This document discusses pain management strategies and non-steroidal anti-inflammatory drugs (NSAIDs). It begins with an introduction on the importance of pain management and the three main categories of pain control medication: narcotics, aspirin and other NSAIDs, and acetaminophen. The document then provides a history of the development of NSAIDs from willow bark to modern drugs. It classifies NSAIDs and discusses their mechanisms of action, beneficial effects, toxicities, properties, and examples like aspirin and salicylates. The document covers the pharmacological actions, pharmacokinetics, adverse effects, precautions, interactions, and uses of aspirin and salicylates.

1. INTRODUCTION
In our so called developing country where we are aping the west and putting forth
a strong competition in all aspects, there is still one aspect where we lag behind
phenomenally and that is, we can purchase almost any drug we want without a legal
prescription at any pharmacy. People just pop pills without knowing their adverse effects
or for how long they should be taking it. Now this, could lead to serious drug abuse.
Among this lot, only a few conscious individuals visit a doctor with symptoms of pain
and then from our perspective pain management strategy is of utmost importance. There
are basically 3 categories of pain control medication they are :
1) Narcotics (steroidal)
2) Aspirin and other NSAIDS
3) Acetaminophen
HISTORY :
Willow Bark (Salix alba) has been used for many centuries as a analgesic and
antipyretic. Salicylic acid was obtained by hydrolysis of the bitter glycoside obtained
from this plant.
 Sodium salicylate was used for fever and pain in 1875.
Its success led to the introduction of acetyl salicylic acid (aspirin) in 1899.
Phenacetin and antipyrine also introduced at the same time.
 1949 – development of phenylbutazone
 1963 – Indomethacin was introduced
 1963 onwards – Propionic acid derivatives referred to as NSAID’s have been
introduced along with some selective COX-2 inhibitors.
 1971 – vane and coworkers observed that NSAID’s blocked PG synthesis
CLASSIFICATION –
According to Tripathy:
A. Analgesic and anti-inflammatory :
1. Salicylates – aspirin, salicylamide, benorylate, diflunisal
2. Pyrazolone derivatives – phenylbutazone, oxyphenbutazone
3. Indole derivatives – indomethacin, sulindac
4. Proprionic acid derivatives – ibuprofen, naproxen, ketoprofen, fenoprofen,
flurbiprofen.
5. Anthranilic acid derivative – mephenamic acid
6. Aryl acetic acid derivatives – declofenac, tolmetin

2. 7. oxicam derivatives – piroxicam, tenoxicam, meloxicam
8. Pyrrolo-pyrrole derivative – ketorolac
9. Sulfonanilide derivative – nimesulide
10. Alkanones – Nabumetone
B. Analgesic but poor anti-inflammatory :
1. Paraaminophenol derivatives – paracetamol (acetaminophen)
2. Pyrazolone derivative – metamizol (dipyrone), propiphenazone
3. Benzoxazocine derivative – nefopam.
Classification according to Goodman and Gillman :
Non selective COX inhibitors :
a) Salicylic acid derivatives – aspirin, sodium salicylate, choline magnesium
trisalicylate, salsalate, diflunisal, sulfasalazine, olsalazine.
b) Para amino derivatives – acetaminophen
c) Indole and indene acetic acid – indomethacin, sulindac
d) Heteroaryl acetic acid – tolmetin, diclofenac, heterolac.
e) Aryl propionic acid – thioprofen, naproxen, flurbiprofen, hetoprofen,
tenoprofen, oxaprozin.
f) Anthranilic acid (fenamates) – mefenamic acid, meclofenamic acid
g) Enolic acids – oxicam (piroxicam, meloxicam)
h) Alkanones – Nabumetone.
Selective COX-2 inhibitor :
a) Diaryl substituted furanones – rofecoxib
b) Diaryl substituted pyrozoles – celecoxib
c) Indole acetic acids – etodolac
d) Sulfonanilides – Nimesulide
MECHANISM OF ACTION :
From a dental perspective, the most common type of odontogenic pain is
characterized by acute pain and the most common management approach is a
pharmacological one.
The initial event for most acutely painful conditions is a noxious stimulus that
results in tissue destruction or injury. The trauma may be initiated by a disease process,
such as an apical abscess or by surgical intervention, such as extraction of a tooth. In
either case the resultant cellular destruction causes the release or synthesis of several
biochemical mediators involved in the pain process i.e. histamine, prostaglandins and
bradykinin. These and other substances interact with peripheral nociceptors (pain
receptors) and free nerve endings to trigger pain signals from the area of tissue injury.

3. The prostaglandins particularly the E type cause hyperalgesia by sensitizing
afferent nociceptors in the periphery to other algsesic mediators, such as histamine and
bradykinin. Once these primary afferent fibres in the oral cavity and face are stimulated
beyond a threshold level, impulses are sent to the CNS along Aδ and C fibres of the
trigeminal, facial, glossopharyngeal and vagus nerves to the trigeminal nucleus caudalis
in the medulla and higher centers where they are decoded and interpreted and appropriate
responses are made.
Peripherally acting analgesics reduce and control pain by directly inhibiting the
biochemical mediators of pain at the site of injury.
The primary mechanism of action of the peripherally acting analgesics is
inhibition of the cyclooxygenase enzyme system that metabolizes arachidonic acid to its
endoperoxide intermediates. Once formed the endoperoxides are converted to
thromboxanes, prostacyclins and prostaglandins. some evidence suggests that several
peripherally acting analgesics may own their exceptional efficacy not only to a more
effective inhibition of important isoenzymes of the cyclooxygenase system at the site of
injury but also to secondary effects of cyclooxygenase inhibitor within the CNS. The
spinal dorsal horn is a probable site of action of NSAIDs and may involve mechanisms
other than inhibiton of cyclo oxygenase.
BENEFICIAL ACTIONS DUE TO PG SYNTHESIS INHIBITION
• Analgesia
• Antipyresis
• Antinflammatory
• Closure of ductus arteriosus
SHARED TOXICITIES DUE TO PG SYNTHESIS INHIBITION
• Gastric mucosal damage
• Bleeding
• Limitation of renal blood flow
• Delay/prolongation of labour
• Asthma and anaphylactoid reactions
COMMON PROPERTIES OF ALL NSAIDS :
1) Analgesia
PGs induce hyperalgesia . NSAIDs do not affect the tenderness induced by direct
application of PGs, but block the pain sensitizing mechanism induced by bradkinin,

4. TNFα interleukins (Ils) and other algesic substances. They are therefore more effective
against inflammation associated pain.
2) Antipyresis
NSAIDs reduce body temperature in fever, but do not cause hypothermia in
normothermic individuals. Fever during infection is produced through generation of
pyrogen, Ils, TNFα, interferons which induce PG production in hypothalamus – raise its
temperature set point. NSAIDs block the action of pyrogens.
3) Anti inflammatory
Antinflammatory action of NSAIDs is considered to be inhibition of PG synthesis
at the site of injury.
4) Dysmenorrhoea
Involvement of PGs in dysmenorrhoea has been clearly demonstrated. level of
PGs in menstrual flow, endometrial biopsy and that of PGF2α metabolite in circulation
are raised in dysmenorrhoeic women. Intermittent ischaemia of the myometrium is
probably responsible for menstrual cramps. NSAIDs lower uterine PG levels – afford
excellent relief in 60 – 70%.
5) Antiplatelet aggregatory
NASIDs inhibit synthesis of both proaggregatory (TXA2) and antiaggregatory
(PGI2) prostanoids, but effect on platelet TXA2 predominates. Therapeutic doses of most
NSAIDs inhibit platelet aggregation. Bleeding time is prolonged.
6) Ductus arteriosus closure
During foetal circulation ductus arteriosus is kept patent by local elaboration of PGE2
and PGI2. Unknown mechanisms switch off this synthesis at birth and the ductus closes.
When this fails to occur, small doses of indomethacin or aspirin bring about closure in
majority of cases within few hours by inhibiting PG production. Administration of
NSAIDs in late pregnancy has been found to promote premature closure of ductus in
some cases.
7) Parturition
Sudden spurt of PG synthesis by uterus probably triggers labour. NSAIDs delay and
retard labour.

5. 8) Gastric mucosal damage
Gastric pain, mucosal erosion/ulceration and blood loss are produced by all
NASIDs to varying extents. Inhibition of synthesis of gastroprotective PGs (PGE2, PGI2)
is clearly involved, though, local action inducing back diffusion of H+
ions in gastric
mucosa also plays a role. Deficiency of PGs reduces mucus and HCO3
-
secrection, tends
to enhance acid secretion and may promote mucosal ischaemia.
9) Renal effects
Conditions leading to hypovolemia, decreased renal perfusion and Na+
loss
induce renal PG synthesis which brings about intrarenal adjustments by promoting
vasodilatation, inhibiting tubular Cl-
reabsorption and opposing ADH action. Renal
effects of NSAIDs are not marked in normal individuals but significant in those with
CHF, hypovolemia, hepatic cirrhosis, renal disease and those receiving diuretics or
antihypertensives Na+
retention and edema can occur, diuretic and antihypertensive
effects are blunted.
10) Anaphylactoid reactions
Aspirin precipitates asthma, angioneurotic swellings, urticaria or rhinitis
SALICYLATES
Aspirinε
(prototype)
Aspirin is acetylsalicylic acid .Rapidly converted in the body to salicylic acid
which is responsible for most of the actions.
PHARMACOLOGICAL ACTIONS
1. analgesic, antipyretic, anti-inflammatory actions
Aspirin is a weaker analgesic than morphine type drugs. Aspirin 600 mg ≤
codeine 60 mg. It relieves inflammatory, tissue injury related, connective tissue and
integumental pain but is relatively ineffective in severe visceral and ischaemic pain.
Aspirin resets the hypothalamic thermostat and rapidly reduces fever by
promoting heat loss.
Antinflammatory action is exerted at high doses (3-6 g/day or 100 mg/kg/day).
Signs of inflammation are suppressed.
2. Metabolic effects
Significant only at antinflammatory doses. Cellular metbolism is increased in
skeletal muscles, due to uncoupling of oxidative phosphorylation → increased heat
production → Increased utilization of glucose→ blood sugar may decrease liver
glycogen is depleted. Hyperglycaemia is often seen at toxic doses. This is due to central
sympathetic stimulation release of Adrenalin and corticosteroids. Chronic use of large

6. doses causes negative N2 balance by increased conversion of protein to carbohydrate.
Plasma free fatty acid and cholesterol levels are reduced.
3. Respiration
At antinflammatory doses respirations is stimulated by peripheral (increased CO2
production) and central (increased sensitivity of respiratory center to CO2) actions.
4. acid – base and electrolyte balance
Antinflammatory doses produce significant changes in the acid-base and
electrolyte composition of body fluids. Initially respiratory stimulation predominates and
tends to wash out CO2 despite increased production → respiratory alkalosis, which is
compensated by increased renal excretion of HCO3. Most adults treated with 4-6 g/day of
aspirin stay in a state of compensated respiratory alkalosis.
Still higher doses cause respiratory depression with CO2 retention, while excess
CO2 production continues → respiratory acidosis. To this are added dissociated salicylic
acid as well as metabolic acids which are produced in excess + metabolically derived
sulfuric and phosphoric acid which are retained due to depression of renal function. All
these combine to cause uncompensated metabolic acidosis .
5. CVS
Aspirin has no direct effect in therapeutic doses. Larger doses increase cardiac
output to meet increased peripheral O2 demand and cause direct vasodilatation. Toxic
doses depress vasomotor center: BP may fall. CHF may be precipitated.
6. GIT
Aspirin and released salicylic acid irritate gastric mucosa → cause epigastric
distress, nausea and vomiting.
7. Urate excretion
< 2 g/day – urate retention and antagonism of all other uricosuric drugs.
2-5 g/day – variable effects, often no change.
> 5 g/day – increased urate excretion.
8. Blood
Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis by platelets.
PHARMACOKINETICS
Aspirin is absorbed from stomach and small intestines. Aspirin is rapidly
deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid. It is
80% bound to plasma proteins and has a volumes of distribution –0.17 L/kg. It slowly
enters brain but freely crosses placenta.

7. The plasma t½ of aspirin as such is 15-20 min, that of released salicylic acid, it is
3-5 hours. Anti-inflammatory doses may be 8-12 hours while that during poisoning may
be upto 30 hours.
ADVERSE EFFECTS
a) Side effects
At analgesic dose (0.3-1.5 g/day) - nausea, vomiting, epigastric distress,
increased occult blood loss in stools. Gastric mucosal damage and peptic ulceration.
b) Hypersensitivity and idiosyncrasy
Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema,
asthma and anaphylactoid reaction. Profuse gastric bleeding.
c) Antinflammatory doses
Produce the syndrome called salicylism which includes dizziness, tinnitus,
vertigo, reversible impairment of hearing and vision, excitement and mental confusion,
hyperventilation and electrolyte imbalance.
d) Acute salicylate poisoning
More common in children. Fatal dose in adults is 15-30 g. serious toxicity is seen
at serum salicylate levels > 50 mg/dl. Manifestations are:
Vomiting, dehydration, electroyte imbalance, acidotic breathing, restlessness.
Delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory
failure + cardiovascular collapse.
Precautions and contraindications
• Aspirin is contraindicated in patients who are sensitive to it and in peptic
ulcer, bleeding tendencies, in children suffering from chicken pox or
influenza. Due to risk of Reye’s syndrome pediatric formulations of aspirin
are prohibited in India and U.K.
• In chronic liver disease: cases of hepatic necrosis have been reported.
• It should be avoided in diabetics. In those with low cardiac reserve or frank
CHF and in juvenile rheumatoid arthritis.
• Aspirin should be stopped 1 week before elective surgery.
• Given during pregnancy it may be responsible for low birth weight babies.
Delayed or prolonged labour, greater postpartum blood loss and premature
closure of ductus arteriosus.
• It should be avoided by breast feeding mothers.
• Avoid high doses in G-6 PD deficient individuals – haemolysis can occur.

8. Interactions
1. It displaces warfarin, naproxen, sulfonylureas, phenytoin and
methotrexate from binding sites on plasma proteins: toxicity of these drugs may
occur. Its antiplatelet action increases the risk of bleeding in patients on oral
anticoagulants.
2. It inhibits tubular secretion of uric acid and antagonizes uricosuric
action of probenecid. Tubular secretion of methotrexate is also interfered.
3. It blunts diuretic action of furosemide and thiazides and blocks the
action of spironolactone.
4. Reduces protein bound iodine levels by displacement of thyroxine
USES
1. As analgesic for headache, backache, myalgia, joint pain, pulled muscle,
toothache, neuralgias and dysmenorrhoea; it is effective in low doses (0.3-0.g /
6-8 hourly).
2. As antipyretic
3. Acute rheumatic fever 4-6g or 75-100 mg/kg/day it brings about marked
symptomatic relief in 1-3 days. Dose reduction may be started after 4-7 days and
maintenance doses (50 mg/kg/day) are continued for 2-3 weeks or till signs of
active disease persist. Withdrawal gradual over the next 2 weeks.
4. Rheumatoid arthritis
5. Osteoarthritis.
6. Postmyocardial infarction and poststroke patients by inhibiting platelet
aggregation it may lower the incidence of reinfarction. 40-325 mg/day ‘New
onset’ or ‘sudden worsening’ angina 300 mg aspirin per day for 12 weeks.
7. Other less established uses :
a) Pregnancy induced hypertension and Preeclampsia
b) Delay labour
c) Patent ductus arteriosus : closure
( ASPIRIN, DISPRIN, ASABUF )
PYRAZOLONES
1. Phenylbutazone
It is a more potent anti-inflammatory comparable to corticosteroids. The
analgesic and antipyretic action is poorer and slower in onset. It is uricosuric by virtue
which inhibits renal tubular reabsorption of uric acid. Causes definite retention of Na+

9. and water by direct action on renal tubules → edema, expansion of plasma volume occur
after 1-2 weeks of use. CHF may be precipitated.
Pharmacokinetics
Completely absorbed orally. It is 98% bound to plasma proteins. completely
metabolized in liver by hydroxylation and glucuronidation. The plasma t ½ is 60 hours.
Dose : 100-200 mg BD or TDS after meals. ZOLANDIN
Adverse effects : more toxic than aspirin. Nausea, vomiting, epigastric distress and
peptic ulceration. Diarrhoea and a variety of CNS side effects. Hypersensitivity: rashes,
serum sickness, hepatitis and stomatitis. Bone marrow depression, agranulocytosis
Stevens – Johnson syndrome. Goiter and hypothyroidism
Interactions : displaces sulfonamides, tolbutamide, warfarin, imipramine and
methotrexate from protein binding sites. Risk of bleeding is increased in patients on
anticoagulants.
It is an inducer of microsomal enzymes: increases its own metabolism as well as
that of many drugs and steroids. It competitively inhibits phenytoin and tolbutamide
metabolism.
Uses
1. Used only in severe cases that does not responding to other drugs. Rheumatic
arthritis and ankylosing spondylitis.
2. Rheumatic fever
3. Acute gout
2. oxyphenbutazone
Major metabolite of phenylbutazone, SIORIL, PHENABID 100,200 mg tab.
3. Metamizol (Dipyrone)
Derivative of amidopyrine it is a potent and promptly acting analgesic and
antipyretic but poor anti-inflammatory. It can be given orally, i.m. as well as i.v. but
gastric irritaion, pain at injection site occurs. Occasionally i.v. injection produces
precipitous fall in BP.
Dose : 0.5-0.1.5 g; ANALGIN, NOVALGIN
4.propiphenazone
Another pyrazolone, similar in properties to metamizol, claimed to be better
tolerated.
Dose : 300-600 mg TDS; SARIDON, ANAFEBRIN

10. INDOLE DERIVATIVES
Potent anti-inflammatory drug, and promptly acting antipyretic. Analgesic action
is better than phenylbutazone, but relieves only inflammatory or tissue injury related
pain.
Pharmacokinetics: well absorbed orally, rectal absorption is slow but dependable. 90%
bound to plasma proteins, plasma t ½ is 2-5 hours.
Adverse effects : Marked gastric irritation, nausea, anorexia, gastric bleeding and
diarrhoea. Frontal headache, dizziness, ataxia, mental confusion, hallucination,
depression and psychosis. Leukopenia, rashes and other hypersensitivity reactions are
also reported. Increased risk of bleeding due to decreased platelet aggregability.
Contraindicated in machinery operators, drives, psychiatric patients, epileptics, kidney
disease, pregnant women and in children.
Interactions : Blunts the diuretic action of furosemide. Decreases the antihypetensives
effects of thiazides, furosemide, β lockers and ACE inhibitors. Displaces warfarin from
protein binding sites.
Dose : 25-50 mg BD-QID.
IDICIN, INDOCAP
Uses : Indicated in rheumatoid arthritis, ankylosing spondylitis, acute exacerbations of
destructive arthropathies and psoriatic arthritis, acute gout.
Malignancy associated fever, closure of patent ductus arteriosus, three 12 hourly doses of
0.1-0.2 mg/kg.
PROPIONIC ACID DERIVATIVES
Ibuprofen was the first member of this class to be introduced in 1969.
Analgesic, antipyretic and anti-inflammatory efficacy is rated somewhat lower
than high dose of aspirin. Naproxen being most potent.
Adverse effects :
Effects are milder and their incidence is lower. Gastric discomfort, nausea and
vomiting.
CNS side effects include headache, dizziness, blurring of vision, tinnitus and depression.
Rashes, itching and other hypersensitivity phenomena are infrequent. Precipitates aspirin
induced asthma.
Fluid retention is less marked not to be prescribed to pregnant women and in
peptic ulcer patient.

11. Pharmacokinetics and Interactions : Well absorbed orally, highly bound to plasma
proteins (90-99%), displacement interactions are not clinically significant. Use with
anticoagulants should be avoided. They are likely to decrease diuretic and
antihypertensive action of thiazides, furosemide and β blockers.
Uses :
1. Simple analgesic and antipyretic. Effective in dysmenorrhoea. Its a ‘over the
counter’ drug.
2. Widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal
disorders.
3. Soft tissue injuries, fractures, vasectomy, tooth extraction, postpartum and post
operatively
Drug Plasma t ½ Dosage Preparations
Ibuprofen 2 hr 400-800 mg TDS BRUFEN,
EMFLAM,
IBUSYNTH
Naproxen 12-16 hr 250 mg BD-TDS NAPROSYN,
NAXID,
ARTAGEN,
XENOBID
Ketoprofen 2-3 hr 100mg BD-TDS KETOFEN,
RHOFENID
Fenoprofen 2-4 hr 300-600mg TDS
Flurbiproen 4-6 hr 50mg BD-QID ARFLUR
ANTHRANILIC ACID DERIVATIVE (FENAMATE)
Mephenamic acid :
An analgesic, antipyretic and anti-inflammatory drug, known from 1950s, but has not
gained popularity because of lower efficacy.
Adverse effects : Epigastric distress, skin rashes, dizziness and other CNS
manifestations. Haemolytic anaemia is rare but serious complication.
Pharmacokinetics : Oral absorption is slow but almost complete. Highly bound to
plasma proteins – displacement interactions can occur; plasma t ½ is 2-4 hours.
Uses : Analgesic in muscle, joint and soft tissue pain, dsymenorrohea, rheumatoid and
ostearthritis
Dosage : 250-500mg TDS; MEDOL, MEFTAL, PONSTAN
ARYL-ACETIC ACID DERIVATIVES :

12. Diclofenac sodium : A newer analgesic-antipyretic-antiinflammatory drug, similar
in efficacy to naproxen. Well absorbed orally, 99% protein bound, metabolized and
excreted both in urine and bile. Plasma t ½ is –2 hours.
Adverse effect : are generally mild: epigastric pain, nausea, headache, dizziness, rashes.
Gastric ulceration and bleeding are less common.
Its indications are similar to those of ibuprofen-rheumatoid and osteoarthritis,
bursitis, ankylosing spondylitis, dysmenorrhoea, post-traumatic and postoperative
inflammatory conditions.
Dose : 50 mg TDS, then BD oral, 75 mg deep i.m. VOVERAN, DICLONAC,
MOVONAC, TOLMETIN.
OXICAM DERIVATIVES
piroxicam : It is a novel long acting potent NSAID with anti-inflammatory potency
similar to indomethacin and good analgesic-antipyretic action.
Pharmacokinetics : Rapidly and completely absorbed: 99% plasma protein bond;
plasma t ½ is long – nearly 2 days. Single daily administration is sufficient.
Adverse effects : Heart burn, nausea and anorexia. Edema and reversible azotemia.
Uses :Rheumatoid and osteo – arthritis, ankylosing spondylitis, acute gout,
musculoskeletal injuries, dentistry, episiotomy, dysmenorrhoea.

14. Dose : 20 mg BD for two days followed 20 mg OD: DOLONEX, PIROX TOLDIN,
PIRICAM
Tenoxicam : A congener of piroxicam with similar properties and uses. TOBITIL
Meloxicam : Recently developed congener of piroxicam, has greater in vitro and vivo
inhibitory action against the inclucible COX-2, which is implicated in the inflammatory
response, than against the COX-1, currently marketed for treatment of rheumatoid and
osteo-arthritis in a dose of 7.5-15 mg/day. Considering its better gastric tolerability,
meloxicam may prove to be an advancement.
PYRROLO – PYRROLE DERIVATIVE :
Ketorolac : A novel NSAID with potent analgesic and modest anti-inflammatory
activity. In postoperative pain it has equaled the efficacy of morphine.
Is rapidly absorbed after oral and i.m. administration. It is highly plasma protein
bound and 60% excreted unchanged in urine. Plasma t ½ is 5-7 hours.
Adverse effects : Nausea, abdominal pain, dyspepsia, ulceration, loose stools,
drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site, rise in
serum transaminase and fluid retention. It should not be given to patients on
anticoagulants.
Use : used in postoperative and acute musculoskeletal pain. 15-30 mg i.m. every 4-6
hours (max. 120 mg/day). It may also be used for renal colic, migraine and pain due to
bony metastasis.

15. Orally it is used in a dose of 10-20 mg 6 hourly continuous use for more than 5 days is
not at present recommended. KETOROL, ZOROVON, KETANOV, TOROLAC.
SULFONANILIDE DERIVATIVE :
Nimesulide : this newer NSAID is a relatively weak inhibitor of PG synthesis (may be
somewhat selective for COX-2); appears to exert its effects by other mechanisms like
reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and TNFα
release, free radical scavenging, inhibition of metalloproteinase activity in cartilage.. the
analgesic, antipyretic and anti-inflammatory activity of nimesulide has been rated
comparable to other NSAIDs. Used primarily for short lasting painful inflammatory
conditions like sports injuries, sinusitis and other ear-nose-throat disorders, dental
surgery, bursitis, low backache, dysmenorrhoea, postoperative pain and osteoarthritis.
Adverse effects : are gastrointestinal (epigastrelgia, heart burn, nausea, loose motions),
dermatological (rash, pruritus) and central (somnolence, dizziness).
Nimesulide is almost completely absorbed orally 99% plasma protein bound,
extensively metabolized and excreted mainly in urine with at t ½ of 2-5 hours.
Dose : 100mg BD; NIMULID, NIMEGESIC, NIMODOL.
PARA-AMINO PHENOL DERIVATIVES :
Phenacetin was introduced in 1887. But is now banned because it was implicated in
analgesic abuse nephropathy.
Paracetamol (acetaminophen) the deethylated active metabolite of phenacetin, was also
introduced in the last century but has come into common use only since 1950.
Actions : The central analgesic action of paracetamol is like aspirin, i.e. it raises pain
threshold, but has weak peripheral anti-inflammatory component. Analgesic action of
aspirin and paracetamol is additive. Paracetamol is a good and promptly acting
antipyretic.
Paracetamol has negligible antiinfllammatory action. It is a poor inhibitor of PG
synthesis in peripheral tissues, but more active on COX in brain.
In contrast to aspirin, paracetamol does not stimulate respiration or affect acid-
base balance. Does not increase cellular metabolism. It has no effect on CVS. Gastric
irritation is insignificant. It does not affect platelet function or clotting factors and is not
uricosuric.
Pharmacokinetics : Paracetamol is well absorbed orally, only about 1/3 is protein bound
in plasma and uniformly distributed in the body. Plasma t ½ is 2-3 hours. Effects after an
oral dose last 3-5 hours.

16. Adverse effects : In isolated antipyretic doses paracetamol is safe and well tolerated.
Nausea and rashes occur occasionally, leukopenia is rare.
Analgesic nephropathy occurs after years of heavy ingestion of analgesics. It manifests
as papillary necrosis, tubular atrophy followed by renal fibrosis. Urine concentrating
ability is lost and the kidneys shrink.
Acute paracetamol poisoning : It occurs specially in small children who have low
hepatic glucoronide conjugating ability. If a large dose ( > 150 mg / kg or > 10 g in an
adult) is taken, serious toxicity can occur. Fatality is common with > 250 mg/kg.
Early manifestations are just nausea, vomiting, abdominal pain and liver
tenderness with no impairment of consciousness. After 12-18 hours centrilobular hepatic
necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycemia
that may progress to coma. Jaundice starts after 2 days. Fulminating hepatic failure and
death are likely if the plasma levels are above the line joining 200 µg/ml at 4 hours and
30 µg/ml at 15 hours.
Mechanism of toxicity : N-acetyl-benzoquinone-imine is a highly reactive arylating
minor metabolite of paracetamol which is detoxified by conjugation with glutathione.
When a very large dose of paracetamol is taken, glucuronidation capacity is saturated,
more of minor metabolite is formed – hepatic glutathione is depleted and this metabolite
binds covalently to proteins in liver cells (and renal tubules) causing necrosis.
Treatment : If the patient is brought early, vomiting should be induced or gastric lavage
done. Activated charcoal is given orally or through the tube to prevent further absorption.
Other supportive measure, as needed, should be taken.
Specific : N-acetylcysteine 150 mg / kg should be infused i.v. over 15 min, followed by
the same dose i.v. over the next 20 hours. Alternatively, 75 mg / kg may be given orally
every 4 – 6 hours for 2 – 3 days.
Uses : is one of the most commonly used ‘over the counter’ analgesic for headache,
musculoskeletal pain, dysmenorrhoea etc. Used as antipyretic.
It does not have significant drug interactions.
Dose : 0.5-1 g TDS ; infants 50 mg ; children 1 – 3 years 80 – 160 mg, 4 – 8 years 240 –
320 mg, 9 – 12 years 300 – 600 mg CROCIN, METACIN, PARCIN.
BENZOXAZOCINE DERIVATIVE :
Nefopam : Recently introduced nonopioid analgesic which does not inhibit PG
synthesis. In traumatic and postoperative pain, it acts rapidly with an efficacy
approaching morphine, yet has no opioid actions. Favourable results have been obtained
in short lasting musculoskeletal pain not responding to other nonopioid analgesics.

17. Nefopam produces anticholinergic (dry mouth, urinary retention, blurred vision
and sympathomimetic (tachycardia, nervousness) side effects, and nausea is often dose
limiting. It is contraindicated in epileptics.
Dose : 30 – 60 mg TDS oral, 20 mg i.m. 6 hourly. NEFOMAX.
Choice of Nonsteroidal anti-inflammatory drug :
1. Mild of moderate pain with little inflammation – paracetamol or low dose
ibuprofen.
2. Acute musculoskeletal, osteoarthritic, injury associated inflammation – a
propionic acid derivative, diclofenac or piroxicam.
3. Postoperative or other acute but short lasting painful conditions with minimal
inflammation – ketorolac, nefopam.
4. Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, actue
rheumatic fever – high dose aspirin, indomethacin, naproxen, piroxicam.
5. Patients with history of asthma or anaphylactoid reactions to aspirin / other
NSAIDs – nimesulide.
6. Combination of two or more NSAIDs is not superior to single agents. It at all
used, combination therapy should be limited to short periods.
SUMMARY OF SELECTED NSAID DRUG INTERACTIONS
Drug Possible effect
Anticoagulants Increase in prothrombin time or bleeding with anticoagulants
(e.g., coumarins)
ACE inhibitors Reduced antihypertensive effectiveness of captopril (especially
indomethacin)
Beta blockers Reduced antihypertensive effects of beta blockers (e.g.
propranolol, atenolol, pindolol)
Cyclosporine Increased risk of nephrotoxicity
Digoxin Increase in serum digoxin levels (especially ibuprofen,
indomethacin)
Dipyridamole Increased water retention (especially indomethacin)
Hydantoins Increased serum levels of phenytoin
Lithium Increased serum levels of lithium
Loop diuretics Reduced effectiveness of loop diuretics (e.g., furosemide,
bumetanide)
Methotrexate Increased risk of toxicity (e.g., stomatitis, bone marrow
suppression)
Penillamine Increased bioavailability (especially indomethacin)
Sympathomimetics Increased blood pressure (especially indomethacin with
phenylpropanolamine)
Thiazide diuretics Reduced antihypertensive effectivnes.

18. Suggested analgesics after certain endodontics procedures or conditions:
Procedure / condition Initial choice If more needed
Canal deberidement Aspirin, tylonol, or NSAID Analgesic with 1/2 g
codeine
Canal Debridement where
considerable
overinstrumentation has
occurred.
Analgesic with ½ g codeine Analgesic with 1g codeine
Canal filling where
overfilling has occurred and
periapical tissue is normal
Analgesic with ½ g codeine Analgesic with 1 g codeine
Root amputation without
flap
Nothing ASA, Tylenol, or NSAID
Periapical or amputational
surgery with minimal
trauma
ASA, Tylenol, or NSAID Analgesic with ½ g codeine
Extensive surgery with
considerable trauma
Vicodin or Lortab 10/500 Demerol, Percodan or
percocet
Call after office hours with
moderate pain
Analgesics with 1g codeine Toradol, Vicodin, or
vicodien ES
Call after office hours with
severe pain
Vicodin or Lortab 10/500 Demerol, Percodan or
percocet
Pain magnagement strategies involves 3D’s
- D-Diagnosis – appropriate diagnosis of pain, how and where it occurs.
- D –definite treatment – to reduce pain
- D drugs - to control pain.
1. Diagnosis
2. Definitive dental treatment
a) Pulpotomy, pulpectomy
b) Extraction
c) Incision for drainage
3. Drugs
a) Pretreat with NSAIDs or acefaminophen when appropriate
b) Prescribe by the clock rather than as necessary.
c) Long acting LA when indicated

19. d) Flexible prescription plan.
Flexible analgesic prescription strategy :
A Flexible analgesic prescription strategy based on research has been developed.
Objective – to obtain maximal analgesia and minimal side effects :
Thus a flexible pain management plan selected optimal analgesic based upon the
patients medical history, level of pain, presence of risk factors for post treatment pain.
The non-narcotic component of a combination drug produces greater analgesia
with fewer side effects than the opioid component. Thus analgesia can be maximized
with fewer side effects by using the strategy of first prescribing the most effective dose
of a non-narcotic analgesic.
Non-narcotic drugs have a ceiling in their dose-response curve. Thus after a
maximally effective dose is ingested, additional amounts of same drug will not provide a
proportionate analgesic effect. This has some clinical implications i.e. patients with
endodontic pain should be asked about how much pain they have (scale of 1-10) and
about recent history of analgesic use, this will guide in selection of an appropriate
analgesic treatment plan.
Flexible pain control
Aspirin like drugs indicated Aspirin like drugs contraindicated
Ibuprofen 200mg Acetaminophen 600-1000mg
NSAIDS (above max. effective dose) or
NSAID + acetaminophen
Acetaminophen 600-1000mg with
equivalent of codine – 60mg.
Ibuprofen 400mg / 4 hourly and
equivalent of acetaminophen 600 /
codeine 60 mg every 4th
hr.
NSAID (max. dose) & acetaminophen /
oxycodone 10mg combination. Acetaminophen 1000mg with
equivalent of oxycodone 10mg

20. This plan is divided into 2 columns for patients who can take NSAIDs and for
patients who cannot (eg. Those with active ulcers, ulcerative colitis or asthma or those
with a potential interaction with certain concomitant drug) each column is then divided
into 3 categories based on analgesic recommendations based on level of pain. The
overall strategy is to first obtain the best analgesia as a result of the use of the non-
narcotic drug and then to aid narcotic drug when needed for additional pain control. This
plan maximizes the analgesic effect and minimizes side effects.
NSAIDs alone is sufficient for patients who can tolerate them because of low
incidence of post treatment pain and slight to moderate pain. Thus a prescription of
NSAIDs such as Ibuprofen 600mg/6 hrly is optimal or patients who cannot tolerate it
then 1000mg of acetaminophen.
Patients with moderate to severe pain adequate relief with single drug approach
not possible. For these patients 2 general analgesic approaches.
1) NSAID + acetaminophen – opiod combination (all 3
are analgesics so additive effect
2) Fixed drug combination of ibuprofen 200mg +
hydrocodone 7.5 mg. (effective for pain of inflammatory migin)
Advances :
Selective COX 2 inhibitors :
Celecoxib, rofecoxib, valdecoxib, etoricoxib, meloxicam, diisopropyl flurophosphate.
Action : Inhibits conversion of arachidonic acid to prostaglandins (COX-2). Have no
effect on prostaglandin formation that mediate normal haemostasis in GIT, kidney and
platelet under control of COX-1.
Celecoxib – p © , l ©
Dose : Osteoarthritis – 200mg /day OD on 100 mg BD,
Rheumatoid arthritis - 200mg /day OD on 100 mg BD
Commerical names : Ulebrex, celib, celfast, ulact
Banned – July 2001 – causes CVS troubles and precipitates myocardial infarction.
Rofecoxib – p © , l ©
Dose – 12.5 mg OD (maximum dose 25mg)
Commercial name, Roff, Rofaday. : Vioxx, Dolib MD, doboroff
Banned – Sept. 2004 – CVS risks and potential life threatening G1 bleeding.
Being reviewed to be in market again.

21. Valdecoxibs :
Dose – 10 –20 mg OD
Commercial name : valed, valus , Vovth, Bextra
Banned – April 7 2005.
- Potential life threatening skin reactions – Steven johnson syndrome, toxic epidermal
necrolysis, erythema multiformae.
Other drugs banned by FDA :
- Benoxaprofen
- Phynylbutazone
- Oxyphenbutazone
- Naprofen
- Piroxicam
FDA announcement
- All NSAID’s are not at risk
- Low doses to be prescribed for short term
- Label showing its adverse effects with recommendation for short term use.
Conclusion :
People say in life nothing is constant but one thing that is constant and everybody
can vouch for it, is the ever increasing population of ours with this increase there is also
an exponential increase in the number of health professionals too. So where does one
stand with the perspective of drug therapy. It is not only important to know what to give,
that anybody can do but where and when to give and how much and for how long to give
so as to provide maximum beneficial effects and minimum side effects. only this makes
all the difference between a quack and a doctor.
References :
1) Effective use of rofecoxib in comparison to ibuprofen in post endodontic pain.
JOE. Jan 2003, Vol. 29, No. 1, pg. 62-64.
2) Evaluation of meloxicam (cox-2 inhibitor) for management of post operative
endodontic pain – A double blind placebo controlled study. JOE, Oct 03, Vol. 29,
No. 10, Pg. 634-637t
3) The efficacy of pain control following nonsurgical root canal treatment using
ibuprofen in a combination of ibuprofen and acetaminophen in a randomized,
double-blind, placebo controlled study. IEJ, 2004, Vol. 37, Pg. 531-541.