Preventive analgesia: Broader definition of preemptive analgesia Perioperative analgesic regimen that able to control pain-induced sensitization Not the timing of the analgesic treatment but the duration and efficacy of an analgesic intervention are more important for an effective postoperative pain relief Adequate preventive analgesia should include multimodal techniques and with a sufficient duration of tretment

1. CURRICULUM VITAE
Name : dr.M. Ramli Ahmad, Sp.An-KAP,KMN
Address : Jl. A.P.Pettarani Blok GA 7/9
Job : Dosen FK UNHAS
Education : - FK UNHAS
- Anestesiologi FK UNAIR
Organization : - IDI
- Ketua PERDATIN SUL-SEL

2. FROM PREEMTIVE TO PREVENTIVE
ANALGESIA
Muhammad. Ramli Ahmad
Department of Anesthesiology Faculty of Medicine
Hasanuddin University
Makassar

3. 0%
20%
40%
60%
Severe Pain Moderate Pain
31%
47%
To breath, cough and
move easier
INTRODUCTION
Surgery with
Pain Control
Better pathophysiology &
pharmacology at the end
1990-s
butMost patients still worried about post operative pain
Apfelbaum JL, Chen C, Mehta SS, Gan TJ.
Postoperative pain experience: results from a national
survey suggest postoperative pain continues to be
undermanaged. Anesth Analg. 2003

4. Introduction
Optimal Postoperative Pain Management
Progress in
medical fields
WHO (2005)  Pain : 5th vital sign
Postoperative Pain Management

5. Introduction

6. Preemptive Analgesia
Before incision Surgery Post operative
Begin in early of 1920’s by Crile & Lower
Incision
(Noxious signal)
Preemptive
Analgesia Note :
Pain modulation by CNS takes a place before perception
Central nervous system (CNS) protection until post operative period

7. Preemptive Analgesia
Pre - Incision Surgery Post operative
Incision
(Noxious Signal)
• Prevent acute pain
• Prevent chronic pain as
a result of untreated
acute pain
Preemptive
Analgesia
Combination of Local-
Regional blockade &
General Anesthesia
Pain stimuli :
Central Sensitization & “Wind-
Up”
• Prevent central
sensitization
•  hyperalgesia

8. PREEMPTIVE ANALGESIA
Preemptive therapy (administration of drugs at pre-incision) was
consider :
 Prevent central sensitization
  hyperalgesia incidence
  severity of postoperative pain
but
Since the end of 1980-s, hundreds study (with various quality) failed to proved
effectively of pain management at pra-incision compared to post-incision

9. Clinical study contradictory

10. New insight
Kissin I, Preemptive Analgesia at the Crossroad,Anesth Analg 2005,100:754-756

11. Preemptive Analgesia
Preemptive analgesia problem is no more about timing (pre
or post), but what is more important issues are:
1. Duration of PreemptiveAnalgesia , must include not only
tissue injury phase but also phase of inflammatory
process
2. Completeness of nociceptive blockade during both
phases above
Kissin I, Preemptive Analgesia at the Crossroad,Anesth Analg 2005,100:754-756

12. Preventive Analgesia
Pre - Incision Surgery Post operative
Incision
(Noxious signal )
Preventive
Analgesia
Duration of action from the agent is longer than preemptive target
Preventive
Analgesia
or
Duration of action from the agent covering
entire perioperative period
Broader definition of preemptive
Preventive
Analgesia

13. Preventive Analgesia
Pre- Incision Surgery Post operative
Incision
(Noxious Signal)
Analgesic effect must covers entire perioperative period,
whenever the drug was administered
MultimodalAnalgesia

14. Target of Preventive Analgesia
Perioperative period
Preoperative Intraoperative Postoperative
Peripheral & central sensitization

15. Definition

16. Preventive Analgesia
Preventive analgesia is prevention
Prevent before central sensitization occur
Analgesic given prior to the surgery
 A preventive approach that aims to block
transmission of the primary afferent injury barrage
before, during, and after surgery

17. Targets of a preventive Analgesia
Perioperative period
 Preoperative (days before surgery and just
minutes before skin incision)
 Intraoperative (after incision to those initiated just
prior to the end of surgery)
 Postoperative (after the end of surgery and may
extend for days thereafter

18. Preemptive to Preventive Analgesia
Earlier Definition:
Preemptive Analgesia has been defined as:
1. Antinociceptive treatment starting before surgery
2. Antinociceptive treatment that prevents central
sensitization
New Definition:
3. Preventing centra sensitization induced byTISSUE
INJURY and INFLAMANTORY INJURY (extending the
period beyond the initial postoperative period)
Preemptive means “ preventive” but this not simply just
“before incison”

19. CENTRAL
SENSI-
TIZATION
P A I N
Initial
Noxious
Stimulus
Changes in
Dorsal Horn
(e.g.
surgical
incision)
Preemptive Analgesia
PREVENTIVE ANALGESIA AS IMPROVEMENT OF
PREEMPTIVE ANALGESIA
Preventive AnalgesiaTo
CENTRAL
SENSI-
TIZATION
P A I N
Another Noxious
Stimulus
(intraoperative
manipulation)
Postoperative
Inflammation
Pain Management
Also applied intra-
& postoperative
Cousins MJ. Physiology and Psychology of acute pain. In Acute Pain Management: Scientific Evidence. Second Edition. Australian and Newzealand Collage of Anesthetists.
Australia 2005. 1-17
Moiniche SM, Kehlet H, Dahl JB. A Qualitative and Quantitative Systemic Review of Preemptive Analgesia for Postoperative Pain Relief. Anesthesiology 2002; 96:725-41
Kissin I. Preemptive Analgesia at the Crossroad. Anesth Analg 2005; 100:754-6
Pain Management
Before Initial
Stimulus

20.  TARGET
 POSTOPERATIVE HYPERALGESIA
 PERIODS : PRE (Pre emptive analgesia, pre emptive anti hyperalgesia)
INTRA
POSTOPERATIVE (general as well regional anesthesia)
 DRUG MECHANISMS :
 PRIMARY SENSITIZATION (PERIPHERY)
 AINS
 Local anesthetics
 SECONDARY SENSITIZATION (CENTRAL)
 NMDA receptors
 Kétamine, Dextromorphan …
 Voltage gated calcium channels (anti hyperalgesic drugs)
 Gabapentine, gabapentinoids, Nefopam…
 a2 adrenegic drugs descending inhibiting pathways)
 Clonidine
PHARMALOGICAL CONTROL OF POSTOPERATIVE
HYPERALGESIA

21. CONTROL OF HYPERALGESIA
Primary Secondary
BULBO-SPINAL
DESCENDING
INHIBITORY
CONTROLS
MORPHINE
a2 ADRENERGICS
(Clonidine)
N.S.A.I.D
s
“Inflammatory soup”
Histamin
Serotonin
Bradykinin
Prostaglandins
.......................
Susbtance (SP)
Neuropeptides
CGRP
Excitatory A.A.
....................……
• NMDA Receptors
• Voltage gated
calcium channels
Péripheral
NMDA RECEPTOR
Kétamine
Dextromorphan
Central
LOCAL
ANAESTHETICS
Protein
kinases
Protooncogen
- C Fos
- C Jun
Second messengerr
+
+
+
WIND.UP
Axon Reflex
5HT
N.E.
Synapse
PRE
POST
+
VOLTAGEGATED
CALCIUM
CHANNELS
. Nefopam
. Gabapentine

23. Clinical Applications of Preemptive
Analgesia
Pro-Contra
Pre - Incision Post - Incision
Preemptive
Analgesia
Post incisional
Analgesia
• NSAIDs
• EpiduralAnalgesics
• LocalAnesthetic Infiltration
• Opioid
• NMDA antagonist
RCTSs Review, Moiniche dkk.,
• Pain intensity
• Onset rescue analgesic 
• Total analgesic requirement

24. PREEMPTIVE ANALGESIA
Moiniche et al
Ong et al
Controversial
80 RCT
Evaluated preemptive
analgesia of NSAID, epidural,
wound infiltration, opiate,
NMDA antagonist
No difference in effectifity
between preemptive analgesia
and post-incision analgesia
66 RCT
Evaluated preemptive analgesia of
NSAID, epidural, wound
infiltration, opiate, NMDA
antagonist
Epidural analgesia preemptive:
 Pain intensity in 24-48 hours
post-operative, onset of first
rescue analgesia, &  total
supplement analgesic
Local infiltration, NSAID, opiate, &
NMDA antagonist preemptive: 
total supplement analgesic ,onset
of first rescue analgesia & failed to
improved pain intensity

25. CLINICAL APPLICATIONS OF PREEMPTIVE
ANALGESIA
NON STEROIDANTI INFLAMMATIONS DRUGS (NSAID)
Pra-Incision Post-incision
 duration of analgesia
 Opiate consumption in 24 hours
 Incidental pain score
Ruben et al
No benefict effect
Moniche et al
 Analgesic consumption
 Onset of First analgesic administration
Not improved pain score
Ong et al

26. CLINICAL APPLICATIONS OF PREEMPTIVE
ANALGESIA
NMDA RECEPTORANTAGONISTS
Pra-Incision Post-incision
Positive effect of preemptive
analgesic, uncertain dose response
McCartney et al
Analgesic effect not consistent
 Analgesic consumption (67%)
 pain score (58%)
Ong et al
Activation of NMDA receptor has important role in central sensitization
On focus in preventive & preemptive analgesia

27. CLINICAL APPLICATIONS OF PREEMPTIVE
ANALGESIA
LOCAL ANESTHETICS
Pra-Incision Post-incision
No epidural regiment that improve
postoperative pain control,
Wound Infiltration, peripheral nerve block,
and intraperitoneal infiltration regiment
had no benefit effect
Moniche et al
Wound Infiltration regiments decreased analgesic drugs
consumption & extend duration of analgesia, but no effect
on pain score
Ong et al
Epidural regiment :
Improve pain intensity
Long duration of action
Ong et al

28. Had more advantages than
Katz & McCartney
Its imporatant to give multimodal analgesic therapy
at all perioperative periode
CLINICAL APPLICATIONS OF PREVENTIVE ANALGESIA
Central Sensitization & Neuroplasticity of Nocisepsy Input
Pra-Incision Intraoperative Intraoperative
More extent than preemptive analgesia, involved all perioperative pain
control regiment

29. From Preemptive to Preventive analgesia

30. Clinical Implication

31. A QUALITATIVE SYSTEMATIC REVIEW OF THE ROLE OF N-METHYL-D-
ASPARTATE ANTAGONISTS IN PREVENTIVE ANALGESIA
Mc CARTNEY C.J.L., SINHA A., KATZ J. Anesth Anal 2004;98:1385-400
META ANALYSIS
 USINGA MEDLINE (1966 - 2003) AND EMBASE
(1985-2003) SEARCH
 FORTY ARTICLES MEETINGTHE INCLUSION CRITERIA
 OUTCOMES :
 Primary reduction of pain, analgesic cunsumption
 Secondary : time for first analgesic request,
adverse effects
 PREVENTIVE EFFECTS OF :
 Dextromorphan (12 articles) = 67 %
 Ketamine (24 articles) = 58 %
 Magnesium ( 4 articles) = none

32. Clinical Implication

33. Clinical Implication (cont.)

34. Clinical Implication (cont.)

35. Korean J Anesthesia 2005:48:S 21-5

36. British Journal of Anaesthesia 100 (2): 256–62
(2008)

37. Reg Anesth Pain Med
2008;33:44-51.

38. Coll. Antropol. 31 (2007) 4: 1071–1075
Original scientific paper

39. Summary of studies of preemptive and
preventive analgesia according to
target agent administered
Agents
No. of
studies
Preemptive effects(%) Preventive effects(%) Opposite
effects(%)
Total No.
effects(%)Positive Negative Positive Negative
Local
anesthetics
65 8(10.7) 16(21.3) 27(36.0) 18(24.0) 6(8.0) 75(100)
Opioids 25 7(25.0) 5(17.9) 10(35.7) 3(10.7) 3(10.7) 28(100)
NSAIDs 25 3(11.5) 12(46.2) 1(3.8) 8(30.8) 2(7.7) 26(100)
NMDA
anatgonists
31 5(13.2) 6(15.8) 19(50.0) 7(18.4) 1(2.6) 38(100)
Clonidine 2 0(0.0) 0(0.0) 2(100.0) 0(0.0) 0(0.0) 2(100.0)
Local
anesthetics
and opioids
21 4(17.4) 5(21.7) 7(30.4) 6(26.1) 1(4.3) 23(100)
Multimodal 6 2(25.0) 0(0.0) 2(25.0) 3(37.5) 1(12.5) 8(100)
Total 175 29(14.5) 44(22.0) 68(34.0) 45(22.5) 14(7.0) 200(100)

40. • Katz J, Clarke H. Preventive analgesia and beyond: current status, evidence, and future directions. In: Macintyre PE,
Walker SM, Rowbotham DJ, eds. Clinical pain management: acute pain. 2nd ed. London: Hodder & Staughton, 2008: 154-
99.

42. • Katz J, Clarke H. Preventive analgesia and beyond: current status, evidence, and future directions. In: Macintyre PE,
Walker SM, Rowbotham DJ, eds. Clinical pain management: acute pain. 2nd ed. London: Hodder & Staughton, 2008: 154-
99.
Katz J, Kavanagh BP, Sandler AN et al. Preemptive analgesia. Clinical evidence of neuroplasticity contributing
to postoperative pain.Anesthesiology. 1992; 77: 439–46.

43. • Katz J, Clarke H. Preventive analgesia and beyond: current status, evidence, and future directions. In: Macintyre PE,
Walker SM, Rowbotham DJ, eds. Clinical pain management: acute pain. 2nd ed. London: Hodder & Staughton, 2008: 154-
99.

44. • Katz J, Clarke H. Preventive analgesia and beyond: current status, evidence, and future directions. In: Macintyre PE,
Walker SM, Rowbotham DJ, eds. Clinical pain management: acute pain. 2nd ed. London: Hodder & Staughton, 2008: 154-
99.

45. PREVENTIVE ANALGESIA

46. PREVENTIVE ANALGESIA

48. Summary

49. Thank you!