Low-Dose Ketamine and Perioperative Analgesia
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1 2015 Winter Anesthesia Conference Low-Dose Ketamine and Perioperative Analgesia Is it the Answer? James R. Hebl, M.D. Professor of Anesthesiology Vice-Chair, Clinical Practice Mayo Clinic Rochester, Minnesota
2 Disclosures No financial relationships to disclose Will be referencing off-label usages(s) of pharmaceuticals or instrumentation within this presentation
3 Disclosures Ketamine FDA-Approved General anesthesia Procedural sedation Ketamine NOT FDA-Approved Refractory cancer pain Neuropathic pain Acute postoperative pain
4 Learning Objectives Understand the analgesic mechanism of ketamine in the treatment of postoperative pain Discuss the potential treatment strategies and clinical benefits of low-dose ketamine Describe the use of low-dose ketamine as a rescue adjuvant in the postanesthesia care unit (PACU)
5 Postoperative Pain Clinical Consequences Deep venous thrombosis Pulmonary embolism Coronary ischemia Delayed rehabilitation Prolonged Hospital LOS Decreased satisfaction Pneumonia Poor wound healing Insomnia Postoperative delirium Chronic pain syndromes Lynch, Anesth Analg 1998 Carr, Lancet 1999 Breivik, Eur J Anaesthesiol 1998
6 Joint Commission Effective: 2001 Pain = 5 th Vital Sign Joint Commission Initiative Declared PAIN as the 5 th Vital Sign Condition of Accreditation Adequate assessment Monitoring Treatment Follow-up Pain management must become part of all patient care activities Speak-Up Campaign Joint Commission Pain Management Standards
7
8 Postoperative Pain 1995 vs vs Patients with Postop Pain (%) Gan (2012) Apfelbaum (2003) Warfield (1995) Any Pain Slight Moderate Severe Extreme Apfelbaum, Anesth Analg 2003 Warfield, Anesthesiology 1995 Gan T, ASRA Fall Meeting 2012
9 Postoperative Analgesic THerapy Observational Study: Practice Patterns in Central and Southern Europe Prospective, cross-sectional, observational, multi-center Randomized hospitals in 7 countries (N=746 hospitals) No institutional training on pain management: 34% No postoperative pain protocols: 75% Pain not assessed: 34% Pain scores not documented: 56% Balanced analgesia: 71% (after major surgery) Benhamou, Pain 2008 Patient Based National Survey on Postoperative Pain Management in France Reveals Significant Achievements and Persistent Challenges 76 surgical centers (N=1900 Adult patients) Postop pain protocols: 74% Pain assessed and documented: 94% (every 4 hrs) Severe pain: 51% (4% at rest) Regional anesthesia (Epidural or PNB): 7% Fletcher, Pain 2008
10 Acute Pain Physiology Major Contributors of Pain: Phase I: Afferent pain signals Phase II:
11 Cerebral cortex Spinal cord A-δ and C-fibers Traumatic injury
12 Acute Pain Physiology Major Contributors of Pain: Phase I: Afferent pain signals Phase II: Inflammatory response
13
14 Opioids Multimodal Perioperative Analgesia Sole analgesic agent Pain 30% Side effects 80%
15 Opioids NSAIDs Respiratory depression Cardiovascular depression Nausea & vomiting Postoperative ileus Urinary retention Pruritus Sedation & dizziness Tolerance & dependence Operative bleeding GI bleeding Renal dysfunction Allergic reactions Bronchospasm Hypertension Pedal edema
16 Multimodal Perioperative Analgesia Opioids Non-steroidal anti-inflammatories COX-II Inhibitors Gabapentin Acetaminophen Peripheral nerve blockade Periarticular local anesthetic injection Ketamine (low-dose) Cryotherapy
17 Gabapentin Clonidine Opioids
18 Multimodal Perioperative Analgesia Opioids Non-steroidal anti-inflammatories COX-II Inhibitors Gabapentin Acetaminophen Peripheral nerve blockade Periarticular local anesthetic injection Ketamine (low-dose) Cryotherapy
19 Ketamine 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
20 Henthorn, Anesthesiology 1999
21 Ketamine Pharmacodynamic Effect Dissociative Anesthesia Thalamocortical - Limbic Cataleptic state Open eyes Slow nystagmus Non-communicative Increased skeletal muscle tone (hypertonus) Purposeless movement Amnestic Intense analgesia
22 Ketamine Pharmacodynamic Effect 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
23 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
24 CP
25 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
26 Low-Dose Ketamine and Postoperative Analgesia
27 Low-Dose Ketamine: Dose-Response Prospective, Randomized, Double-blinded, Placebo-controlled N = 140 Elective Outpatient Surgery (GA) Hardware removal Inguinal hernia Breast or LN biopsy 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
28 Low-Dose Ketamine: Dose-Response 150 Morphine Use (mcg/kg) * * * 40% * P < Placebo Ketamine Ketamine Ketamine 50 mcg/kg 75 mcg/kg 100 mcg/kg
29 Low-Dose Ketamine: Dose-Response VAS Pain Scores * * * * * * Placebo Ketamine 50 Ketamine 75 Ketamine % 10 * P < PACU 30 min PACU Arrival Discharge
30 Low-Dose Ketamine: Dose-Response 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
31 Low-Dose Ketamine: Timing of Administration Prospective, Randomized, Double-blind, Placebo-controlled N = 45 ACL Reconstruction Standardized General Anesthetic (Sufentanil infusion) CONTROL PRE- POST- PRE-INCISION Normal Saline Ketamine (150mcg/kg) Normal Saline PRE-CLOSURE Normal Saline Normal Saline Ketamine (150mcg/kg) Menigaux, Anesth Analg 2000
32 Low-Dose Ketamine: Timing of Administration 70 Control Morphine Use (mg) * * * * Pre- Post- * P < hrs 48 hrs
33 24 Hour Post-Op Rehabilitation Degrees of Flexion Morphine Use (mg) * * * * * P < nd Qtr 3rd Qtr Control Pre- Post- 0
34 Side-Effect Control Pre- Post- Urinary Retention Nausea & Vomiting Pruritus Respiratory Depression Sedation Dysphoria Hallucinations Diplopia NS between groups
35 Low-Dose Ketamine: Timing of Administration Conclusions 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
36 Low-Dose Ketamine: Monitored Anesthesia Care Prospective, randomized, double-blinded N = 40 Elective ambulatory procedures (M.A.C.) Tubal ligation Cervical conization Ventral hernias Biopsies Skin lesions Wrist/hand Randomized: 1. Propofol (30-50 mcg/kg/min) 2. Propofol + Ketamine ( mcg/kg/min) Mortero, Anesth Analg 2001
37 Low-Dose Ketamine: Monitored Anesthesia Care Perioperative Endpoints Intra-op ventilation Perceptual changes Post-op sedation Mood states Pain intensity Cognition Thought process Discharge Follow-up (5 Days) Pain intensity Physical activity Opioid requirements Patient satisfaction Mortero, Anesth Analg 2001
38 Intraoperative Ventilation 60 End Tidal PCO * * * * 20 Propofol 10 Prop + Ket * P < Arrival 15 min 30 min 45 min 60 min
39 Postoperative Mood States * * * * * * Mood VAS Propofol Prop + Ket Elation Agreeable Energy Composure Confidence Clearheaded
40 Postoperative Analgesia * Days to Normalization Propofol Prop + Ket 5 * * * 0 * P < VAS Pain No rest pain No pain with Resume Score activity normal activity
41 Low-Dose Ketamine: Monitored Anesthesia Care Conclusions Provided adequate sedation Improved ventilation Enhanced mood state No perceptual changes Earlier recovery of cognition Superior Acute and Extended Pain Relief Faster return to normal activities Mortero, Anesth Analg 2001
42 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
43 PACU (Aldrete score of 9) Ambulatory Unit (6 hrs) Oriented x 3 Stable Vitals Pain Control Absence of Nausea Ability to Void 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
44 Ketamine (n=25) Control (n=25) Sedation Scores Time 0 NS NS Time 15 NS NS Time 30 NS NS Aldrete (Score = 9) Time % 96% Time % 100% Home Readiness Time % 100% Ambulation Time 15 88% 68% Time % 96% Morphine (% require) 12% 36% * Outpatient Propoxyphene (tabs) *
45 Ketamine (n=25) Control (n=25) Sedation Scores Time 0 NS NS Time 15 NS NS Time 30 NS NS Aldrete (Score = 9) Time % 96% Time % 100% Home Readiness Time % 100% Ambulation Time 15 88% 68% Time % 96% Morphine (% require) 12% 36% * Outpatient Propoxyphene (tabs) *
46 PACU-Ambulatory Unit VAS Pain Scores 50 Control Group * * * * * Ketamine Group * * * 10 0 * P < Time (min)
47 Rest VAS Pain Scores * Control Group Ketamine Group * Day 1 Day 2 Day 3 * P < 0.01
48 Rehabilitation VAS Pain Scores * * Control Group Ketamine Group Day 1 Day 2 Day 3 * P < 0.01
49 Distribution of Ambulation Post-Op Day * P < 0.05 * Normal 1-3 hrs < 1 hr Ketamine 1-3 hrs < 1 hr Control
50 Low-Dose Ketamine: Knee Arthroscopy No Differences Nausea Vomiting Dysphoria Hallucinations Diplopia Cognitive or Memory impairments Respiratory Depression Menigaux, Anesth Analg 2001
51 Low-Dose Ketamine: Knee Arthroscopy Conclusions Ketamine + Multi-modal Analgesic regimen Less Postoperative Pain VAS Pain Scores Analgesic Requirements Extend 48 hours Post-op Provide Analgesia at Rest & with Movement Facilitates Early Rehabilitation Menigaux, Anesth Analg 2001
52
53 Ketamine and THA Prospective, Randomized, Blinded 30 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 Patients with Pain after THA (%) * P = Saline bolus + infusion Remerand, Anesth Analg mo. 3 mo. 6 mo. 0
54 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
55 Wind-Up Pain Placebo (N=-10) 10 Ketamine (N=10) Patients with Wind-up Pain * * * 0 * P<0.01 Day 1 Day 3 Day 7 Days after Surgery
56 Postoperative Hyperalgesia 200 Area of Hyperalgesia (cm2) * * * Day 1 Day 3 Day 7 * P<0.01 Days after Surgery
57 Area of Hyperalgesia Von Frey Filament Surgical Incision: Median length 26 cm Stubhaug, Acta Anaesthesiol Scand 1997
58 Hyperalgesia and Chronic Pain Eisenach, Reg Anesth Pain Med 2006
59 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
60 Chronic Pain: Opioid Requirements Saline Saline Morphine Equivalents (mg) Ketamine 30% * 37% * Ketamine * Morphine Equivalents (mg/hr) PACU 24 hrs 48 hrs 6 weeks * P<0.05 Loftus, Anesthesiology 2010
61 Chronic Pain: VAS Pain Scores Saline 10 Ketamine VAS Pain Scores % * 26% * 0 PACU 24 hrs 48 hrs 6 weeks * P<0.05 Loftus, Anesthesiology 2010
62 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
63
64 Low-Dose Ketamine: Pediatric Surgery Side-Effects No differences in N/V No reports of adverse effects Dysphoria Hallucinations Diplopia Bad dreams Psychological sequelae Elhakim, Acta Anaesth Scand 2003
65 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
66 PACU Pain Scores
67 Respirations and Sedation
68 Wakefulness and Well-Being
69 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
70 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
71 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
72 Perioperative Ketamine 1. Single-dose Ketamine 2. Continuous infusion 3. Patient-controlled analgesia (with morphine)
73 Single-Dose Ketamine Significant Benefit
74 Continuous Infusion Ketamine Significant Benefit
75 Ketamine+Morphine PCA No Beneficial Effect
76 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
77 Cochrane Review MEDLINE ( ) and EMBASE ( ) 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
78 27 of 37 trials Perioperative sub-anesthetic doses of ketamine Reduced (1) Need for rescue analgesia; (2) VAS pain scores; or (3) Both
79 Ketamine reduced 24-hr opioid requirements and PONV Adverse events: Mild-to-Absent
80 Ketamine and Postop Analgesia: Summary Low-dose Ketamine effective analgesic agent (Adjuvant) Single-Dose: mg/kg I.V. Infusion: mg/kg/hr Significantly improves VAS pain scores Reduces opioid requirements by 40-60% Acute & Chronic Decreased risk of PONV, Sedation, and Hypoventilation May provide earlier hospital discharge and improved rehabilitation Minimal psychomimetic effects
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