasal, PR

 Addition of ketamine improves effectiveness of morphine2

 Intrathecal ketamine infusions in refractory neuropathic

pain

1 Benítez-Rosario et al. A strategy for conversion from subcutaneous to oral ketamine in cancer pain patients: Effect of a 1:1 ratio. J Pain Symptom Manage. 2011
2 Bell RF et al. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database Syst Rev. 2012
 Chronic non-cancer pain
 Mild-moderate effect in chronic pain conditions –
neuropathic pain, central pain syndromes, headaches, TMJ
disorders 1

 Phantom limb pain2

 Complete remission of pain at infusion 300μg/kg in 60ml
solution over 3 hours 3

1 Bell RF. Ketamine for chronic non-cancer pain. 2009

2 Schug SA et al. Acute pain management: scientific evidence. 2015
3 Shanthanna H et al. Early and effective use of ketamine for treatment of phantom limb pain. Indian J Anaesth. 2010
 OIH and opioid tolerance
 State of nociceptive hypersensitivity caused by exposure to
opioids

 Increase in opioid dose can cause increase in pain

 Observed after acute use of strong opioids like remifentanil

or in long term opioid therapy
 NMDA receptor likely to be involved

 Ketamine thus reduces or opposes clinical features of

OIH

 Reduced opioid consumption

 Regional/Local Use
 BEFORE
 Before the application of painful blocks
 IV 0.5 mg/kg before neuraxial blockade – reduces shivering, prevents recall1
 IV 1 mg/kg - good hemodynamic stability in elderly undergoing TURP2

 DURING
 As sole neuraxial agent
 Addition of intrathecal ketamine to bupivacaine for Caesarean3
 Sedation/analgesia
 In low doses (IV 0.5 mg/kg) + IV diazepam/midazolam
 Low dose ketamine infusions (5–25 mg/kg/min)

 AFTER
 Supplemental analgesia for inadequate blocks
 Better early post op analgesia in lower limb amputation3

 No analgesic benefit shown for topical, perineural, intra-articular or wound

infiltration routes 3
1 Wason R et al. Randomized double-blind comparison of prophylactic ketamine, clonidine and tramadol for the control of shivering under neuraxial anaesthesia.
Indian J Anaesth. 2012
2 Ozkan F et al. The effect of intravenous ketamine in prevention of hypotension during spinal anaesthesia in patients with benign prostatic hyperplasia. Nobel Medicus. 2011
3 Schug SA. Acute pain management: scientific evidence. 2015
 Well established clinical applications
 IV induction agent in hypotensive patients

 Reactive airways disease

 Protect against asthma in asymptomatic patients1
 Alleviate bronchospasm in patients with respiratory distress prior to
induction 1
 Rescue therapy for refractory bronchospasm/status asthmaticus

 Sedation/analgesia in burns care

 Preserves airway and spontaneous respiratory function2
 IM administration for poor venous access3
 Effective sedoanalgesia: Ketamine + midazolam/propofol4

1 Goel S, Agrawal A. Ketamine in status asthmaticus: A review. Indian J Crit Care. 2013
2 Gündüz et al. Comparison of effects of ketamine, ketamine-dexmedetomidine and ketamine-midazolam on dressing changes of burn patients. J Anaesthesiol ClinPharmacol. 2011
3 Dundee JW et al. Intravenous Anasethesia. NewYork: Churchill Livingstone; 1988
4 Samad MA et al. Evaluation of ketofol (ketamine-propofol combination) as total intravenous anaesthetic for burn dressing in adult patient. J Med Coll Bangladesh. 2012
Other clinical applications - ketamine as an option
 Adjunct to IV regional anaesthesia (IVRA)
 Ketamine + lignocaine
 increases tourniquet tolerance, improves the quality of anaesthesia and
decreases analgesic consumption1

 Prevention of post-anaesthesia shivering2

 low dose prophylactic IV ketamine 0.25–0.75 mg/kg

 Paediatrics
 For premedication3
 IM induction drug in children/mentally challenged patients4

1 Khanna P et al.Adjuvants for intravenous regional anaesthesia. J Anaesthesiol Clin Pharmacol. 2010
2 Kamal MM et al. Prevention of postspinal shivering by using ketamine plus midazolam in comparison Egypt J Anaesth. 2011
3 Reves JG et al. Intravenous anaesthetics, Miller's Anaesthesia. 7th ed. 2010
4 Stoelting RK, Hillier SC. Nonbarbiturate intravenous anaesthetic drugs. Pharmacology and Physiology in Anaesthetic Practice. 4th ed. 2006.
 Renewed interest– ketamine in low dose
 Procedural sedation
 Uncooperative/mentally disabled1
 Single IV/IM loading dose to achieve dissociative sedation1
 Ketofol in colonoscopy and short gynaecological procedures2

 Sedation and analgesia in ICU

 Reduces inotropic support
 Anti-inflammatory effect against the sepsis process3

 Co-induction and total IV anesthesia (TIVA)

 In combination with propofol/midazolam/dexmedetomidine for TIVA4
 In a study on 80 elderly patients, ketofol provided good LMA insertion
conditions and less requirement of ephedrine5

1 Green SM et al. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med.
2 Khutia SK et al. Intravenous infusion of ketamine-propofol can be an alternative to intravenous infusion of fentanyl-propofol for deep sedation and analgesia in paediatric patients
undergoing emergency short surgical procedures. Indian J Anaesth. 2012
3 Yoon SH. Concerns of the anesthesiologist: Anesthetic induction in severe sepsis or septic shock patients. Korean J Anesthesiol. 2012
4 Smischney NJ et al. Ketamine/propofol admixture (ketofol) is associated with improved hemodynamics as an induction agent: A randomized, controlled trial. J Trauma Acute Care Surg. 2012
5 Erdogen MA et al. Comparison of effects of propofol and ketamine mixture (ketofol) on laryngeal mask airway insertion conditions and haemodynamics in elderly patients. J Anaesth. 2013
 What’s next?
 Anti-depressant?
 Randomised double blind trial spanning Australia/NZ launched in 20161

 Versatile
 Pain, palliative care, intensive care, and procedural sedation

 Current trend
 Use in low doses
 As an adjunct to other drugs

 Selective NMDA receptor antagonists in the future

1’First gold standard trial of ketamine’s anti-depressant effects launched’ The Guardian Health Aug 2016
Ketamine for chronic pain: updated
Use for Acute Postoperative Pain
 Adjuvant treatment with IV racemic, or S(1) ketamine is
common, to improve postoperative pain relief and reduce
opioid requirements.
Ketamine- Usage in Chronic Pain
Chronic Non-Cancer Pain
 It is more difficult to formulate clear indications for the use of
ketamine in chronic noncancer pain.
 Given ketamine’s range of adverse effects and the lack of safety
data concerning long-term treatment, there is good reason to be
cautious when treating complex chronic pain problems with this
drug.
 Possible indications could be refractory neuropathic or
inflammatory pain with, or without, depression in carefully
selected patients.
 Intermittent IV infusions
 Patients may be offered hospital admission and infusion treatment
over several days
Chronic Non-Cancer Pain- Evidence for
Efficacy and Adverse Effects
Ketamine- Usage in Psychiatry
 Rapid and robust antidepressant effects in mood and anxiety
disorders that were previously resistant to treatment
 However, evidence is limited- small sample sizes, lack of
longer term data on efficacy, limited data on saftey
 Use is OFF-label
 Useful in some patients
 But important to consider limitations of available data
 Remember potential risks
Ketamine- Considerations in High BMI
Patient Selection
 Contraindications
 Not suitable if muscle relaxation needed

 Exacerbates hypertension and schizophrenia

 Increase in ICP

 Increase in intraocular pressure

 Sympathomimetic effect
 caution in thyroid disorders, IHD
Clinical Experience and Training
Treatment Setting
Drug Delivery
 Adverse Effects
 Dose dependent side effects
 Dizziness, sedation, nausea, agitation, hallucinations, nightmares

 Vomiting (IM > IV) – 5-15% incidence

 Increase in salivation can cause laryngospasm especially in

children

 Can cause addiction

 Ketamine-induced uropathy 1

1 Bell RF. Ketamine for chronic non-cancer pain: concerns regarding toxicity 2012
Adverse Effects
 Anaesthetic concentrations of ketamine could exert
antagonistic actions on both μ and k opioid receptors 1

 Unclear neurotoxicity 1

 Possible neuronal damage at high doses2

1 Madhuri S et al. Ketamine: current applications in anaesthesia, pain and critical care. 2014
2 Olney JW et al. Drug induced apoptotic neurodegeneration in the developing brain. 2012
Adverse Reactions
 Emergence reaction
 Dreamlike state, vivid imagery, hallucinations, and/or
delirium

 Least common in children <15 yr, elderly > 65 yr, or

when administered IM 1

 May occur up to 24 hr postoperatively

 Occurrence may be decreased by using benzodiazepine 1

 Transient diplopia and blindness reported 2

1 Madhuri S et al. Ketamine: current applications in anaesthesia, pain and critical care. 2014
2 Fine, J et al. Side effects after ketamine anesthesia: transient blindness. 1974
Potential Drug Abuse
 Especially with chronic non-cancer pain
 Double-blind, cross-over study
 Patient population: 30 adults, treatment-resistant depression
 Planned interim analysis after studying 14 participants
 12 completed both conditions in randomised order- placebo
or 50mg of naltrexone preceding IV infusion of 0.5mg/kg of
ketamine
Transnasal Ketamine
 Unavailable in SGH
Thank you!
 References
 Journal articles
 Ketamine: an old drug revitalised in pain medicine
PY Tsui et al. BJA Education, March 2017
 Ketamine: current applications in anaesthesia, pain and critical care
Madhuri S. Kurdi et al. NCBI, Sept 2014
 Clinical practice guideline for emergency department ketamine dissociative
sedation: 2011 update
Steven M. Green et al. Annals of emergency medicine, May 2011

 Websites
 http://reference.medscape.com/drug/ketalar-ketamine
 http://ketamine.com/history-of-ketamine/
 http://www.frca.co.uk/article.aspx?articleid=100644
Rachel Craven. Ketamine in anaesthestic practice, 2006
 https://www.theguardian.com/australia-news/2016/aug/16/mental-health-
large-scale-ketamine-trial-to-investigate-effect-on-depression
 Google Images