ANALGECICS

@drashishagg
PAIN

An unpleasant sensory & emotional

experience associated with actual or
potential tissue damage, or described in
terms of such damage

-IASP
Management of pain

SYSTEMIC TOPICAL
MEDICATIONS MEDICATIONS
Analgesic

A drug that selectively relieves pain by acting in the CNS or on

peripheral pain mechanisms, without significantly altering
consciousness
Classes of analgesic drugs

• Opioid analgesics

• Nonsteroidal anti-inflammatory drugs (NSAIDS)

• Enzyme derived analgesics

Prostaglandin synthesis and
inhibition
Cell membrane phospholipids
Phospholipase A2 Steroid’s
Arachidonic acid
Cyclooxygenase NSAIDs
(COX-1; COX-2)
Endoperoxide
(PGG, PGH)

PGE
PGI TXA PGF
 NON-STEROIDAL
ANTI-INFLAMMATORY
DRUGS (NSAIDS)
INTRODUCTION

- Analgesic, Antipyretic & Anti-inflammatory actions.

- Act primarily on Peripheral Pain Receptors

& CNS to raise the pain threshold

- Compared to Morphine
- Weaker analgesics
- Do not depress CNS
- Do not produce physical dependence
& have no abuse liability
 CLASSIFICATION
A) NONSELECTIVE COX INHIBITORS
(CONVENTIONAL NSAIDS)

1. Salicylates: Aspirin, Diflunisal

2. Pyrazolone derivatives: Phenylbutazone,

Oxyphenbutazone

3. Indole derivatives: Indomethacin, Sulindac

4. Propionic acid derivatives: Ibuprofen, Naproxen,

Ketoprofen
5.Anthranilic acid derivative: Mephenamic acid
6.Aryl-acetic acid derivatives: Diclofenac, Tolmetin
7.Oxicam derivatives: Piroxicam, Tenoxicam
8. Pyrrolo-pyrrole derivative: Ketorolac

B) PREFERENTIAL COX-2 INHIBITORS –

Nimesulide, Meloxicam, Nabumetone

C) SELECTIVE COX-2 INHIBITORS -

Celecoxib
D) ANALGESIC-ANTIPYRETICS WITH
POOR ANTI-INFLAMMATORY ACTION -
1. Paraaminophenol derivative: Paracetamol
(Acetaminophen)
2. Pyrazolone derivatives: Metamizol, Propiphenazone
3. Benzoxazocine derivatives: Nefopam

@drashishagg
 Mechanism of action
- Act as Non-selective
Inhibitors of the enzyme
cyclooxygenase, inhibiting
both, COX-1 & COX-2
isoenzymes

- Cyclooxygenase catalyses
the formation of PGs &
TBX 2 from arachidonic
acid
COX-1
- Present as part of everyday physiological function.
- Protects the stomach by limiting acid secretion
- Helps platelets limit bleeding by increasing their
adhesiveness

COX-2
- Its expression is induced by various stimuli such as
the inflammation or at the site of the injury
Pharmcological actions

ANALGESIA

ANTIPYRESIS

ANTI-INFLAMMATORY
 GASTRIC MUCOSAL DAMAGE

ANTIPLATELET AGGREGATION

DUCTUS ARTERIOSUS CLOSURE

 PARTURITION AND IN
DYSMENORRHOEA

RENAL EFFECTS

ANAPHYLACTIC REACTIONS
 SALICYLATES
ASPIRIN
• Analgesic, Antipyretic & Anti-inflammatory Effects.

• RESPIRATORY SYSTEM
-Increases rate & depth.

• GIT
- Irritates the gastric mucosa  causes epigastric distress,
nausea & vomiting

- Promotes the local back diffusion of the acid  acute

ulcers, erosive gastritis, microscopic
@drashishagg haemorrhages
• CVS
- No direct effect
- Larger doses increase cardiac output to meet increased
peripheral O2 demand caused by direct vasodilation

• BLOOD
- Inhibits TXA2 synthesis by platelets
- Interferes with Platelet aggregation (BT)

• METABOLIC EFFECTS
- Increased utilization of Glucose, blood sugar may
decrease specially in diabetics

@drashishagg
Pharmacokinetics
- Poor Absorption- Stomach & Small Intestine
- Metabolism- Gut wall, Liver, Plasma & other tissues
to release salicylic acid. Excretion- Urine

Adverse effects
- Nausea,Vomiting, Epigastric distress & occult
blood in stools, rashes, urticaria, asthma, angioedema
- Anti-inflammatory doses – syndrome Salicylism –
dizziness, tinitus, reversible impairment
of hearing & vision, excitement

@drashishagg
 analgesic
patent ductus
arteriosus antipyretic

Acute
rheumatic
to delay labour fever

use

pregnancy
induced Rheumatoid
hypertension & arthritis
preeclampsia

Post MI & Osteoarthriti

post stroke s
patients

DOSE: 300-900 mg every 4 hrs (Max 3.6 gm) ( ASA, ASCAD,

ECOSPRIN 50mg,75mg Tab.)
PYRAZOLONE DERIVATIVES
PHENYLBUTAZONE
- Potent anti-inflammatory drug.
- Poor analgesic & antipyretic activity
Adverse effects:
- More toxic than Aspirin
- Bone marrow depression, Agranulocytosis
- Banned in some countries
DOSE: 100-200 mg BD or TDS after meals
(ZOLANDIN 100,200 mg Tab)

@drashishagg
INDOLE DERIVATIVES
INDOMETHACIN
- Potent anti-inflammatory, antipyretic & good
analgesic
- Analgesic action better than PBZ
Adverse effects:
- High incidence of GI & CNS side effects
- C/I in drivers, epileptics, pregnancy & children
Uses:
- Rheumatoid Arthritis not controlled by aspirin
- Acts rapidly in Acute Gout
DOSE: 25-50 mg BD /TDS (INDOCAP, IDICIN)
@drashishagg
 PROPIONIC ACID DERIVATIVES

IBUPROFEN

- Analgesic, Antipyretic & Anti-inflammatory activity

is lower than aspirin
- Inhibit platelet aggregation & prolong bleeding time
Adverse effects:
- Better tolerated than aspirin (Incidence is lower)
- Gastric discomfort, nausea & vomiting are most
 common side effects
- Headache, dizziness, blurring of vision, tinnitus
Pharmacokinetics:
 - Absorbed orally, highly bound to plasma proteins
 (90-99%)
 - Metabolized in liver & excreted in urine & bile
- Enter brain, synovial fluid & cross placenta

Interactions:
- As they inhibit platelet function, use with
 anticoagulants should be avoided
 - Likely to decrease diuretic & antihypertensive action
 of thiazides, furosemide and -blockers
Uses
- As Analgesic & Antipyretic
- In Rheumatoid Arthritis, Osteoarthritis & other
Musculoskeletal Disorders, specially where pain is
more prominent than inflammation
- Indicated in soft tissue injuries, fractures, tooth
extraction, supppress swelling & inflammation

DOSE: 400-800 mg TDS

(BRUFEN, EMFLAM, IBUGESIC
200, 400, 600 mg Tab)
 ANTHRANILIC ACID DERIVATIVE
MEPHENAMIC ACID

- An Analgesic, Antipyretic & Anti-inflammatory drug,

- Exerts Peripheral as well as Central Analgesic Action

Adverse effects :
- Diarrhoea
- Epigastric distress is complained, but gut bleeding is
 not significant
Pharmacokinetics:
- Oral absorption is slow but almost complete
- Partly metabolized & excreted in urine & in bile
Uses:
 - Analgesic in muscle, joint & soft tissue pain where
 strong anti-inflammatory action is not needed (MPDS)
- Useful in rheumatoid & osteoarthritis
DOSE: 250-500 mg TDS
(MEFTAL, PONSTAN, MEDOL
250, 500 mg cap)

@drashishagg
GOOD MORNING
 Contents
• Introduction
• Opioid analgesics –Classification
- Mechanism of action
-Morphine
-Other opioids
-Uses
• Prostaglandin synthesis & inhibition
• NSAIDS - Classification
- Mechanism of action
-Aspirin
-Other NSAIDS
 CLASSIFICATION
A) NONSELECTIVE COX INHIBITORS
(CONVENTIONAL NSAIDS)

1. Salicylates: Aspirin, Diflunisal

2. Pyrazolone derivatives: Phenylbutazone,

Oxyphenbutazone

3. Indole derivatives: Indomethacin, Sulindac

4. Propionic acid derivatives: Ibuprofen, Naproxen,

Ketoprofen
5.Anthranilic acid derivative: Mephenamic acid
6.Aryl-acetic acid derivatives: Diclofenac, Tolmetin
7.Oxicam derivatives: Piroxicam, Tenoxicam
8. Pyrrolo-pyrrole derivative: Ketorolac

B) PREFERENTIAL COX-2 INHIBITORS –

Nimesulide, Meloxicam, Nabumetone

C) SELECTIVE COX-2 INHIBITORS -

Celecoxib
ARYL-ACETICACID DERIVATIVE
DICLOFENAC SODIUM
- Analgesic, Antipyretic, Anti-inflammatory action
- Inhibits PG synthesis & has short lasting antiplatelet
 action

Pharmacokinetics:
- Well absorbed orally, metabolized & excreted both
 in urine & bile
- Has good tissue penetrability & conc. in synovial
 fluid is maintained longer period, exerting extended
 therapeutic action in joints
@drashishagg
Adverse effects
- Are generally mild: Epigastric pain, nausea,
headache, dizziness, rashes
- Gastric ulceration & bleeding -less common

Uses:
- Most extensively used NSAID
- Rheumatoid & Osteoarthris, post-traumatic
inflammatory conditions - affords quick relief of
pain & wound edema (Dental Extractions)

DOSE: 50 mg TDS, 75 mg i.m

(VOVERAN, DICLONAC, DICLOMAX
(25, 50 mg Tab., 75 mg /3ml inj)
@drashishagg
 OXICAM DERIVATIVES
PIROXICAM
 - Long acting potent NSAID with good anti-
 inflammatory, analgesic & antiplatelet action

 - Reversible inhibitor of COX; lowers PG conc. in
 synovial fluid & inhibits platelet aggregation-
 prolonging bleeding time

 - In addition, it decreases the production of IgM

 rheumatoid factor
 Pharmacokinetics:
- Rapidly & completed absorbed
- Metabolized in liver & excreted in urine
- Plasma t1/2 is 2 days. So, single daily administration
 is sufficient

Adverse effects:
- Heart burn, nausea & anorexia, but it is tolerated &
less ulcerogenic than PBZ; causes less faecal blood
loss than aspirin

@drashishagg
Uses:
- Suitable for use as short term analgesic as well as long
term anti-inflammatory action in –
Rheumatoid & Osteo-arthritis, Ankylosing spondylitis,
acute gout, musculoskeletal injuries, dental pain

DOSE: 20 mg BD for 2 days followed by 20 mg OD

(DOLONEX, PIROX)
10, 20 mg cap)
PYRROLO-PYRROLE DERIVATIVE
KETOROLAC
- Potent analgesic & modest anti-inflammatory activity.
- In postoperative pain it has equalled the efficacy of
morphine
- Inhibits PG synthesis & is believed to relieve pain by
a peripheral mechanism
- Rapidly absorbed after oral & i.m. administration
& excreted unchanged in urine
Adverse effects:
- Nausea, abdominal pain, dyspepsia, ulceration, loose
stools, drowsiness, headache, dizziness, nervousness,
pruritus, pain at injection site
- Rise in serum transaminases & fluid retention have
been noted

Contra-indications:
- Should not be given to patients on the anti-coagulants
 Uses:
- In post-operative & acute musculoskeletal pain:
 15-30 mg every 4-6 hours (max. 90 mg/ day)

- Also for renal colic, migraine & pain due to

 due to bony metastasis

- Used in a dose of 10-20 mg 6 hourly short term

 management of moderate pain

AVAILABLE : KETOROL, KETANOV (10 mg Tab)

 Preferential COX-2 inhibitors

NIMESULIDE
- Sulfonamide derivative
- Selective inhibitor of PG synthesis & there is
some relative COX-2 selectivity
Uses
 - Short lasting painful inflammatory conditions like
 sports injuries, sinusitis & other ENT disorders,
 dental surgery, bursitis, low backache, Postop pain,
 osteoarthritis & for fever

@drashishagg
Pharmacokinetics:
 - Completely absorbed orally
 - Metabolism-Liver & Excretion- Urine

Adverse effects
- Epigastralgia, heart burn, loose motions
- Dermatological rash, pruritus
- Hepatic failure & Renal failure in neonate (BANNED)

DOSE- 100mg BD
( NIMULID, NIMEGESIC, NIMODOL 100 mg Tab)
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NABUMETONE

- Recently developed preferential COX-2 inhibitor

- Has less analgesic, antipyretic activities, effective
in the treatment of rheumatoid & osteoarthritis as
well as soft tissue injury
- Lower incidence of gastric erosions, ulcers &
bleeding

DOSE: 500 mg OD
(NABUFLAM, NILTIS 500 mg Tab)
 Selective COX-2 inhibitors

CELECOXIB, ETORICOXIB,PARECOXIB
• Directly targets COX-2 which is produced at the site
of inflammation
• Selectivity for COX-2 can half the risk of peptic
ulceration
• Cox-2-selectivity might be an increase in the risk for
heart attack, thrombosis & stroke by a relative
increase in thromboxane

@drashishagg
Uses-
- Osteoarthritis
- Rheumatoid arthritis
- Ankylosing spondylitis
- For the management of acute pain in adults

Pharmacokinetics:
- Slow absorption
- Metabolism-Liver & Excretion- Urine
Dose :
- Celecoxib- 100-200 mg BD (CELACT,ZYCEL)
- Etoricoxib- 60-120 mg OD (ETODY,ETOXIB)
- Parecoxib- 40 mg 6-12 hrs (REVALDO,PAROXIB)

Precautions:
- In patient who has clinical signs of liver toxicity or if
systemic manifestations arise, valdecoxib should be
discontinued
- Should be used with caution in patients with CHF or
hypertension since fluid retention & edema can occur
Para-amino phenol derivatives

PARACETAMOL (ACETAMINOPHEN)

-- Central Analgesic action is like aspirin, i.e. it raises

- pain threshold, but has weak Anti-inflammatory

- action

- Paracetamol is a good & promptly acting Antipyretic

Uses:
-Most commonly used analgesic for Headache,
 Musculoskeletal pain
- Best drug to be used as Antipyretic
- Can be used in All Age groups(infants to elderly),
 pregnant/lactating women, & in patients in whom
 aspirin is contraindicated

Adverse effects:
Safe & Well tolerated, Nausea occur occasionally,
High doses-Hepatic necrosis
Pharmacokinetics:
Well absorbed orally. Metabolism-Liver
 Excretion in Urine

DOSE- 0.5-1gm TDS 500mg Tab

(CROCIN, PARACIN, METACIN, PYRIGESIC)
Drug interactions with NSAIDs
Diuretics : ↓ Diuresis
-blockers : ↓ Anti-hypertensive effect
ACE inhibitors : ↓ Anti-hypertensive effect
Anticoagulants :↑ risk of G.I. Bleed
Sulfonylureas : ↑ Hypoglycaemia
Alcohol : ↑ risk of G.I. Bleed
Cyclosporine : ↑ Nephrotoxicity

@drashishagg
Contraindications

 Allergy to Asprin or any NSAID

 Peptic Ulcers

 During Pregnancy / Breast feeding

 Anticoagulant Therapy

 Suffering from blood clotting system disorders

 Chronic liver diseases

- Mild To Moderate Pain With Little Inflammation
– PARACETAMOL or low dose IBUPROFEN

- Acute Musculoskeletal Pain, Osteoarthritic,

Injury Associated Inflammation
- IBUPROFEN, DICLOFENAC

- Postoperative or other acute but Short Lasting Painful

Conditions With Minimal Inflammation
- KETEROLAC, NEFOPAM
- Patients with history of asthma/ anaphylactoid reaction
- NIMESULIDE

- Gastric intolerance to conventional NSAID

-CELECOXIB, ETORICOXIB,PARECOXIB
TOPICAL PREPARATIONS

@drashishagg
Advantages of topical medications

• Greater safety
• Rapid onset of action
• High concentrations can be attained at desired site
without exposing the rest of the body
• Fewer chances of drug interactions
• Non-invasive
• Better acceptability
TOPICAL PREPARATIONS
MEDICATIONS EXAMPLE
Topical anesthetics •Benzocaine in orabase (20%)
•Lidocaine gel
•Eutectic mixture of local
anesthetic (EMLA cream)
Neuropeptides •Capsaicin cream (0.025% &
0.075%)
NSAIDs •Ketoprofen (10-20%)
•Diclofenac (10-20%)
Sympathomimetic •Clonidine (0.01%)
agents
MEDICATIONS EXAMPLE
NMDA blocking •Ketamine (0.5% in orabase)
agents

Anti-convulsants •Carbamazapine (2% in PLO

base)
Tricyclic •Amitriptyline (2% in PLO
medications base)
Anti-spasmodics •Baclofen (2% in PLO base)
NEUROPEPTIDES
(CAPSAICIN)

Available as:
 Cream

Indications:
 Post herpetic neuralgia
 Diabetic Neuropathy
 Postmastectomy pain syndrome
 Trigeminal neuralgia
 TOPICAL ANESTHETICS
(BENZOCAINE,LIDOCAINE)

Available as - Gels
- Ointments
- Sprays
- Adhesive patches

Indications:
• Post Herpetic Neuralgia
• Oral ulcers
• Burning mouth syndrome
NSAIDs
(KETOPROFEN,DICLOFENAC)
Available as:
 Cream
 Patch

Indications:
 Localized treatment of acute pain associated
with soft tissue injury e.g. Musculoskeletal pain
Local drug delivery systems

• Mucoadhesive creams
• Transdermal creams
• Medicated chewing gums
• Dissolving tablets & lozenges
• Adhesive patches & powders
• Mouthwashes
Drugs used in management of chronic
pain
- NSAIDs
- Acetaminophen
- Opioids
- Antidepressants
- Anticonvulsants
- Neuroleptics
- Corticosteroids
- Systemic L. A.’s
- Alpha adrenergic agonists
- Botulinum toxin
Analgesics in pregnancy
• Acetaminophen
-Most Useful
-Any Stage
• Morphine
• Meperidine
• Aspirin (Not in 3rd trim.)
• Ibuprofen (Not in 3rd trim.)
• Pentazocine (With Caution)
NSAIDS as host modulating agent in
periodontal disease

In vitro model

The first evidence that NSAIDs block PG production in

gingival tissue ( Gomes & co workers in 1976 )

He demonstrated that inflamed gingival fragment taken

from monkey, release PG in culture medium ,&
indomethacin reduced the PG production by 90 %
• NSAIDS block PGE2 production , thereby reducing
inflammation & inhibiting osteoclast activity in
periodontal tissue

• Studies have shown that systemic NSAIDS such as

indomethacin, flurbiprofen & naproxen administered
daily for upto 3 yrs significantly slowed the rate of
alveolar bone loss compared with placebo

• However daily administration for extended period is

necessary for periodontal benefits
• NSAIDS are associated with severe side effects

• Research shows that periodontal benefits of taking long term NSAIDS

are lost when patient stops taking drug
 Trombelli et al 1996

Parallel double blind RCT ,pt undergoing periodontal surgery

Pre op ketarolac 20 mg vs placebo

Hourly VAS scores for 10 hrs ,time & dose of rescue analgesics

Pre op ketarolac reduced pain scores & delayed the onset of

post op pain compared to placebo
• Sakuma et al+ and Miyaura et al* - IL-1α, TNF- α, lipopolysaccharide,
and basic fibroblast growth factor failed to induce osteoclast formation
in EP4- deficient mice cultures
• Suggesting that osteoclast formation is mediated by EP 4 receptors by
PGE2, which was produced through COX-2

+
J Bone Miner Res 2000:15:218-227
*J Biol Chem 2000:275: 19819-19823
CONCLUSION

• Analgesics are definitely useful in reducing

pain & improving the quality of life but have
their own spectrum of adverse effects.

• No single drug is superior to all others for

every patient. Choice of drug is inescapably
empirical.
 REFERENCES

• Essentials of Medical Pharmacology

- K.D.TRIPATHI (6th Ed.)
• Drugs, Diseases and the Periodontium
-Robin A. Seymour and Peter A. Heasman
• Pharmacology
- DALE,RANG AND RITTER (4th Ed.)
• The role of COX-2 and prostaglandin E2 in periodontal
diseases periodontology 2000,vol.40,2006,144-163
• Dental Therapeutic Update October 2002
THANK YOU