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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 : [email protected] : 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
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.
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