low-dose ketamine and postoperative analgesia...• chronic back pain x 3 months; daily opiate use x...
TRANSCRIPT
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Low-Dose Ketamine and Postoperative Analgesia Is it the Answer?
James R. Hebl, MD Professor of Anesthesiology Vice-Chair, Clinical Practice Mayo Clinic Rochester, Minnesota
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Ketamine FDA-Approved • General anesthesia • Procedural sedation
Ketamine NOT FDA-Approved
• Refractory cancer pain • Neuropathic pain • Acute postoperative pain
Disclosure Summary
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Postoperative Pain Clinical Consequences
• Deep venous thrombosis
• Pulmonary embolism
• Coronary ischemia
• Pneumonia
• Poor wound healing
• Insomnia
• Postoperative delirium
• Chronic pain syndromes Lynch, Anesth Analg 1998 Carr, Lancet 1999 Breivik, Eur J Anaesthesiol 1998
• Delayed rehabilitation
• Prolonged Hospital LOS
• Decreased satisfaction
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Pain = 5th Vital Sign Joint Commission Initiative
• Joint Commission • Effective: 2001 • Declared PAIN as the 5th Vital Sign
• Condition of Accreditation • Adequate assessment • Treatment • Monitoring • Follow-up
• Pain management must become part of all patient care activities
• Speak-Up Campaign Joint Commission Pain Management Standards www.jointcommission.org
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Acute Pain Physiology
Major Contributors of Pain:
• Phase I:
Afferent pain signals
• Phase II:
Inflammatory response
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A-δ and C-fibers
Spinal cord
Cerebral cortex
Traumatic injury
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• Opioids
• Sole analgesic agent Pain 30% Side effects 80%
Multimodal Perioperative Analgesia
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Opioids Respiratory depression Cardiovascular depression Nausea & vomiting Postoperative ileus Urinary retention Pruritus Sedation & dizziness
Tolerance & dependence
NSAIDs Operative bleeding GI bleeding
Renal dysfunction
Allergic reactions
Bronchospasm
Hypertension
Pedal edema
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• Opioids • Non-steroidal anti-inflammatories • COX-II Inhibitors • Gabapentin • Acetaminophen • Peripheral nerve blockade • Periarticular local anesthetic injection • Ketamine (low-dose) • Cryotherapy
Multimodal Perioperative Analgesia
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Gabapentin Clonidine Opioids
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Ketamine • Phencyclidine derivative (1962)
• Commercial preparation • Racemic mixture S (+) and R (-)
• Short distribution and elimination half-lives (t½ = 2.5 hrs)
Kohrs, Anesth Analg 1998
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Henthorn, Anesthesiology 1999
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• Phencyclidine derivative (1962)
• Commercial preparation • Racemic mixture S (+) and R (-)
• Short distribution and elimination half-lives (t½ = 2.5 hrs)
• Extensive hepatic cytochrome p450 metabolism
• Primary metabolite: Norketamine • 1/3 to 1/5 potency
• Renal and biliary excretion Kohrs, Anesth Analg 1998
Ketamine
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• “Dissociative Anesthesia” • Thalamocortical - Limbic
• Cataleptic state • Open eyes • Slow nystagmus • Non-communicative • Increased skeletal muscle tone (hypertonus) • Purposeless movement
• Amnestic
• Intense analgesia
Pharmacodynamic Effect
Ketamine
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• “Dissociative Anesthesia” • Thalamocortical - Limbic
• Cataleptic state • Open eyes • Slow nystagmus • Non-communicative • Increased skeletal muscle tone (hypertonus) • Purposeless movement
Reduces secondary hyperalgesia and Prevents central sensitization from peripheral pain
Pharmacodynamic Effect
Ketamine
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Analgesic Effect
1. Partial opioid receptor agonist • µ (analgesia) • σ (dysphoria)
2. N-methyl-D-aspartate (NMDA) Antagonist • Readily crosses Blood-Brain Barrier • Antagonize glutamate & opioid activation of NMDA-r
• Cortical and Spinal Effects
• Analgesic Effect: Somatic >> Visceral
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CP899615-18
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Low-Dose Ketamine and Postoperative Analgesia
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Low-Dose Ketamine: Dose-Response
• Prospective, Randomized, Double-blinded, Placebo-controlled
• N = 140
• Elective Outpatient Surgery (GA) • Hardware removal • Breast or LN biopsy • Inguinal hernia • CTR or Nerve decompression
• Randomized: Morphine (50 mcg/kg IV bolus) 1. Placebo 2. Ketamine (50 mcg/kg IV) 3. Ketamine (75 mcg/kg IV) 4. Ketamine (100 mcg/kg IV) Suzuki, Anesth Analg 1999
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0
50
100
150
Mor
phin
e U
se (m
cg/k
g)
Placebo Ketamine Ketamine Ketamine 50 mcg/kg 75 mcg/kg 100 mcg/kg * P < 0.05
* * *
40%
Low-Dose Ketamine: Dose-Response
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0
10
20
30
40
50
60
70
VAS
Pai
n S
core
s
PlaceboKetamine 50Ketamine 75Ketamine 100
PACU 30 min PACU Arrival Discharge * P < 0.05
* *
* *
* *
35%
Low-Dose Ketamine: Dose-Response
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NO DIFFERENCES
• Sedation • Time to Discharge
• Nausea & Vomiting • Cognitive Function
• Time to Fluid Intake • Mood Disturbance
• Phase I (PACU) Recovery • Dissociative State (Perception)
Suzuki, Anesth Analg 1999
Low-Dose Ketamine: Dose-Response
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Low-Dose Ketamine: Timing of Administration
• Prospective, Randomized, Double-blind, Placebo-controlled • N = 45 • ACL Reconstruction • Standardized General Anesthetic (Sufentanil infusion) PRE-INCISION PRE-CLOSURE
CONTROL PRE- POST-
Normal Saline Normal Saline
Ketamine (150mcg/kg) Normal Saline
Normal Saline Ketamine (150mcg/kg)
Menigaux, Anesth Analg 2000
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0
10
20
30
40
50
60
70
Mor
phine
Use
(mg)
ControlPre-Post-
24 hrs 48 hrs * P < 0.01
* *
* *
Low-Dose Ketamine: Timing of Administration
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24 Hour Post-Op Rehabilitation
0
10
20
30
40
50
2nd Qtr 3rd Qtr
5
4
3
2
1
0
Control Pre- Post-
Degrees of Flexion Morphine Use (mg)
* *
* *
* P < 0.05
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Side-Effect Control Pre- Post- Urinary Retention 1 1 1 Nausea & Vomiting 3 2 1 Pruritus 0 0 0 Respiratory Depression 0 0 0 Sedation 0 0 0 Dysphoria 0 0 0 Hallucinations 0 0 0 Diplopia 0 0 0
NS between groups
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• Delays first request for analgesics (3-fold)
• Produces a significant (50%) reduction in morphine use within the first 48 hrs
• Facilitates knee mobilization (24 hrs)
• Effects independent of the timing of intra-operative administration
Menigaux, Anesth Analg 2000
Conclusions
Low-Dose Ketamine: Timing of Administration
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Low-Dose Ketamine: Knee Arthroscopy
• Prospective, Randomized, Double-blinded • N = 50
• Outpatient knee arthroscopy
• Standardized General Anesthesia • Propofol Infusion • Bupivacaine 0.5% (20cc) • Alfentanil (20 mcg/kg) • Morphine (5 mg) • 60% Nitrous
• Randomized: (Post-Induction Administration) • Control: Normal Saline • Ketamine: 150 mcg/kg IV
Menigaux, Anesth Analg 2001
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• PACU (Aldrete score of 9) • Ambulatory Unit (6 hrs)
• Oriented x 3 • Absence of Nausea • Stable Vitals • Ability to Void • Pain Control • Ability to Ambulate
• Analgesia • PACU: Morphine 3 mg prn (VAS < 3) • Ambulatory Unit: Naproxen 550 mg p.o. • Home: Naproxen b.i.d. and Propoxyphene q 6 hrs prn
• Discharge: Daily Questionnaire x 3 days
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Sedation Scores Time 0 NS NS Time 15 NS NS Time 30 NS NS Aldrete (Score = 9) Time 15 100% 96% Time 30 100% 100% Home Readiness Time 120 100% 100% Ambulation Time 15 88% 68% Time 30 100% 96% Morphine (% require) 12% 36% * Outpatient Propoxyphene (tabs) 13 27 *
Ketamine Control (n=25) (n=25)
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Sedation Scores Time 0 NS NS Time 15 NS NS Time 30 NS NS Aldrete (Score = 9) Time 15 100% 96% Time 30 100% 100% Home Readiness Time 120 100% 100% Ambulation Time 15 88% 68% Time 30 100% 96% Morphine (% require) 12% 36% * Outpatient Propoxyphene (tabs) 13 27 *
Ketamine Control (n=25) (n=25)
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0
10
20
30
40
50
PACU-Ambulatory Unit VAS Pain Scores
Control Group Ketamine Group
0 15 30 45 60 120 240 360
Time (min) * P < 0.05
*
* * * * * * *
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0
5
10
15
20
25
30
35
Rest VAS Pain Scores
Control Group Ketamine Group
Day 1 Day 2 Day 3
* P < 0.01
*
*
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0
5
10
15
20
25
30
35
Rehabilitation VAS Pain Scores
Day 1 Day 2 Day 3
* P < 0.01
*
*
Control Group Ketamine Group
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0
20
40
60
80
100
Ketamine Control
Distribution of Ambulation Post-Op Day 1
* P < 0.05
Normal
1-3 hrs
1-3 hrs
< 1 hr < 1 hr
*
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• Nausea
• Vomiting
• Dysphoria
• Hallucinations
• Diplopia
• Cognitive or Memory impairments
• Respiratory Depression Menigaux, Anesth Analg 2001
No Differences
Low-Dose Ketamine: Knee Arthroscopy
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0
5
10
15
20
25
30Prospective, Randomized, Blinded
N=154
Total Hip Arthroplasty
Standardized GETA • I.V. Acetaminophen
• I.V. Ketoprofen
• I.V. Morphine (PCA)
Randomized
1. Ketamine 0.5 mg/Kg (Pre-incision)
Infusion (2 mcg/kg/min) x 24 hr
2. Saline bolus + infusion
Remerand, Anesth Analg 2009 1 mo. 3 mo. 6 mo.
Pati
ents
wit
h Pa
in a
fter
TH
A (%
)
Ketamine and THA
* P = 0.008
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Postoperative Hyperalgesia • Prospective, Randomized, Double-blinded • N=20 • Donor nephrectomy • Standardized GETA • Randomized
1. Ketamine 0.5 mg/kg I.V. Infusion 2 mcg/kg/min x 24 hrs Infusion 1 mcg/kg/min x 24 hrs 2. Saline control
• Endpoints: Punctate mechanical hyperalgesia Mechanical stimuli causing “wind-up pain”
Stubhaug, Acta Anaesthesiol Scand 1997
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0
2
4
6
8
10
Wind-Up Pain
Days after Surgery
Day 1 Day 3 Day 7
Pati
ents
wit
h W
ind-
up P
ain
* * *
* P<0.01
Placebo (N=-10) Ketamine (N=10)
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0
40
80
120
160
200
Postoperative Hyperalgesia
Days after Surgery
Day 1 Day 3 Day 7
Are
a of
Hyp
eral
gesi
a (c
m2)
* * *
* P<0.01
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Von Frey Filament
Surgical Incision: Median length 26 cm
Area of Hyperalgesia
Stubhaug, Acta Anaesthesiol Scand 1997
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Eisenach, Reg Anesth Pain Med 2006
Hyperalgesia and Chronic Pain
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Ketamine and Chronic Pain • Prospective, randomized, double-blinded, placebo • N=165 • Opiate-dependent patients • Chronic back pain x 3 months; Daily opiate use x 6 wks • Major lumbar spine surgery • Randomized:
1. Ketamine (0.5 mg/kg I.V. bolus + 10 mcg/kg/min infusion) • Induction to Wound closure
2. Saline
• Endpoints: Opioid requirements, VAS pain scores Adverse side-effects (6-wk follow-up)
Loftus, Anesthesiology 2010
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0
50
100
150
200
250
300
350
Chronic Pain: Opioid Requirements M
orph
ine
Equi
vale
nts
(mg)
3 2
1
Morphine Equivalents (m
g/hr)
PACU 24 hrs 48 hrs 6 weeks
Loftus, Anesthesiology 2010 * P<0.05
Saline Ketamine
Saline Ketamine
*
*
*
37%
30%
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0
2
4
6
8
10
Chronic Pain: VAS Pain Scores VA
S Pa
in S
core
s
PACU 24 hrs 48 hrs 6 weeks
Loftus, Anesthesiology 2010 * P<0.05
Saline Ketamine
* *
26%
26%
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Low-Dose Ketamine: Pediatric Surgery
• Prospective, Randomized Clinical Trial • N = 50 • Tonsillectomy (Standardized GA) • Randomization Pre-med:
• Ketamine 0.1 mg/kg I.M. • Placebo • 20-min before induction
• Rectal diclofenac (2 mg/kg)
• Fentanyl (1 mcg/kg IV)
Elhakim, Acta Anaesth Scand 2003
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Postoperative Pain Scores
0 2 4 6 8 10
1-hour
12-hour
VAS Pain Scores
Ketamine Placebo
*
*
* P < 0.05
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Side-Effects • No differences in N/V
• No reports of adverse effects • Dysphoria • Hallucinations • Diplopia • Bad dreams • Psychological sequelae
Elhakim, Acta Anaesth Scand 2003
Low-Dose Ketamine: Pediatric Surgery
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Low-Dose Ketamine: Rescue Analgesia
• Prospective, Randomized, Double-blinded • N=245
• General surgical patients
• PACU with severe pain (VAS ≥ 6) • Despite >0.1 mg/kg morphine IV last 30 min
• Randomized: (Up to 3 boluses) 1. Morphine 30 mcg/kg IV + Saline 2. Morphine 15 mcg/kg IV + Ketamine 250 mcg/kg
Weinbroum, Anesth Analg 2003
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PACU Pain Scores
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Respirations and Sedation
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Wakefulness and Well-Being
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Ketamine: Rescue Analgesia Side- Effects
Morphine Group • More nausea & vomiting (38% vs. 12%) • More pharmacologic interventions (nausea + pain)
Ketamine Group • Light-headed sensation x 1-2 min (7% vs. 0%) • One (0.7%) patient experienced a “bad-dream”
• Required 2-doses
Weinbroum, Anesth Analg 2003
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Limitations of Ketamine
Perioperative Ketamine Does Not Prevent Chronic Pain After Thoracotomy
• Prospective, Randomized, Placebo-Controlled Trial assessing chronic neuropathic pain
• N = 86
• Randomized 1. Ketamine 1 mg/kg at induction 2. Ketamine 1 mg/kg/hr (surgery) + 1 mg/kg (over 24 hr.) 3. Normal saline (Placebo)
• No difference in neuropathic pain at 6 wk and 4 mo follow-up
Dualé, European J Pain 2009
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Limitations of Ketamine
Low-Dose Ketamine with Multimodal Postcesarean Delivery Analgesia: A Randomized Controlled Trial
• Prospective, Randomized, Placebo-Controlled Trial assessing pain after Cesarean Delivery
• N = 174
• Spinal anesthesia (Bupiv + Fentanyl + Morphine)
• Randomized 1. Ketamine 10 mg I.V. after delivery 2. Saline (Placebo)
• No analgesic benefits identified at 24, 48, or 72 hrs
Bauchat, Intl J Obstet Anesth 2011
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Perioperative Ketamine 1. Single-dose Ketamine 2. Continuous infusion 3. Patient-controlled analgesia (with morphine)
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Single-Dose Ketamine
Significant Benefit
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Continuous Infusion Ketamine
Significant Benefit
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Ketamine+Morphine PCA
No Beneficial Effect
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• Prospective, randomized, double-blinded studies • N = 11 studies (887 patients) • Combined Ketamine + Opioid PCA • Orthopedic or Abdominal Surgery = No Benefit • Thoracic Surgery = Benefit
• Caution: Large heterogeneity + Small sample sizes
Carstensen, Br J Anaesth 2010
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Cochrane Review
• MEDLINE (1966-2004) and EMBASE (1980-2004) studies
• Randomized Controlled Trials (Adult patients)
• Independent quality and validity assessments (2 Reviewers)
• Endpoints: 1. VAS Pain scores 2. Opioid requirements 3. Adverse side-effects
• 37 trials
• 2240 patients
• Multiple surgical procedures 2010
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• 27 of 37 trials • Perioperative sub-anesthetic doses of ketamine • Reduced (1) Need for rescue analgesia;
(2) VAS pain scores; or (3) Both
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• Ketamine reduced 24-hr opioid requirements and PONV
• Adverse events: Mild-to-Absent
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Ketamine and Postop Analgesia: Summary
• Low-dose Ketamine effective analgesic agent (Adjuvant)
• Single-Dose: 0.15-0.4 mg/kg I.V. Infusion: 0.1-0.3 mg/kg/hr
• Significantly improves VAS pain scores
• Reduces opioid requirements by 40-60%
• Decreased risk of PONV, Sedation, and Hypoventilation
• May provide earlier hospital discharge and improved rehabilitation
• Minimal psychomimetic effects
Acute & Chronic