Nonsteroidal Antiinflammatory

Drugs
and Antipyretic-Analgesics
 Pain = Algos

A distressing, emotional and sensory experience, related to potential

tissue damage, originating from any part of the body, and also
associated with the individual's past experiences.
International Association for the Study of Pain (IASP)
 Painful
stimuli

Pain
Transmission
Pathway
Afferent Neurons
(Sensory Neurons)

Efferent Neurons
(Motor Neurons)
Pain
• Pain is unique to each individual
• This experience is shaped by biological factors (like nerve
signals), psychological factors (like mood or past trauma),
and social factors (like cultural beliefs or support systems)

• People learn the concept of pain through life experiences.

• A person’s report of pain should be respected.
• Pain can be adaptive, but also harmful (acute→chronic)
Pain
Components of pain

• Perception – How we feel pain?

• Reaction – How we respond to the pain?
• Modulation – How the body and brain control or adjust the pain
signal?

• By understanding these components, you can better manage pain in

your patients, improving both their comfort and your clinical outcomes.
Inflammation
Inflammation is a fundamental response of
the body’s defense system to various harmful
stimuli, such as:
• Infection
• Physical injury
• Chemical agents
• Immune reactions
• Edema (tumor)
• Redness (rubor)
• Heat (calor)
• Pain (dolor)
• loss of function
Signs of Inflammation

Redness Caused by increased blood flow (vasodilation)

Heat Increased chemical activity and increased blood
flow to skin surface
Swelling Due to accumulation of blood and damaged tissue
cells
Pain Result of chemical mediators and direct injury to
nerve fibers
Loss of function Reduced movement or use of the affected area
Causes of Inflammation
 1-Acute inflammation
Types of Inflammation
2-Chronic inflammation
Arachidonic Acid Pathway
Tissue injury

Cause bronchoconstriction
Asthma attacks
Smooth muscle contraction Cause
platelet
aggregation

Cause pain
inflammation
Inflammatory mediators
• Inflammation begins when different types of cells in our body get
irritated or injured.
• These cells then produce eicosanoids from arachidonic acid to
coordinate the inflammatory response.

• These mediators work together—but in balance—to control

inflammation, pain, blood flow, and clotting.

• Disruption in this balance can contribute to diseases, including those

seen in the oral cavity, like periodontitis or post-extraction
complications.
Inflammatory mediators
1. Irritated cells of any type
These cells release Prostaglandins
Effect:
• Prostaglandins are responsible for pain
• They also cause fever and swelling

This is one of the main reasons why we use NSAIDs like ibuprofen—
they block prostaglandins.
Inflammatory mediators

2. Vascular endothelial cells

These produce Prostacyclin (PGI₂) *Anti-thrombotic effects
Effect:
• Reduces platelet aggregation
• Decreases vascular permeability

This helps to regulate blood flow and prevent excessive clotting

during inflammation.
Inflammatory mediators
3. Platelets
These produce Thromboxane (TXA₂) *Pro-thrombotic effects
Effect:
• Increases platelet aggregation
• Promotes clot formation

This is important in stopping bleeding, but too much thromboxane

can lead to unwanted clotting.
 Analgesics

• Nonsteroidal anti- • Opioid Analgesics –

inflammatory drugs Narcotics /
(NSAIDs) Morphine-like
Non-Opioid analgesics / analgesics
Non-narcotic analgesics
Non Steroidal Anti-inflammatory Drugs (NSAIDs)

Analgesic effect: Pain-relieving

Anti-inflammatory effect: Anti-

inflammatory

Antipyretic effect: Fever-

reducing
 COX
• COX-1 constitutively
expressed in most tissues

• COX-2 Induced at sites of

inflammation, expressed
constitutively in brain and
kidney

• COX-1, but not COX-2, is

present in platelets
 Non Steroidal Anti-inflammatory Drugs
(NSAIDs)

Analgesic Effect - Inhibition of COX Enzymes

• NSAIDs inhibit cyclooxygenase (COX) enzymes.
• COX-1 and COX-2 are enzymes responsible for producing
prostaglandins.
• By inhibiting these enzymes, NSAIDs reduce inflammation and pain.

NSAIDS COX inh Prostaglandins ↓ Inflammation and Pain ↓

in sensory nerve endings
Non Steroidal Anti-inflammatory Drugs
(NSAIDs)
Antipyretic Effect - Fever (Pyrexia)
• Body temperature is controlled by the thermoregulatory center
in the hypothalamus.
• Infections, tissue damage, inflammation, graft reactions, tumors,
etc., lead to an increase in the production of cytokines (IL-1β, IL-
6, interferons, TNFα).
• Cytokines increase the synthesis of PGE2 around the ventricular
area in the preoptic hypothalamic region, and PGE2 stimulates
the thermoregulatory center, raising body temperature.
NSAIDS X PGE2 FEVER ↓
Non Steroidal Anti-inflammatory Drugs
(NSAIDs)
Anti-inflammatory Effect

• NSAIDs reduce the synthesis of inflammatory mediators by

inhibiting prostaglandin (PG) synthesis

NSAIDS Prostaglandins ↓ Vascular Permeability ↓

Less fluid leakage and swelling
Help to control inf response
 Non-selective COX inhibitors
Preferential COX2 inhibitor
NSAIDs Classification Selective COX2 inhibitor
Analgesic – antipyretic with poor
anti-inflammatory action
1) Salicylates (eg. Aspirin)
2) Para-aminophenol derivatives (eg. Paracetamol)
3) Pyrazolone derivatives (eg. Dipyrone)
4) Proprionic acid derivatives (eg. Ibuprofen, Naproxen, Flurbiprofen)
5) Phenylacetic acid derivatives (eg. Diclofenac)
6) Indoleacetic acid derivatives (eg. Indometacin)
7) Fenamic acid derivatives (eg. Mephenmic acid)
8) Oxicams (eg. Piroxicam)
9) Selective COX2 inhibitors (eg. Celecoxib)
Salicylates (Aspirin and Sodium Salicylate)
• The most commonly used NSAID
• It is usually taken orally; parenteral use is limited.
• It maintains its value as an analgesic and anti-inflammatory drug.
• It has relatively low toxicity.
• It also has antipyretic effects.
Aspirin
• Analgesic
• Antipyretic
• Anti-inflammatory
• Antiplatelet activity.

• non-selectively inhibits COX-1 and COX-2 enzymes.

• Aspirin causes irreversible inactivation of COX.

• It is the only NSAID to do this. (The inhibition produced by other NSAIDs
is reversible.)
• Aspirin inhibits the COX enzyme in
platelets irreversibly in a selective
and potent manner, exhibiting
antiplatelet (anti-aggregant) effects.

• The anti-aggregant effect occurs at

low doses.

• Aspirin inhibits platelets from

working, and this effect lasts until
new platelets are made — about 9
days.
Aspirin Dosage:
• Antithrombotic Effect:
80-325 mg once daily
• Analgesic – Antipyretic Effect:
0.5-0.9 g – orally every 4-6 h (adults)
Anti-inflammatory Effect (for Rheumatoid Arthritis):
3-4 g/day

• Max daily dose: 4 g

Aspirin Pharmacokinetics:
Bioavailability: 80-100%
Onset: PO, 5-30 min
Indications: Duration: PO, 4-6 hr
• Mild to moderate pain
• Fever
• Rheumatoid arthritis
• Acute rheumatic fever
• Prevention and prophylaxis of cardiovascular diseases (myocardial
infarction, stroke)
• Angina pectoris
Aspirin-Side Effects
• Aspirin’s main side effects are gastric intolerance, and gastric and
duodenal ulcers.
• Patients with severe hepatic damage, hypoprothrombinemia, vitamin
K deficiency, or hemophilia should avoid aspirin because the inhibition
of platelet hemostasis can result in hemorrhage.
• Use of aspirin has been associated with Reye syndrome in children.
• Overdose of aspirin is called salicylism. Symptoms include ringing in
the ears (tinnitus), dizziness, headache, fever, and confusion.
• Bronchospasm
Aspirin and other NSAIDs

• The concomitant administration of aspirin and other NSAIDs

antagonizes their reversible platelet inhibition induced by aspirin.

• Thus, treatment with other NSAIDs may limit the cardioprotective

effects of aspirin.

• It has been shown that if taken 2 hours after aspirin, NSAIDs do not
interact. Thus, patients should take the NSAID 2 hours after aspirin.
Paracetamol - Acetaminophen
• Paracetamol has analgesic and antipyretic
actions, but does not have anti-
inflammatory or antiplatelet activity.

• Paracetamol is used as an antipyretic agent

in children
Paracetamol - Acetaminophen

PK
• Orally administered, it is well absorbed and its effects start early.
• Does not cause irritation or bleeding in the stomach.
• Does not bind extensively to plasma proteins.
• The half-life of paracetamol is 2 hours
• The presence of food delays absorption
Dosage:
• Acute pain and fever maybe effectively treated
with 325–500 mg 4 times daily and
proportionately less for children.
• Dosing in adults is recommended not to exceed 4
g/day.
• Single doses for children 2–11 years old depend
on age and weight (~10–15mg/kg); no more than
five doses should be administered in 24 hours.
• Combinations containing narcotic and
non narcotic analgesics, caffeine,
antihistamines, antitussives, cold and flu
preparation….
• iv. preparation is also available
Paracetamol (Acetaminophen) poisoning:
• When taken in an overdose (150-200 mg/kg or 7.5-10 g), it can lead to
fatal acute liver necrosis.
• The treatment involves N-acetylcysteine (NAC), which is effective if
administered within the first 8-10 hours via intravenous infusion.
• Chronic use of acetaminophen increases the risk of analgesic
nephropathy.

• Analgesic nephropathy occurs when NSAIDs reduce renal blood flow,

leading to
• acute tubular necrosis
• interstitial nephritis,
• result in both acute and chronic kidney failure
Ibuprofen
• Profenes are among the most • Uses:
commonly used analgesic drugs • Headache
after aspirin and acetaminophen. • Toothache
• Dysmenorrhea (menstrual pain)
• Mild to moderate
• The most widely used drug in this postoperative pain
• Also used as a fever reducer.
group is ibuprofen.
Ibuprofen
• Has analgesic, antipyretic, and • It binds extensively to plasma
anti-inflammatory activities. proteins (about 99%).
• Inhibits platelet aggregation less • It is metabolized in the liver and
than aspirin inactivated.
• The analgesic effect of ibuprofen
begins quickly (within 1 hour) after
oral administration.
• It is rapidly absorbed with about
80% bioavailability.
Dosage:
• Ibuprofen is often prescribed in lower doses (<1600mg/day)
(analgesic but not anti-inflammatory)

• The maximum recommended daily dose of ibuprofen is 3200mg.

• Adults: 200–800 mg 3–6 times/day with food

• Ibuprofen, 400 mg, provides prompt relief and good overall efficacy
in post surgical dental pain.
• Ibuprofen is indicated for mild-to moderate pain, primary
dysmenorrhea, rheumatoid arthritis and osteoarthritis.

• Ibuprofen is used as an antipyretic agent in children.

• Children: 4–10 mg/kg/dose, 3–4 times/day

• Recommended anti-inflammatory dosage is 600 mg 4 times/day.

Naproxen
• It has analgesic, anti-inflammatory,
and antipyretic effects.
Pharmacokineti
cs:
• Among the profen group, it has the Bioavailability: 95%
longest duration of action (2 Onset: 30-60 min
times/day) Duration: < 12 hr

• Inhibits platelet aggregation and

prolongs bleeding time
Clinical Uses:
• Naproxen is indicated for pain, primary dysmenorrhea,
tendonitis, juvenile and rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, and acute gout.

Dosage:
• 250 mg 3 – 4 times/day; mild pain
• 250–550mg 2 times/day; moderate pain
• 750–1000mg Daily (extended release)
chronic pain cond - rheumatoid arthritis
Naproxen

Naproxen is supplied
as tablets,
delayed-release
tablets, extended-
release tablets,
gelcaps and
suppositories.
Flurbiprofen

• Inhibits synthesis of prostaglandins in body tissues by

inhibiting both of COXs - cyclooxygenase-1 (COX-1) and -2
(COX-2)

• Indicated for rheumatoid arthritis, osteoarthritis, ankylosing

spondylitis, dysmenorrhea, and dental pain.
Flurbiprofen
Pharmacokinetics
• Bioavailability: 96%
• Onset: rapidly
• Onset of action: 1-2 hr
• Half-life elimination: 4.7-5.7 hr

• 200–300 mg/day in 2–4 divided

doses
Diclofenac

• A preferential COX-2 inhibitor

• Analgesic, antipyretic, and anti-inflammatory activities.

• Long-term symptomatic treatment of rheumatoid arthritis,

osteoarthritis, ankylosing spondylitis, pain, primary dysmenorrhea,
and acute migraine
Pharmacokinetics
• Bioavailability: 55%
• Half-life: 2 hours.
• Peak plasma time : 1 hours.

• The usual daily oral dosage is 50–150 mg, given in several divided
doses.
• Recommended anti-inflammatory dosage is 50-75mg, 4 times a day.
Meloxicam
A preferential COX-2 inhibitor

• Clinical uses: osteoarthritis, rheumatoid

arthritis and ankylosing spondylitis, acute
intestinal arthritis, acute muscular system
pain, postoperative pain and dysmenorrhea
Pharmacokinetics
Dosage: •Bioavailability: 89%
• 7.5-15 mg PO qDay; not to exceed 15 mg/day •Half-life: 15-20 hr
•Peak plasma time : 6hours
Etodolac
A preferential COX-2 inhibitor

• Clinical uses: Osteoarthritis, rheumatoid

arthritis and ankylosing spondylitis, acute
intestinal arthritis, acute muscular system Pharmacokinetics
pain, postoperative pain and Bioavailability: 80-100%
dysmenorrhea Half-life: 5-8 hr
Peak plasma time : 1-2 hr
Onset: 2-4 hr
Dosage:
Duration: 4-6 hr
• 200-400 mg PO q6-8hr; not to exceed 1200
mg/day
COX-2 Selective Inhibitors
• Celecoxib
• Etoricoxib
• Rofecoxib
• Valdecoxib

• Have a reduced risk of gastrointestinal effects, including gastric ulcers and

gastrointestinal bleeding.
• Clinical data suggested a higher incidence of increased risk of myocardial
infarction, stroke and thrombosis associated with COX-2 inhibitors such as
rofecoxib and valdecoxib, resulting in their withdrawal from the market.
Celecoxib
• Selective inhibitor of COX-2 about 10–20 times more
selective for COX-2 than for COX-1.
• acute pain , osteoarthritis, rheumatoid arthritis and
ankylosing spondylitis, primary dysmenorrhea, migraine
Pharmacokinetics
Dosage: Peak plasma time: ≤3 hr
Acute Pain Half-life: 8-12 hr
• 400 mg initially as a single dose, followed by an additional dose
of 200 mg, if necessary, on the first day.
• For continued relief, 200 mg twice daily as needed.
Side Effects of NSAIDs
Side Effects of Nonselective COX Inhibitors
Gastrointestinal Side Effects Risk Factors
• Age over 65 years
• Previous history of peptic ulceration
• High doses and prolonged use of NSAIDs
• Concomitant use of corticosteroids, anticoagulants and other NSAIDs
• Accompanying hepatic or renal disease
• Heavy smoking and alcohol use NSAIDs
Current Approaches to Prevent GI Side Effects of NSAIDs

The Gastrointestinal side effects of NSAIDs may be reduced

by;
• Taking NSAIDs with food
• Co-prescription of a proton pump inhibitor, or an H2-
receptor blocker
• Enteric coating
Cardiovascular Side Effects of NSAIDs

• All NSAIDs (except aspirin) increase the risk of myocardial

infarction, stroke and thrombosis

• NSAID use is contraindicated before or after coronary artery

bypass graft surgery

• Paracetamol is considered safe for use if necessary

Cardiovascular Side Effects of NSAIDs

Patients with a cardiovascular disease;

• Should take the NSAID at lowest possible doses for the

shortest possible period

• Should avoid taking more than one NSAID concomitantly

Renal Side Effects of NSAIDs Prostaglandins normally
•Maintain renal blood
NSAIDs block the production of vasodilator flow
prostaglandins, especially PGE₂ and PGI₂, in the kidneys. •Support glomerular
filtration,
•Promote natriuresis
• Decreased glomerular filtration rate (GFR) (excretion of sodium in
• Reduced renal blood flow urine).

• Increased sodium and water reabsorption in the renal Chronic kidney disease
tubules (anti-natriuretic effect) Heart failure
Or those taking other
• Salt and water retention in the body nephrotoxic drugs
Respiratory Side Effects of NSAIDs

• “Aspirin-associated asthma”
may occur in patients with asthma, nasal polyps, or chronic urticaria.

• NSAID use is contraindicated in patients with asthma unless it is

prescribed by a physician.

• Paracetamol is considered safe for use if necessary.

Important for Dentists
• NSAIDs should be taken after food.

• NSAIDs should be avoided in patients with peptic ulcer as it may

aggravate the condition.

• Preferred analgesics for patients with peptic ulcer are paracetamol and
selective COX-2 inhibitors.

• Patients on aspirin should inform the doctor if surgery/dental

procedure is planned.
Important for Dentists

• Educate patient about adverse effects and drug interactions of

aspirin. Advise patient to report signs of bleeding, if any.

• The preferred analgesic in patients with chronic renal failure is

paracetamol.

• Of particular interest to periodontists is that flurbiprofen (in addition

to some other NSAIDs) taken on a long-term basis has been shown to
slow the progression of alveolar bone resorption in different
experimental models of periodontal disease.
Please note:

• No class on the following week (18.04.2025)