NON-OPIOID

ANALGESIC
A. M. Takdir Musba
Department of Anesthesiology, Intensive Care and Pain
Management
Faculty of Medicine, Hasanuddin University

Good Drug in the Right

Doctor

PHARMACODYNAMIC
MECHANISM OF ACTION
PHARMACOKINETIC
METABOLISM AND ELIMINATION

NON OPIOID DRUGS

Paraceta
mol

NsNSAI
Ds

COXIBs

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 COXenzyme

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-acetylpbenzoquinine 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): 285292.

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): 6428

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, 3rd edition, ANZCA, 2010 )

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, antiinflammatory,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 (2040 %)

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
Expressed:

GI mucosa
Kidneys
Platelets
Vascular
endotheliu

Inducible
Expressed:

Site of
injury
CNS

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 riskof
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 (HippisleyCox 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 III2).

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:
Qualitative Systematic Review of Analgesic Efficacy for Acute Postoperative Pain

Cliff K. S. Ong, et al (Anesth Analg 2010;110:11709)

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): 7617 (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

COX-1
selective
inhibitor

preferentially

COX-1
selective
inhibitor

Dual
COX
inhibitor

Diclofenac
Meloxicam
Nimesulide

preferentially

COX-2
selective
inhibitor

CV Incidence
GIT Incidence

Acetosal

Indomethacin
Piroxicam

Ibuprofen
Nabumetone
Etodolac
Dexketoprofen

Celecoxib
COXIB
Rofecoxib
Valdecoxib

COX-2
selective
inhibitor

Efficacy Analgesic

Number needed to treat (NNT) for at least 50% pain relief over
4 to 6 hours compared with placebo in third molar extraction
trials.
British Dental Journal (Barden J, et al. Br Dent J.
2004;197:407-411).

PCT, NSAIDs, COXIBs

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

Other adjuvant analgesic : not just the

Paracetamol, NSAIDs, COXIBs

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 kg1 reduced opioid consumption
compared with dexamethasone 0.05 mg kg1, which may be
beneficial for improving recovery
Olievera D., et al. Br. J.
Anaesth. (2011) 107 (3): 362-371.

Gabapentin and Pregabalin as

protective premedication.
Ca2+

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, 2009
et al (2006),
Ho(8)
KY, :716-33.
et al (2006)
Tiippana
EM,alet al (2007)
Curr Drug
Target
Aug;10
Douri
M., et
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

ALGORITHM FOR NEUROPATHIC PAIN

MANAGEMENT PRIMARY CARE

Gilron, I. et al. CMAJ 2006;175:265-275

Anti Neuropathic Drug :

Prescription consideration