This document provides information on multimodal regiments for acute pain management. It discusses the goals of multimodal analgesia including reducing opioid use through additive or synergistic effects. Key points: - Multimodal analgesia involves using two or more analgesics with different mechanisms to better treat multiple pain sources and reduce side effects. - Postoperative pain involves peripheral and central sensitization, so multimodal regiments target both levels. - Common regiments discussed include paracetamol, NSAIDs, COXIBs, ketamine, gabapentinoids, clonidine and opioids. Low dose ketamine and gabapentinoids are highlighted for their anti-hyperalgesic effects. - Combining

1. CURRICULUM VITAE

2. Multimodal Regiments for Acute
Pain Management
A. Husni Tanra
Department of Anesthesiology IC and Pain Management
Faculty of Medicine Hasanuddin University
Makassar Indonesia

3. 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

4. 1. Synergetic ............. 2+2>4
2. Additive ................ 2+2=4
3. Subadditive ........... 2+2=3

5. Why we need multimodal analgesia
for posoperative pain?
No single analgesic is perfect and no
single 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.

6. Characteristic of Postoperative Pain
Postop
pain
Nociceptor
sensitisation
Somatic
Pain
muscle, fascia,
ligament
Cortical
Responses
Cutaneous
Somatic
pain
Visceral
Pain
Reflex
response
Muscle
spasm
Referred
pain

7. 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
Different
procedures

8. •Tissue damage
•Inflamed tissue
Surgery
Nociceptive
input
PAIN
Surgery has a biphasic insults to the body
1. Trauma to tissue
2. Inflammatory response

9. ASIC/BNC
1.Peripheral sensitization

10. PERIPHERAL
ACTIVITY
CENTRAL
SENSITIZATION
Decreased
threshold to
peripheral
stimuli
Increased
spontaneous
activityExpansion of
receptive
field
Hyperalgesia
Allodynia
Tissue damage
Primary Hyperalgesia
Nerve damage
Spontaneous
pain
Secondary Hyperalgesia
2 .Central Sensitization

11. So, after the surgery there is a
change in NS
what we called:
“Neuro-Plasticity of the
Nervous System”

12. Neuro-Plasticity of the NS
Primary hyperalgesiaPeripheral sensitization
Secondary
hyperalgesia
Spinal “wind-up”
Central sensitization
Histamine, Leukotrienes,
Norepinephrine, Cytokines,
Bradykinin, Prostaglandins,
Neuropeptides, 5-HT,
Purines, H+/K+ions
Modify by AHTAfter the injury the NS will changed  neuro-plasticity

13. After surgery  Pain Sensitization:
Hyperalgesia and Allodynia
Normal
pain response
Sensitised
pain response
Injury
X
HYPERALGESIA
Stimulus intensity
Pain intensity
for stimulus X
normal
pain response
Pain intensity
for stimulus X
sensitised
pain response
ALLODYNIA
Painintensity
10
8
6
4
2
0

14. • ALLODYNIA
• HYPERALGESIA
• PROLONGED PAIN
• REFERRED PAIN
CLINICAL PAIN
(PATHOPHYSIOLOGICAL
PAIN )
Vanished
after healing
Chronic
Pain (1 %)X

15. Basic Principle of Postop Pain
Management is
preemptive
analgesia
Peripheral
and
Central sanitization
prevent the occurrence of
reduced the process of Neuroplasticity
By Giving
Anti-hyperalgesic &
Anti-allodynia

16. 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

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

18. Anti-hyperalgesic Therapy:
Opioid-Sparing
~30%
reduction
Opioid
Opioid
Painintensity
X
Stimulus intensity
Anti-
hyper
algesic
Normal
pain
response
Sensitised
pain response
Partially desensitised
pain response

19. Philosophy of Multimodal Analgesia
Not 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 be synergetic or addictive.
• Must be proven by laboratory or clinical data.
• Some drugs may act at several point at nociceptive
pathway.

20. Local anesthetics
Corticosteroids
NSAIDs
COXIBs
Local Anesthetic
DRG
Opioids
Gabapentinoids
Clonidine
Modify by AHT
Ketamin
Paracetamol
COXIBs
Transduction
TransductionModulation
Perception
Transmission
Modulation
Target Point of Analgesic Drugs

21. WHAT IS THE MOST REGIMENTS
There are many regiments for multimodal analgesia,
but the most popular are:
Opioid Local Anesthetic
Paracetamol
NSAIDs and Coxibs
NMDA Antagonist
(Ketamin)
-2 antagonist
(Clonidine)
2 (subunit of Ca
Channel) agonist
(Gabapentinoid)

22. 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

23. 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) Inhibition
Activation of the endocannabinoid system
and serotonergic pathways)
prevent prostaglandin
production at the
cellular level.

24. 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

25. 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

26. 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

27. 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: 5min
Peak at ideal time: 30min
IV paracetamol for dental
Good residual effect at >6hrs

28. Paracetamol has Opioid Sparing Effects
I.V. paracetamol in these studies
was administered as a bio-
equivalent dose of propacetamol.

29. Quantitative Systemic Review 2010
Paracetamol and NSAIDs (cox1 and cox2)
Combination of paracetamol and an NSAIDs may offer
superior analgesia compared with either drug alone
(Anesth Analg 2010)

30. Combination of paracetamol and parecoxib may useful in
patients
who are susceptible to haemorrhagic complications of
NSAIDs
Parecoxib and Acetominophen

31. 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 + Codeine
In post-operative dental pain

32. 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

33. Advantages 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 To
PCA 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

34. NSAIDs 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

35. 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

36. Anesthesia 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

37. Ketamin
More 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.

38. Why I gave ketamin low dose to this patient?

39. 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
NMDA unblocked
NMDA blocked (AP5)
Stimulus frequency applied to
C-fiber nerve endings
Actionpotentialdischargein
Secondorderspinalneurons
60
50
40
30
20
10
0
2 4 6 8 10 12 14

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

48. • Low-dose ketamine is not really an ‘analgesic’,
but better described as:
‘anti-hyperalgesic’
‘anti-allodynic’
‘tolerance-protective’ of opioid
 Opioid-induced Hyperalgesia

49. Gabapentin 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
Gabapentin
and
pregabalin
Provide anti-hyperalgesiacan synergically with NSAID
Pregabalin
Superior to either single
drugs for postoperative
pain following spinal
fusion surgery
and Celecoxib

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

51. Paracetamol and Gabapentin
Paracetamol
+
Gabapentin
Analgesic
+
Antihyperalgesic
 postoperative
pain scores &
Rescue
Analgesics
but
more episodes of nausea and vomiting and higher levels of sedation

54. 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
Clonidine
(intravenous)
REDUCED DOSES
•  Opioid postoperative requirements
IMPROVED EFFECACY
• Improved Postoperative Analgesia
REDUCE SIDE EFFECTS
• Nausea and Vomiting
Cautions !!!
• Sedation and Hypotension  dose-
dependent
Alpha-2 Agonist
Clonidine

55. Alpha-2 Agonist
Intrathecal (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

56. 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)

57. 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

58. 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 Blockade
Epidural can only block pain tranmissions but not humoral respons

59. Epidural Block
Local Anesthetic
ACTH
ADH
GH
TSH
Central
COX-2
inhibition
Cytokines
IL-1β
IL-2
IL-6
TNF
Norepinephrine
Epinephrine
Cortisol
Aldosterone
Renin
Sympathetic
efferent
Modify by AHT

60. 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.

61. Multimodal Analgesia
Using 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

62. 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.

63. OPIOID
NSAID
COXIB
Tramadol
Ketamine
Gabapentanoid
(Gabapentin,Pregabalin)
PARACETAMOL
Local Anesthetic (Epidural
Block, Nerve Block)
Clonidine

64. Multimodal
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

65. 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