NON OPIOID

NSAID , Paracetamol

CPD Pain Management

ISAPM & P2KB PERDATIN
WHO Analgesic Ladder  most pain management by multi modal
analgesia

Step 3
Severe Strong opioids (e.g., morphine)
with or without non-opioids

Step 2
Moderate Weak opioids (e.g., codeine)
with or without non-opioids

Step 1
Mild Non-opioids (e.g., NSAIDs,
acetaminophen = paracetamol)
 Non-Opioid:
COX Inhibitors
• Non Selective COX • Preferential COX – 2
inhibitors: inhibitors:
• Non competitive • Nimesulide
• Aspirin • Meloxicam
• Competitive • Nabumetone
• Phenylbutazone
• Ibuprofen
• Naproxen
• Diclofenac • Selective COX -2
• Piroxicam inhibitors:
• Ketorolac • Celcoxib
• Analgesic with Antipyretic • Rofecoxib
without anti inflammatory • Valdecoxib
action: • Etoricoxib
• Paracetamol • Parecoxib
• Metamizol • Lumoracoxib
• Nefopam
 Perception

Modulation
Transmission

Transduction
 Physiological stimulus B.
Inflammatory stimulus
A.
(tissue injury, chronic arthritis)
clotting, parturition,
gastrointestinal macrophages/other cells
and renal protection
COX-2
COX-1 induced by cytokines (e.g.,
constitutive TNF)
Proteases Prostaglandins Other inflammatory
Prostacyclin PGE2 especially PGE2 mediators
TXA2 potent vasodilators, (histamine, etc)
Kidney:
platelet antithrombotic,
antiproliferative, anti- arteriolar
aggregation inflammatory properties
stomach mucosa: dilation;
 H+,  HCO3-, Na+/H2O
PGF2  mucus excretion Inflammation,
parturition redness,
swelling, pain

Actions of two known isoforms of cyclooxygenase(COX)

 Cyclooxygenase

• An enzyme involved in prostaglandin synthesis:

• cyclooxygenase-1 (COX-1): beneficial prostaglandins
• cyclooxygenase-2 (COX-2): harmful prostaglandins
COX Enzyme: Prostaglandin Effects

COX-1: beneficial COX-2: harmful

Peripheral injury Inflammation
site
Brain Modulate pain
perception
Promote fever
(hypothalamus)
Stomach protect mucosa
Platelets aggregation

Kidney vasodilation
Pharmacokinetic Variability of Non-Selective COX-Inhibitors

Name Time to peak ½ life parent

(hours) ½ life*active
Aspirin 1-2 0.25-0.33
(*3-10 L-H)
Naproxen 2-4 12-15
Oxaprozin 3-5 42-50

*Sulindac (pro-drug) 2-4 7.8

(*16.4)
Ketorolac (inj) .5-1 3.8-8.6

Ibuprofen 1-2 1.8-2.5

Mechanisms
• COX-2 reduced prostaglandin I2 (PGI2 or
prostacyclin) production by vascular
endothelium with little or no inhibition of
potentially prothrombotic platelet thromboxane
A2

• COX inhibition in general associated with

elevations in blood pressure (<5 mm Hg
elevations in systolic blood pressure)

• COX-2 role in vascular remodelling

NSAIDs

 Display a ceiling effect for analgesia (not as effective as opioids)

 Can be used in combination with opiate analgesics (summation effect)
 NSAIDs act via inhibition of cyclooxygenase
(COX) isoenzyme, discovered >100 years ago.

Key component of the pharmacological

management acute and chronic pain.

COX-1 and COX-2 have different biological

function.

Analgesic activity primary associated with

inhibition COX-2

Different side effect results from inhibition of

COX-1 and COX-2.

(Brune and Patrigani, Journal of Pain Research, 2015)

 All NSAIDs are associated with potential side
effect, particularly gastrointestinal and
cardiovascular effect related to their selectivity for
COX-1 dan COX-2.

Since all NSAIDs exert their therapeutic activity through

inhibition the COX enzyme, strategies needed to reduce
the risk associated with NSAIDs.

(Brune and Patrigani, Journal of Pain Research, 2015)

 Nonsteroidal Anti-Inflammatory

• The term NSAIDs is used to refer to both NSAIDs and coxibs (COX-2
selective inhibitors)
• NSAIDs have a spectrum of analgesic, anti-inflammatory and
antipyretic effects and are effective analgesics in a variety of acute
pain states
• Many effects of NSAIDs can be explained by inhibition of
prostaglandin synthesis in peripheral tissues, nerves and the CNS

Schug, et al. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management. 2015. http://www.anzca.edu.au/resources/college-publications.
 Peripheral & Central Sensitization
Peripherally & Centrally Induced COX-2

Peripheral Central
Trauma/inflammation Central sensitization
IL-6?

Release of arachidonic acid

IL-1ß PAI
COX -2 N

 Prostaglandins E2  Prostaglandins

PAI
COX -2
N

Peripheral sensitization
 Nonsteroidal Anti-Inflammatory
• COX-2 was inducible, and the inducing stimuli included pro-
inflammatory cytokines and growth factors, implying a role for
COX-2 in both inflammation and control of cell growth.
• The two isoforms of COX are almost identical in structure but
have important differences in substrate and inhibitor selectivity
and in their intracellular locations.

Vane. Annu. Rev. Pharmacol. Toxicol. 1998. 38:97–120

 Prostaglandin
• Prostaglandins regulate many
physiological functions including:
– gastric mucosal protection,
– bronchodilation,
– renal tubular function
– intrarenal vasodilation.
• Production of endothelial prostacyclin
• Vasodilation, prevents platelet adhesion
• thromboxane, produced from platelets by
COX
• platelet aggregation, vasoconstriction

Schug, et al. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management. 2015. http://www.anzca.edu.au/resources/college-publications.
 Prostaglandin and COX
• Protective PGs, which preserve the integrity of the stomach lining and maintain
normal renal function in a compromised kidney, are synthesized by COX-1.
• In addition to the induction of COX-2 in inflammatory lesions, it is present
constitutively in the brain and spinal cord, where it may be involved in nerve
transmission, particularly that for pain and fever. PGs made by COX-2 are also
important in ovulation and in the birth process.
• The discovery of COX-2 has made possible the design of drugs that reduce
inflammation without removing the protective PGs in the stomach and kidney made
by COX-1.

Vane. Annu. Rev. Pharmacol. Toxicol. 1998. 38:97–120

 COX-1 and COX-2
Physiological Inflammatory
Stimulus Stimulus
Inhibition by Inhibition by
NSAIDs NSAIDs

COX-1 Macrophages/other Cells

Constitutive
COX-2
Induced
Other
TXA2 PGI2 PGE2 Proteases inflammatory
platelets Endothelium Kidney mediators
Stomach Mucosa Prostaglandin

Physiological Functions Inflammation

Side effects of Anti-inflammatory
NSAIDs Effects of
NSAIDs

Vane. Annu. Rev. Pharmacol. Toxicol. 1998. 38:97–120

 THE ANTIINFLAMMATORY,
ANALGESIC, AND ANTIPYRETIC
Mechanisms of ACTIVITIES ARE MEDIATED BY THEIR
INHIBITION OF PROSTANOID
action of BIOSYNTHESIS.

NSAIDs: Prostanoid are synthesized from arachidonic acid,

a fatty acid present in cell membrane as
COX-1 and phospolypid esther.

COX-2
COX isoenzyme convert arachidonic acid first to
inhibition prostaglandin (PG) G2 and then to PGH2
PGD2, PGE2, PG2α, PGI2
(prostacyclin) and thromboxane A2
(TXA2).

(Ricciotii and Fitzgerald. Arterioscler Thrombo Vasc Biol.2011)

 NSAIDs : Mechanism Of
Action
Arachidonic Acid

Traditional NSAIDS

Coxibs

Cox-1 Cox-1 Cox-2

Platelets Gastric Mucosa Joints Endothelium

Tromboxane (TxA2) Prostaglandins E2 and I2 Prostacyclin (PGI2)

•Vasocontriction Prostaglandins E2 and I2 •Pain •Vasodilatation
•Inhibits gastric acid
•↑ Platelet Aggregation •Inflamation •↓ Platelet Aggregation

Atchison, et all., JMCV 2013

 SIDE
EFFECT
NSAIDS

Wallace, 2008
COX Expression Function Inhibitors

organ pain, platelet

constitutively function, stomach NSAIDs including
COX-1 throughout the body aspirin
protection
Inducible: inflammation,
Inducible and NSAIDs, COX 2
pain, fever
COX-2 constitutively in brain, inhibitors including
Constitutive: synaptic
kidney celecoxib (Celobrex )
plasticity

Constitutively, high in pain pathways, not acetaminophen some

COX-3 inflammation pathways NSAIDs
brain, heart
 Mechanisms
 COX-2 reduced prostaglandin I2 (PGI2 or prostacyclin) production by
vascular endothelium with little or no inhibition of potentially
prothrombotic platelet thromboxane A2

 COX inhibition in general associated with elevations in blood pressure (<5

mm Hg elevations in systolic blood pressure)

 COX-2 role in vascular remodelling

NSAIDs

• Display a ceiling effect for analgesia (not as

effective as opioids)
• Can be used in combination with opiate
analgesics (summation effect)
 Less GI side effects
More GI side effects
Diclofenac Celecoxib
Acetosal Indomethacin Ibuprofen
Ketorolac Piroxicam Ketoprofen
Meloxicam
Nimesulide
COXIB
Rofecoxib
Valdecoxib

preferentially non- preferentially

COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

anti-inflammatory
analgesic
 • GI (stomach)
– Cox-1 mediated production
PGE2 and PGI2regulating
production bicarbonate and
mucous protective cell the
wall stomach from erosive
SIDE EFFECTS effect.
OF NSAIDs – Inhibition Cox-1 (by aspirin
and non selective
coxincrease incidence
peptic ulceration
PATHOGENE
SIS OF
GASTRIC
DAMAGE BY
NSAIDS
(Feldman, 2014)
 • Kidney
– Renal prostaglandins function primarily as
vasodilator in kidney.
– In healthy individual: the impact of
prostaglandins on renal perfusion is
relatively limited.
– Under condition prolonged renal
vasoconstriction (age, heart and kidney
failure) upregulated synthesis
prostaglandinpreserve renal blood flow
and protect the GFR by decreasing pre-
glomerulus arterial resistance.
– In this setting: episodic use of NSAIDs
decease blood flow through the glomerulus
SIDE EFFECT and increase risk of acute kidney injury.
NSAIDS (CONT)
(Feldman, 2014)
Renal Prostaglandin Expression & Function

Luciano & Perazella, 2015

Anwar, 2015
 Advanced age

History peptic ulcer and gastric bleeding.

Serious comorbid medical condition.

Risk factor
Concomitant Helicobacter pylori infection, use
for GI side corticosteroid, antiplatelet, anticoagulant.

effects High NSAIDs dose.

Cigarrette smoking.

Brune and Patrignani, Journal of Pain Research. 2015:8 105-118

 Unstable angina

Myocardiac infarction.

Rescent bypass surgery, placement of a

Risk factor cardiovascular stent.

for CV side High NSAIDs dose

effects Hypertension

Heart failure.

Brune and Patrignani, Journal of Pain Research. 2015:8 105-118

 Prevention Strategies for GI and CV Risk Treated with
NSAIDs
• Low risk
• intermediate or highly Cox-2 selective NSAIDs (standard dose) alone or
non selective NSAIDs + gastroprotector therapy (PPI, misoprotol).
• One or two risk factor
• intermediate or highly Cox-2 selective NSAIDs + gastroprotector
therapy
• History of ulcer bleeding:
– Highly cox-2 selective NSAIDs + gastroprotector therapy
– Avoid non selective NSAIDs (naproxen).
– Eradicate H. pylori infection.
(Brune and Patrigani, Journal of Pain Research, 2015)
Prevention Strategies for GI and CV Risk Treated with NSAIDs
(cont’d)
Previous CV event or risk for CV events (patients under treatment
with low dose aspirin)
• Low risk for GI events
• non selctive NSAIDs (naproxen) + gastroprotector (PPI):
aspirin and naproxen must be administered at different time
• High risk for GI events :
– Avoid use NSAIDs (including non selective and intermediate or
high Cox-2 selective
– Eradicate H. pylori infection.
– Avoid use of ibuprofen (interfere with aspirin antipletelet effect).
– Substitution of aspirin with other antiplatelet (clopidogrel) not
recommended.
(Brune and Patrigani, Journal of Pain Research, 2015)
National Institute for Health and Clinical Excellence
•
Recommendations for Chronic Pain
Firstly, it is recommended to administer paracetamol or topical NSAIDs (esp. for
musculoskeletal pain such as osteoarthritis). When maximum response has not been
achieved, additional oral NSAID/COX-2 inhibitor can be considered.
• Oral NSAID/COX-2 inhibitor should be given at the lowest effective doses in the
shortest period of time, recommended to be co-prescribed with a PPI.
• Types of oral NSAID/COX-2 inhibitor prescribed should be tailored to individual risk
factors with regard to its potential side effects.
• If the patient consumes aspirin, other analgesics should be considered before
prescribing oral NSAID/COX-2 inhibitor.

Shah S, Mehta V. Controversies and advances in non-steroidal anti-inflammatory drug (NSAID) analgesia in chronic pain management. Postgrad Med J 2012; 88:73-8
Recommendation for NSAIDs in CKD Patients

Use is linked to 3-times higher risk for acute renal failure

COX-2 inhibitors have similar renal effect

Short-term NSAID use is well tolerated if patient is well hydrated and has good renal
function and absence of heart failure, diabetes, or hypertension

Long-term use not recommended

Serum creatinine should be checked every 2 to 4 weeks in early treatment

1. Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007; 1575(10): 1487-96
Paracetamol

• Is a common analgesic  for the relief of fever,

headaches, and other minor aches and pains
• It is a major ingredient in numerous cold and flu
medications and many prescription analgesics
• It is  safe in standard doses, but deliberate or
accidental overdoses are common.
COX-3  Paracetamol

• Now, recent research has shown  cyclooxygenase enzyme COX-3

 in the brain and spinal cord
• Is selectively inhibited by paracetamol
• Is distinct from the two already known cyclooxygenase enzymes
COX-1 and COX-2
• Is now believed  selective inhibition of the enzyme COX-3 in the
brain and spinal cord explains the effectiveness of paracetamol in :
• relieving pain and
• reducing fever
• without having unwanted gastrointestinal side effects
COX-3
 Site of Action  Paracetamol?
Tissue damage, release of pyrogens and phospholipids from
cell membrane

Archidonic acid

NSAID block Paracetamol blocks

COX –1 and COX –2 PG3 PG3 PG3 COX-2 and COX-3 ?
in periphery and CNS in CNS

Fever and Pain

Paracetamol
• Paracetamol approved FDA (USA)
• OTC – status since 1955
• Consider safer in asthmatic patients
• COX – 1 still intack
Paracetamol Pharmacokinetics

• Bio availability above 80%

• Peak plasma concentration occur between 15
mins and 2 hours after ingestion
• It has few pharmacokinetics drug interaction
Paracetamol Pharmacokinetics
• Metabolism: major and minor pathways
• Half-life: 1-3 hours
• Time to peak concentration: 10-60 min
• Treatment for overdose:  Acetylcystein
• his results in a toxic metabolite, N-acetyl-p-
benzoquinone imine (NAPQI), which is itself
inactivated by glutathione, rapidly preventing any
harm
 Paracetamol Liver Metabolism

1. Major pathway  majority of drug is metabolized to

produce a non-toxic metabolite
2. Minor pathway  produces a highly reactive
intermediate (acetylimidoquinone) to be inactivated
 conjugates with glutathione

• At toxic paracetamol levels  minor pathway

metabolism  liver’s supply of glutathione is limited,
causing an increase in the reactive intermediate which
leads to hepatic toxicity and necrosis
Adverse Effects

• Excellent safety records at therapeutic doses

• Excellent safety in patient of all age
• No associated risk of major upper GI bleed or
mucosal damage
Side Effect

• Haemostasis
• Meth- haemoglobinaemia.
• Thrombocytopenia
• Anaemia
• Agranulocytosis
• Hepatotoxicity
• Nephrotoxicity
Side Effect

• Haemostasis
• Meth- haemoglobinaemia.
• Thrombocytopenia
• Anaemia
• Agranulocytosis
• Hepatotoxicity
• Nephrotoxicity
Contraindication and Precaution
• Apart from hypersensitivity, no absolute
contraindication.
• Suitable in all areas with a wide range of medical
conditions:
• Children
• Elderly
• Patients with mild to moderate liver disease,
renal disease, GI problems.
• Asthmatics
Paracetamol Overdose
• Excellent safety and tolerability.
• Effective antidote for paracetamol  available.
• Therapeutic overdose is rare
• Acute toxic dose  150 mg/kg or 10 times the
recommended dose.
• Over dose is usually suicidal and appropriate over
a period of time
IV Paracetamol

“Is more effective & has a faster onset than oral

paracetamol”
 Onset of action is fast and effective – within 5 minutes
Means of pain intensity differences (VAS)

Sindet-Pedersen S. Br Jr Anesth 2005. 94 (5): 642-8

 Key Messages
• NSAIDs are commonly use for pain relief
• Antiinflammatory, analgetic and antipyretic action are acquired by means of cox
inhibition which is responsible in catalyzing arachidonic to prostaglandin
• NSAIDs inhibition cox-1 and cox-2 have beneficial for pain relief, but adverse effect GIT
• Cox-2 selective have beneficial for pain relief without/minimal adverse effect GIT but
increase CV adverse effect.
• A meta-analysis demonstrated similar CV adverse effect between cox-2 and cox-1
• NSAIDs CAN BE COMBINED WITH PARACETAMOL FOR PAIN
MANAGEMENT