ANALGESICS AND ANTI-INFLAMMATORY DRUGS

DR Bhaumik ThakkarPart-1 P.G

Dept of Periodontology and Implantology

INTRODUCTIONANALGESICS

A drug that selectively relieves pain by acting in CNS or on peripheral pain mechanism, without significantly altering consciousness.

ANAESTHESIA Anaesthesia means loss of sensation. Anaesthetic

agent is one which bring about loss of all modalities of sensation, particularly pain, along with a reversible loss of consciousness.

PAIN (ALGESIA) An unpleasant sensory and emotional experience

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

CLASSIFICATIONDivided into 2 groups:

1. Opioid Analgesics -Narcotics/Morphine like analgesics

2. Non Opioid Analgesics -NSAIDs/Non narcotic/aspirin like analgesics

History of Opioid. Obtained from poppy { papaver

somniferous } capsule called “ opium ”, known from earliest times.

Mentioned in Eber’s papyrus[1500BC] and in writings of theophrastus [300BC] and Galen [ 2nd century AD ]

Serturner ,a pharmacist isolated the active principle of opium in 1806 and named it ‘ morphine ’ after a Greek god of dreams Morpheus .

OPIOID ANALGESICS Natural Opium alkaloids Morphine & Codeine.

Semi synthetic opiates DiacetylmorphineoxymorphonePholcodeine

Synthetic opioids Pethidine Fentanyl Methadone Dextropropoxyphene Ethoheptazine Tramadol

NON OPIOID ANALGESICS& NSAIDs

Analgesic and Anti inflammatory

A. NON-SELECTIVE COX INHIBITORS

1. Salicylates – Aspirin, Salicylamide, Benorylate, Diflunisal.

2. Pyrazolone derivatives – Phenyl butazone, Oxyphenyl-butazone.

3. Propionic acid derivatives – Ibuprofen, Naproxen, Ketoprofen, Fenoprofen, Flurbiprofen, Oxaprozin.

4. Indole derivatives – Indomethacin, Sulindac.5. Anthranilic acid derivative – Mephanimic acid,

Flufenamic acid.6. Aryl acetic acid derivative – Diclofenac, Tolmetin..7. Oxicam derivative – Piroxicam, Tenoxicam.8. Pyrrolo pyrrole derivatives – Ketorolac, Feprazone.

B. Preferential COX-2 inhibitors- Nimesulide- Meloxicam- Nabumetone

C. Selective COX-2 inhibitors- Valdecoxib- Celecoxib- Rofecoxib

D. Analgesics with poor Anti inflammatory action-

1. Paraminophenol derivative - Paracetamol (Acetaminophen)2. Pyrazolone derivative

- Metamizol, Propiphenazone3. Benzoxazocine derivative

- Nefopam

Pharmacological Actions

1.CNS – Depressant and stimulant action2.CVS – Causes vasodilation 3. GIT – Constipation 4. Smooth muscles – Increased ureter

contraction, Broncho constriction 5. ANS – Mild hyperglycemia

Adverse effects Analgesics doses are usually well tolerated but anti-

inflammatory doses are usually associated with adverse effects whed used for a long period.

A. G.I tract:- Epigastric distress, nausea, vomiting, erosive gastritis, peptic ulcer, increase occult blood loss in stools are common

B. Allergic reactions are not common and may be manifested as rashes, photo sensitivity..etc

C. HaemolysisD. NephrotoxicityE. Reye’s syndromeF. Salicylism G. Acute salicylate intoxication

Functions of NSAIDs Analgesia – PGs induce hyperalgesia by affecting the

transducing property of free nerve endings – stimuli that normally do not elicit pain are able to do so . NSAIDs do not affect the tenderness induces by direct application of PGs but block the pain sensitization mechanism induced by bradykinin .

Antipyresis – NSAIDs reduce body temperature in fever ,

but do not cause hypothermia in normothermic individuals . NSAIDs block the action of pyrogens but not that of PGE2 injected into the hypothalamus .

Anti - inflammatory – Due to inhibition of PG synthesis at the site of injury.

Inflammatory cells express integrins and selectins and NSAIDs act by inhibiting some of these molecules . Growth factor like GM-CSF, IL-6, lymphocyte transformation factor may also be affected. Stabilization of leukocyte lysosomal membrane and antagonism of certain actions of kinin may be contributing to NSAIDs action.

Antiplatelet aggregatory – NSAIDs inhibit synthesis of both proaggregatory { TXA2 } and antiaggregatory { PGI2 } prostanoids , but effect on

platelet aggregation TXA2 predominated producing therapeutic doses of most NSAIDs inhibit platelet aggregation : bleeding time is prolonged .

Ductus arteriosus closure- Administration of NSAIDs in late pregnancy has been found to promote premature closure of ductus in some cases.

Parturation – Sudden spurt of PG synthesis by uterus probably triggers labor and facilitates its progression .NSAIDs has the capacity to retard and delay labor .

Gastric mucosal damage – Gastric pain , mucosal damage are produced

by all NSAIDs .Inhibition of synthesis of PG { PGE2 , PGI2 } is clearly involved . Deficiency of PGs reduces mucus and HCO3- secretions , tends to enhance acid secretion and may promote mucosal ischaemia. Thus, NSAIDs enhance aggressive factors and contain defencive factors in gastric mucosa – which are ulcerogenic. PCM, a very weak inhibitor of COX is practically free of gastric toxicity and selective COX – 2 inhibitor are safer..

Anaphylactoid reaction – Aspirin PPts asthma , angioneuretic

swellings , urticaria or rhinitis in certain susceptible individual . These subjects react similarly to chemically diverse NSAIDs ,ruling out immunological basis for the reaction .

Uses

Acute or chronic conditions where pain and inflammation are present.

(Rossi, 2006)

Rheumatoid arthritis Osteoarthritis Inflammatory arthropathies (e.g. ankylosing spondylitis, ) Acute gout Dysmenorrhoea Metastatic bone pain Headache and migraine Postoperative pain Mild-to-moderate pain due to inflammation and tissue injury Pyrexia Renal colic They are also given to just born infants whose ductus arteriosus is

not closed within 24 hours of birth

Prostaglandins synthesis inhibiton

Membrane phospholipidsPhospholipase A

Arachidonic acidCyclo oxygenase

PG G2 + PG H2

Isomerases Thromboxane sythetase

Prostacyclin synthetase

PG E2, PG D2, PG F

TX A

TX B2

PG I2PG E2, PG D2, PG F

TX A2

Physiological Functions of Prostaglandins

- Pain: PGI2 and PGE2 sensitize nerve endings to bradykinin, histamine

- Inflammation: PGI2, PGD2 and PGE2 are vasodilators (edema, erythema)

- Protection of the gastric mucosa: PGI2 - Maintenance of renal blood flow: PGE2

- Fever: PGE2

- Platelets: PGI2 and PGD2 inhibit platelet aggregation. TXA2 stimulates platelet aggregation

- Uterus: PGD2 contracts uterus - Other:PGE2 keeps ductus arteriosus open following birth

COX-2 Hypothesis (1990s)Normal Tissue Inflammation Site

Physiolgical ProstaglandinProduction

PathologicalProstaglandinProduction

COX-1Constitutive

COX-2Inducible

Arachidonic Acid

Normal Functions Inflammation, pain, fever

NSAIDs

CytokinesGrowth factors+

Role of PGs in inflammationBy 2 roles:1. Promote development 2. Modulate and regulate inflammatory cell function{ Gordon et

al 1976 } PG can induce pain , edema , redness and vasodilation when

they are induced by other mediators . PG inhibits lysosomal enzyme release during phagocytosis ,

enhances chemotaxix , chemokinesis { Estensen et al 1973 }

Inhibit clonal proliferation of macrophages stem cells migration of macrophages

On lymphocytes it supress cell transformation { Mihas 1975 }

Role in Bone Resorption In number of ways and may induce bone resorption by facilitating

the release of osteoclasts activating factor from lymphocytes { Yoneda & Mundy 1979 }

Inhibit bone collagen formation which result in inhibition of the repair of resorbed bone { Raisz & Koolemans – Beynen 1974 }

Role in periodontal destruction –

Production of arachidonic acid metabolites : Recently the role of host’s immuno inflammatory system is

understood . After activation of inflammatory cells in the periodontium by bacteria , phospholipids in the plasma membrane of cells become available for actions by phospholipase. This leads to free arachidonic acid in the area {AAP 1992}

INDICATIONS OF NSAIDS IN DENTISTRY

Irreversible pulpitis Apical periodontitis Acute alveolar abscess Infected cyst Sinusitis TMJ Arthritis MPDS After tooth extraction Dry socket Recurrent apthous ulcers Lichen planus Agranulocytosis Cyclic neutropenia

GENERAL CONTRAINDICATIONS Ulcer Asthma Patient with nasal polyp Diabetes Gout Influenza (Reye’s syndrome) Hypo coagulation state Chronic allergic disorders Chronic liver disease Renal failure Salicylate allergy Breast feeding mothers Pregnancy

NSAIDs as Host Modulation Therapy

Treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or downregulating destructive aspects of host response and upregulating protective or regenerative responses.

(CARRANZA) HMTs are systemically or locally delivered

pharmaceuticals that are prescribed as part of periodontal therapy and are used as adjuncts to conventional periodontal treatments.

HMTs offer the opportunity for modulating or reducing this destruction by treating aspects of the chronic inflammatory response.

HMTs do not “switch off” normal defense mechanism or inflammation; instead, they ameliorate excessive of pathologically elevated inflammatory processes to enhance opportunities for wound healing.

The Effect of Non-Steroidal Anti-Inflammatory Drugs on Bleeding During Periodontal Surgery

Journal of Periodontology July 2005, Vol. 76, No. 7, Pages 1154-1160 15 medically healthy subjects (seven males and eight

females), each having two sites requiring periodontal surgery of similar complexity, type, and duration, were selected for the study. The subjects were instructed to take ibuprofen prior to one of the surgeries. A standard bleeding time and papillary bleeding index score were recorded at initial consultation, and prior to the first and second surgeries.

The volume of aspirated blood was measured during each surgery by subtracting the amount of water used for irrigation from the total volume of fluid (blood + irrigation water) collected at 15-minute intervals during the surgery.

In vivo models

First evidence that NSAID block PG

production in gingival tissue was produced by Gomes in 1976 , who demonstrated that inflammed gingival fragments taken from monkeys consistently release PG into the culture medium , and that the pyrazole compd indomethacin reduced the amount of PG released by at least 90% . The NSAID indomethacin , ibuprofen , piroxicam , flurbiprofen , and zomepirac sodium have significant inhibitory effect on the production of PG.

NSAIDS block PGE2 production , thereby reducing inflammation & inhibiting osteoclast activity in periodontal tissue

Studies have shown that systemic NSAIDS such as

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

However daily administration for extended period is

necessary for periodontal benefits

ASPIRIN Acetylsalicylic acid

Pharmacological actions- Analgesic, antipyretic, antiinflammatory actions- Metabolic effects: Blood sugar may decrease, plasma

free fatty acid & cholesterol levels reduced- Respiration: Hyperventilation in salicylate poisoning- Acid base & electrolyte balance: Compensated

respiratory alkalosis- CVS: Vasodilation, increase in cardiac output- GIT: Epigastric distress, nausea & vomiting- Blood: Prolongs bleeding time

ADVERSE EFFECTS: - Nausea, vomiting, epigastric distress, increased

blood loss in stools- Rashes, fixed drug eruptions, urticaria,

rhinorrhea, angioedema, asthma, anaphylactoid reaction

- Salicylism – dizziness, tinnitus, vertigo, impairment of hearing & vision, excitement & mental confusion, hyperventilation & electrolyte imbalance

- Acute salicylate poisoning: Fatal dose in adults 15-30g, lower in children

USES:- Analgesic- Antipyretic- Acute rheumatic fever- Rheumatoid arthritis- Osteoarthritis- Postmyocardial infarction- Patent Ductus Arteriosus- Familial colonic polyposis- Prevention of colon cancer- Treatment of Bartter’s syndrome

Precautions & Contraindications:- Peptic ulcer- Bleeding tendencies- Children with chicken pox or influenza- Chronic liver disease- Diabetics- Pregnancy- Breast feeding mothers

•Dose- 0.3-0.6 g 4-6 hrly orally

Commercially available as:• Aspirin: 350 mg tab.• Disprin: 350mg tab.• Colsprin: 100, 325,650mg tab.• Ecosprin: 75, 150, 325mg tab.

Dental consideration in a patient who is on aspirin therapy

BT CT PT INR

INDOMETHACIN Indole derivative Potent inhibitor of PG synthesis & suppresses neutrophil

motility Well absorbed orally & t ½ is 2-5 hrs Adverse effects: Gastric irritation, nausea, anorexia,

gastric bleeding & diarrhoea, frontal headache, dizziness, ataxia, mental confusion, depression, psychosis, leukopenia, rashes, increased risk of bleeding

Contraindicated in machinery operators, drivers, psychiatric patients, epileptics, kidney disease, pregnant women & children

Dose: 25-50mg BD-QID Commercially available as- Idicin, Indocap, Indoflam : 25mg, 75mg tab

IBUPROFEN Propionic acid derivative

Adverse effects:- Gastric discomfort, nausea & vomiting- Headache, dizziness, blurring of vision, tinnitus &

depression- Avoided in pregnancy, peptic ulcer patient &

asthmatic patients

USES:

- Analgesic & Antipyretic- Rheumatoid arthritis, osteoarthritis, musculoskeletal

disorders- Soft tissue injuries, fractures, vasectomy, tooth

extraction- Postpartum & postoperatively : suppress swelling &

inflammation- Dose: 400-800 mg TDS

• Comercially available as- Brufen, Emflam, Ibusynth : 200, 400, 600mg tab. Ibugesic : 100mg, 400 mg tab.

DICLOFENAC SODIUM Aryl-acetic acid derivative Well absorbed orally Plasma t ½ - 2 hrs Adverse effects: Epigastric pain, nausea, headache,

dizziness, rashes Uses: Rheumatoid arthritis, ankylosing spondylitis,

dysmenorrhea, post traumatic & post inflammatory conditions

Dose: 50mg TDS, then BD oral, 75mg deep i.m Commercially available as: Voveran, Diclonac, Movonac : 50 mg tab. Diclomax : 25, 50 mg tab.

KETOROLAC Pyrrolo-pyrrole derivative Potent analgesic & modest anti inflammatory Rapidly absorbed after oral & i.m administration Plasma t ½ is 5-7 hrs Adverse effects: Nausea, abdominal pain,

dyspepsia, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritis, pain & fluid retention

Not be given to patients on anticoagulants

USES:- Postoperative & acute musculoskeletal pain: 15-

30 mg i.m or i.v every 4-6 hrs- Used for renal colic, migraine, pain due to bony

metastasis- Orally in a dose of 10-20 mg 6 hrly.- Commercially available as – Ketorol, Zorovon, Ketanov, Torolac : 10mg tab.

NIMESULIDE Preferential COX-2 inhibitors Used for short lasting painful inflammatory

conditions like sports injuries, sinusitis, ear nose throat disorders, dental surgery, bursitis, low backache, dysmenorrhoea, post operative pain, osteoarthritis & for fever

Completely absorbed orally, excreted in urine, t ½ of 2-5 hrs

Adverse effects:- Epigastralgia, heart burn, nausea, loose motions,

rash pruritus.- Hematuria & fulminant hepatic failure in few

cases Useful in asthmatics, bronchospasm or intolerance

to aspirin & other NSAIDs Dose: 100 mg BD Commercially available as- Nimulid, Nimegesic, Nise, Nobel, Nimodol :

100mg tab.

Conclusion Analgesics are definitely useful in

reducing pain & improving the quality of life but

have their own spectrum of adverse effects.

No single drug is superior to all others for

every patient. Choice of drug is inescapably

empirical.