NON-OPIOID ANALGESIC

 Paracetamol
 NsNSAID
 Selective COX-2 inhibitor
 Dexamethasone
 Gabanoids
 Anti-neurophatic
PARACETAMOL
PARACETAMOL HISTORY
 1878, synthesized by Morse
 1893, introduced for medical usage
 1955, reintroduced as an analgesic in US
 Most popular and widely used drug for the first line
treatment of fever and pain
 1985, intravenous a pro-drug preparation, propacetamol
 Recent introduction to the market of a ready-to-use
intravenous formulation
Mechanism of Action :
Still under discussion
 Act peripherally and/or centrally ?
 Which analgesic pathway mainly affected ?

But, Efficacy has no doubt

Paracetamol is an effective analgesic for acute pain;

the incidence of adverse effects comparable to
placebo (S) (Level I [Cochrane Review]).
Acute Pain Management: Scientific Evidence, 3rd edition, ANZCA, 2010
Potential mechanisms of action

 Inhibition of COX isoenzymes

 Interaction with endogenous opioid pathway
 Activation of serotoninergic bulbospinal pathway
 Involvement NO pathway
 Increase in cannabinoid/vanilloid tone
Two activities of COX- enzyme
Inhibition COX isoenzym
 Reducing agent is required to convert COX enzym
from active to inactive
 Paracetamol, a substituted phenol, act as a reducing
agent
 Weak inhibitor of PG synthesis in broken cells
( hydroperoxides is high )
 Peroxide-dependent COX inhibiton
 PCT is not active at peripheral site of inflammation (high
peroxide concentration ),but
 active in the brain (low peroxide concentration)
Peripheral vs Central effect
 Selective inhibition of COX in CNS support
hypothesis PCT does not possess anti-inflammatory
efficacy similar to NSAIDs
 Not associated with gastric side effect and
inhibition platelet activity
 COX-3 , unlikely to be the elusive target of PCT in
human tissues
Interaction with endogenous opioid pathway,
serotoninergic and NOS system

 Self-synergistic interaction between spinal dan

supraspinal
 Activation of descending opioid pathways
 Centrally acting component of paracetamol
involves serotoninergic inhibitory descending
pathway
 Inhibitory nitric oxyde synthase ( NOS ) via inhibited
substance P-mediated hyperalgesia
Safety and toxicity profile
 Safer than NSAIDs
 Small minority  life threatening liver injury

 Toxic metabolite N-acetyl-pbenzoquinine imine

(NAFQI)
 Paracetamol overdoses significant cause toxicity

 Suicide attempts
 Unintentional overdoses
 Plasma concentration
 Minimum plasma concentration for analgesia
and anti-pyresis 10-20 mg/L
 Potential hepatotoxicity 150 mg/L

 Median dose that will developed acute liver

failure is 24 grams
Intravenous 15 mg/kg  7 mg/L and detectable in CSS
at 5 minutes
Intravenous 1 gr  14.4 mg/L in 20 minutes
Oral 1 gr  large and unpredictable variability
( subtherapeutic plasma conc. in 80 min )
The Metabolism of Acetaminophen and
NAPQI production

N Engl J Med. 2008 July 17; 359(3): 285–292.

Risk factor PCT-induced hepatotoxicity

 Excessive dosing
 Increased P-450 activation

 Decreased gluthatione availability

 Chronic severe ethanol abuse

Effect in coagulation function
 Weak inhibitor of platelet COX-1 with a dose
dependent anti-aggregatory effect
 Platelet aggregation is more impaired by diclofenac
than PCT
 Antiaggregatory effect does not seems to be clinical
relevant and no surgical bleeding attributable to PCT
 Significant increased in INR and reduction Vit-K
dependant clotting factors in patients receiving stable
treatment warfarin who received PCT 4 gr/day for
14 days
Several studies about safety use of PCT

 No evidence in the literature of an increased risk of hepatotoxicity

in chronic liver disease with the recommended doses
 Benson GD, et al, Am J Ther 2005;12:133-41

 Alcoholic patients treatment with 4 gr/day for three

consecutive days did not develop increase in serum
transminase or other measures of liver injury
 Kuffner EK. Et al, BMC Med 2007;53:13
 Only minor effect in on renal function, does not affect
COX-1 enzym
 Koppert W. et al, Anesth Analg 2006; 103:1170-6
Pain relief after IV and Orally

Moller, S. Sindet P. British Journal of Anaesthesia 2005 ; 94 (5): 642–8

Intravenous Paracetamol
 Faster onset analgesia
 Predictable plasma concentration achieved
 Route of choice when oral administration no possible
 IV paracetamol was an effective analgesic after
surgery ( Level II, Acute Pain Management: Scientific Evidence, 3 edition, ANZCA, 2010 )
rd
 Paracetamol evidence
 In the same doses, paracetamol was less effective
and of slower onset : rectal < orally < intravenous
 IV paracetamol was an effective analgesic after
surgery (Level II).
• There is no evidence that patients who have depleted
glutathione stores (eg patients who are malnourished, or who
have cirrhosis, hepatitis C or human immunodeficiency virus
[HIV]) are at increased risk of liver dysfunction when
exposed to therapeutic doses of paracetamol (Benson et al,
2005 Graham et al, 2005; Oscier & Milner, 2009).
Non-Steroid Anti Inflammatory Drugs
NsNSAID
 Exhibit a spectrum of analgesic, anti-inflammatory,antiplatelet
and antipyretic by inhibition COX enzyme
 Most commonly prescribed analgesic medications in the world.
i.e. Metamizole, Ketorolac, Diclofenac, Ketoprofen
 Many used as the sole method of treatment mild to moderate
pain
 “Opioid sparing effect“ (20–40 %)
Non-Specific NSAID efficacy evidence

 Single doses of nsNSAIDs are effective in the

treatment of pain after surgery
( Derry et al 2009 Level I)
 NsNSAIDs are inadequate as the sole analgesic
agent in the treatment of severe postoperative
pain. (Elia et al, 2005 Level I )
 Adverse effects of NSAIDs are significant and may
limit their use
 Adverse effect due to
Non-selective COX-1 and COX-2 inhibitor

ARACHIDONATE

COX-1 COX-2

prostaglandins prostaglandins

• “Constitutive” • “Inducible”
• Expressed: • Expressed:
– GI mucosa – Site of injury
– Kidneys – CNS
– Platelets
– Vascular
endothelium
NSAIDs and Renal Function
 With proper selection and monitoring, the incidence of
NSAID-induced perioperative renal impairment is low
and NSAIDs need not be withheld in patients with
normal preoperative renal function (Lee A et al, 2007
Level I).
 No differences between patients given diclofenac,
ketorolac, indomethacin (indometacin) or ketoprofen
(Lee A et al, 2007 Level I).
 NSAIDs and Coxib have similar adverse effect on renal
function ( Level I )
NSAIDs and Bleeding

 In meta-analyses of tonsillectomy in both adult and

paediatric patients, nsNSAIDs were found to increase
the risk of reoperation for bleeding (NNH 29 to 60)
(2003 Level I) but surgical blood loss was not
significantly increased (Moiniche et al, 2003 Level I)
 Looking at studies in children only, there was no
increase in the risk of reoperation for bleeding after
tonsillectomy (Cardwell et al, 2005 Level I).
 After a variety of different operations, the use of
nsNSAIDs showed a significant increase in risk of severe
bleeding from 0 to 1.7% (Elia et al, 2005 Level I).
NSAIDs and GI Ulcer
 A large case-controlled study using a general practice
database identified 10 892 patients over4 years with
a ‘first ever’ diagnosis of an upper GI ulcer or bleeding
and compared them with matched controls (Hippisley-
Cox et al, 2005 Level III-3). Where individual drugs
were specified in the results, the risks were shown to be
significantly increased for patients using naproxen,
diclofenac, ibuprofen and aspirin.
 Concurrent use of a proton-pump inhibitor (PPI)
significantly reduced the incidence of nsNSAID-related
peptic ulcer disease (Targownik et al, 2008 Level III-2).
Selective CO-2 Inhibitor
Selective COX-2 inhibitor
 Larger molecul with side chain fitted the hydrophilic
side of COX-2 isoform but did not fit COX-1
isoform
 COX-2 in peripheral and central nerve system
 As a part of multimodal analgesia
 Offer significant advantages over NsNSAIDS with
regard to several adverse effect ( not in renal
function )
COXIB evidence
 Coxibs are effective in the treatment of acute
postoperative pain (N) (Level I [Cochrane
Review]).
 Coxibs were as effective as nsNSAIDs in the
management of postoperative pain (Romsing &
Moiniche, 2004 Level I).
 Preoperative coxibs reduced postoperative pain
and opioid consumption and increased patient
satisfaction (Straube et al, 2005 Level I)
PCT, NsNSAID, COXIB with OPIOID : the evidence

 decrease in 24 h morphine consumption when paracetamol, NSAID, or

COX-2 inhibitors are given in addition to PCA morphine after surgery,
with no clear difference between them.
 Similarly, the benefits in terms of reduction in morphine-related adverse
effects do not strongly favour one of the three non-opioid analgesics.
PCT, NsNSAID, COXIB combination : the new evidence
Human studies ( n=21) , 1909 pts , The NSAIDs used were ibuprofen (n=6),
diclofenac (n=8), ketoprofen (n=3), ketorolac (n= 1), aspirin (n=1), tenoxicam (n
=1), and rofecoxib (n=1).
The combination of paracetamol and NSAID was more effective than paracetamol
or NSAID alone in 85% and 64% of relevant studies, respectively.
Combining Paracetamol (Acetaminophen) with Nonsteroidal Antiinflammatory Drugs:
A Qualitative Systematic Review of Analgesic Efficacy for Acute Postoperative Pain
Cliff K. S. Ong, et al (Anesth Analg 2010;110:1170–9)

Parecoxib and acetaminophen effectively reduce postoperative opioid

requirements after thyroid or parathyroid surgery. The combination of these
drugs is not associated with a further reduction in opioid consumption.
Postoperative analgesia with parecoxib, acetaminophen, and the combination of both: a randomized,
double-blind, placebo controlled trial in patients undergoing thyroid surgery.
Gehling, et al . British Journal of Anaesthesia 104 (6): 761–7 (2010 )

Combined parecoxib 40 mg i.v and paracetamol 1 gr provides additional

analgesic effect with better postoperatibe satisfaction in patient undergoing
naterior cruciate ligament construction
Elseify Z. et al. Saudi Journal of Anaesthesia, Vol 5 issue 1, 2011
cyclooxygenase inhibitor
Ibuprofen Diclofenac
Indomethacin Nabumetone
Acetosal
Piroxicam Etodolac
Meloxicam COXIB
Celecoxib
Dexketoprofen Nimesulide Rofecoxib
Valdecoxib

preferentially preferentially
COX-1 COX-1 Dual COX-2 COX-2
selective selective COX selective selective
inhibitor inhibitor inhibitor inhibitor inhibitor

CV Incidence

GIT Incidence
PCT, NSAIDs, COXIBs

J Can Dent Assoc 2002; 68(8):476-82

Other adjuvant analgesic
 Dexamethasone

 Anti-inflammatory action  reducing local tissue pressure

and  release of potent pain mediators.
 Direct effects on pain neurons and receptors   neuropeptide release,
inhibit signal transmission in C fibers, and stimulate the secretion of
endogenous endorphins.
 Direct effects on blood capillaries   permeability and vasodilatation.

 Benefit after oral surgery, tonsillectomy, lumbar disc surgery, laparoscopic

cholecystectomy, arthroscopic surgery and lung resection (Gilron, 2004; Kehlet, 2007).
 Dexamethasone compared with placebo, reduces postoperative pain, nausea and
vomiting, and fatigue (Level II) ANZCA 2010
 Dexamethasone demonstrated dose-dependent effects on quality of recovery.
Dexamethasone 0.1 mg kg−1 reduced opioid consumption compared with
dexamethasone 0.05 mg kg−1, which may be beneficial for improving recovery
Olievera D., et al. Br. J. Anaesth. (2011) 107 (3): 362-371.
 Gabapentin and Pregabalin as Ca2+

“protective premedication.” Ca2+

Ca2+ Ca2+ Ca2+

 A number of meta-analyses have shown that perioperative gabapentinoids improved

analgesia (at rest and with movement) and reduced postoperative opioid consumption,
but increased the incidence of sedation compared with placebo ( Level I ).
 Hurley RW, et al (2006), Ho KY, et al (2006) Tiippana EM, et al (2007)

Curr Drug Target 2009 Aug;10 (8) :716-33. Douri M., et al

Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of
the recent clinical evidences
Gabapentin and pregabalin reduce pain and opioid consumption after surgery in confront with
placebo, but comparisons with other standard post-operative regimens are not sufficient.

Br J Anaesth 2011 Apr;106(4):454-62 Zhang J., et al

Efficacy of pregabalin in acute postoperative pain: a meta-analysis.
• In this systematic review, we evaluated randomized, controlled trials (RCTs) for the analgesic
efficacy and opioid-sparing effect of pregabalin in acute postoperative pain.
• 11 valid RCTs that used pregabalin for acute postoperative pain.
• Perioperative pregabalin administration reduced opioid consumption and opioid-related adverse
effects after surgery.
NEUROPATHIC DRUG
Anti Neuropathic Drug :
Prescription consideration
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