Multimodal and Preventive

Analgesia in Managing
Postoperative Pain
What is Postoperative Pain ?

Postoperative pain is a complex of unpleasant sensory,

emotional and mental experiences associated with
autonomic, psychological, and behavioral responses
precipitated by the surgical injury.

(Henrik Kehlet, Postoperative Pain ACS Surgery, 2005)

Pathogenesis of Postoperative Pain

Surgery

•Tissue damage Nociceptive PAIN

•Inflamed tissue input

Surgery has a biphasic insults to the body

1. Trauma to tissue
2. Inflammatory response
Pain Transmission
PERCEPTION

Pain

Descending
modulation Dorsal Horn MODULATION
Ascending Dorsal root
input ganglion

TRANSMISSION

Spinothalamic
Peripheral
TRANSDUCTION
tract
nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Different Surgical Procedures have
Characteristic Pain Profiles

Different types Different pain

of pain intensity

Different
procedures

Different risks
and benefits of Different
analgesic location of
techniques pain
Consequences of postop pain

Physiological Psychological/ emotional

disturbances disturbances
■ Sympathetic overactivity ■ Fear
– Tachycardia, hypertension ■ Anxiety
– Increased cardiac work ■ Apprehension
– Increased oxygen consumption,
etc
■ Respiratory dysfunction
■ GIT dysfunction  ileus Suffering
■ Renal suppression  oligouria
■ Immunosuppression
■ thromboembolic

Increases morbidity Pain behavior

and mortality (chronic pain)
Why postop pain must be treated?
Recently; postoperative pain relief is being viewed as
■ BASIC HUMAN RIGHT (ethical as well as morally)
■ Unrelieved pain may adversely affect the outcome of
surgery ( MORBIDITY AND MORTALITY)
■ May lead to chronic pain ( FINANCIAL AND 
SOCIAL COST)
■ Pain should be viewed as the FIFTH VITAL SIGN
(recorded, assessed and managed regularly )
Aim of postoperative Pain Management

It has two practical aims :

1. Provision of subjective comfort (humanitarian reasons)
2. Inhibition of trauma induce nociceptive impulses
– to blunt autonomic and somatic reflex responses to pain
– to enhance restoration of body function by allowing the
patients to breathe, cough, and move easily
– these effects reduces pulmonary, cardiovascular,
thromboembolic and other complication
– may lead to improve postoperative outcome
Postoperative Pain
Despite of advanced knowledge and
techniques in postoperative pain
management,
MORE than 70% patients do not
receive adequate postoperative
pain relief
(Filos KS, Lehmann KA. Eur Surg Res 2002)
Contributing Causes of Inadequate Pain
Treatment

Insufficient knowledge of drug pharmacology

Uniform (p.r.n) prescriptions
Lack of concern for optimal pain relief
Failure to give prescribed analgesics
Fear of side effects

(Kehlet, H. Postoperative pain, ACS Surgery, 2005)

Multimodal Analgesia
Except for a very mild surgery, no single drug may
produce optimal analgesia without adverse effect

Multimodal analgesia, is the best method for

postoperative pain management.
“Combination of analgesic that act by different
mechanisms result in synergic analgesia”
Multimodal Analgesia
OPIOID
- Systemic
PERCEPTION - Epidural
- Subarach
Pain Ketamin, Tramadol

COX-2, COX-3
LOCAL ANESTHETIC
MODULATION - Epidural
Descending
modulation Dorsal Horn - Subarachnoid
Ascending Dorsal root
input ganglion

TRANSMISSION LA
COX-1
COX-2
Spinothalamic
Peripheral
tract TRANSDUCTION
nerve

Trauma
Peripheral
nociceptors

No single drug can produce optimal analgesia without adverse effect

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
Benefits of Multimodal Analgesia

Opioids

• Reduced doses of each

analgesic

Potentiation • Improved pain relief due

to synergistic or additive
effects
• May reduce severity of
side effects of each drug
NSAIDs,
acetaminophen,
nerve blocks
1Kehlet H et al. Anesth Analog. 1993;77:1048-1056.
Multimodal Analgesia

Ketamine
Deksketoprofen
iv NMDA
iv
Cox-2 agents antagonists

NSAIDs Better analgesia

iv
– Synergy
Multimodal – Additivity
Reduce side effects
Paracetamol
iv

NorAdr & iv Local Anaesthesia

Opioids 5HT antagonists
iv
Tramadol Jin et al. J Clin Anesth;13:524, 2001
Kehlet et al. Anesth Analg;77:1048. 1998
Woolf CJ, Science, 288:1765-1768, 2000
Methods of Postoperative
Pain Management

1. PRE-EMPTIVE ANALGESIA
– Analgesics is given PRIOR to procedures
- Using LA, opioids and NSAIDs

– An attractive working hypothesis

– 93 RCTs failed to demonstrate benefits
Methods of Postoperative
Pain Management
2. PREVENTIVE ANALGESIA
• Preventive analgesia encompassing
multimodal antinociceptive interventions,
started preoperatively and given for an
increased duration including the
postoperative period, was found to be more
effective in terms of decreasing
postoperative pain and reducing analgesic
consumption in the postoperative period.
Methods of Postoperative
Pain Management
3. POST-OPERATIVE ANALGESIA
The mainstay of post-op pain control
– Opioids analgesic:
- Morphine, meperidine, fentanyl
- (Tramadol, ketamine)
– Non-opioids analgesic:
- NSAID (prostaglandin synthesis inhibitor)
Step Ladder of Multimodals Analgesia
Step 3 Severe Postoperative Pain
Step 1 and Step 2 Strategies
AND
Local Anesthetic Peripheral Neural Blockade
(With or Without Catheter)
Use of Sustained Release Opioid Analgesics

Step 2 Moderate Postoperative Pain

Step 1 Strategy
AND
Intermittent Doses of Opioid Analgesics

Step 1 Mild Postoperative Pain

Nonopioid Analgesic
Acetaminophen, NSAIDs, or COX-2 Specific Inhibitors
AND
Local Anesthetic Infiltration

Modification of WFSA analgesic ladder

Crews JC, JAMA 2002;288:629-32
Some Drugs Are Superior to Others

Dexketoprofen

• Potent analgesia
• Higher therapeutic index
• Less pharmacokinetic variability
• Less long term side effects
Separation of Ketoprofen Racemic Mixtures

Racemic Mixtures of Ketoprofen

1:1
Dextro / S(+)-enansiomer Levo / R(-)-enansiomer
Strong, fast, and safe analgetic Inactive, accumulate, ulcerogenic
when administered as the racemate
Separation of Ketoprofen Racemic Mixtures
• 2X more effective as COX inhibitor compare to rasemic ketoprofen

• Effective dose : ketoprofen 50 & 100 mg vs dexketoprofen 25 & 50 mg

• Higher selectivity on target

• Higher therapeutic index

• Less pharmacokinetic variability

• Less renal and liver load

• Less long term side effects

Dexketoprofen Trometamol

Benefits:
•high water solubility
•fast oral absorption
•low upper GI contact time
•rapid onset (within 30
minutes)

water-soluble salt of the dextrorotatory

enantiomer of ketoprofen

Mauleón D. Drugs 1996

CLINICAL STUDIES
Double blind, randomised, parallel group study of the safety, efficacy and influence on morphine
usage of intravenous dexketoprofen trometamol (50 mg) in comparison to intravenous tramadol
(100 mg) or placebo in the relief of pain following orthopaedic surgery
Hanna, et al. Br J Clin Pharmacol. 2003 Feb;55(2):126-33

60

50
Mean VAS pain intensity score (mm)
intensitas nyeri , VAS (mm)

40
Rata-rata skor

30

20

10

0
0,5 1 2 4 6 8 10 12
Waktu (jam)
placebo+ morfin
PLASEBO + MO RFIN
tramadol + morfin
TRAMADO L 100 mg IV + MO RFIN
dexketoprofen + morfin
KETESSE IV 50mg + MO RFIN
CLINICAL STUDIES
Double blind, randomised, parallel group study of the safety, efficacy and influence on morphine
usage of intravenous dexketoprofen trometamol (50 mg) in comparison to intravenous tramadol
(100 mg) or placebo in the relief of pain following orthopaedic surgery
Hanna, et al. Br J Clin Pharmacol. 2003 Feb;55(2):126-33

2.5
p<0.0015 2.24

2
1.73 57,6
Morphine (mg/hr)

1.6 Kebutuhan morfin per-jam pasca

1.5 operasi antara ke-2 kelompok obat
tidak berbeda bermakna
1

0.5

0
Dexketoprofen Tramadol Placebo
50 mg 100 mg
CLINICAL STUDIES
Efficacy and Tolerability of Intramuscular Dexketoprofen in
Postoperative Pain Management following Hernia Repair Surgery
Jamdade, et al, 2011, Anesthesiology Research and Practice

Single dose of dexketoprofen

trometamol 50 mg given
intramusculary provided
faster, better, and longer
duration of analgesia in
postoperative compared to
diclofenac
CLINICAL STUDIES
Randomised controlled trial of the onset of analgesic efficacy of dexketoprofen and
diclofenac in lower limb injury
Leman, et al, 2003, Emerg. Med. J.

Dexketoprofen
trometamol is an
effective and
rapidly acting
analgesic for the
treatment of acute
muscoskeletal
injuries
CLINICAL STUDIES
Effect of perioperative administration of dexketorprofen on opioid
requirements and inflammatory response following hip arthroplasty
Iohom, et al., 2002, British Journal of Anasthesia
CLINICAL STUDIES
Effect of perioperative administration of dexketorprofen on opioid
requirements and inflammatory response following hip arthroplasty
Iohom, et al., 2002, British Journal of Anasthesia

Perioperative administration
of dexketoprofen 25 mg
markedly improves
analgesia and decreases the
postoperative pro-
inflammatory response
Safety and Tolerability
Comparison of the efficacy and safety of intravenously administered dexketoprofen
trometamol and ketoprofen in the management of pain after orthopaedic surgery: A
multicentre, double-blind, randomised, parallel-group clinical trial
Zippel H, Wagenitz A., Clin Drug Investig. 2006;26(9):517-28

Dexketoprofen
trometamol
appeared to show a
trend towards a
better tolerability
profile compared
with the racemic
compound
Take Home Message
 Postoperative pain is the most understood form of pain
that we know.
 MULTIMODAL ANALGESIA is the best method.
 Care should be individualized, holistic (physical &
psychological), and organized through Acute Pain Service
 Dexketoprofen has higher selectivity on target &
therapeutic index, less pharmacokinetic variability & long
term side effects
THANK YOU
 Profile Produk

Profile Produk

Terapetik Class : New Generation Ketoprofen (NSAID)

Mekanisme aksi :
Memiliki potensi penghambatan dual COX inhibitor (COX-1 and COX-2) dan
memberikan efek analgesik & anti inflamasi dengan efek minimal

Komposisi : 50 mg/2ml Dexketoprofen Trometamol

Indikasi : Efektif dan kuat untuk nyeri sedang-berat(pre and post surgery, renal
colic, skeletal pain)
Dosis dan pemberian
Dosis rekomendasi 100-150 mg sehari, diberikan 50 mg tiap 8-12 Jam.

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