Dr.

Girish Meravanige
College of Medicine, KFU
 Analgesics

 NSAID’s (Aspirin like/non narcotic/non opioid)

 Opioids (Morphine like /narcotic)

 Learning Objectives

 Understand the mechanisms of action of the NSAIDs.

 Know the untoward effects of prostaglandin inhibitors

 Know the therapeutic utility of NSAIDs

 Know which drugs can be used in combination, and those

that should not be used concomitantly to treat
inflammatory disorders, fever, pain.
 Classification

 Non selective irreversible COX inhibitors : Aspirin

 Non selective reversible COX inhibitors : Ibuprofen,
Indomethacin, Naproxen, Diclofenac, Ketorolac
 Preferential COX-2 inhibitors : Etodolac, Nimesulide,
Meloxicam
 Selective COX-2 inhibitors : Celecoxib, Etoricoxib
 Analgesic with poor anti-inflammatory :
Paracetamol (Acetaminophen)
 Common Characteristics of All NSAID’s

 No Steroid moiety
 All are analgesic, antipyretic, anti-inflammatory agents (Except
paracetamol)
 Do not produce CNS or respiratory depression at therapeutic
doses
 Do not produce drug dependence
 Act by inhibiting PG’s synthesis
 Gastrotoxoicity is common side effect (Except coxibs,
nimuselide & paracetamol)
 Pathophysiological roles of PGs

 Inflammation

 Fever

 Pain
 Mechanism of action of NSAIDs

X
NSAIDs PGs

 Analgesia : Blocking the pain sensitizing mechanism

(Bradykinin, TNFα, ILs etc.,)

 Antipyretic : Suppresses PGE2 activity in hypothalamus

 Anti-inflammatory : Potency varies in different NSAIDs

 PHOSPHOLIPID
(-)
PLA2 Corticosteroids

Arachidonic Acid
(-) (-)
NSAIDS COX 1,2 5-Lipoxygenase Zileuton

Cyclic 5-HPETE--LTA4
Endoperoxides

Prostacyclin Thromboxane LTB4 LTC4 LTD4

LTE4 LTF4

Prostaglandins (-)
Zafirlukast

RECEPTORS RECEPTORS

ACTIONS ACTIONS
 Cyclooxygenase (COX) Enzymes

COX-1 COX-2

1 Constitutive Inducible

2 Present in most tissues Inflammatory cells

(e.g. stomach, (macrophages, synoviocytes,
platelets, kidneys) chondrocytes, endothelial cells)

3 Physiological Pathological
 Pharmacological actions
Aspirin (Acetyl salicylic acid)

Actions : Irreversible non selective COX inhibitor

 Analgesic, antipyretic, antiplatelet, anti-inflammatory : (Anti-

inflammatory action at 3-6g/day)

 Acid base & electrolyte balance :

. Compensated respiratory alkalosis (higher doses)

. Respiratory acidosis ( very high or toxic doses)
 GIT : Gastrotoxic effects

 Blood : Irreversibly inhibits TXA2 synthesis in platelets - Bleeding

time prolonged
 CVS : <100mg daily - Cardio-protective
 Adverse effects

 “Gastro toxicity”
 Kidney : Salt & water retention, analgesic nephropathy
 Blood : Increased risk of hemorrhage
 Pregnancy : Prolongation of gestation, inhibits labor pain,
closure of patent ductus arteriosus
 Hypersensitivity : Angioneurotic edema, urticaria, Ppt ASTHMA,
rhinitis
 Precautions & contraindications

 Peptic ulcer
 Children's with viral fever (“REYE’S syndrome”)
 Pregnancy
 Asthma
 Renal failure
 Hypertension
 Bleeding disorders
 Paracetamol (Acetaminophen)

 Compare to aspirin :
- Does not affect platelet functions
- Gastric irritation is insignificant
 Paracetamol poisoning: (N-acetyl benzoquinoeimine)
- Analgesic nephropathy
- Fatal hepatic necrosis
- Treatment : N-acetyl cysteine or methionine
 Best drug for fever, headache & musculoskeletal pain
 Propionic acid derivatives

Iburofen
 Better tolerated than aspirin

 Adverse effects are less

Naproxen
 Stronger anti-inflammatory activity

 Longer duration of action

 Recommended in chronic inflammatory conditions

 Diclofenac

 Efficacy similar to naproxen

 Preferentially it inhibits COX-2
 Antiplatelet action is not appreciable due to sparing of COX-1,
risk of MI and stroke
 Good tissue penetrability
 ADR: Gastro-toxicity
 Uses: Acute and chronic inflammatory conditions
 Dose: 50mg TDS
 Indomethacin

 Indole acetic acid derivative

 Highly potent anti-inflammatory drug
 High incidence of GIT and CNS adverse effects
 Uses: Only in conditions requiring a potent anti-inflammatory
actions. For closure of ductus arteriosus
 COXIBS

E.g. Celecoxib, etoricoxib

Major advantage:  Indication: Only in high risk
 No or minimal gastro toxicity acid peptic disease patients.
 Do not ppt bronchial asthma  Dose: Lowest dose with
shortest period
 No antiplatelet action – No

bleeding  Contraindications: IHD,

HTN, CHF, Cerebrovascular
Major drawback:
disease patients
 Exert prothrombotic

influence and enhance CADs

 Renal toxicity
 Therapeutic uses of NSAID’s

 As analgesic
 As Antipyretic (Paracetamol- 325 to 650mg TDS)

 As anti-inflammatory: Rheumatoid arthritis, Osteoarthritis

 As antithrombotic (Aspirin- dose 75 to 100mg/day) Post MI &

post stroke patients
 To close ductus arteriosus (Indomethacin)

Newer Uses: Colorectal cancer and Alzheimer's disease

 Therapeutic uses of NSAID’s – In Dentistry

 Mild to moderate dental/postoperative pain:

- Short acting, non-selective NSAIDs are more appropriate for treating
acute dental pain- Ibuprofen (gold standard), ketoprofen, naproxen
- Long acting, selective NASIDs are appropriate for managing chronic
pain (e.g. temporomandibular disorders)
 Moderate to severe dental/postoperative pain: Managed by using
combination of analgesics. One of the limitations of NSAIDs is that
they have a ceiling effect, this problem can be overcome by adding
another NSAID e.g. paracetamol to ibuprofen or paracetamol to
diclofenac. In severe range may require opioid analgesic (codeine
or hydrocodone) with NSAID.
 NSAIDs drug dosages used in dentistry

Drug Dosage form Adult dose Pediatric dose

Aspirin Tablets 325-650 mg q4h 10-15 mg/kg/dose q4-6h
Diclofenac Tablets/ 50 mg/8 h PO 2 to 3 mg/kg/d in divided doses 2-4
- Aceclofenac suppositories/ 75 mg/24 h IM times daily. Maximum daily dose
injection 200 mg
Ibuprofen Tablets 200-400 mg/q4-6h 20 mg/kg/d in 3-4 doses
Liquid 20-40 mg/cc solution
q4-6h
Ketoprofen Tablets 25-50 mg q8-12h 1.5-2 mg/kg/d in 3-4 doses

Naproxen Tablets 250-500 mg/q8-12h 10 mg/kg/d in 2 doses

Liquid 125 mg/5 mL
solution q8-12h
 NSAIDs drug dosages used in dentistry

Drug Dosage form Adult dose Pediatric dose

Indomethacin Capsules 200-400 mg/q6-8h Not recommended under
14 years (hepatotoxic)

Celecoxib Tablets 100-200 mg q12h Safety not evaluated in

children

Acetaminophen Tablets/intravenous 325-650 mg/q4-6h 10 mg/kg q4h

/paracetamol infusion /suspension/ 1 g/8 h 15 mg/kg q6h
suppositories
Ketorolac Tablets/IM injection 10 mg/q4-6h Not recommended under
IM: 30 mg q6h 16 years (nephrotoxic)
(limit 5 days)
 NSAIDs and opioid combination dosing regimen
for dental pain

NSAID + opioid Dosage form Dosage

combination
Paracetamol + codeine Tablets/liquid Acetaminophen 300 mg
Codeine: 30 mg q4-6h, as needed
2 tablets q4-6h, as needed
Paracetamol + Tablets/liquid Acetaminophen 500 mg
hydrocodone Hydrocodone 5 mg q4-6h, as needed
2 tablets q4-6h, as needed
Ibuprofen þ hydrocodone Tablets/liquid Ibuprofen 200 mg
Hydrocodone 7.5 mg q4-6h, as needed
2 tablets q4-6h, as needed
Paracetamol + oxycodone Tablets/liquid Acetaminophen 325-500 mg
Oxycodone 2.5-7.5 mg; 2 tablets q4-6h, as
needed PO
Paracetamol + tramadol Tablets Acetaminophen 325 mg
hydrochloride Tramadol 37.5 mg; 2 tablets q4-6h, as needed
 NSAID’s - Clinical implications in Dentistry

 Aspirin:
- Combine aspirin with codeine but not with other NSAIDs (like
ibuprofen or diclofenac). Discontinue aspirin use at least 7-10 days
prior to dental procedure (if pt. currently using aspirin for
thromboembolic risk): Risk of post operative bleeding.
- Avoid using aspirin or other NSAIDs in small children's with viral
infection: Risk of ‘Reye’s syndrome’.
- Caution in pts. who are anticoagulant therapy
- Overlapping drug toxicity: e.g. NSAIDs with antibiotics (e.g.
metronidazole) both produce common ADR on GIT
 NSAID’s - Clinical implications in Dentistry

 Paracetamol: It is substituted if the pt. has allergy, bleeding

problems or GIT distress due to aspirin or other NSAIDs
- Its analgesic efficacy is similar to aspirin (except anti-inflammatory
effects)
- It is often used in combination with opioid analgesic for relieving
post operative dental pain.
- Caution/avoid using paracetamol in pts. with pre-existing liver
damage, malnutrition, chronic alcoholics- Risk of hepatotoxicity
 NSAID’s - Clinical implications in Dentistry

 Coxibs:
- Analgesic efficacy is comparable to other NSAIDs but with a longer
duration of action, lack of GIT adverse effects & lack of antiplatelet
action. Therefore it can be given prior to surgical procedure.
- However, long-term use in pts. with coronary artery disease or stroke,
should be avoided as they disturb the PGI2: TXA2 ratio and thus exert
prothrombotic effects.

 Opioid analgesics: Should be used cautiously for short period

otherwise drug addiction liability or drug seeking behavior may
develop in patients. Dentist should be aware of common side effects
of opioid analgesics & how to suspect opioid addicts by looking at
there pupil size.
 Drug interactions

E.g.
 NSAIDs (aspirin) displaces warfarin, sulfonylureas,
phenytoin etc. – Toxicity

 NSAIDs blunts antihypertensive action of beta-

blockers, diuretics and ACE inhibitors
THANK YOU
Reference: Rang & Dale’s pharmacology,
7th Edition, Chapter no.26