Name : Prof. dr. A. Husni Tanra, Sp.An-KICPlace, Date of Birth : Sengkang, January 29, 1943Address : Hertasning Street E7/ 15 Makassar, 90222

South Sulawesi, IndonesiaEmail : ahusni_tanra@yahoo.co.idEducation : MD : 1975 in Hasanuddin University, Faculty of Medicine, Makassar,

South Sulawesi, Indonesia. Ph.D : 1981 in University of Hiroshima, School of Medicine, Hiroshima City,

Japan. Visiting scholar : 1987 – 1988 in Multidiciplinary Pain Center in

Departement of Anesthesiology, School of Medicine, University of Washington, Seattle USA.

Lemhanas KSA VIII : in 2000Organization :

Member of the Indonesian Doctors Association Member of Indonesian Society of Anesthesiologist and Reanimation Member of The Asian and Oceanic Society of Regional Anesthesia

(AOSRA) Member of The World Association for Study of Pain (IASP) Past President of Indonesian Pain Society (IASP chapter Indonesia)

CURRICULUM VITAE

Multimodal Regiments for Acute Pain Management

A. Husni Tanra

Department of Anesthesiology IC and Pain ManagementFaculty of Medicine Hasanuddin University

Makassar Indonesia

What is multimodal analgesia?

Is a combination of two or more analgesics that act at different

mechanisms, produce additive or synergistic analgesia

Main goals of Multimodal Analgsia is to reduce the amount of Opioid

COMBINE DRUGS MAY HAVE 3 EFFECTS

1. Synergetic ............. 2+2>4

2. Additive ................ 2+2=4

3. Subadditive ........... 2+2=3

Why we need multimodal analgesia for posoperative pain?

No single analgesic is perfect and nosingle analgesic can treat all types of pain.

Multimodal Analgesia potentiating in efficacy, reduced doses, minimal adverse effect. Improve the outcome.

Most of the pain is a multifaceted and multiple-sources.

Characteristic of Postoperative Pain

Postoppain

Nociceptorsensitisation

Somatic Pain

muscle, fascia, ligament

Cortical Responses

CutaneousSomatic

pain

VisceralPain

Reflexresponse

Musclespasm

Referredpain

Different types of pain

Different pain intensity

Different location of

pain

Different risks and benefits of

analgesic techniques

Different surgical procedures have characteristic pain profiles

Differentprocedures

• Tissue damage• Inflamed tissue

Surgery

Nociceptiveinput

PAIN

Surgery has a biphasic insults to the body1. Trauma to tissue2. Inflammatory response

SURGERY AND PAIN

ASIC/BNC

1.Peripheral sensitization

PERIPHERAL ACTIVITY

CENTRAL SENSITIZATION

Decreased threshold to peripheral

stimuli

Increased spontaneous

activityExpansion ofreceptive

field

HyperalgesiaAllodynia

Tissue damagePrimary Hyperalgesia

Nerve damage

Spontaneous pain

Secondary Hyperalgesia

2 .Central Sensitization

So, after the surgery there is a change in NS

what we called:

“Neuro-Plasticity of the Nervous System”

Neuro-Plasticity of the NS

Primary hyperalgesiaPeripheral sensitization

Secondary hyperalgesia

Spinal “wind-up” Inflammatory mediators

Central sensitization

CNS

Histamine, Leukotrienes, Norepinephrine, Cytokines, Bradykinin, Prostaglandins,

Neuropeptides, 5-HT, Purines, H+/K+ions

Modify by AHTAfter the injury the NS will changed neuro-plasticity

After surgery Pain Sensitization:Hyperalgesia and Allodynia

Normalpain response

Sensitisedpain response

Injury

X

HYPERALGESIA

Stimulus intensity

Pain intensityfor stimulus X

normalpain response

Pain intensityfor stimulus X

sensitisedpain response

ALLODYNIA

Pain

inte

nsity

10

8

6

4

2

0

• ALLODYNIA• HYPERALGESIA• PROLONGED PAIN• REFERRED PAIN

CLINICAL PAIN (PATHOPHYSIOLOGICAL

PAIN )

Vanished after healing

Chronic Pain (1 %)X

Clinical Features of Postoperative Pain

Basic Principle of Postop Pain Management is

preemptive analgesia

Peripheral and

Central sanitization

prevent the occurrence of

reduced the process of NeuroplasticityBy Giving

Anti-hyperalgesic & Anti-allodynia

Antihyperalgesic Drugs• NSAIDs (Nonsteroidal anti-inflammatory drugs)• COXIBs (Selective COX-2 inhibitors)• lidocaine (iv and topical)• Ketamine (low-dose) and other NMDA antagonist• Clonidine (iv and Intrathecal)• Gabapentinoid (Gabapentin and Pregabalin)• Amitriptyline• TENS• Midazolam (Intratheca

Antiallodynic Drugs• Lidocaine iv• Ketamine (low-dose) & other NMDA antagonist• Gabapentin (Oral and intrathecal)• Clonidine (iv and intrathecal)• Propofol (low dose)• Midazolam (intrathecal)

Anti-hyperalgesic Therapy: Opioid-Sparing

~30%reduction

Opi

oid

Opi

oidPa

in in

tens

ity

XStimulus intensity

Anti-hyper

algesic

Normalpain

response

Sensitisedpain response

Partially desensitisedpain response

Philosophy of Multimodal AnalgesiaNot only just giving 2 or more drugs which different mechanism, but;

• One drug should be effective at peripheral

sensitization and other at central sensitization.

• Combine drugs must synergetic or addictive.

• Must be proven by laboratory or clinical data.

• Some drugs may act at several point at nociceptive

pathway.

Local anesthetics

CorticosteroidsNSAIDsCOXIBs

Local Anesthetic

CNS

DRG

OpioidsGabapentinoids

Clonidine

Modify by AHT

KetaminParacetamol

COXIBs

Transduction

TransductionModulation

Perception

TransmissionModulation

Target Point of Analgesic Drugs

WHAT IS THE MOST REGIMENTSThere are many regiments for multimodal analgesia, but the most popular are:

Opioid Local AnestheticParacetamol

NSAIDs and Coxibs

NMDA Antagonist (Ketamin)

-2 antagonist (Clonidine)

2 (subunit of Ca Channel) agonist (Gabapentinoid)

1. Paracetamol Acetaminophen/APPA

Para-aminophenol

Analgesic Effects Antipyretic Effect

Route of Administration- Orally- Rectally- Intravenously

Oscier CD & Milner QJ (2009) Peri-operative use of paracetamol. Anaesthesia 64(1): 65–72.

No Anti-Histamine Effects

Central Antinociceptive Effect

Bertolini et al, 2006; Botting, 2006; Pickering et al, 2006; Mallet et al, 2008; Pickering et al, 2008; Mancini et al, 2003

Mechanism Of Action

Central COX (Cyclooxygenase) Inhibition1

Activation of the endocannabinoid system and serotonergic pathways)2

prevent prostaglandin production at the cellular level.

3

Paracetamol is very safe drug as long as it is given within recommended doses

(Adult < 4 gr/day, Infant and children 20-40 mg/kgBW)

1. All Age – from Infant to Elderly

2. From pregnant to Lactating Woman

3. Can be used for patients with renal and

hepatic impairment.

Paracetamol

PARACETAMOL , NSAIDS & COXIBS

Guidelines line for postoperative pain management state that:

“Unless contraindication, all patients should receive an around-the clock(ATC) regiment on NSAIDs, COXIBs, or Paracetamol”.

American Society of Anesthesiologists Task Force on Acute Pain Management 2004;100:1573-1581

Hyllested M, Jones S, Pedersen JL et al (2002) Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 88(2): 199–214.

Paracetamol can be the best alternative to NSAID especially for high risk patients

It is appropriate to administer acetaminophen with NSAID, or COXIBs additive or synergistic effects

Intravenous form of paracetamol has more predictable onset and duration of actions

Qualitative Review of Paracetamol and NSAIDs

1. Sindet-Pedersen S.1997. Data on file.

* I.V. paracetamol was administered as a bio-equivalent dose of propacetamol.

Fast onset of action *1

Sindet-Pedersen S, 1997

Rapid onset: 5minPeak at ideal time: 30min

IV paracetamol for dental

Good residual effect at >6hrs

Paracetamol has Opioid Sparing Effects

I.V. paracetamol in these studies was administered as a bio-

equivalent dose of propacetamol.

Quantitative Systemic Review 2010Paracetamol and NSAIDs (cox1 and cox2)

Combination of paracetamol and an NSAIDs may offer superior analgesia compared with either drug alone

(Anesth Analg 2010)

Combination of paracetamol and parecoxib may useful in

patients

who are susceptible to haemorrhagic complications of

NSAIDs

Parecoxib and Acetominophen

A combination of 1000 mg paracetamol and 30mg codeine was significantly more

effective in controlling pain for 12 hours following third molar removal, with no

significant difference of side effects during the 12 hour period studied

Paracetamol vs Paracetamol + CodeineIn post-operative dental pain

Tramadol/paracetamol combination tablets provided

analgesic efficacy with a better safety profile to

tramadol capsules in patients postoperative pain

following ambulatory hand surgery.

Paracetamol + Tramadol

METAANALYSISAdvantages of Multimodal Analgesia

Elia N, Lysakowski C & Tramer MR (2005) Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology 103(6): 1296–304.

Acetaminophen, NSAIDs, or

COXIBs

Added ToPCA Morphine

All of analgesic agent provided an opioid-sparing effect

However, the decrease in morphine use did not consistently result in a decrease in opioid-releted adverse effects

NSAIDs + Morphine was associated with a decrease in the incidence of PONV and sedation

SYSTEMIC REVIEWNSAIDs vs COXIBs For Postoperative Pain

Romsing J & Moiniche S (2004) A systematic review of COX-2 inhibitors compared with traditional NSAIDs, or different COX-2 inhibitors for post-operative pain. Acta Anaesthesiol Scand 48(5): 525–46.

Demonstrate Equipotent Analgesic Efficacy After Minor and Major Surgical Procedure

NSAIDs COXIBs

COXIBs Better Alternative TO NSAIDs in the perioperative

setting

COXIBs associated with:

Reduce gastrointestinal side effects

Absence of anti-platelet activity

Limitation of Traditional NSAIDS:(Aspirin/NSAID) sensitive asthma

• The COX-2 selective inhibitors celecoxib1,2 and rofecoxib3,4 given orally do not cause bronchospasm in patients with aspirin/conventional NSAID-sensitive asthma

1. Gyllfors et al. Allergy Clin Immunol 2003;111:1116;2. Martin-Garcia et al. J Investig Allergol Clin Immunol 2003;13:20;

3. Stevenson et al. J Allergy Clin Immunol 2001;108:47; 4. Martin-Garcia et al. Chest 2002;121:1812

2. KETAMINAnesthesia Dose more than 2 mg/kg (iv) anesthesia + produce side effects such us Psychomimetic effect

• Excessive sedation• Cognitive Dysfunction• Hallucination• Nightmares

Subanesthesia Dose (Low Dose) < 1 mg/kg demonstrated significant analgesic efficacy without these side effects

Very Low dose (0,15 mg/kg) single intraoperative injection of ketamine 0,15 mg/kg improve analgesia and passive knee mobilization 24 hour after arthroscopy

KetaminMore Frequently Use in Postorthopedic Surgical Pain Management

Arthroscopic Anterior Cruciate Ligament

Surgery

Outpatient Knee Arthroplasty

Total Knee Arthroplasty

A Single intraoperative injection of ketamin (0,15 mg/kg) improved analgesia and passive knee mobilization 24 hour after surgery

Improved Postoperative Outcome

When combine with epidural or femoral nerve block, increase postoperative pain relief for total knee arthroplasty.

• Menigaux C, Guignard B, Fletcher D, Dupont X, Guirimand F, Chauvin M. Anesth Analg. 2000;90:129–135.• Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X, Chauvin M. Anesth Analg. 2001;93:606–612.

• Himmelseher S, Ziegler-Pithamitsis D, Agiriadou H, Martin Jjelen-Esselborn S, Koch E. Anesth Analg. 2001;92: 1290–1295.• Adam F, Chauvin M, Du Manoir B, Langlois M, Sessler DI, Fletcher D. Anesth Analg. 2005;100:475–480.

Why I gave ketamin low dose to this patient?

progressive increase in response of second order neurons to repetitive C-fiber input

“Wind-Up”

Mendel and Wall, 1965

Now is appreciated that “wind-up” is a crucial factor for chronic pain after surgery

wind-up

NMDA unblockedNMDA blocked (AP5)

Stimulus frequency applied toC-fiber nerve endings

Actio

n po

tenti

al d

ischa

rge

inSe

cond

ord

er sp

inal

neu

rons

60

50

40

30

20

10

02 4 6 8 10 12 14

Ongoing activation after injury, the receptive fields of these neurons expand, leading to spread of pain.

Recruitment

KETAMIN

• Low-dose ketamine is not really an ‘analgesic’, but better described as:

‘anti-hyperalgesic’

‘anti-allodynic’

‘tolerance-protective’ of opioid

Opioid-induced Hyperalgesia

GABAPENTINOIDSGabapentin and Pregabalin

Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Anesth Analg. 2000;91:185–191.Hurley RW, Chatterjea D, Rose Feng M, Taylor CP, Hammond DL.. Anesthesiology. 2002; 97:1263–1273.

Gilron I, Orr E, Tu D, O’Neill JP, Zamora JE, Bell AC. Pain. 2005;113:191–200.Reuben SS,Buvanendran A,Kroin JS, Raghunathan. Anesth Analg. 2006;103:1271–1277.

Enhanced Analgesic effects of:Gabapentin

Morphine NSAIDs

COXIBs

Gabapentin and

pregabalinProvide anti-hyperalgesiacan synergically with NSAID

Pregabalin

Superior to either single drugs for postoperative pain following spinal fusion surgery

and Celecoxib

Sedation can be interpreted as a negative outcome of gabapentin ,however its can be benefical in the perioperative setting

as an anxiolysis

Paracetamol and Gabapentin

Paracetamol +

Gabapentin

Analgesic+

Antihyperalgesic

postoperative pain scores &

Rescue Analgesics

but more episodes of nausea and vomiting and higher levels of sedation

De Kock MF, Pichon G & Scholtes JL (1992) Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth 39(6): 537–44.Jeffs SA, Hall JE & Morris S (2002) Comparison of morphine alone with morphine plus clonidine for postoperative patient-controlled analgesia. Br J Anaesth 89(3): 424–

7.Marinangeli F, Ciccozzi A, Donatelli F et al (2002) Clonidine for treatment of postoperative pain: a dose-finding study. Eur J Pain 6(1): 35–42

Potentiation

Clonidine (intravenous)

Opioid (iv or PCA)

REDUCED DOSES

• Opioid postoperative requirements

IMPROVED EFFECACY

• Improved Postoperative Analgesia

REDUCE SIDE EFFECTS

• Nausea and Vomiting

Cautions !!!• Sedation and Hypotension dose-

dependent

Alpha-2 AgonistClonidine

Alpha-2 AgonistIntrathecal (SAB)

De Kock MF, Pichon G & Scholtes JL (1992) Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth 39(6): 537–44.Jeffs SA, Hall JE & Morris S (2002) Comparison of morphine alone with morphine plus clonidine for postoperative patient-controlled analgesia. Br J Anaesth 89(3): 424–

7.Marinangeli F, Ciccozzi A, Donatelli F et al (2002) Clonidine for treatment of postoperative pain: a dose-finding study. Eur J Pain 6(1): 35–42

Advantages Clonidine 15-150 mcg + Local anesthetic

Prolonged time of regression Prolonged time to analgesic request Increased speed of onset and duration. Improved early analgesia Prolonged analgesia

Continuous PNB

Chelly JE, Ben-David B,Williams BA,KentorML.. Orthopedics. 2003;26:S865–S871.Capdevilla X, Barthelet Y, Biboulet P, Ryckwaert Y, Rubenovitch J, d’Athis F.. Anesthesiology. 1999;91:8–15.

Richman JM, Liu SS, Courpas G, et al.. Anesth Analg. 2006;102:248–257.

Advantages Superior Pain Relief with movement Reduce Surgical Stress Improved Rehabilitation Reduced opioid consumption and

reduced opioid-related side effects

Disadvantages Required technical skill Infrastructure to manage catheter,

especially outpatient

Peripheral Nerve Block (PNB)

Adams HA, Saatweber P, Schmitz CS, Hecker H. Postoperative pain management in orthopedic patients: no differences in pain score, but improved stress control by epidural anaesthesia. Eur J Anaesthesiol. 2002;19:658–665.

De Leon-Casasola OA. When it comes to outcome, we need to define what a perioperative epidural technique is. Anesth Analg. 2003;96:315–318.

Advantages

Significant pain relief Reduced Neuroendocrine Response Superior to either PNB or PCA in blunting surgical

response ↓ Incidence of pulmonary complications,

myocardial infarction, DVT and Pulmonary Embolism

Epidural Blockade

Reuben SS, Buvanendran A, Kroin JS, et al. Postoperative modulation of central nervous system prostaglandins E2 by cyclooxygenase inhibitors after vascular surgery. Anesthesiology. 2006;104:411–416.

Samad TA, Sapirstein A,Woolf CJ. Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends Mol Med. 2002;8:390–396.

Limitation

Has no effects on humoral cytokine

proinflammatory response (it may be

blocked only by COXIBs).

Epidural BlockadeEpidural can only block pain tranmissions but not humoral respons

EPIDURAL BLOCK

Epidural BlockLocal Anesthetic

NeuroendocrineStress Response

ACTHADHGHTSH

Central COX-2

inhibition

CytokinesIL-1βIL-2IL-6TNF

NorepinephrineEpinephrineCortisolAldosteroneRenin

Sympathetic efferent

Modify by AHT

Humoral stress response

From this theory

• We can conclude that epidural with LA alone, may not able to prevent/block release cytokines due to tissue injury.

• So combine Epidural with Coxibs may produce excellent analgesia.

• It can be the future analgesia.

Multimodal AnalgesiaUsing 5 Type of Analgesic Drugs

(a preliminary study)

1. Gabapentin 1200 mg

2. Dexamethasone 8 mg 3. Ketamine 0.15 mg/kgBW

4. Paracetamol 1000 mg

5. Ketorolac 15 mg

1. Paracetamol 1000 mg

2. Ketorolac 15 mg

3. Placebo

superior in pain control than

Group I Group II

PARACETAMOL• Paracetamol as a single analgesic is

only for mild and moderate pain.• However it can be combined with

many analgesics to provide strong effect.

• So, it can be the basic regiment for Multimodal Analgesia.

OPI

OID

NSA

ID

COXI

B

Tram

adol

Keta

min

e

Gaba

pent

anoi

d(G

abap

entin

, Pre

gaba

lin)

PARACETAMOL

Local Anesthetic (Epidural Block, Nerve Block)

Clon

idin

e

Multimodal

Analgesia Improved Analgesia

Lowered Dose Reduced Side Effects

• Early Mobilization• Early Enteral Feeding• Rapid Recovery • low cost

Aggressive preemtive multimodal including epidural or nerve block not only produce optimal analgesia but also may prevent the

occurrence of chronic pain after surgical

Conclusion

Crile 1913

“Patients Given Inhalation anesthesia still need to be protected by regional anesthesia, otherwise they might suffer persistent central nervous systems changes and enhanced postoperative pain ”

Stated That: This is not new

Thank youvery much