Dental Analgesics Guide: NSAIDs, Classifications, Mechanisms

ANALGESICS IN
DENTISTRY
INDIAN DENTAL ACADEMY
Leader in continuing Dental
Education
www.indiandentalacademy.com

Contents
 Introduction
◦ Pain
◦ Analgesia
 Analgesics
 Classification
 NSAID’s
◦ History of NSAID’s
◦ Classification of NSAID’s
◦ Mechanism of action (PG synthesis inhibition)
◦ Adverse effects
◦ Individual drugs
 Analgesic combinations
 Conclusion
 References.

Pain
Pain is a subjective experience which can not
be objectively defined or quantified
satisfactorily.
“An unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage” ……..Beth Fahlberg
“Pain is an ill-defined, unpleasant sensation,
usually evoked by an external or internal
noxious stimulus" www.indiandentalacademy.com

Indian Dental academy
• www.indiandentalacademy.com
• Leader continuing dental education
• Offer both online and offline dental
courses

Pain
 It is a warning signal and primarily protective in
nature
 But causes discomfort and suffering (sometimes
which are unbearable)
 Pain is the most important symptom for which a
patient visits a doctor (especially dentist)

Goals of pain management
 To relieve suffering
 Increase functional capacity
 Improve quality of life

Analgesics
“Analgesics are drugs that selectively relieve pain by
acting in the CNS or on the peripheral pain
mechanisms, without significantly altering
consciousness”.
Analgesics relives pain as a symptom without affecting
its cause.

Routes of analgesic
administration
 Oral
 Intramuscular Injection
 Intravenous Injection
 PCA : patient controlled analgesia
 Other routes
◦ Transdermal
 Fentanyl patch
◦ Sublingual
 Morphine
◦ Epidural Administration
◦ Spinal and Caudal Administration

Classification of Analgesics
 Non-narcotic
(non opioid / antipyretic / asprin like analgesics or
NSAID’s)
 Narcotic
(opioid / morphine like analgesics)
 Consider placebo effect
 Local anaesthetics
 Various centrally acting non opioid drugs, for ex:
◦ Antidepressants (amitriptyline)
◦ Drugs for specific painful conditions
(carbamazepine in trigeminal neuralgia,
ergotamine in migraine) www.indiandentalacademy.com

History of NSAID’s
 BC: Ancient Greeks and Romans used salicylate
extracts derived from willow leaves as analgesics
and antipyretics
 Middle Ages: Medicinal herb gardens featured
salicylate containing wintergreen and meadowsweet
plants
 1763: Edward Stone reported on use of willow bark
powder as an anti-inflammatory
 1853: Von Gerhardt synthesized a crude form of
aspirin (acetylsalicyclic acid)
 1860: Felix Hoffman working for Bayer synthesizes
pure aspirin www.indiandentalacademy.com

NSAIDs: A History of COX
Inhibition
 1949: The NSAID Phenylbutazone introduced
 1963: Indomethacin introduced
 1971: Vane and Piper demonstrated NSAIDs inhibit
prostaglandin production
 1974: Ibuprofen introduced
 1976: Miyamoto et al purified the COX-1 enzyme
 1989: Simmons et al identified the COX-2 enzyme
 1999: The COXIBs Celebrex (celecoxib) and Vioxx
(rofecoxib) introduced

Classification of NSAID’s
 Non selective COX inhibitors (conventional NSAID’s)
◦ Salicylates: Asprin
◦ Propionic acid derivatives: Ibuprofen, Naproxen,
Ketoprofen, Flurbiprofen
◦ Anthranilic acid derivative: Mephenamic acid
◦ Aryl-acetic acid derivatives: Diclofenac
◦ Oxicam derivatives: Piroxicam, Tenoxicam
◦ Pyrrolo-pyrrole derivative: Ketorolac
◦ Indole derivative: Indomethacin
◦ Pyrazolone derivatives: Phenylbutazone,
Oxyphenbutazone

Classification of NSAID’s
contd…
 Preferential COX-2 inhibitors
◦ Nimesulide, Meloxicam, Nabumetone
 Selective COX-2 inhibitors
◦ Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib
 Analgesics-antipyretics with poor anti inflammatory
action
◦ Para aminophenol derivative: Parcetamol
(Acetaminophen)
◦ Pyrazolone derivatives: Metamizol (Dipyrone),
Propiphenazone
◦ Benzoxazocine derivative: Nefopam

NSAID’s and prostaglandin (PG)
synthesis inhibition
 In 1971, Vane and coworkers made the landmark
observation that asprin and some NSAID’s blocked
PG generation

Cellular Arachidonic Acid Metabolism

Cyclo oxygenase pathway

 MECHANISM OF ACTION:
- During inflammation, pain & fever, arachidonic
acid is liberated from phospholipid fraction of
the cell membrane.
- AA is then converted via cyclo-
oxygenase(COX-1&2) pathways to PGs. The
steps are
1. Oxidation of AA to the endoperoxide PGG2 &
PGH2.(unstable)
2. Its subsequent reduction to hydroxy
endoperoxide PGH2- this is transformed in to
the primary prostanoids PGE2, PGF2, PGD2,
PGI2 (endothelium)& TXA2(platelets).

- COX-1 activity is constitutively present in
nearly all cell types at a constant level & is
involved in tissue homeostasis , protection of
gastric mucosa, maintenance of renal function.
- COX-2 activity is normally absent from
cells(except those of kidney & brain) but is
induceble by bacterial liposaccharides IL2 &
TNF in activated leucocytes & other
inflammatory cells.
- Thus, COX-1 is physiological & COX-2 is
usually pathological

PATHOPHYSIOLOGICAL ACTIONS OF PG’s
 PG I2 act as local vascular dilators.
 Pg e2 and pg i2- believed to be continuously
produced locally in ductus arteriouses during foetal
life-which keep it patent; at birth its synthesis is
inhibited and closure occurs.
 TX A2 and PG I2 act as mutually antagonistic
system: preventing aggregation of platelets while in
circulation and inducing aggregation on injury.
 PGs produced by foetal tissues at term probably
mediate initiation and progression of labour.
 Dysmenorrhoea in many women is associated with
increased PG synthesis by the endometrium.

 Asthma may be due to an imbalance between
constrictor PGs(f 2a,PGD2,TXA2) and LTs on one
hand and dilator ones(PG E2,PG I2) on the other.
 PG,s appears to play a role in the growth of colnic
polyps and cancer.
 PG s(especially pg i2) appears to be involved in
regulation of gastric mucosal blood flow and PG E2
enhances gastric mucus production.
 Pg appears to function as intra renal regulation of
blood flow as well as tubular reabsorption in
kidneys.
 PG E2 may induce bacterial or other pyrogen
induced fever and malaise at the level of
hypothalamus.

 PG s (especially E2 and I2) sensitize afferent nerve
endings to pain inducing chemical and mechanical
stimuli.
 PGs appears to serve as algesic agent during
inflammation .They cause tenderness and amplify
the action of other algesic.

Physiological actions of PG’s
PGE2, PGF, and PGI2
RELAX VASCULAR
SMOOTH MUSCLE
PGE2 and PGI2
INCREASE
RENAL BLOOD FLOW
PGE2 and PGI2
RELAX BRONCHIAL
SMOOTH MUSCLE;
PGF CONTRACTS IT
PGE2 and PGF
CONTRACT UTERINE
SMOOTH MUSCLE;
PGI2 RELAXES IT
PGE2 and PGI2
PROTECT
GASTRIC MUCOSA
TxA2 PROMOTES
PLATELET AGGREGATION;
PGI2 INHIBITS IT

- Actions of NSAIDS:;
- most NSAIDs inhibit COX-1 & COX-2
nonselectively,
- but now some selective COX-2 inhibitors have
been produced
- aspirin inhibits COX irreversibly by acetylating
one of its serine residues, return of COX activity
depends on synthesis of fresh enzyme.
- others- competative & reversible inhibition of
COX

 BENIFICIAL ACTIONS DUE TO PG SYN
INHIBITION:
1. Analgesia,
2. Antipyretic,
3. Anti-inflammatory
4. Antithrombotic
5. Closure of ductus arteriouses

SHARED TOXICITIES :
1. Gastric mucosal bleeding, inhibition of platelet
function
2. Limitation of renal blood flow- Na & water
retention
3. Asthma & anaphylactoid reactions in suceptible
individuals.
4. Delay/ prolongation of labour.

SALICYLATES (esters of salicylic acid)
Eg: methyl & sodium Salicylates & aspirin(acetyl salicylic
acid) Can be combined with codeine
Aspirin :
Aspirin is one of the oldest analgesic- anti inflammatory
drugs and is still widely used.
Aspirin is a weaker analgesic than morphine type drugs:
aspirin 600mg= codeine 6o mg.
Aspirin rapidly converted in the body to salicylic acid ,
which is responsible for most of the actions.

Pharmacological action-
1. Local actions:
- salicylic acid & methyl Salicylates are irritants,
salicylic acid also has keratolytic, antiseptic &
fungistatic action.
- Salts of salicylic acid do not irritate unbroken
skin but when ingested, may release free
salicylic acid in stomach causing local irritation.
2. CNS:
Analgesia-act predominantly at peripheral by
obtunding of peripheral pain receptors and
prevention of pg mediated sensitization of
nerve endings.

• In smaller dose-only analgesic action.
•Larger doses- anti inflammatory activity, relieve vascular
congestion & edema.
3).Antipyretic action-
•By resetting the hypothalamic thermostat.
• reduces fever by promoting heat loss( sweating,
coetaneous vasodilatation),but does not decrease
heat production.

4. Anti inflammatory & anti rheumatic
effect-
• exerted at high doses (3-5 g /day or 100
mg/kg/day)
•By inhibiting pg synthesis.
•By reducing capillary permeability
•By inhibition of neutrophil aggregation and activation
5. Immunologic phenomenon-
•Prevent release of histamine .
• May reduce CMI.

7.Respiration:
 At anti inflammatory doses, respiration is
stimulated by peripheral( increased co2
production) and central ( increased sensitivity of
respiratory center to co2) actions.
 But at high doses- causes respiratory depression,
 Death –due to respiratory failure.
8 .Acid base balance & electrolytes:-
• Compensated respiratory alkalosis.
• dehydration
• in a toxic doses-metabolic acidosis.

9.GIT:- Salicylates may produce
• Dyspepsia, nausea & vomiting, gastric irritation.
• Peptic ulceration, GI bleeding, hematemesis,
malena.
Due to decrease in PGE2 & PGI2-loss of protective
effect of PG on stomach.
• also reduce motility of stomach & increase gastric
emptying time.
• Alkalis reduce gastric irritation & absorption of
salicylates.
•Soluble aspirin tablets containing calcium
carbonate+ citric acid and other buffered preparations
are less liable to cause gastric ulcerations.

10. Blood & Platelets:
•Does not affect normal leukocyte count
• Reduce the high ESR in acute rheumatic fever
• Inhibit platelet aggregation (suppression of TXA2 in
platelets).
•Long term intake of large doses decreases
synthesis of clotting factors in liver and predispose
the bleeding – can be prevented by prophylactic vit-k
therapy.
•Non acetylated salicylates such as sodium salicylate
do not posses antiplatelet action.
11. On CVS:
12.Metabolic effects: www.indiandentalacademy.com

Absorption, fate & excretion-
• Absorbed from intact skin, when given orally.
• Absorbed in stomach & upper small intestine.
• Aspirin is rapidly deacetylated in the gut wall, liver ,
plasma and other tissue to release salicylic acid.
• Plasma t½ life- 2-8 hrs.
• Dose dependent pharmacokinetics
1. Lower dose- 300-600mg- Ist order kinetics.
2. Higher dose- 1-2g- zero order kinetics
• Mainly excreted in urine.

Adverse effects-
1.Intolerance
2. GIT: Dyspepsia, nausea & vomiting, gastric irritation.
2). Peptic ulceration, GI bleeding, hematemesis,
malena.
also reduce motility of stomach & increase gastric
emptying time
3).On hemopoietic system: platelet aggregation.
4).Reye’s syndrome
5).Salicylism
6).Acute salicylate intoxication
• 1

S
s
a
SALICYLISM
-High doses of salicylates may produce a
condition of mild salicylate intoxication termed
Salicylism.
-Syndrome usually develops when the plasma
salicylate levels >25mg% characterized by
headache, dizziness, vertigo, tinnitus, difficulty in
hearing n sight, drowsiness, lethargy, mental
confusion, nausea, vomiting & diarrhea may
occur may also be associated with tachyapnea &
respiratory alkalosis.
-signs & symptoms are reversible on cessation
of drug.

ACUTE SALICYLATE INTOXICATION
-During overzealous therapy in infants or accidental
ingestion
- Mild toxicity at 50mg% & potentially fatal > 75mg%.
-characterized by acid base electrolyte disturbances,
hypoglycemia, hyperpyrexia, gastro intestinal irritation,
restlessness, vertigo, tremors , convulsions ,coma.
moderate doses cause respiratory alkalosis,
with higher doses the respiratory centre is depressed
leading to metabolic acidosis

Principles of management of salicylate
poisoning
1. Hospitalization
2. Gastric lavage
3. Correct hyperthermia, dehydration /over hydration,
hypokalemia, acid-base disturbances.
4. Alkalinization of urine.
5. Vit-K, blood transfusion.

Preparations & dosage-
1. Acetyl salicylic acid (aspirin- 300mg tab)
2. Soluble aspirin tab contain aspirin 300mg, citric acid 30mg,
CaCo3- 3mg.
3. Buffered aspirin tab – aspirin & antacid like MgOH, AlOH,
AL- glycinate.
4. Sodium salicylate- 500mg tab.
5. Methyl salicylate (oil of wintergreen): Methyl salicylate 25% in
peanut oil, Methyl salicylate ointment 50% in bees wax &
hydrous wool fat.
6. Salicylic acid: ointment contains 2 - 6% Salicylic acid, while
Whitfield ointment contains 6% benzoic acid,& Salicylic acid
3%.
7. Lysine acetyl salicylate (injisprin, biosprin) as IV infusion
preparations.

Uses-
1. As analgesic( in headache, toothache, myalgia
,joint pain, neuralgia , dysmenorrhoea.
2. antipyretic
3. As anti-inflammatory.
4. As anti-rheumatic.
5. As anti platelet agent.(60-100mg/day)
6. Closure of ductus arteriosis.
7. Suppress familial colonic polyposis
8. Prevention of colon cancer.
TRADE NAME:ASPIRIN ,DISPIRIN 350 mg tab,
COLOSPIRIN 100 ,325.,650 mg tab. ECOSPIRIN
75, 150,325 mg tab

Propionic acid derivatives
 E.g: ibuprofen, naproxen, ketoprofen, flubiprofen .
 Ibuprofen - first introduced member of this class
 Anti inflammatory efficacy is lower than aspirin
 Inhibit PG synthesis
 Naproxen – most potent
Adverse effects
◦ Milder and better tolerated than aspirin
◦ GI and CNS disturbances are present
◦ Precipitate aspirin-induced asthma.
◦ Hypersensitivity reactions
◦ Avoided in peptic ulcer patients, c/I in pregnant
women www.indiandentalacademy.com

Propionic acid derivatives
Pharmacokinetics
◦ Well absorbed orally
◦ Bind plasma proteins and also enters brain,
synovial fluid, cross placenta
◦ Metabolized in liver and excreted in urine and bile
Uses
◦ Simple analgesic and antipyretic
◦ Osteoarthritis and musculoskeletal disorders…
where pain is more prominent than inflammation
◦ Soft tissue injuries, tooth extraction, fractures,
vasectomy, post partum and post operatively
Very popular in dentistry

 Ibuprofen (4oomg) has been found equally or more
efficacious than aspirin (650)+ codeine (60 mg) in
relieving dental surgery pain.
Dosage and preparation
 Ibuprofen: 400-600 mg tds.
BRUFEN, EMFLAM,IBUSYNTH 200,400,600 mg
tab, IBUGESIC 100 mg/ 5ml susp.
 naproxen 250 mg bd –tds
NAPROSYN, NAXID,ARTAGEN 250 mg, 500mg.

Anthranilic acid derivative (fenamates)
 Mephenamic acid
◦ Inhibits COX and also antagonizes certain
actions of PG’s
◦ Exerts peripheral as well as central analgesic
action
 Pharmacokinetics
◦ Oral absorption is slow but complete
Adverse effects
◦ Diarrhea – most commonly
◦ Rarely hemolytic anemia.
Uses
◦ Analgesic in muscle, joint and soft tissue pain
◦ Effective in dysmenorrhoea
◦ Dosage: 250-500 mg tid
◦ Trade name: MEDOL, MEFTAL-250,500 mg tab.www.indiandentalacademy.com

Aryl-acetic acid derivative
 Diclofenac sodium
◦ Inhibits PG synthesis
◦ Has short lasting anti platelet action
◦ Mild Adverse effects like epigastric pain, nausea,
headache, dizziness, rashes
◦ Well absorbed orally
◦ Excreted both in urine and bile
Uses
◦ Rheumatoid arthritis and osteoarthritis
◦ Toothache , ankylosing spondylitis, dysmenorrhoea.
◦ Post operative and post traumatic inflammatory
conditions.

 Dosage: 50 mg tid / 75 mg deep I.M
 Trade name: VOVERAN , DICLONAC, MOVONAC
50 mg, 100 mg S.R tad, 25 mg/ ml in 3ml amp.

OXICAMS:Eg- piroxicam(feldene, pirox)
-this is structurally different from other agents
-well absorbed when given orally
-longer half life(38-45hrs)-hence administered once a
day
-doses- 10-20mg(antipyretic & analgesic)
20-40mg(anti-inflammatory)
-causes GI & CNS disturbances
-USES: Rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, acute gout
-has no much advantage except a longer duration of
action
- other oxicams are tenoxicam, meloxicam &www.indiandentalacademy.com

 Dosage: 20 mg bd for two days followed by 20 mg
o.d
 Trade name:
DOLONEX, PIROX 10, 20 mg cap, 20 mg / ml inj in 1
and 2 ml amp , PIRICAM 10, 20 mg cap.

Pyrrolo - pyrrole derivative:
 E.g: ketorolac
 Potent analgesic and modest anti inflammatory
activity.
 Inhibiting pg synthesis and relives pain by peripheral
mechanism.
Pharmacokinetics:
 Rapidly absorb by oral and i.m administration.
 Plasma t1/2 is 5-7 hrs.
 Metabolized in liver and excreted in urine.
Adverse effects:
 nausea, vomiting, loose stools ,drowsiness,
headache, pain at injection

◦ Uses:
 Post operative dental and acute musculoskeletal
pain: 15-30 mg i.m or i.v,4-6hrly
 Also used in renal colic, migraine and pain due to
bony metastasis
 Orally 10-20mg -6 hrly -for postoperative dental
pain ,which is superior to aspirin 650 mg,
paracetamol 600mg.
 But its use for more than 5 days is not
recommended.
Trade names: KETOROL, ZOROVON, KETANOV
10 mg tab , 30 mg in 1ml amp.

Indole derivative:
e.g: Indomethacin.
• Potent anti inflammatory drug with prompt anti
pyretic action.
• Relives only inflammatory or tissue injury related
pain.
• Highly potent inhibitor of pg synthesis and
suppresses neutrophil motility
• Pharmacokinetics:
• Well absorbed orally, slow rectal absorption.
• Metabolized in liver , excreted by kidneys.
• Plasma t1/2: 2-5 hrs.
• adverse effects:
• High incidence of Gastrointestinal and CNS side
effects
• Frontal headache(very common),hypersensitivity
reactions www.indiandentalacademy.com

 Leucopenia , increased incidence of bleeding..
 Contra indicated in machinery operators, drivers,
psychiatric patients , epileptic, kidney diseases,
pregnant women and in children.
 Dose: 25-50 mg bd-qid.
 Trade name; IDICIN, INDOCAP , ARTICID,
INDOFLAM 25 mg cap, 75 mg SR cap.
 USES:
 Conditions requiring potent anti inflammatory
action like ankylosing spondylitis, acute
exacerbation of destructive arthopathies, psoriatic
arthritis , acute gout ( when not responded to
better tolerated NSAIDS).
 Malignancy associated fever.
 Medical closure of patent ductus arteriouses.

Pyrazolones
 Metamizol and propiphenazone are used as
analgesic and antipyretics (marketed in India)
 Metamizol banned in USA and some European
countries- found to cause agranulocytosis
 dose: 0.1.5 g tab oral/ i.m /i.v
 Trade names:
 ANALGIN 0.5 g tab,NOVALGIN,BARALGAN 0.5 g
tab, 0.5 g/ml in 2ml and 5 ml amp.
 Propiphenazone: another Pyrazolone with similar in
properties to Metamizol, but without agranulocytosis.
 Trade names : SARIDON,ANAFEBRIN.:
propiphenazone 150 mg plus parecetomal 250 mg
tab.

Preferential COX -2 inhibitors:
nimesulide, meloxicam, nabumetone
Nimesulide:
 Weak inhibitor of pg synthesis wit relative COX – 2
selectivity.
 Analgesic, antipyretic, anti inflammatory activity is
comparable to other NSAID’s.
 Primarily used for short lasting painful inflammatory
conditions like sports injuries, dental surgery, ENT
disorders, dysmenorrhoea, post operative pain,
osteoarthritis and for fever.
 Most of the asthmatics and those who develop
bronchospasm or intolerance to aspirin do not cross
react with nimesulide.
 Nimesulid is almost completely when given absorbed
orally.
 Plasma t1/2: 2-5 hrs.

 Adverse effects: Gastric tolerability of nimesulide
is better.
 But some adverse effects like epigastralgia, heat
burn, nausea, loose motions are seen.
 Dermatological (rash , pruritis), central
(somnolence , dizziness) are seen
 Nimesulide causes nephrotoxicity & hepatotoxicity.
So drug should be avoided in children & old
people.

SELECTIVE COX-2 INHIBITOR NSAID’S:
- Selectively block COX-2 activity more than COX-1
activity, thus interfering less with the protective action
of COX-1 in the stomach, BV & kidneys.
-Eg:, Celecoxib, rofecoxib & valdecoxib.
- given orally, their absorption is complete.
- effective analgesic-anti inflammatory action(single
dose)
- effective in treatment of osteoarthritis & rheumatoid
arthritis.

ADVANTAGES:
-fewer gastric ulcers
- do not inhibit platelet aggregation
DISADVANTAGES:
-have prothrombotic effect, leading to a higher incidence
of cardiovascular events.
-A/E:-N, V, dyspepsia, abdominal pain, diarrhea & edema
of lower extremities
- renal A/Es like decrease renal blood flow
- edema & dose related worsening of hypertension.
-studies in animals suggest that inhibiting COX-2 may
interfere with wound(ulcer) healing, bone remodeling,
ovulaton & prenatal renal development.www.indiandentalacademy.com

C/I:
-children, pregnant women, lactating mothers
-Celecoxib is contraindicated in pts allergic to sulfonamides.
- recently, the use of rofecoxib & valdecoxib has been reported
to be associated with increase incidence of MI & stroke. Hence,
COX-2 inhibitors are under suspicion regarding their long term
toxicity.

DRUG ½ LIFE(Hrs) DOSE-mg
NABUMETONE(
RELIFEX)
24 500-1000 OD
NIMUSULIDE
(NIMULID,
NISE)
<5 100 TID
MELOXICAM(
MUVERA,
MOBIC)
20 7.5-15 OD
CELECOXIB
(CELEBREX)
11 200-400 OD/BID
ROFECOXIB
(VIOXX)
17 12.5-15 OD
VALDECOXIB
(BEXTVA)
8 10 OD

PARA AMINOPHENOL DERIVATIVES-
Eg- Paracetamol, Acetanilid, Phenacetin
Paracetamol-
Most commonly used ‘over the counter’ drug for headache,
musculoskeletal pain, toothache, dysmenorrhoea,etc.,
Best antipyretic, analgesic with less anti – inflammatory effects.
Lesser GI irritation, acid base imbalance , electrolyte disturbances
when compared to salicylates
Can be used in all age groups, also in pregnant and lactating women
Absorption , fate & excretion-
- Rapidly absorption with oral administration..
-Has plasma T½ of 2-3 hrs.
-metabolized in liver and excreted in urine as conjugate products of
glucuronic & sulfuric acid

Adverse Effects
-Hepatic & renal toxicity (7-10gm)
-liver toxicity due to N-acetyl-p-benzoquinonamine
-fever , neutropenia, thrombocytopenia, nephropathy & skin reaction
-rarely produces anemia as a result of hemolysis &
methemoglobinaemia.
Preparation and dosage
1.250-500MG TAB analgesic & antipyretic (adult 2.5g)
2.liquid dosage form in children
3.inj Febrinil- 150mg/ml
TRADE NAMES:
CROCIN, METACIN, PARACIN;500 mg tab,1.0 g tab. 125 mg/ 5ml
syrup, ULTRAGIN CALPOL 500mg tab/, 125 mg/ 5ml syrup.

Acute paracetamol poisoning
 Large dose (>150 mg / kg or> 10 g ) in an adult.
 fatality with> 250 mg / kg
 Specially in small children with low hepatic glucuronide
conjugating ability and Chronic alcoholics.
c/m: nausea, vomiting, abdominal pain and liver
tenderness without impairment of consciousness.
 After 12 -18 hrs centrilobular hepatic necrosis , renal
tubular necrosis , hypoglycemia which leading to coma.
Treatment:
 Hospitalization
 Gastric lavage , activated charcoal – to prevent further
absorption
 N- acetylcysteine ( specific antidote) infusion.
 Other supportive measures.

Conclusion
 NSAID’S act as a mainstay for management of
dental pain.
 Selection of NSAID’S done
-based on the cause,
-nature of the pain(mild , moderate, severe; acute,
chronic; ratio of pain : inflammation)
-along with consideration of risk factors .
-is any alternative / protection feasible??

Guidelines for use of NSAID’s
 Mild – moderate pain with little inflammation:
paracetamol or low dose ibuprofen
 Post extraction: ketorolac, Diclofenac, nimesulide
or asprin
 Gastric intolerance to conventional NSAID’s:
selective COX-2 inhibitor or paracetamol
 Patients with history of asthma: nimesulide
 Pediatric patients: paracetamol, aspirin,
ibuprofen, naproxen –preferred
 Pregnancy: parecetomal- safest, low dose aspirin-
2nd best
 Hypertensive, diabetic, IHD, epileptic patients on
long term medications- possibility of drug
interactions

Analgesic combinations
 No convincing evidence that combinations are
superior to single agents
 Combination of aspirin and paracetamol is additive
 Combination of codeine with aspirin or paracetamol
is additive and also provides analgesia beyond the
ceiling effect of aspirin or paracetamol.

REFERENCES
 Pharmacology and therapeutics for
dentistry
- Yagiela , Dowd , Deidle.
 Essential pharmacology for dentistry, 1st
edition
- K.D. Tripathi.
 Internet .

THANK YOU

History Of Opium
 Opiates are one of the oldest types of drugs in history
 Opium is extracted from poppy seeds (Paper
somniforum)
 Undisputed reference to opium found in writings
(Theophrastus) from the third century BC
 Use of Opium recorded in China and Mesopotamia
over 2000 years ago
 Greeks dedicated the Opium poppy to the Gods of
Death (Thanatos), Sleep (Hypnos), and Dreams
(Morpheus)
 Sixteenth Century is the first reported use of Opium
for its Analgesic qualities www.indiandentalacademy.com

History of Opioids
 Preparations of opium in the form of elixirs became
increasingly popular in the 17th, 18th, and 19th
centuries
 By the 19th century Opium in various forms was
considered “as legitimate as tobacco or tea”
 Invention of the hypodermic needle in 1856
produced drug abusers who self administered
opioids by injection
 Controlling the widespread use of opioids has been
unsuccessful because of the euphoria, tolerance
and physiological dependence that opioids produce

Opiod analgesics
 Opium contains two types of alkaloids
◦ Phenanthrene derivatives
 Morphine (10% in opium)
 Codeine (0.5% in opium)
 Thebaine (0.2% in opium), (non analgesic)
◦ Benzoisoquinoline derivatives (non analgesic)
 Papaverine(1%)
 Noscapine (6%)

Morphine
◦ Principal alkaloid of opium
◦ Still widely used
 Pharmacological actions
 CNS
◦ Analgesia
 Strong analgesic
 Nociceptive pain arising from peripheral pain
receptors is better relieved than neuretic pain
 Reactions associated with intense pain –
apprehension, fear, autonomic effects … are also
depressed
 Suppression of pain perception is selective
(unlike general anaesthetics)

Morphine
◦ Sedation
 Drowsiness and indifference to surroundings as
well as to own body without motor incoordination
occur, ataxia and apparent excitement also occur
 Higher doses produce sleep and coma
◦ Mood and subjective changes
 Calming effect
 Loss of apprehension, feeling of detachment,
lack of initiative, mental clouding and inability to
concentrate

Morphine
◦ Respiratory and cough centres
 Depressed
◦ Temperature regulating and vasomotor centre
 Depressed
◦ CTZ, Edinger Westphal nucleus, vagal centre,
certain cortical areas and hippocampal areas are
stimulated
◦ GIT
 Constipation is a prominent feature

Morphine
 Neuro-endocrine
◦ Acting on hypothalamus reduces FSH, LH and
ACTH release
◦ Increases prolactin and GH release
◦ Enhances ADH release and so urine volume is
reduced
◦ Causes sympathetic stimulation – mild
hypoglycemia
 CVS
◦ Causes vasodilation
◦ Cardiac work is consistently reduced due to
decrease in peripheral resistance

Morphine
◦ Oral absorption is unreliable – high and variable
first pass metabolism
◦ Freely crosses placenta, affects foetus more than
the mother
 Adverse effects
◦ Mental clouding, sedation and lethargy
◦ constipation
◦ Acute morphine poisoning
 50mg of morphine produces serious toxicity
 Death is due to respiratory failure

Morphine
 Tolerance and dependence
◦ Partly pharmacokinetic (enhanced rate of
metabolism) but mainly pharmacodynamic
(cellular tolerance)
◦ Treated by substitution with oral methadone
Precautions and contraindications
◦ Infants and elderly
◦ Bronchial asthma
◦ Head injury
◦ Unstable personalities

Classification of opioids
 Natural opium alkaloids
◦ Morphine, codeine
 Semi synthetic opiates
◦ Diacetylmorphine (heroin), pholcodeine
◦
 Synthetic opioids
◦ Pethidine (meperidine), fentanyl, methadone,
dextropropoxyphene, tramadol

Codeine
 Is methyl morphine
 Occurs naturally in opium
 Less potent than morphine (1/10th as analgesic)
 Is more selective cough suppressant
Heroin
 3 times more potent than morphine
 Euphorient and highly addicting
 No outstanding therapeutic advantage over morphine
 Banned in most countries except UK

Pethidine
 Synthesized as an atropine substitute in 1939
 Interacts with opioid receptors (mu)
 Similar to morphine in most of its properties
◦ Uses
 As analgesic (substitute to morphine) and
 In pre anaesthetic medication

Methadone
 Chemically dissimilar but pharmacologically similar to
morphine
 Used
◦ primarily as substitution therapy for opioid
dependence
◦ Also in methadone maintenance therapy

Tramadol
 Centrally acting analgesic
 Unlike other opioids inhibits reuptake of NA and 5-
HT and thus activates monoaminogeric spinal
inhibition of pain
 100mg tramadol equianalgesic to 10mg morphine
 Uses
◦ Mild to moderate intensity short lasting pain due
to diagnostic procedures, injury, surgery,
dentistry etc

Opioid receptors
 Opioids interact with specific receptors present on
neurones in the CNS and peripheral tissues
 Radioligand binding studies divide receptors into
◦ mu, kappa and delta
 Each has specific pharmacological profile and
pattern of anatomical distribution
 Pattern of effect of particular agent depends on the
nature of its interaction with different opioid receptors
and also its relative affinity to these receptors

Opioid receptors
mu kappa delta
Analgesia
Resp. depression
Sedation
Euphoria
Miosis
Reduced GI motility
Physical dependence
Analgesia
Resp. depression
Dysphoria,
hallucinations
Miosis
Sedation
Physical
dependence
Analgesia
Resp. depression
Affective behavior
Reinforcing
actions
Reduced GI
motility

Complex action opioids and opioid
antagonists
 Agonist- antagonist (kappa analgesics)
◦ Nalorphine
◦ Pentazocaine
◦ Butorphanol
 Partial /weak agonist
◦ Buprenorphine
 Pure antagonist
◦ Naloxone, naltrexone

Pentazocaine
 Indicated in post operative and moderately severe
pain in burns, trauma, cancer
Naloxone
 It is N-alylnor oxymorphone
 Competitive antagonist for all opioid receptors
 Injected i.v (0.4- 0.8mg) it antagonizes all actions of
morphine
 Drug of choice in morphine poisoning

Opioids in dental pain
 Opioids are less effective and suitable than NSAID’s
for dental pain
 Mostly used as additional drugs with NSAID’s to
boost their analgesic effect
 Among opioids oral codeine is most suited
 Oral tramadol and pentazocine are alternatives
 Injected opioids like morphine, pethdine and fentanyl
are limited to intra-operative or peri-operative use to
supplement anaesthesia and to allay apprehension

Adjuvants
 To supplement the action of analgesics
 To limit the side effects of analgesics
 Co - analgesics
◦ Steroids
◦ Anti arrythmics
◦ Anti depressants
◦ Anti epileptics
◦ Serotonin reuptake inhibitors
◦ Muscle relaxants
Adjunct medications are mostly used for chronic pain

Pain Management Strategies
 Preoperative preparation
 Pain history
 Postoperative pain
◦ Regular & frequent dosing intervals in early post op
period
 PCA, Epidural, IV
 Opioid + NSAID
 Switch to oral dosing when taking po
◦ Medicate prior to anticipated pain
 Ambulation & physical therapy
 Dressing changes

Pain Management Strategies
 Benefits of effective post operative pain management
◦ Early mobilization
◦ Shorter hospital stay and reduced cost
Pre emptive analgesia (PEA)
◦ Is administration of effective analgesia prior to
surgical trauma
◦ PEA reduces acute pain scores and analgesic
requirements
◦ Timing of initiation and prevention of sensitization
are central to use of PEA

Cancer Pain
 Causes:
◦ Tumor progression
◦ Operations and other invasive procedures
◦ Toxicity of chemotherapy and radiation
◦ Infection
◦ Limited physical activity
 Pain-related pathology
◦ Bone Metastasis
◦ Spinal cord or nerve compression
◦ Peripheral neuropathy
◦ Abdominal tumors
◦ Mucositis

The WHO three-step analgesic
ladder

Pain Management in the Elderly
 More sensitive to pain medications
 Longer duration of pain relief
 More sensitive to sedation &
respiratory depression

THE FUTURE
Fentanyl PCTS
Iontophoretic patient controlled transdermal system

THE FUTURE
 ACRUX
 Analgesics, anxiolytics, antiemetics

Related articles…
 The Analgesic Efficacy of Intravenous Versus Oral
Tramadol for Preventing Postoperative Pain After Third
Molar Surgery. IJOMS, May 2005
◦ Cliff K.S. Ong DDS, Phillip Lirk MD, Juliana M.H. Tan
MD and Belle W.Y. Sow DPharm
 Conclusions
◦ We conclude that preoperative intravenous tramadol is
superior to oral tramadol for preventing post - operative
pain following third molar surgery. However, it should be
noted that there is a difference in the bioavailability
between the 2 formulations of up to 30%, which may
explain the findings.

Related articles…
 Postoperative analgesia after lower third molar
surgery: Contribution of the use of long-acting local
anesthetics, low-power laser, and diclofenac. IJOMS
, Feb 2006
◦ Aleksa B. Marković DDS, MSc, PhD and Ljubomir
Todorović DDS, MSc, PhD
 Results
◦ The results of the first part of the study showed a
strikingly better postoperative analgesic effect of
bupivacaine than lidocaine/epinephrine (11 out of
12; 4 out of 12, respectively, patients without
postoperative pain). In the second part of the study,
low-power laser irradiation significantly reduced
postoperative pain intensity in patients
premedicated with diclofenac, compared with the
controls. www.indiandentalacademy.com

Related articles…
 Do selective cyclo-oxygenase-2 inhibitors and
traditional non-steroidal anti-inflammatory drugs
increase the risk of atherothrombosis? Meta-analysis
of randomised trials. BMJ. 2006 Jun
3;332(7553):1302-8
◦ Kearney PM, Baigent C, Godwin J, Halls H, et. al.
 COX-1 and COX-2 inhibitors have been found to
increase the risk of atherothrombosis even with short
term use. A 2006 analysis of 138 randomised trials
and almost 150 000 participants showed that
selective COX-2 inhibitors are associated with a
moderately increased risk of vascular events, mainly
due to a two fold increased risk of MI, and also that
high dose regimens of some traditional NSAIDs such
as diclofenac and ibuprofen are associated with a
similar increase in risk of vascular events.www.indiandentalacademy.com

Related articles…
 Trouble with tramadol
Aust Prescr 2004;27:26–7
◦ Karen Kaye
As of March 2004 the Australian Adverse Drug
Reactions Advisory Committee (ADRAC) has
received 726 reports of adverse events associated
with tramadol, detailing 1922 reactions.
Nausea, vomiting, dizziness, confusion and seizures.
The potential for serious drug-drug interactions
should not be underestimated.
For most patients, a combination of paracetamol and
codeine will be equally effective and possibly better
tolerated than tramadol

Conclusion
 When using NSAIDS and opioid
analgesics….
◦ Is the patient ‘at risk’?
◦ Is any alternative / protection feasible?
◦ Which drug to choose?

References
 Pharmacology, 4th edition
◦ H. P. Rang, M. M. Dale, J. M. Ritter
 Pharmacology and Therapeutics for Dentistry
◦ Yagiela, Dowd, Neidle
 Oral and Maxillofacial Surgery Clinics of North
America – Pharmacology, Feb 01
◦ Orett E. Ogle
 Essential Pharmacology for Dentistry, 1st edition
◦ K. D. Tripathi
 The Analgesic Efficacy of Intravenous Versus Oral
Tramadol for Preventing Postoperative Pain After
Third Molar Surgery. IJOMS, May 2005

References
 Postoperative analgesia after lower third molar
surgery: Contribution of the use of long-acting local
anesthetics, low-power laser, and diclofenac.
IJOMS , Feb 2006
 Do selective cyclo-oxygenase-2 inhibitors and
traditional non-steroidal anti-inflammatory drugs
increase the risk of atherothrombosis? Meta-analysis
of randomised trials.
BMJ. 2006 Jun 3;332(7553):1302-8
 Trouble with tramadol
Aust Prescr 2004;27:26–7

Opioid receptors
Opioid receptor transducer mechanism

 SERRATOPEPTIDASE
◦ Enhances Tissue Repair Process
◦ Increase Antibiotic Penetration
◦ Resolves Fibrosis Quickly
◦ Accelerates Healing

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Dental Analgesics Guide: NSAIDs, Classifications, Mechanisms

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Dental Analgesics Guide: NSAIDs, Classifications, Mechanisms