Ketamine: After Fifty Year Reign – from Pre-op to...

Objectives

1) Review the history of ketamine

2) Revisit the mechanism of action of ketamine

3) Discuss the pharmacokinetics,

pharmacodynamics, and adverse effects of

ketamine

4) Examine the pain pathway and role of NMDA

receptor in acute and chronic pain

5) Describe use of ketamine in various pain

syndromes

The History of Ketamine

1956

Phencyclidine discovered

1958

Park-Davis (MI) developing

phencyclidine surgical

anesthetic

1960s

Phencyclidine (Sernyl) for

human surgical anesthesia

1967

Phencyclidine (Sernylan) enters US veterinary medicine

market

1970

Ketamine (Ketalar) for human and animal use

Domino EF. Anesthesiology 2010;113:678-86. Olmedo RE. Chapter 85. Phencyclidine and Ketamine. Goldfrank's

Toxicologic Emergencies, 9e (2011).

Ketamine: Quick Facts

0 Rapid-acting general anesthetic

0 Commercial preparation of racemic mixture of

two enantiomers, S(+) ketamine and R(–)

ketamine.

0 S(+) ketamine has four times the affinity of R(–)

ketamine for the NMDA receptor

0 S(+) ketamine also binds to mu and kappa opioid

receptors.

Ketamine in Practice

Mechanism of Action

G

G G

AC

Decrease cAMP

Decrease neurotransmitter

release

Decrease intracellular Ca2+

Increase K+

efflux

Mechanism of Action

G

G G

AC

Decrease neurotransmitter release

Decrease intracellular Ca2+

Decrease Ca2+ entry

Ketamine Effects Central Nervous

System

Sympathetic

System

0 NMDA receptor

antagonism

0 Anesthesia

0 Sedation

0 Analgesia

0 Antidepressant

effects

0 Cholinergic

activation

0 Hemodynamic

changes

0 Bronchodilation

0 Sialorrhea

Ketamine Drug Properties

Pharmacology and Adverse Effects

Absorption and Distribution 0 Absorption

0 Distribution 0 Low protein binding 0 Large volume of distribution (3L/kg)

0 Highly lipophilic

0 T ½ α (distribution): 10-15 minutes

Ketamine. Pediatric and Neonatal Lexi-Drugs Online. 2014.

Ketamine. MICROMEDEX Healthcare Series. 2014. Ketamine. FDA drug label. Available at http://dailymed.nlm.nih.gov

Route Bioavailability Comments

Oral 20% Extensive first-pass effect Mix oral solution in cola to disguise taste Rectal 25%

Intranasal 50% pH 3.5-5.5 Intravenous product contains preservative (benzethonium chloride

0.1mg/mL)

Intramuscular 90%

Intravenous 90%

Metabolism and Elimination 0 Metabolism via liver

0 CYP450 metabolism 0 Substrate of CYP2B6 (major), CYP2C9 (major), CYP3A4

(major)

0 Active metabolites

0 Eliminated via urine 0 T ½ (elimination) = 2-3 hours

Ketamine. Pediatric and Neonatal Lexi-Drugs Online. 2014, Ketamine. MICROMEDEX Healthcare Series. 2014.

Ketamine. FDA drug label. Available at http://dailymed.nlm.nih.gov

Ketamine Pharmacodynamics

Ketamine. Pediatric and Neonatal Lexi –Drugs Online. 2014.

Anesthesia Analgesia

Onset of Action

PO < 30 minutes

IM 3-4 minutes 10-15 minutes

IV < 30 seconds

Duration of action

IM 12-25 minutes 15-30 minutes

IV 5-10 minutes 1-2 hours

Recovery

IM 3-4 hours

IV 1-2 hours

Ketamine Adverse Effects: Brain

0 Dissociative analgesia

0 Catalepsy

0 Amnesia

0 Emergence delirium

0 Hallucinations

Olmedo RE. Chapter 85. Phencyclidine and Ketamine. In: Nelson LS. Goldfrank's Toxicologic Emergencies, 9e (2011). Accessed October 10, 2014.

Patel PM. Chapter 19. General Anesthetics and Therapeutic Gases. In: Brunton LL. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e (2011). Accessed October 10, 2014.

Eilers H. Chapter 25. General Anesthetics. In: Katzung BG. Basic & Clinical Pharmacology, 12e (2012). Accessed October 10, 2014.

Ketamine Adverse Effects: Cardiovascular

0 Hemodynamic changes

0 Increases blood pressure

0 Increases stroke volume

0 Increases heart rate

0 Increases myocardial oxygen demand

Olmedo RE. Chapter 85. Phencyclidine and Ketamine. In: Nelson LS. Goldfrank's Toxicologic Emergencies, 9e (2011). Accessed October 10, 2014.

Patel PM. Chapter 19. General Anesthetics and Therapeutic Gases. In: Brunton LL. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e (2011). Accessed October 10, 2014.

Eilers H. Chapter 25. General Anesthetics. In: Katzung BG. Basic & Clinical Pharmacology, 12e (2012). Accessed October 10, 2014.

Ketamine Adverse Effects: Respiratory

0 Transient apnea

0 Occurs with rapid IV injection (<60 seconds)

0 Bronchodilation

Olmedo RE. Chapter 85. Phencyclidine and Ketamine. In: Nelson LS. Goldfrank's Toxicologic Emergencies, 9e (2011). Accessed October 10, 2014. Patel PM. Chapter 19. General Anesthetics and Therapeutic Gases. In: Brunton LL. Goodman & Gilman's The Pharmacological Basis of

Therapeutics, 12e (2011). Accessed October 10, 2014. Eilers H. Chapter 25. General Anesthetics. In: Katzung BG. Basic & Clinical Pharmacology, 12e (2012). Accessed October 10, 2014.

Ketamine Adverse Effects: Miscellaneous

0 Increased skeletal muscle tone

0 Improves with benzodiazepine administration

0 Increased salivation and secretions

0 Mixed evidence of treatment with

anticholinergics

0 Increased intra-ocular pressure

0 Nystagmus and blurred vision

0 Decreases with physostigmine

0 Crosses placenta

Olmedo RE. Chapter 85. Phencyclidine and Ketamine. In: Nelson LS. Goldfrank's Toxicologic Emergencies, 9e (2011). Accessed October 10, 2014. Patel PM. Chapter 19. General Anesthetics and Therapeutic Gases. In: Brunton LL. Goodman & Gilman's The Pharmacological Basis of

Therapeutics, 12e (2011). Accessed October 10, 2014. Eilers H. Chapter 25. General Anesthetics. In: Katzung BG. Basic & Clinical Pharmacology, 12e (2012). Accessed October 10, 2014.

Ketamine for Treatment of Pain Review of pain pathways

http://www.physioprescription.com/2014/01/06/chronic-pain-all-in-my-head-1/

Types of Pain

Pain

Acute Chronic

Nocicoceptive Neuropathic

Central Peripheral

Visceral Mixed

Adapted from Figure 1. Pain classification and representative indications. Melnikova, I. Nature Reviews Drug Discovery 2010;9:,589-

590.

Biology of Acute versus Chronic Pain

Brookoff D. Hospital Practice. 2000;45-49.

Ketamine for Treatment of Pain

Acute and Chronic Pain: Evidence-based medicine

Ketamine IV Single Dose + IV Opioids Study Surgery

Group (N) KET Dose Opioid Pain

Scores TFA TSD Side

Effects

Menigaux 2001

Adult, Athroscopic menisectomy (50)

0.15 mg/kg preop

Alfentanil P<0.05 - P<0.05 NS

Kudoh 2002

Adult, Orthopedic (70)

1 mg/kg preop

Fentanyl P<0.05 @ 8, 16hr

- - NS

Weinbroum 2003

Adult, Thoracic, Orthopedic

(245)

0.25 – 0.75 mg/kg post

Fentanyl intra, Morphine

post

P<0.001 - P<0.001 ↓ PONV, ↑ central side

effects in KET

Xie 2003

Adult, Gastrectomy (28)

0.5 mg/kg preop

Fentanyl P<0.05 P<0.05 P<0.05 NS

*All studies are randomized double-blind controlled trials. KET=ketamine group; Morph=morphine; NS=not statistically significant; PONV=post-operative nausea and vomiting; Sufent=sufentanil; TFA=time to first request for analgesia; TSD=total supplemental analgesic requirement

Adapted from Table 4 in Subramaniam K. Anesth Analg 2004;99:482-95.

Ketamine PCA + Morphine IV Study Surgery Group (N) Pain Scores Morph

Use Side Effects

Javery 1996

Adults, Lumbar microdiscetomy (44)

P<0.001 P<0.001 ↓ nausea, pruritus, urinary retention in KET (P<0.05)

Hercock 1999

Adults, Lower abdominal,

Hysterectomy (49)

NS NS ↓ sleepiness, ↓ anti-emetics in KET (P<0.05)

Burstal 2001

Adults, Lower abdominal, Hysterectomy (70)

NS NS ↑ SE in KET (P<0.05)

Reeves

2001 Major upper

abdominal (71) NS NS RR = 1.8 for vivid dreams in KET

Murdoch 2002

Adults, Lower abdominal, Hysterectomy (40)

NS NS ↓ pruritus in KET (P<0.05)

Unlegenc

2003 Major abdominal (58) P<0.001 @

15 & 30 min NS NS

*All studies are randomized double-blind controlled trials.

KET=ketamine group; NS=not statistically significant


Ketamine Continuous Infusion + IV Opioids

Study Surgery Group (N)

KET Dose

KET Admin

Pain Scores

TFA TSD Side Effects

Edwards 1993

Adults, Upper abdominal (40)

5, 10, 20 mg/hr

Intra and post x 24hr

NS - NS ↑ dreams in KET (P<0.05)

Stubhaug 1997

Adults, Donor nephrectomy (20)

0.12 mg/kg per hr

Pre, intra, and post x 48hr

P<0.05 in 1hr post

P<0.05 P<0.05 in 4hr post

P<0.05 for PONV

Adriaenssens

1999 Adults, Major

abdominal (30)

0.15

mg/kg per hr

Post x

48hr P<0.05

in 1hr post

- P<0.05 P<0.05 PONV

Heinke and Grimm 1999

Adult, Gyn laparotomy (26)

0.6 mg/kg per hr

Pre and intra

P=0.05 for Day 2

P<0.01 NS NS


KET=ketamine group; NS=not statistically significant; PONV=Post-operative nausea/vomiting; TFA=time to first

request for analgesia; TSD=total supplemental analgesic requirement


Ketamine Continuous Infusion + IV Opioids


KET Dose

KET Admin

Pain Scores


Jaksch 2002

Adult, Knee arthroscopy

(30)

0.12 mg/kg

per hr

Pre, intra, post x 2hr

NS NS NS NS

Guignard 2002

Adult, Open colorectal (50)

0.12 mg/kg per hr

Pre and Intra

P<0.05 in 15 min

P<0.01 P<0.01 NS

Guillou

2003 Adult, Major

abdominal (93)

0.12

mg/kg per hr

Post x

48hr P<0.05

at 16, 2, 40, and 44hr

- P<0.05 NS

*All studies are randomized double-blind controlled trials. KET=ketamine group; NS=not statistically significant; TFA=time to first request for analgesia;

TSD=total supplemental analgesic requirement


Ketamine Continuous Infusion + Epidural Opioids


KET Dose KET Admin Opioid Pain Scores

TSD Side Effects

Ilkjaer 1998

Adults, Nephrectomy (52)

10 mg/hr Pre, intra, post

Morph NS NS ↑ sedation wit KET

Aida 2000

Adults, Gastrectomy (61)

0.5 mg/kg per hr

Pre, intra Morph P<0.05 P<0.05 -

De Kock 2001

Adults, Rectal surgery (60)

0.125 – 0.25

mg/kg per hr

Pre, intra Sufent NS NS NS

Kararmaz 2003

Adults, Renal (40)

0.5 mg/kg per hr

Pre, intra Morph P<0.01 P<0.01 ↓ nausea and pruritus in

KET (P<0.05)

*All studies are randomized double-blind controlled trials. KET=ketamine group; Morph=morphine; NS=not statistically significant; Sufent=sufentanil; TSD=total supplemental analgesic requirement


Epidural Ketamine + Epidural Opioids Study Surgery Group

(N) KET Dose and

Admin

Opioid Pain Scores


Subramaniam 2001

Adult, Upper abdominal (40)

1 mg/kg postop

Morphine - P<0.05 P<0.05 ↑ sedation in KET

Santawat

2002

Adult,

Gynecology (80)

30mg

pre and postop

Morphine NS NS NS NS

Taura 2003

Adult, Hepatectomy (104)

20mg, 30mg postop

Morphine P<0.05 P<0.05 P<0.05 NS

Xie 2003

Adult, Gastrectomy (28)

0.5 mg/kg preop

Fentanyl, PCEA morphine

P<0.05 P<0.05 P<0.05 NS


KET=ketamine group; Morph=morphine; NS=not statistically significant; PCEA=patient controlled epidural

analgesia; PONV=post-operative nausea and vomiting; Sufent=sufentanil; TSD=total supplemental analgesic

requirement


Ketamine for Acute Pain in Children


Study Surgery Group

(N) KET Dose

and Admin Opioid

used Pain

Score TFA TSD

Side

Effects

Ozbek 2002

1-9yrs, Hypospadias repair (109)

0.5 mg/kg caudal preop

Alfentanil NS P=0.001

P<0.01 NS

Dix 2003

7-16yrs, Appendectomy (75)

0.5 mg/kg preop ± 4

mcg/kg per

min postop

Fentanyl NS - NS ↑ in CI KET

Elhakim 2003

5-12yrs, Tonsillectomy (50)

0.1 mg/kg IM preop

Fentanyl P<0.05 P<0.01 P<0.05 NS

O’Flaherty 2003

3-12yrs, Tonsillectomy (80)

0.15 mg/kg IV preop

Fentanyl NS - NS NS


CI=continuous infusion; KET=ketamine group; NS=not statistically significant; TSD=total supplemental analgesic

requirement

Summary: Ketamine for Acute Pain

0 Ketamine is viable option for addition to

standard practice opioid analgesia in children

and adults

0 Showed greatest utility in abdominal surgery

patients as continuous infusion

Summary: Opioid-sparing Effects of Ketamine

0 Statistically significant decrease in opioid use

with single dose, continuous infusion, and

epidural ketamine

0 No reduction in PONV, pruritus, or respiratory

depression

0 Little to no increase hallucinations and sedation

Ketamine for Cancer Pain

Yang 1996

Methods Randomized, blinded, placebo-controlled,

crossover

Study Group Hospitalized patients with terminal cancer

N=20

Intervention Intrathecal morphine vs. KET 1mg intrathecal +

morphine intrathecal

Outcomes Total morphine dose: Low-dose IT KET reduces

amount of morphine needed

Adverse effects: Frequency not statistically

different between groups. Pruritus, constipation,

urinary retention, N/V, hallucinations noted.

Bell RF, Cochrane Database Syst Rev. 2012 Nov 14

Ketamine for Cancer Pain

Mercandante 2000

Methods Randomized, blinded, placebo-controlled,

crossover

Study Group Neuropathic cancer pain, morphine-resistant

N=10

Mean age=57 years

Intervention Saline vs. KET 0.25 mg/kg IV bolus vs. KET 0.5

mg/kg IV bolus

Outcomes Pain Intensity – decreased with KET

Adverse effects: 4/10 experienced hallucinations,

drowsiness, confusion

Bell RF, Cochrane Database Syst Rev. 2012 Nov 14

Ketamine for Cancer Pain Hardy 2012

Methods Randomized, double-blinded, placebo-

controlled

Study Group Multi-center, palliative care patients with

refractory chronic pain secondary to cancer or its

treatment

N=185

Mean age=63 years

Intervention Subcutaneous saline infusion or subcutaneous KET

infusion (100, 300, 500mg) x 5 days

Outcomes Pain improvement – no difference between

groups

Adverse effects: Double the adverse effects in

KET arm compared to baseline

NNT=25; NNH=6

Hardy J. J Clin Oncol. 2012;30:3611-17.

Summary: Ketamine for Cancer Pain

0 Limited evidence available

0 Small sample sizes

0 Heterogeneous groups

0 Many unanswered questions

0 Optimal dose?

0 Optimal route?

0 Optimal duration?

Ketamine for Chronic Pain Syndromes Patil 2012 CRPS

(N=18)

Non-CRPS

(N=31)

Total

(N=49)

Age (years) Median, (Range)

46 (21-55) 42 (18-68) 45 (18-68)

Gender

n (%) F: 11 (61.1)

M: 7 (38.9) F: 20 (64.5)

M: 11 (35.5) F: 31 (63.3)

M: 18 (36.7)

Number of Infusions Median, (Range)

5.5 (1-36) 3 (1-34) 4 (1-36)

Baseline VAS Mean (SD)

8.2 (1.7) 6.7 (1.9) 7.2 (2)

Infusion Dose (mg/kg) Median, (SD)

1 (0.5) 0.9 (0.4) 0.9 (0.4)

Infusion Duration (minutes) Median, (Range)

43.8 (30-60) 34.7 (30-165) 38.3 (30-165)

Post-Infusion VAS Median, (Range)

0.8 (0-6) 1 (0-9) 0.9 (0-9)

CRPS=complex regional pain syndrome; SD=standard deviation; VAS=visual analog scale

Patil S. Pain Medicine. 2012;13:263-9.

Ketamine for Chronic Pain Syndromes Chronic Pain

Condition Authors (N) Dose and Duration

of IV KET Infusion Method Results

(Pain Relief)

Central neuropathic pain

Eide 1995 (9)

60 mCg/kg, 6 mCg/kg per min, 17-21 min

Crossover Ketamine > Placebo

Kvarnstrom 2004 (10)

0.4 mg/kg, 40 min Crossover Ketamine > Placebo

Peripheral nerve pain

Eichenberger 2008 (20)

0.4 mg/kg over 1hr Crossover Ketamine > Placebo

Jorum 2003 (12) 60 mCg/kg, 6 mcg/kg per min, 20 min


Felsby 1996 (10) 0.2 mg/kg over 10 min, 0.3 mg/kg per hr x 1hr


Leung 2001 (12) Plasma concentration

targets


Kosharskyy B. Pain Physician. 2013;16:231-49.

Ketamine for Chronic Pain Syndromes Chronic Pain

Condition Authors (N) Dose and Duration of IV

KET Infusion Method Results

(Pain Relief)

Post-herpatic neuralgia

Eide 1994 (8) 0.15 mg/kg, 10 min Crossover Ketamine > Placebo

Gottrup 2006 (20)


CRPS Sigtermans 2009 (60)

5 – 30 mg/hr x 4.2 days Parallel Ketamine > Placebo

Schwarztman 2009 (19)

25 mg/hr x 4hrs x 10 days Parallel Ketamine > Placebo

Fibromyalgia Graven-

Nielsen 2000 (29)

0.3 mg/kg, 30 min Crossover Ketamine >

Placebo

Sorensen 1995 (11)


Noppers 2011

(24) 0.5 mg/kg, 30 min Parallel Ketamine >

Placebo

Kosharskyy B. Pain Physician. 2013;16:231-49

Summary: Ketamine for Chronic Pain Syndromes

0 Ketamine performs better than placebo for

chronic pain syndromes

0 Downfalls:

0 Many small studies, many indications

0 No standard dosing approach (bolus vs.

continuous infusion vs bolus + continuous infusion)

0 No standard duration of ketamine exposure

Final Synopsis: Ketamine for Treatment of Acute and Chronic Pain

0 Ketamine for treatment of acute pain well

established

0 Ketamine for treatment of chronic pain shows

promise

0 Many gaps in chronic pain treatment evidence

0 Necessary to study ketamine further in special

populations

Future Direction

0 Creation of ideal dosage form for both

inpatient and outpatient use

0 Investigate ketamine for treatment of pain in

special populations

0 Cancer

0 Sickle cell crisis

0 Opioid-resistant populations (substance abusers,

back pain patients, chronic pain sufferers)

Ketamine: After Fifty Year Reign – from Pre-op to...

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