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

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.

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 A 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,

TNF 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, TNF, 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 PGF2 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.

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

Aspirin (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

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.

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.

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+

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

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, 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.

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 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 :

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.

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.

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 TNF

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.

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 g/ml at 4 hours and

30 g/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.

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.

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

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

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.

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.