Role NSAID in

Perioperative Period
dr. Asmin Lubis, DAF, Sp.An,
KAP, KMN
Pediatric Anesthesia Consultant and Pain
Management
Anesthesiology and Intensive Department
Faculty of Medicine
Universitas Sumatera Utara

What is Pain

An

unpleasant

emotional
with

sensory

experience

actual

or

and

associated

potential

tissue

damage or described in terms of

such damage.
IASP Pain Definition (1994, 2008)

Why Prevent Pain?

Basic human right!
pain and suffering
complications
likelihood of chronic pain
development
patient satisfaction
speed of recovery length of stay
cost
productivity and quality of life

Adverse Effects of Poor Pain Control

Respiratory; increases risk of chest
infection/pneumonia.
Cardiovascular; Hypertension, tachycardia,
platelet aggregation and venous stasis due to
poor pain control
Gastrointestinal; Nausea and vomiting
Genitourinary; Urinary retention
Endocrine; The stress response from pain
causes release of hormones
Psychological; anxiety, sleep deprivation
Smith J, Acute Pain Management in Surgical Patients,
http://www.jjs.me.uk/teaching/acutepain, 2013

When start for controlling pain?

We must do the pain management;
before, during, and after a
procedure that are intended
to
reduce or eliminate pain before
discharge
(
Perioperative
Pain
Management)
ASA Task Force on Acute Pain Management. Practice Guidelines for
acute pain management in the Perioperative Setting.
Anesthesiology 2012;116:248-73

1d. Preemptivve & Preventive

Methods to Treat Pain

Treatment based on path physiology of pain
Pharmacologic
Medications
Acetaminophen
NSAID
Opioids
Gabapentin
NMDA antagonists
Alpha-2 agonists
Procedures
Regional Anesthesia
LA infiltration at incision site
Surgical Intervention
Non-Pharmacologic / Non-Surgical

Multimodal Analgesia
Combinations of varying agents for pain
control
Always consider multimodal analgesia when
treating pain
Different drugs with different mechanisms/sites
of action along pain pathway
Each with a lower dose than if used alone
Can provide additive or synergistic effects
Provides better analgesia with less side effects
(mainly opiate related S/E)

The use of multimodal analgesia technique

offers
multiple benefits for the patient and the
healthcare
system in line with the goals of modern
ambulatory
(day-case) surgery

NSAID (Non-Steroidal Antiinflammatory Drug)

Have been use for treating pain for decades
NSAID is an all-inclusive term denoting a
varied group of drugs possessing
analgesic, anti-inflammatory, and
antipyretic effect
All NSAIDs, including selective COX-2 inhibitors:

Antipyretic, analgesic, and antiinflammatory, with

the exception of acetaminophen, which is
antipyretic and analgesic but is largely devoid of
antiinflammatory activity.

Categorized:

Conventional non spesific inhibitors of both

isoform of COX (ibuprofen, naproxen, aspirin,
acetaminofen, ketorolac)
COX 2 selective inhibitor (celecoxib, rofecoxib,
valdecoxib, parecoxib)

Characteristic of NSAIDs

Decrease activation and

sensitization of peripheral
nociceptors
Attenuate inflammatory
response
Absence of dependence or
addiction potential
Synergistic effect with
opioid
Preemptive analgesia
(decrease neural
sensitization)
Absence of depression of
breathing
Less nausea and vomiting
compared with opioid
Long duration of action
Less dose variability compared
with opioid
No pupillary change
Absence of cognitive effects

Common issues of NSAIDs

Different chemical families
Different pharmacokinetics and potency
Common mechanism of action (COX inhibition)
Different selectivity to COX-1 and COX-2

Common clinical indications

Analgesic (CNS and peripheral effect) may involve
non-PG related effects
Antipyretic (CNS effect)
Anti-inflammatory (mainly by PG inhibition)
Effective dose for analgesic anti-inflammatory
antipyretic

Common analgesic ceiling effect

Current view in selecting analgesic and

anti-inflammatory drugs
Efficacy (indication)
Safety (side effect)

Not only GI toxicity

Cardiovascular toxicity
Renal toxicity
Bleeding
Bone healing impairment etc

Suitability (contra-indication)
Availability
Pharmacokinetics and drug interaction
Daily cost
Evidence based medicine

Factors to consider when

choosing NSAID as pain killer

Drug issues
Efficacy
Tolerability
Safety
Dosage
Cost

BENEFITS
efficacy

RISKS
safety

Patient issues
Type, severity
Risk factors: GI,
platelet, renal and
cerebro-cardiovascular
system.
Co-prescription.
Co-morbidity.
Compliance.

phospholipids
arachidonic acid
COX-2

COX

COX-1

cyclic
endoperoxides
PGI2

stimulates platelet
aggregation,
vasoconstriction

hyperalgesia
PGD2
inhibits platelet
aggregation,
vasodilator

5-HPETE
TXA2

inhibits platelet
aggregation,
vasodilator,

PGE2
vasodilator,

LOX

PGF2alfa
bronchodilatation
myometrial contr.

hyperalgesia hyperalgesia

LTA4
LTB4
chemotaxis

LTC4
LTD4
LTE4

brochoconstriction
increase
vascular
permeability

COX-1 or COX-2
The detrimental effects of some NSAIDs
(eg, renal dysfunction, gastrointestinal
mucosal compromise, platelet inhibition)
are mediated by inhibition COX-1
The
analgetic
effect
and
antiinflammatory effects are attributable
primarily to inhibition of COX-2
Experimental
evidence
showing
that
prostaglandin E2 (PGE2), which is generated
by the COX-2 pathways, plays a critical
role in the induction of both peripheral
and central sensitization

Adverse Effects of NSAIDs

Ototoxic

Bronchospam

Hepatotoxic

Bleeding

Allergy

Color blindness

CHF

UGIB
UGIB
Nephrotoxic

Tocolytic

Mechanism of = Mechanism of
therapeutic effects
adverse effects

platelet
aggregation

fewer heart attack

COX-1
inhibitor

platelet
aggregation

more heart attack

platelet
aggregation

hemorrhagic stroke
GI
bleeding

bleeding

COX-2
inhibitor

GI
bleeding

blood coagulation
Lelo, 2000

COX-1/COX-2 selectivity of NSAIDs

COX-2
selective

Pref.
COX-2

non
selective

Pref.
COX-1

COX-1
selective

analgesic
anti-inflammation

COX 1 SELECTIVE

Ketorolac

Ketorolac is a potent analgesic but only a moderately effective

antiinflammatory drug.
Pharmacokinetics and Metabolism
Rapid onset of action
Half life 4-6 hours, Peak plasma 30-60 after IM
Extensive protein binding
Short duration of action
Oral bioavailability is about 80%.
Urinary excretion accounts for about 90% of eliminated drug, with
about 10% excreted unchanged and the remainder as a glucuronidated
conjugate
The rate of elimination is reduced in the elderly and in patients with
renal failure
Common adverse effects
Side effects at usual oral doses include somnolence, dizziness,
headache, gastrointestinal pain, dyspepsia, nausea, and pain at the
site of injection.
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

COX 1 SELECTIVE

Ketorolac

Only use < 5 days

>65 years: 10 mg every 4-6 hours (not to
exceed 40 mg/24 hours)

<65 years
20 mg (orally), then 10 mg every 4-6 hours
(not to exceed 40 mg/24 hours)

Given parenterally
60 mg IM followed by 30 mg every 6 hours
Or 30 mg IV every 6 hours
Available as ocular preparation 0.25%, 1
drop every 6 hours
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

COX 1 SELECTIVE

Ketoprofen

Pharmacokinetics
Peak plasma 1-2 hours, Half life 2 hours
Protein binding 98%
Half-life in plasma of about 2 hours except in the elderly, in whom it
is slightly prolonged
Conjugated with glucuronic acid in the liver, and the conjugate is
excreted in the urine. Patients with impaired renal function eliminate
the drug more slowly.

Dose
Analgesia: 25 mg (3-4 times/day)
Antiinflammatory: 50-75 mg 3-4 times/day

Common adverse effects

Approximately 30% of patients experience mild gastrointestinal
side effects
Fluid retention and increased plasma concentrations of
creatinine.
Renal function shouldGoodman
be monitored
such patients.
& gilman's thein
pharmacological
basis of therapeutics - 11th ed. (2006)

Pref. COX-1

Ibuprofen

Pharmacokinetics
Absorbed rapidly, bound avidly to protein, and undergoes hepatic
metabolism
Renal excretion of metabolites.
Peak 15-30 minutes, half-life is roughly 2-4 hours
Slow equilibration with the synovial space means that its antiarthritic
effects may persist after plasma levels decline
In experimental animals, ibuprofen and its metabolites readily cross the
placenta
Dose
Analgesia 200-400 mg every 4-6 hours
Antiinflammatory 300 mg every 6-8 hours or 400-800 mg 3-4 times/day
Common adverse effects
5% to 15% of patients experience gastrointestinal side effects.
Can be used occasionally by pregnant women; however, the concerns
apply regarding third-trimester effects, including delay of parturition
Excretion into breast milk is thought to be minimal, so ibuprofen also can
be used with caution by women who are breastfeeding.
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

non Mefenamic
selective

Acid

Pharmacological Properties
Peak plasma 2-4 hours, half life 3-4 hours
May have central action
The fenamates are a family of NSAIDs first discovered in the 1950s that are
derivatives of N-phenylanthranilic acid. They include mefenamic,
meclofenamic, and flufenamic acids.
The fenamates are typical tNSAIDs. Mefenamic acid has central and
peripheral actions, and meclofenamic acid (and perhaps other fenamates)
may antagonize directly certain effects of prostaglandins, although it is not
clear that receptor blockade is attained at therapeutic concentrations.
These drugs are absorbed rapidly and short durations of action.
Approximately 50% of a dose of mefenamic acid is excreted in the urine
Twenty percent of the drug is recovered in the feces
,Dose
500-mg load, then 250 mg every 6 hours
Common Adverse Effects and Precautions
Approximately 25% of users develop gastrointestinal side effects at
therapeutic doses.
The fenamates are contraindicated in patients with a history of
gastrointestinal disease
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

non
selective

Piroxicam

Pharmacological Properties
Piroxicam is effective as an antiinflammatory agent
Absorbed completely after oral administration and undergoes
enterohepatic recirculation;
Peak concentrations in plasma 3-5 hours, Half life 45-50
minutes
Food may delay absorption
Estimates of the half-life in plasma have been variable; the average is
roughly 50 hours
Extensively (99%) bound to plasma proteins
Less than 5% of the drug is excreted into the urine unchanged
60% of the drug excreted in the urine and feces.
Dose
The usual daily dose is 20 mg and because of the long half-life,
steady-state blood levels are not reached for 7 to 12 days
Common adverse effects
Toxicity includes gastrointestinal symptoms (20% of patients),
dizziness, tinnitus, headache, and rash. When piroxicam is used in
dosages higher than 20 mg/d, an increased incidence of peptic ulcer
and bleeding is encountered.
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Pref.
COX-2

Meloxicam

Pharmacological Properties
Some COX-2 selectivity, especially at
lower doses
Peak 5-10 hours, Hall life 15-20 hours
Protein binding 99%
Meatbolisme di hati melalui Hydroxylation

Dose
7.5-15 mg/day
7.5 to 15 mg once daily for osteoarthritis
and 15 mg once daily for rheumatoid
arthritis
Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Pref.
COX-2

Celecoxib

Pharmacological Properties
Peak 2-4 hours, Half-life 6-12 hours, protein binding 97%
Metabolites Carboxylic acid and glucuronide conjugates
Celecoxib is metabolized predominantly by CYP2C9.
Little drug is excreted unchanged; most is excreted as carboxylic acid and glucuronide
metabolites in the urine and feces
Renal insufficiency is associated with a modest, clinically insignificant decrease in
plasma concentration
Dose
Celecoxib is approved in the United States for the treatment of osteoarthritis and
rheumatoid arthritis
The recommended dose for treating osteoarthritis is 200 mg per day as a single dose or
as two 100-mg doses.
Common Adverse Effects and Precautions
Studies in mice and some epidemiological evidence suggest that the likelihood of
hypertension on NSAIDs reflects the degree of inhibition of COX-2 and the selectivity
with which it is attained.
Risk of thrombosis, hypertension, and accelerated atherogenesis are
mechanistically integrated. The coxibs should be avoided in patients prone to
cardiovascular or cerebrovascular disease.

Goodman & gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Pref.
COX-2

Diclofenac

Pharmacological Properties
Diclofenac has analgesic, antipyretic, and antiinflammatory
activities
Diclofenac has rapid absorption , Peak 2-3 hours, a short half-life,
Half-life 1-2 hours
There is a substantial first-pass effect, such that only about 50% of
diclofenac is available systemically.
Diclofenac accumulates in synovial fluid after oral administration,
which may explain why its duration of therapeutic effect is considerably
longer than the plasma half-life
Diclofenac is metabolized in the liver
Metabolites are excreted in the urine (65%) and bile (35%)
Dose
100 to 200 mg, given in several divided doses
50 mg 3 times/day or 75 mg 2 times/day
short-term treatment of acute musculoskeletal pain, postoperative
pain, and dysmenorrhea
Common Adverse Effects
Diclofenac produces side effects (particularly gastrointestinal) in about
20% of patients
Modest elevation of hepatic transaminases in plasma occurs in 5% to
15% of patients
CNS effects, rashes, allergic reactions, fluid retention, and edema, and
rarely impairment of renal
function.
Goodman
& gilman's the pharmacological basis of therapeutics - 11th ed. (2006)

Paracetamol

Pharmacological Properties
Analgesic-antipyretic agent
Weak COX-1 and COX-2 inhibitor and no significant anti-inflammatory effect
Peak blood in 30-60 minutes, half-life is 2-3 hours
Relatively unaffected by renal function.
With toxic doses or liver disease, the half-life may be increased twofold or
more.
Less than 5% is excreted unchanged.
Dose
10-15 mg/kg every 4 hours (maximum of 5 doses/24 hours)
Common Adverse Effects and Precautions
Rash and other allergic reactions occur occasionally
The use of acetaminophen has been associated anecdotally with
neutropenia, thrombocytopenia, and pancytopenia.
Overdosage: Fatal hepatic necrosis.
Renal tubular necrosis and hypoglycemic coma also may occur.

Correlation between absorption,

T-max and onset of action
Concentration

NSAID short half

life

rapid onset
but short duration

NSAID long half

life

long
duration
but slow onset

Effective concentration

Time
Acute

Slowly Chronic

How to change the onset of action of the

long half-life NSAID
Concentration

NSAID long half life

Acute

o
r
long duration e
but slow onset ng
a
D
increased
By increasing the dose ???:
?
onset!becomes earlier
the dose
c
i
but adverse effects enhanced
h
t
E
Effective concentration
?
e
v
Sa
?
l
a
Time
n
o
i
t
Slowly

Chronic
a
R

The Implications of NSAID Selectivity

Cardiovascular Risk

Gastrointestinal Risk

Thrombosis,
Myocardial Infarction

Bleeding Ulcer
Complications

Discontinuation

Discontinuation

Et
or
ic
Ro oxi
b
fe
co
xi
b
C
Di ele
cl c
of ox
en ib
ac
Ib
up
ro
fe
n
Na
pr
ox
en

Blood Pressure
Increase

COX-2

COX-1

Degree of Selectivity
Adapted from Antman EM, et al. Circulation. 2007;115:1634-