IT IS A SHAME THAT WE POSSESS SUCH INSUFFICIENT KNOWLEDGE CONCERNING

THE CHARACTER OF PAIN—THOSE SYMPTOMS WHICH REPRESENT THE

ESSENTIAL PART OF ALL BODILY SUFFERING OF MAN (GOLDSCHEIDER 1894).

PRESENTED BY :- DR JAYESH

P.G STUDENT

DEPARTMENT OF ORAL AND MAXILLOFACIAL SURGERY

ANALGESIC

• INTRODUCTION

• FEW TERMS

• WHAT IS PAIN

• BRIEF THEORIES ABOUT PAIN

• BRIEF OF PAIN PATHWAYS

• CLASSIFICATIONS OF ANALGESICS

• OPIOID ANALGESICS

• VARIOUS OPIOID ANALGESICS AND THERE PROPERTIES

• CLASSIFICATION OF NSAIDS

• VARIOUS NSAIDS AND THERE PROEPRTIES

• CONCLUSION

• REFERENCES

A FEW TERMS

• ALGESIA(pain)- is an ill defined, unpleasent sensation, usually evoked by an external or internal noxious stimulus

• Pain :- An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.(IASP)

• Allodynia :- Pain due to a stimulus that does not normally provoke pain.• Hyperalgesia :- Increased pain from a stimulus that normally provokes painANALGESIcs :-Analgesics are a class of drugs which obtunds the perception

of pain without producing unconsciousness”

“Analgesics are drugs that selectively relieve pain by acting in the CNS or on the peripheral pain mechanisms, without significantly altering consciousness”

• Nociceptor -A high-threshold sensory receptor of the peripheral somatosensory nervous system that is capable of transducing and encoding noxious stimuli

• Neuropathic pain-Pain caused by a lesion or disease of the somatosensory nervous system

• THE WORD IS DERIVED FROM TWO GREEK WORDS

• AN + GESIC

• NO PAIN

WHAT IS PAIN

• It is a subjective expèrience which is hard to define even if we know what we mean by it.

• Before treating pain we must know its proper etiology

• It can be of either or combination of the following two types

• A. Due to peripheral nociceptive afferent neuron, which is activated by noxious stimuli. For eg :- direct response to an untoward incedence associated with tissue damage like injury, inflammation, cancer. It can

• B. Central mechanism by which afferent input generates a pain sensation

BRIEF ABOUT PAIN

• Theories of pain

• The Specificity Theory refers to the presence of dedicated pathways for each somatosensory modality. The fundamental tenet of the Specificity Theory is that each modality has a specific receptor and associated sensory fiber (primary afferent) that is sensitive to one specific stimulus (Dubner et al. 1978).

• This is the fundamental tenet of the Specificity Theory, which postulates that there is a dedicated fiber that leads to a dedicated pain pathway to the sensory modality's region of the brain. This model, therefore, suggests that a pathway specific to pain exists

• INTENSITY THEORY OF PAIN

• First, conceptualized in the fourth century BCE by Plato in his oeuvre Timaeus (Plato 1998), the theory defines pain, not as a unique sensory experience but rather, as an emotion that occurs when a stimulus is stronger than usual.

• This theory competed with the Specificity Theory of Pain, which was championed by von Frey. However, the theory lost support with Sherrington's evolutionary framework for the Specificity Theory and postulated the existence of sensory receptors that are specialized to respond to noxious stimuli, for which he coined the term “nociceptor”.

• PATTERN THEORY OF PAIN

• J. P. Nafe postulated a “quantitative theory of feeling” (1929). This theory ignored findings of specialized nerve endings and many of the observations supporting the specificity and/or intensive theories of pain. The theory stated that any somaesthetic sensation occurred by a specific and particular pattern of neural firing and that the spatial and temporal profile of firing of the peripheral nerves encoded the stimulus type and intensity

• GATE CONTROL THEORY OF PAIN

• In 1965, Ronald Melzack and Charles Patrick

• Melzack and Wall accepted that there are nociceptors (pain fibers) and touch fibers and proposed that that these fibers synapse in two different regions within the dorsal horn of the spinal cord: cells in the substantia gelatinosa and the “transmission” cells. The model proposed that signals produced in primary afferents from stimulation of the skin were transmitted to three regions within the spinal cord: 1) the substantia gelatinosa, 2) the dorsal column, and 3) a group of cells that they called transmission cells. They proposed that the gate in the spinal cord is the substantia gelatinosa in the dorsal horn, which modulates the transmission of sensory information from the primary afferent neurons to transmission cells in the spinal cord. This gating mechanism is controlled by the activity in the large and small fibers. Large-fiber activity inhibits (or closes) the gate, whereas small-fiber activity facilitates (or opens) the gate.

BRIEF ABOUT PAIN PATHWAY• The ascending pathways that mediate pain

consist of three different tracts:

• 1.the neospinothalamic tract,

• 2. the paleospinothalamic

• 3.archispinothalamic tract.

• SITES OF ANALGESIC ACTION :

• PAIN PATHWAY :

• A and C-fibers provide the initial transduction mechanism for mechanical, thermal and chemical noxious stimulus.

• The resultant action potentials evoked in the unmyelinated C-fibers and myelinated A fibers propagates to the spinal and dorsal horn where they synapse with both spinal interneuron’s and projection neurons, however it must also be appreciated that retrograde action potential transmission may evoke local “axon reflex”-- mediated peripheral release of neuropeptides attributed to inflammation and peripheral sensitization following injury.

• The axons of peripheral nociceptors project to the spinal cord, C-fibers synapse primarily in laminar II, whereas A fibers synapse in both laminar I and V of the dorsal horn.

• Projection neurons from the spinothalamic, spinoreticular and other ascending tracts relay nociceptive information through thalamic nuclei to cortical center of pain representation.

• The pharmacology of cortical representation is somewhat obscure, and it is at this sub thalamic levels that a clear picture of the inhibiting mechanisms modulating afferent nociceptive input emerges.

• GENERAL PRINCIPLESOF PAIN CONTROL:

• It is not considered a good practice to treat pain or distress without first understanding the cause of of the symptoms.

• If the cause cannot be determined immediately from a short but adequate history and appropriate physical examination, it is permissible to control the pain or distress symptomatically for time being.

• A suitable programme for the control of pain can be selected to fit the individual case when the specific causative factor for the occurrence of pain has been established .

• As for as the control of pain by the use of drug is concerned ,it is accomplished by 3 major pharmacological actions.

• Counteracting the cause of pain.

• Blocking the peripheral pain impulses.

• Modifying the central reception of pain

CLASSIFICATIONS

• Analgesics are divided into two groups,• A. Opioid/narcotic/morphine-like analgesics

• B. Nonopioid I non-narcotic/ aspirin-like I antipyretic or anti-inflammatory analgesics

OPIOIDS

• What are opioids?• Opioids are a class of drugs that are commonly prescribed for their analgesic, or pain-killing,

properties. They include substances such as morphine, codeine, oxycodone, and methadone

• Opium A dark brown, resinous material obtained from poppy (Papaver somniferum) capsule

• It contains two types of alkaloids.

Phenanthrene derivatives• Morphine (10% in opium)

• Codeine (0.5% in opium)

• Thebaine (0.2% in opium),

Benzoisoquinoline derivatives• Papaverine (1 %)

• Noscapine (6%)

OPOIDS

• Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album .

• Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium. Thomas Sydenham

• OPIOID ANALGESICS

CHARACTERISTICS :

• Morphine like drugs produce analgesia, drowsiness, changes in mood and mental clouding.

• Action is relatively selective in that other sensory modalities are not affected.

• Continuous dull pain is relived more effectively than sharp, intermittent pain, but with sufficient amount of opioids.

• Behavioral and pharmacological evidence of mood alterations point to the role of dopaminergic pathway particularly involving the nucleus accumbens (NACC) in dry-induced reward.

• Alters the hypothalamic thermostat of the patient lower temperature by chronic use.

• Inhibits the secretion of GnRH and CRF, thus decreasing concentrations of FSH, ACTH and -endorphin.

• Therapeutic doses increases accommodative power and lowers intraocular tension in both normal and glaucomatous eyes.

• Excess dosage causes convulsions which are antagonized by naloxone.

C LASSI FICATION OF O P I O I DS

1. Natural opium alkaloids:

Morphine, Codeine

2. Semisynthetic opiates:

Diacetylmorphine (Heroin), Pholcodeine.

3. Synthetic opioids:

Pethidine (Meperidine),Fentanyl, Methadone, Dextropropoxyphene, Tramadol.

CONTDD...• Opioid drugs include

• 1. full agonists:- Natural: morphine, codeine

synthetic: pethidine, methadone

• 2.partial agonists:- naloxone, naltrexon

• 3. antagonists:- pentazocain, nalorpine,nalbupine

SYNTHETIC DERIVATIVES1.Phenylpiperidine series :- eg. Pethidine. 1° synthethic morphine like drug. Is chemically unlike morphine but pharmacologically similar

Other egs- Fentanyl and Sufentanil

2. Methadone series – eg methadone. Structurlly its not at all similar to mprphine but in solution assumes a similar conformation. Longer acting than morphine .

Other eg- Dextropropoxyphene (no longer used as is cardiotoxic)

3. Benzomorphan series :- eg pentazocine and cyclazocin. They differ from morphine in receptor binding site

4. Thebain series:- eg Etorphine and buoreirophine

ENDOGENOUS OPIOIDS

• Discovered during the 1970s

• One of the observation that naloxone administration had little effect , although the drug was effective in reversing or preventing the effects of exogenous opioids.

• 1° physiological evidence of them came when analgesia produced by electrical stimulation of brain was reversed by naloxone.

• And in 1973 3 labs demonstrated opiate binding sites in brain.

• Up until now the actions of morphine, heroine as antinociceptive abd addicitve properties were described in context of interaction with other neurotransmitter systems.

• In 1975 Hughes and associates identified ENKEPHALIN and then dynorphine and endorphines where identified

OPIOID RECEPTORS

AGONISTS AND ANTAGONISTS1. Pure Agonist – eg morphine, have high affinity for mue receptor and less for kappa

and delta sites

2. Partial agonists and mixed agonist-antagonist- nalorphone and pentazocine. Have a degree of agonist and antagonist acitivity on different receptors

ANALGESICS

• MORPHINE• Morphine is the principal alkaloid in opium and still widely used

• Is named after the greek god of dream MORPHEUS

• Isolated inpure form first by Sertumer in 1806

• Followed by Codein in 1832 by Robiquet and Papaverine in 1848

• The drugs toxic and adictive side effects have led to a search for a synthetic substitue which dont share the same side effects,

• The search of opoid agonist lead to synthesis of opoid antagonist and compounds with agonist-antagonist properties

PHARMACOLOGICAL ACTIONS

1. CNS :-Morphine has site specific depressant and stimulant actions in the CNS by interacting primarily with the mue opioid receptor as a full agonist. The depressant actions are

• Analgesia :- Is a strong analgesic depending on dose.

• Has spinal and Supraspinal components.

• Acts in the substantia gelatinosa of dorsal horn to inhibit release of excitation transmitters from primary afferents carrying pain impulses.

• Causes orthostatic hypotension through peripheral vasodilatation causing decrease in peripheral resistance in supine

• SEDATION :

• Drowsiness and indifference to surroundings occurs without motor incoordination, ataxia or apparent excitement (contrast alcohol ).

• Higher doses progressively cause sleep and coma

• MOOD AND SUBJECTIVE EFFECTS :

• Has a calming effect.

• Loss of apprehension, feeling of detachment.

• Has got euphoric effect.

• RESPIRATORY CENTER:

• Depresses respiratory center in a dose dependent manner.

• TEMPERATURE

• It is depres'd; hypothermia occurs in cold surroundings.

• Vasomotor centre

• It is depressed at higher CONCENTRATIONs and contributes to the fall in BP.

• Morphine stimulates:1. chemoreceptor trigger zone (CTZ)

2. Edinger Westphal nucleus of III nerve

3. Vagal centre- It is stimulated bradycardia is the usual response.

4. Neuro-endocrine

5. CVS

6. GIT

7. Other smooth muscles

• PHARMACOKINETICS :

• can cross placenta freely

• Oral absorption is unrelaible with high 1° pass.

• Oral bioavalibility is 1/6 to ¼.

• 30% is bound to plasma protein

• In liver by glucuronide conjugation to morphine 6 glucuronide which is actove and a poten metabolite

• Plasma half life is 2-3 hours and parentral is 4-6 hours.

• 90% is exctreted within 24 hours

AADVERSE EFFECT OF MORPHINE• Acute posioning – in non tolerant adults even 50 mg i.m produces toxicity

• seen as coma,flacciity,shallow and occasional breathing, canosis, fall in B.P shock, convulsions

• Treatment – respiratory support, Maintaincence of I.V fluids, gastric lavage with pot. Permanganate

• Naloxone 0.4-0.8mg I.V repeated every 2-3 minutes till respiration picks uo

TOLERANCE AND DEPENDENCE• Mainkly due to enhanced metabolism and cellular tolerance. With addicts tolerating

morphine in grams( much beyond the normal lethal dose)

• Treatment – substituion with oral methadone with later gradual taper of methadone

• PRECAUTIONS• 1. infants and elderly more susceptible to respiratory deprresant action of morphine

• 2. patients with respiratory insufficiency

• 3.bronchial asthma- as morphine can precipitate histamine release

• 4.head injuries- a. Retains CO2--- increased intracranial pressure

b.vomiting,miosis and altered mental state interferes with patient assesment

c.respiratory depression

• 5.Hypotension and hypovolumeia

• 6.elderly male- urinary retention

• 7.hypothyroid, liver and kidney disease- patients are more sensitive

• 8.Unstable personalities

• DOSAGE

• 10-50 mg oral, 10-15 mg i.m or s.c

• 2-6 mg i.v

• 2-3 mg epidural/intrathecal

• Children 0.1-0.2mg/kg

MORPHINE AND ITS CONGENERS• CODEINE

• Methyl-morphine, converted to morphine in body.

• Less potent than morphine in actions(1/10th )

• Almost comparable to aspirin

• Has got more selective cough suppressant action.

• Good activity by oral route (4 to 6 hrs action).

• Prominent side effect- constipation.

• Analgesic action is due to generation of morphine due to demethylation

• HEROIN : • 3 times more potent than morphine

• Has got more euphoric effect and is highly addictive.

• PETHIDINE :

• Was synthesized as an atropine substitute in 1939.

• Chemically unrelated to morphine but has similar actions with less unwanted actions.

• Used as an analgesic (substitute of morphine).

• As a preanesthetic medication but not for cough or diarrhoea.

• Dose to dose 1/10° in analgesic potency but efficacy approaches near morphine and more than codeine

• Metablolized in liver

• T1/2 is 2-3 hours

• Overdose -> tremors. Mydriasis,delerium due to accumulation of norpethidine

• Dose 50-100 mg IM, SC.

• FENTANYL- 80-100 times more potent than morphine

• Fast acting (5 minutes after i.v)

• Short duration 30-45 minutes.

• T1/2 is 4 hours

• Transdermal Fentanyl is used for chronic pain like cancer

• METHADONE- synthetic opioid

• Actions similar to morphine

• High oral to parentral ratio

• In single doses its slightly more potent than morphene but on repeate dosages the potency increases due to release of the medicine from absorption sites(has a high affinity to tissue proteins),

• T1/2 on chronic use -24-36 hours

• Metabolized in liver by demethylazition and cyclization

• Excreted in urine

• Used mainly in Morphene addiction withdrawal.

• 1mg for 4 mg of morphene

• DOSAGE :- 10mg i.m

• TRAMADOL• Centally acting

• Releaves pains by opioid and other mechanisms

• Mue receptor affinity

• Activates monoaminergic spinal inhibtion

• Action only partially reversed by antagonist naloxine

• 100mg iv tramadol = 10 mg of morphine

• Oral:parentral is 1.2:1

• T1/2 is 3-5 hours

• Well tolerated

• For mild to medium short lasting pain as well as chronic pain of cancer but is not effective in severe pain

• DOSAGE- 20-100 oral/i.v/slow i.v

• Children 1-2mg/kg 4-6 hourly

USES OF MORPHINE AND ITS CONGENERS1. ANALGESIC – in severe pain of any type

2. Preanaesthetic mediciation- morphine and pethidine

3. Relief of anxiety and apprehenson- morphine and pehtidine . Esp in myocardial infarction ,internal bleeding

4. Acute left ventricular failue- morphine .

5. Cough- codeine is used

6. Diarrhoea- codeine constipating action

OPIOID COMPLICATIONS AND SIDE EFFECTS:

COMMON SIDE EFFECTS:

SEDATION, DIZZINESS, NAUSEA, VOMITING, CONSTIPATION(highest incidence), PHYSICAL DEPENDENCE, TOLERANCE AND RESPIRATORY DEPRESSION

LESS COMMON SIDE EFFECTS:

DELAYED GASTRIC EMPTYING, HYPERALGESIA, IMMUNOLOGICAL AND HORMONAL DYSFUNCTION, MUSCLE RIGIDITY AND MYOCLONUS.

Proper patient screening, education, and preemptive treatment of potential side effects may aid in maximizing effectiveness while reducing the severity of side effects and adverse events.

• ENDOGENOUS OPIOID PEPTIDES :

• Have morphine like actions, isolated from brain, pituitary, spinal cord and GIT.

• Have high affinity for opioid receptor.

• 3 Distinct types include

• Endorphins ( endorphin)

• Enkephalins (Methionin-enkephalin)

• Dynorphins (DYN-A, DYN-B).

• Has got neuromodulator or neurotransmitter actions.

A HISTORY

IMPORTANCE OF CYCLOOXYGENASE

MECHANISM OF ACTION OF NSAID’S

SALICYLATES• Eg :- Aspirine ie acetyl salicylic acid

• Pharmacological action1. Analgesia :- good analgesic.as they inhibit PG sysnthesis

2. Antipyretic :-good anti pyretic.

3. Anti inflammatory :- at higher dosage aspirin is a good anti inflammatory

4.Acid –Base and Electrolyte Balance :- a. Anti inflammatory doses. B. At Toxic levels

5.Ductus Arteriosus closure:-

6.GI tract:- all NSAIDs are gastric irritants to various levels.

7.Respiratory:-A. at therapeutic dosaes..B. Toxic dosage

8.CVS :- A. Therapeutic dosage. B. Toxic dosage

9. Immunological:- interferes AB-AG rxn . Helps in rheumatic fever

10. Uric acid:- 1-2 gm /day – increases plasma urate by preventing excretiing from DCT. At 5gm /day increase excretion by preventing resorption from PCT(such such hig dose are not advisable)

11. blood-irreversibly inhibit platelet cyclooxygenase

TXA2 is generated from prostaglandin H2 by thromboxane-A synthase

TXA2(Thromboxane A2)

PHARMCOKINETICS• Salicylates are well Absorbed in stomach and upper small intestine(aspirin is a exception)

• Aspirin is deacetylated in liver, plasma and other tissues to release salicylic acid

• Plasma T1/2 of aspirin is 3-5 hours

• Elimination is dose dependent and follows 1° order kinetics in small and zero order kinetics in higher dosages

• Excreted in urine

ADVERSE EFFECTS1. GI tract :- nausea, epigastric distress

2. Allergy :- is uncommon. As rash, urticaria,photosensitivity,rhinorrhoea,asthma

3. Hemolysis :- in patient with G6PD deficiency

4. Nephrotoxicity :- All NSAIDs are nephrotoxic on long term usage . Salt and water retention with impaired renal function

5. Hepatotoxicity :-

6. Reyes syndrome:- is a form of hepatic encephalapahy, seen in children following a viral fever.. Can be fatal. So asprin is contraindicated in children with viral fever

7. Pregnancy and infancy :- as PG synthesis is inhibited leads to delay of onset of labor at term. Premature closire of ductus arteriosus maylead to portal hypertension in foetus

8. Salicylism:- chronic use of salicylates. Seen as headache ,vertigo , dizziness, tinnitus ,vomiting. reversble

DOSAGE, PRECAUTION AND CONTRA INDICATIONS• Aspirin :- analgesic 300-600 mg every 6-8 hrs

• Anti inflammatory :- 4-6 gm/day

• Anti platelet :- 75-300 mg /day

• Precaution :- in peptic ulcer, liver diseases, bleeding tendencies, viral fever in children,

Pregnancy ,

Treatment with NSAIDs should be stopped one week before any surgery

USES• Analgesic :- headache, backache,myalgias, neuralgias, dysmenorrhoea,

• Fever :-

• Inflammatory condition :_ arthritis

• Acute Rheumatic fever :- 4-6 gm /day in 4-6 divided doses

• Rheumatoid artheritis :- symtomatic relief only. 4-6 gm /day in 4-6 divided doses

• Osteoartheritis

• Post myocardial infarction. 50-300 mg /day.

FEW OTHER NSAIDS• PARA-AMINO PHENOL DERIVATIVES

• (paracetamol )

• Is a meabolite of phenacetin(1° drug of the gruop)

Actions :-

• Analgesic, good antipyretic and weak antiinflammatory(due to weak PG inhibitory activity)

• Acts on cyclooxygenase on the brain (antipyretic)

• No action on respiration,acid base balance , cellular metabolism, cardio vascular system and platelet function

• Pharmacokinetics :- well absorbed orally

• Metabolised by hepatic microsomal enzymes by glucoronide conjugation and glutathione conjugation

• Adverse reaction:- in large dose> acute paracetamol poisoning can occur.

• children more susciptable

• Hepatotoxic . Seens as

• Increased serum transaminase. Jaundice,liver tenderness, and prolonged prothrombin time.

• nephrotoxic

• USES :- headaches, musculoskelatal pain, toothache ,

• Dose to dose is equally affective as aspirin for non inflammatory condition

• DOSE :- 0.5-1 gm TDS

• infants -50mg

• Children – 1-3 yrs 80-160 mg

• 4-8 years 240-320 mg

• 9-12 yrs – 300-600 mg

• PROPIONIC ACID DERIVATIVE

• Eg :- ibuprofen,

• Antiinflammatory efficacy >high dose aspirin

• Adv effect :- same as aspirin but it is better tolerated. Asthma,

• Not prescribed to pregnant women and in patients with peptic ulcer

• Pharmacokinetics decrease diuretic and anti hypertensive action of thiazides and beta blockers

• Uses:-

• analgesic and anti pyretic as aspirin

• Rheumatoid artheritis

• Soft tissue injuries, toooth extraction, fractures,post partum, supressing swelling and inflammation (ibuprofen 400mg better than aspirin 650+codeine 60mg)

OTHER PROPIONIC ACID DERIVATIES AND DOSAGE

s.No Drug Plasma t1/2 Dose

1. Ibuprofen 2hr 400-600mg TID

2 Naproxen(most potent) 12-16 hrs 250 mg BD-TD

3 Ketoprofen 2-3 hrs 50-100mg BD-TD

4 Flurbiprofen 4-6 hrs 50mg BD-QID

ANTHRANILIC ACID DERIVATIVE• MEPHENAMIC ACID :- is a analgesic,antipyretic and anti inflammatory .

• It inhibits COX and antagonises certain actions of PG’s

• Adverse effect – diarrhoea, epigastric distress

• PHARMACOKINETICS

• :- oral absorption is slow but complete

• :- plasma t1/2 2-4

• Uses :- analgesic in painjoint soft tissue pain where strong antiinflammatory action is not needed

• DOSE :- 250-500 mg TDS

ARYL- ACETIC ACID • DICLOFENAC SODIUM :- is analgesic- antipyretic-anti inflammatory . Similar in efficacy

to naproxen

• Inhibits PGs synthesis and has short lasting anti platelet action

• Plasma t1/2 is 2 hrs

• Adv – mild epigastric pain. Nausea vomiting.

• Uses. Rheumatoid and osteosrthritis. Toothache. Ankylosing spondilitis. Post operative inflammatory conditions.

• DOSE- 50 mg TDS the BD oral

• 75 mg deep I.M

OXICAM DERIVATIVEPIROXICAM• Long acting.

• Potent anti inflammatory . Good analgesic and antipyretic action

• Reversible inhibitor or COX

• Lower PG in synovial fluids . Decreases IgM . So inhibits inflammation

• Prolongs bleeding time

PHARMACOKINETICS

• Metabloised in liver by hydroxylation and glucuronide conjugation.

• Excreted in urine.

• Plasma t1/2- upto 2 days

• Adv – heart burns, nausea

USES – short term analgesic and long term anti inflammatory

DOSE – 20 mg BD for days followed by 20 mg OD

PYRROLO-PYRROLO DERIVATIVE

• Eg ketorolac

• Potent analgesic and modest antiinflammatory

• Postoperative efficacy is as good as morphine but free of opioids side effects

• In short lasting pain is comparable to aspirin

Pharmacokinetics

• Metabolism in liver by glucurinidation

• Plasma t1/2 is 5-7 hrs

Use :- postoperative pain, musculoskelatal pain.

Dose :- 10-20 mg 6 hrs for short term

# in dental pain it is rated superior to

Aspirin 650 mg,PCM 600 mg, and equivalent to ibuprofen 400mg

Not to be used for more than 5 days

INDOLE DERIVATIVE• Eg :- indomethacine

• Antiinflammatory and prompt antipyretic. Only relieves inflammatory or tissue related pain

• High potency inhibitor or PG and supresses neutrophil motility

Pharmacokinetics :-

• Partly metabolized in liver.

• Excreted by kidneys

• Plasma t1/2 – 2-5 hours

Adv- GI and CNS side effects

-increased risk of bleeding

Contraindicatied in – machinary operators, drivers, psychatric patients, epileptics, kidney disorders , pregnant women

Dose :- 25-50 mg BD-QID

USE- because of the contraindications its used as a reserve drugs where potent antiinflammatory drugs are needed like gouts, ankylosing spondilitis,and in closure of patent ductus arteriorus

PYRAZOLONES• Eg – Metamizol

• Potent analgesic and antipyretic but poor antiinflammatory .

• Can be given orally or iv (can cause fal of B.P sometimes)

Adverse - agranulocytosis

Dose – 0.5-1.5 mg oral/i.m/i.v

Eg- Propiphenazone(saridon)

Better than metamizol

No report of agranulocytosis

PREFERENTIAL COX 2 INHIBITOREg- Nimesulide• Weak PG inhibitor and relative COX 2 selective

• Used for short lasting painful inflammatory conditions like sports injuries, sinusitis,

T1/2 is 2-5 hrs

Adverse – GI troubles, dermatological, and central(dizziness)

Usefull only in patient .asthamatics and those who develop bronchospasm to aspirin

Dose – 100 mg BD

Eg- Meloxicamcongenar of piroxicam.

More selective for COX 2

same as piroxicam

DOSE – 7.5 mg-15mg OD

SELECTIVE COX 2 INHIBITOR• COX 2 have a theoratical advantage of inhibiting COX2 without affecting cox 1.

• Eg :- celecoxib

• Is antiinflammatory, analgesic and antipyretic with low ulcerogenic potential

• In rheumatoid artheritis 0 naproxen or diclofenac

• T1/2 is 11 hrs

• In osteroartheritis and rheumatoid artheritis

Dose – 100-200 mg BD

Eg- Etriocoxib

Dose – 60-120 mg OD

• IMPLICATIONS FOR DENTISTRY :

• Dental pain is most amenable to treatment by NSAID analgesics and acetaminophen

• Opioid combination drugs are most useful in patients with a strong emotional component to their pain.

• The co-administration of L.A and parenteral opioid analgesics is a common and generally safe practice. HOWEVER,

• Large doses display supradditive toxicity with likely respirators of acidosis caused by an opioid can increase the entry of a local anesthetic into the CNS.

• In general, the co-administration of CNS depressants produces summation of effects and occasionally a greater than anticipated depression (i.e. supradditive effect).

• CONCLUSION:

• Nociception is the ability to perceive potentially tissue damaging energy to promote avoidance behaviour & minimize the insult.Pain perception also aids in the repair of minor

tissue injuries by limiting activity & splinting the injured tissue..Beyond this neuronal activity can be attenuated by analgesic pharmacotherapy.

• With the acknowledgement that nociceptive pathway can suffer these deleterious changes, preemptive therapy may be able not only to attenuate the nociceptive signal but

also prevent the progression to chronic, recalcitrant neurogenic pain, Appreciation of currently available analgesics & an anticipation of those in development will allow for the

judious management of the pain patient.

REFERENCES• http://www.iasp-pain.org/Taxonomy

• RANG AND DALE’S PHARMACOLOGY 6° EDITION

• BASIC AND CLINICAL PHARMACOLOGY .BERTRAM G KATZUNG AND ANTONY J TREVOR 13° EDITION

• K.D. Tripathi - Essentials of Medical Pharmacology, 6th ed

• Textbook Of Medical Pharmacology By Padmaja Udaykumar

• Good man and gillman the pharmacological basis of therapeutics

• Theories of pain: from specificity to gate control Massieh Moayedi, Karen D. Davis Journal of Neurophysiology Published 1 January 2013 Vol. 109 no. 1, 512

• ORAL & MAXILLOFACIAL SURGERY CLINICS OF NORTH AMERICA-PHARMACOLOGY 2002