PARACETAMOL AS A BASIC

MULTIMODAL ANALGESIA, WITH

REFERANCE OF CADIAC SURGERY
A. Husni Tanra
Dept. of Anesthesiology, Intensive Care and Pain Management
Faculty of Medicine, Hasanuddin University Makassar
 What and Why we need
multimodal analgesia for
pain management?
 What is multimodal
analgesia?
 Is a combination of two or more
analgesics that act at different
mechanisms, produce additive
or synergistic analgesia:
4 reasents WHY MULTIMODAL ?
Most of the pain is a multifaceted or
multiple-sources.
No single analgesic is perfect and no
single analgesic can treat all types of pain.
Each agent has advantage and disadvantage
compered to others.
Multimodal Analgesia potentiating in
efficacy, reduced doses, minimal adverse
effect. Improve the outcome.
 SIMPLE CONDITION
Even in a very simple condition such as
osteoarthritis may has multifaceted and multiple
sources of pain.
 OSTEOARTHRITIS
Source of pain may come from
o Synovial membrane
o Joint capsule
o Periarticular ligaments
o Muscles
o Periosteum or
o Subchondral bone
Nature Of Postoperative Pain
Nociceptor
sensitisation
Somatic
Pain Referred
muscle, fascia, pain
ligament

Postop
pain Reflex
Visceral response
Pain Muscle
spasm

Cortical Cutaneous
Responses Somatic
pain
Multimodal Analgesia

Opioids
• REDUCED DOSES
of each analgesic
• IMPROVED EFFECACY
Potentiation due to synergistic or
additive effects
• REDUCE SIDE EFFECTS
of each drug
NSAIDs,
Paracetamol
nerve blocks

1
Kehlet H et al. Anesth Analog. 1993;77:1048-1056.
Prof. Henrik Kehlet, MD, PhD.
Department of Surgical Gastroenterology, Hvidovre University Hospital, Hvidovre Denmark
WHAT IS PARACETAMOL?

 Is a non-opioid analgesic
 is very unique
 it is not belongs to NSAIDs
 It has analgesic and antipyretic
effect but no anti-inflammatory.
 PARACETAMOL(Chemical)
 Chemical name:
Para - acetylaminophenol  Paracetamol
Para -acetylaminophenol  Acetamoniphen
N-acetyl-para - aminophenol  APAP
Daniel Simmon (2002)  COX-3 inhibitor
 Trade name:
Panadol in UK, Australia, Indonesia
Tylenol in US
Perfalgan iv form in Australia, Farmadol di Ina
Other name - Tempera - Eferalgan
- Datrin - ( India)
- Anocin - Napal (Bangladesh)
 PARACETAMOL (Clinical)
 Commonly used for relief of fever, head
aches and minor pain.
 Major ingredient in numerous cold and
flu remedies.
 Is a non prescription drug (free
marketing)
 The most consume drug after amoxicillin
in Indonesia.
 PARACETAMOL (Safety)
 Is considered as a very safe analgesic
& anti pyretic
 It is safe from neonate to old age,
pregnant even lactation women.
 It is very cheap analgesic, and the
only analgesic which can be used for
long term treatment .
The mystery is, how
paracetamol exerts an
analgesic effect without
affecting COX-1 and COX-2?
 POSSIBLE MECHANISM OF ACTION
1. Inhibition of cycloaxygenase isoenzymes.
2. Interaction with the endogenous opioid
pathway.
3. Activation of the serotoninergic pathway.
4. Inhibition of NO production.
5. Modulation in endogen cannabinoid
system.
 ENKEPHALIN GABA

NOREPINEPHRINE

SEROTONIN

ENKEPHALIN
ENKEPHALIN
SEROTONIN
SEROTONIN
Inhibition of NO synthesis

NMDA-R WIND-UP
+ Ca++
sGC

PKGI NOS

Glutamate

NO
Activation of endogenous
cannabinoids
Recent findings have shown that;

 Analgesic effect of paracetamol involves a

“self-synergistic” interaction between
spinal and supraspinal sites with recruitment
of endogenous opiod pathways.
 Paracetamol is an analgesic and antipyretic
drug and has no or very little anti-
inflammatory effect which work centrally.

Raffa. Self-synergistic spinal-supraspinal antinociception by acetominophen.

J. Pharmacol Rxp Ther 2000; 295:291-1-4.
Safe drug
Paracetamol is very safe drug as long as
given in recommended dose.
 Short-term
 < 4 gm / day
 Long-term
 < 3.2 gm /day
 < 2.4 gm /day,
*elderly, debilitated
* alcohol drinking
But large dosage may cause acute liver necrosis.
 How Safe iv Paracetamol is?
 A Rct, compared the analgesic efficacy and safety of iv
paracetamol;
 On 1 and 2 g in a total 165 patients undergoing third molar
surgery regarding hepatic function, no significant adverse
events were recorded. Only 1 patient showed 
aminotranferases.
(Juhl GI, Eur, Pain 2006; 10:371-7)
 On one large dose of 3 g of iv paracetamol in 35 patients
undergoing tonsillectomy only 1 patient showed a reversible
 aminotranferases and return to normal withing 2-4 days.
(Silvanto Metal, Acta Anesthesiology Scand 2007; SI: 1147-54)
 How Safe iv Paracetamol is?
 In larger dose 4,6 - 8 g/day for 3 days to evaluate
tolerability of iv paracetamol in healthy young adults
showed that paracetamol did not accumulate during
3 days and concentration of aminotranferases remain
normal value.

These studies showed us, that even in a large dose of

iv paracetamol has safety profiled and tolerability.
(Gelotte CK at al, clin pharmacol ther 2007; 81: 840-8481)
 Is paracetamol should be avoided in
chronic liver disease?
 No evidence in literature of an increase risk of
hepatotoxicity in these patients with recommended
doses. (Benson GD, Am J Ther 2005; 12: 133-141)
 Alcoholism patients treated with maximum dose of
paracetamol (4g dialing for 3 consecutive days) did
not develop increases in serum transaminases.
(Kuffner EK, BMC Med 2007;5:13)

Therefore, paracetamol can also be used safely in

patients with liver disease
POTENTIAL TOXICITY

 Liver is that is most affected by acute

paracetamol toxicity
 Damage to the liver, is not due to the
paracetamol it self, but toxic
metabolite; N-Acetyl-P-benzo
Quinone Imine (NAPQI)
Metabolism of
Paracetamol
Liver Kidney
Cytochrome P450
Deacetylation
Glucuronide 5%
Conjugation (90%)
NAPQI Para-aminophenol
(N-acetyl-p-benzo-quinon imine) (PAP)

Liver Damage
Non toxic Glutathione Oxidation
Metabolite Conjugation
Kidney Damage
Malnutrition
Low protein diet
Fasting
Excretion Alcoholism
Drugs (e.g., statins, phenytoin) PBQI
 Available Forms
Paracetamol is commonly available in:
 Tablet
 Capsule
 Liquid Suspension
 Suppository
 I.M. (Intramuscular)
 I.V. (Intravenous)
Common doses is 500 – 1000 mg.
Paracetamol iv for postoperative pain treatment

 Acetaminophen  Intravenous administration > 15 ‘

 Analgesic onset occurs rapidly within 5 – 10 min.
 Peak analgesic effect is obtained in 1 hour, and duration is
obtained approximately 4-6 hours.
 1 gr iv solution  had a better tolerability
 In one study : 2gr iv paracetamol as starting dose, was
superior to recommendation dose ( 1 gr) maximal
concentration reach 235 – 521 μmol/l and  stays far
below the 1000 μmol/l ( threshold of hepatotoxicity )
Moller PL et al. onset of acetaminophen analgesia : comparison of oral and intravenous routes after third molar surgery. BJA
2005;94:642 – 648
Piguet et al. Lack of acetaminophen ceiling effect on R – III nociceptive flexion reflex. Eur J Clin Pharma
1998;53:321 – 324 Juhl et al. Analgesic efficacy and safety of intravenous paracetamol adminitration as a 2 g
starting dose following third molar surgery. Eur J Pain 2006;10: 371 - 377
 1
Fast onset of action *
Rapid onset: 5min
Peak at ideal time: 30min

Good residual effect at >6hrs

IV paracetamol for dental

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

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

Sindet-Pedersen S, 1997
 Level of Evidence

1. Paracetamol is an effective analgesic for acute pain

(Level I).
2. Paracetamol is an effective adjunct to opioids (Level I).
3. Paracetamol given in addition to NSAID improve
analgesia (Level I).
4. Paracetamol and COX-2 inhibitors are valuable
components of multimodal analgesia (Level II).
5. IV paracetamol is an effective analgesic after surgery
(Level II), is as effective as ketorolac (Level II) and
equivalent to morphine (Level II).
Efficacy of paracetamol
Number-Needed-to-Treat (v placebo)
NNT (95%CI)
Codeine 60 mg 16.7 (11-48)
Paracetamol 1000 mg 3.8 (3.4-4.4)
Morphine 10 mg (IM) 2.9 (2.6-3.6)
Ketorolac 10 mg 2.6 (2.3-3.1)
Ibuprofen 400 mg 2.4 (2.3-2.6)
Diclofenac 50 mg 2.3 (2.0-2.7)
Paracetamol + Codeine 60 mg 2.2 (1.7-2.9)
Parecoxib 40 mg (iv) 2.2 (1.8-2.7)
Lumiracoxib 400mg 2.1 (1.7-2.5)
Diclofenac 100mg 1.9 (1.6-2.2)
Oxford acute pain league table
www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics
Opioid-sparing effect of Paracetamol

I.V. paracetamol in these studies

was administered as a bio-
equivalent dose of propacetamol.
 PARACETAMOL
 Paracetamol is a non-opioid analgesic drug
for mild to moderate pain only.
 It needs combination with other drug (mostly
opioid) to get optimal analgesia.
 It has been used as a basic component in
many multimodal guidelines.
Choice of Analgesic Technique
(Analgesic Ladder of WFSA)

Opiate Oral route available – give orally

Pain And
NSAID Oral route unavailable –
Intensity and
Rectal paracetamol & NSAID Opiate: High
Tech: PCA
Paracetamol Low tech: IM algorithm Epidural infusion
analgesia

NSAID
and
Paracetamol

Pain decreases Paracetamol

as time passes
Severe
WFSA Analgesic
Ladder for
+ postopeative
+ Parenteral
Analgesia
pain
PARENTERAL
+
Pain Intensity

ANALGESIA
(IV PARACETAMOL + Regional
NSAIDS OR COX-2 ) spinal/epidural +
+ and/or
Oral + Opioid
REGIONAL nerve block
+ + +
SPINAL/EPIDURAL
Oral NSAIDs or
AND/OR Oral + Opioid COX-2 inhibitor Oral NSAIDs or
NERVE BLOCK
+ COX-2 inhibitor
or acetaminophen
Oral NSAIDs or or acetaminophen
COX-2 inhibitor or
acetaminophen
Mild
TIME
World Health Organization
Pain Ladder

Opioid for Moderate

3 to Severe Pain
Paracetamol + Morphine
± Adjuvant
IN
PA
G

Opioid for Mild

2
N

to Moderate Pain
SI
EA

Paracetamol + Codeine
R

± Adjuvant
C
IN

1 Paracetamol
NSAID (COX-1 or COX-2
± Adjuvant
 The Role of Paracetamol
in cardiac surgery.
Pain After Cardiac
Surgery (CABG) due to

1. Sternotomy.
2. Chest tube incertion.
3. Leg vein incision.
 Postopertative pain management
after cardiac surgery
 Traditionally pain management after cardiac surgery

Opioid alone + Combination with

NSAIDs

Side effects Side Effect

 Excessive sedation
  Postoperative bleeding
 Respiratory depression.
 Biliary spasm
due to platelate inhibition.
  GI motility.  GI ulceleration.
 PONV.  Renal dysfucation.
 Confusion in older pts.

Drowback this combination, NSAID can be replaced by

paracetamol which is not produce unwanted SE of NSAID
 In this prospective, randomized, double blinded study, efficacy of paracetamol as
adjunctive analgesic after cardiac surgery was evaluated.
 79 patients for elective CABG.
 40 patients received IV propacetamol 2 g in 6 h interval for 72 h
 39 patients received placebo
 Standard analgesic was oxycodon given by PCA
Result
 comulative oxycodone consumption offer 72 h was 123.5 mg in propacetamol group
while 141.8 mg oxycodone in placebo group. Different in mean = 18.3 mg
 Pain score did not differ in two group at rest or deep breath.
No significant difference in oxycodone consumption as well as in pain score.
 113 Patients Were Participated In This DRCT
 56 received 1 g paracetamol IV 15’ before and end of surgery and every 6 h for 72 h.
 57 received placebo
 Standard analgesia was tramadol and oudansetron in prophylactic anti emetic were given in both
group
 Loading dose of 200 mg tramadol administered IV in 30’ just before the administration of study
drug, follawed by a continous infusion of 300 mg of tramadol during 24 h period. Tramadol
started at the end of intervention and was continuous for 72 h.
 Morphine 2 -5 mg IV given as rescue if the VAS more 3 at rest

Conclusion
In patients undergoing cardiac surgery, IV paracetamol in combination with tramadol provide
effective pain control
Conclusion, paracetamol as
adjunctive treatment for pain
relief after cardiac surgery
IV paracetamol is a rational adjunctive drug
for postoperative pain after cardiac-
surgery, due to unwanted SE of NSAID,
are not present in paracetamol.
The problem is which combination of opioid
is the best (tramadol, pethidine, morphine,
Fentanyl, ect.) to get optimal analgesia,
needs further studies and evaluation.
 NSAID

COXIB

Tramadol
OPIOID

Ketamine
(Morphine, Fentanyl)

PARACETAMOL Gabapentanoid
(Gabapentin, Pregabalin)
Sekian dan Terima Kasih
Semoga Ada Manfaatnya
Sekian dan Terima Kasih
Semoga Ada Manfaatnya