ANALGESIA ANALGESIA

AND AND

ANALGESICSANALGESICS

What is PAIN?

Pain is defined as an “unpleasant sensory and Pain is defined as an “unpleasant sensory and emotional experience associated with actual or emotional experience associated with actual or potential tissue damage or described in terms of potential tissue damage or described in terms of such damage.”such damage.”

PATHWAYS OF PAINPATHWAYS OF PAIN

STEPS IN CONDUCTION STEPS IN CONDUCTION

TRANSDUCTIONTRANSDUCTION

TRANSMISSIONTRANSMISSION

MODULATIONMODULATION

PERCEPTIONPERCEPTION

PAIN MODULATIONPAIN MODULATION

Neural impulses re altered, changed or Neural impulses re altered, changed or modulated as they travel up neural axismodulated as they travel up neural axis

Experience of pain is more complex than Experience of pain is more complex than simple perception – reaction mechanismsimple perception – reaction mechanism

PAIN MODULATION PAIN MODULATION

In the trigeminal spinal tractIn the trigeminal spinal tract

based on the Gate control theory of painbased on the Gate control theory of pain

Pain modulation in reticular formationPain modulation in reticular formation

for examplefor example

locus cerulus - norepinephrinelocus cerulus - norepinephrine

nucleus raphe - serotoninnucleus raphe - serotonin

substantia nigra - Dopaminesubstantia nigra - Dopamine

DESCENDING INHIBITORY SYSTEMDESCENDING INHIBITORY SYSTEM

Modulation effects of endorphins.Modulation effects of endorphins.

Pain modulation by psychological factorsPain modulation by psychological factors

Excitatory modulating factorsExcitatory modulating factors

Inhibitory modulating factorsInhibitory modulating factors

TERMINOLOGIESTERMINOLOGIES

ANALGESIAANALGESIAANALGESICSANALGESICSHYPOALGESIAHYPOALGESIAHYPERALGESIAHYPERALGESIAALLODYNIAALLODYNIA

TREATMENT OF PAINTREATMENT OF PAINGOALS OF THERAPYGOALS OF THERAPY

• Decrease the frequency and / or severity Decrease the frequency and / or severity of the painof the pain

• General sense of feeling betterGeneral sense of feeling better

• Increased level of activityIncreased level of activity

• Return to workReturn to work

• Decreased health care utilizationDecreased health care utilization

• Elimination or reduction in medication Elimination or reduction in medication usageusage

MANAGEMENT OF MANAGEMENT OF OROFACIAL PAINOROFACIAL PAIN

PHARMACOLOGICAL THERAPY

PHYSICAL THERAPY

PSYCOLOGICAL COUNSELLING

ANALGESIC AGENTS

ANAESTHETIC AGENTS

ANTIINFLAMMATORY

MUSCLE RELAXANTS

ANTI DEPRESSANTS

ANTICONVULSIVE

ANTIANXIETY

PHARMACOLOGICAL THERAPYPHARMACOLOGICAL THERAPY

VASOACTIVE AGENTSVASOACTIVE AGENTS

NOREPINEPHRINE NOREPINEPHRINE BLOCKERSBLOCKERS

ANTIMICROBIALSANTIMICROBIALS

ANTIVIRALSANTIVIRALS

ANTIHISTAMINE AGENTSANTIHISTAMINE AGENTS

NEUROLYTICSNEUROLYTICS

URICOSURIC AGENTS ETCURICOSURIC AGENTS ETC

B. B. PHYSICAL THERAPY PHYSICAL THERAPY 1 MODALITIES1 MODALITIES

A.A. SENSORY STIMULATIONSENSORY STIMULATIONCUTANEOUSCUTANEOUSTRANSCUTANEOUSTRANSCUTANEOUSPERCUTANEOUSPERCUTANEOUS

B.B. ULTRASOUNDULTRASOUNDC.C. ELECTROGALVANIC STIMULATIONELECTROGALVANIC STIMULATIOND.D. DEEP HEATDEEP HEAT

2. MANUAL TECHNIQUES2. MANUAL TECHNIQUESA.A. MASSAGEMASSAGEB.B. SPRAY & STRETCH TECH.SPRAY & STRETCH TECH.C.C. EXERCISEEXERCISED.D. PHYSICAL ACTIVITYPHYSICAL ACTIVITY

C. PSYCHOLOGIC THERAPYC. PSYCHOLOGIC THERAPY1.1. COUNSELLINGCOUNSELLING2.2. BEHAVIORAL MODIFICATION TRAININGBEHAVIORAL MODIFICATION TRAINING

A. STRESS REDUCTION TRAININGA. STRESS REDUCTION TRAINING B.RELAXTION PROGRAMMEB.RELAXTION PROGRAMME

OPIOID ANALGESICSOPIOID ANALGESICS

Opioid refers to all compound related to opiumOpioid refers to all compound related to opium

Opium derived from ‘opos’ the Greek word for Opium derived from ‘opos’ the Greek word for juicejuice

poppy flower poppy flower PapaverPapaver somniferam somniferam

11stst mentioned mentioned inin Ebers papyrus 1500 BC.Ebers papyrus 1500 BC.

Opium contains more than 20 alkaloids.Opium contains more than 20 alkaloids.

1806 Serturner isolated and named ‘morphine’ 1806 Serturner isolated and named ‘morphine’ after Morpheus the Greek god of dreams .after Morpheus the Greek god of dreams .

1975 Hughes and associates identified 1975 Hughes and associates identified endogenous opioid enkephalinendogenous opioid enkephalin

Natural opioids occur in 2 Natural opioids occur in 2 places:places:

1) In the juice of the opium poppy 1) In the juice of the opium poppy (morphine and codeine)(morphine and codeine)

2) As endogenous endorphins2) As endogenous endorphinsAll other opioids are prepared from either All other opioids are prepared from either

morphine (semi synthetic opioids such as morphine (semi synthetic opioids such as heroin) or they are synthesized from heroin) or they are synthesized from precursor compounds (synthetic opioids precursor compounds (synthetic opioids such as fentanyl)such as fentanyl)

Endogenous OpioidsEndogenous Opioids

Pro-opiomelanocortin peptides:Pro-opiomelanocortin peptides:-endorphin-endorphin

Pro-enkephalin peptides:Pro-enkephalin peptides:met-enkephalin and leu-enkephalinmet-enkephalin and leu-enkephalin

Prodynorphin peptides:Prodynorphin peptides: Dyn-A, Dyn-B and Dyn-A, Dyn-B and -neo-endorphin-neo-endorphin

Endomorphins:Endomorphins:Endomorphin-1 and Endomorphin-2Endomorphin-1 and Endomorphin-2

MECHANISMMECHANISM

3 TYPES OF RECEPTORS3 TYPES OF RECEPTORSMU MU KAPPAKAPPADELTADELTAN/OFQN/OFQ

ACTION produced on binding of these ACTION produced on binding of these receptors by opioids.receptors by opioids.

Binding of opioid agonistBinding of opioid agonist

Inhibition of adenyl cyclase activityInhibition of adenyl cyclase activity

activation of receptor operated k+ currentactivation of receptor operated k+ current

suppression of voltage gated Ca+ currentsuppression of voltage gated Ca+ current

hyperpolarisation of membrane potentialhyperpolarisation of membrane potential

Blockade of neurotransmitter release and pain Blockade of neurotransmitter release and pain transmissiontransmission

Classification of OPIOIDSClassification of OPIOIDS

NaturalNatural

morphine 10% morphine 10% codeine 0.5% codeine 0.5% thebaine 0.2% thebaine 0.2%

semi syntheticsemi synthetic heroin heroin oxymorphone oxymorphone HydromorphoneHydromorphone

syntheticsynthetic meperidine meperidine methadone methadone morphinians morphinians benzamorphans benzamorphans

Opioid AgonistsOpioid AgonistsA. Opium alkaloids and derivativesA. Opium alkaloids and derivativesB. Synthetic compoundsB. Synthetic compounds

AntagonistsAntagonists

Mixed agonist-antagonistsMixed agonist-antagonists

Partial agonistsPartial agonists

Morphine Morphine prototypic opioid analgesic prototypic opioid analgesic

Trade names – Rumorf ,Duramor ,Rilimorf etcTrade names – Rumorf ,Duramor ,Rilimorf etc

Dose 10 -100mg alone or in combinationDose 10 -100mg alone or in combination

Pharmacological actionsPharmacological actions

AnalgesiaAnalgesia

Dose dependent Symptomatic relief Dose dependent Symptomatic relief

involves sensory discriminative component and involves sensory discriminative component and motivational affective component, action with in limbic motivational affective component, action with in limbic systemsystem

Changes our reaction and perception of pain Changes our reaction and perception of pain most effective against continuous dull aching pain most effective against continuous dull aching pain Pain relief increases with age.Pain relief increases with age.

Peripheral analgesiaPeripheral analgesia

SedationSedation EuphoriaEuphoria

sense of well being, tranquility loss of sense of well being, tranquility loss of apprehensionapprehension

reason why morphine is abused reason why morphine is abused

Mediated by dopamine release in nucleus Mediated by dopamine release in nucleus accumbanceaccumbance

Inhibition of noradrenalin release - allay fear and Inhibition of noradrenalin release - allay fear and apprehension. apprehension.

ConvulsionsConvulsions

At high doses At high doses

TemperatureTemperature

Alters equilibrium pt of hypothalamus- body temp Alters equilibrium pt of hypothalamus- body temp falls slightlyfalls slightly

Cough centreCough centre

is depressedis depressed

Vasomotor centre Vasomotor centre

Depressed at high doses resulting in fall in BP.Depressed at high doses resulting in fall in BP.

Depression of respiration Depression of respiration

related to dose related to dose decrease rate decrease rate decrease volume decrease volume decrease tidal exchange decrease tidal exchange CNS becomes less responsive to pCO2 thereby CNS becomes less responsive to pCO2 thereby

causing a build up of CO2 causing a build up of CO2 Indifference to breathing seenIndifference to breathing seen

Pure oxygen produces apnea loss pf hypoxic Pure oxygen produces apnea loss pf hypoxic drivedrive

Pupillary reactionPupillary reaction miosis (pinpoint pupils) kappa receptor effect miosis (pinpoint pupils) kappa receptor effect pinpoint pupils still responsive to bright light pinpoint pupils still responsive to bright light Edinger Westphal nucleus ooculomotor nerve Edinger Westphal nucleus ooculomotor nerve

(CN3) is stimulated(CN3) is stimulated Nausea and vomitingNausea and vomiting Stimulation of CTZ, in area postrema of medulla Stimulation of CTZ, in area postrema of medulla Has a vestibular component as more common in Has a vestibular component as more common in

ambulatory patientsambulatory patients

Neuro endocrine EffectsNeuro endocrine Effects

inhibit the release of GnRH and CRF,thus decreasing circulating concentrations of LH, FSH, ACTH, and b- endorphin;

the concentrations of testosterone and cortisol in plasma decline.

Prolactin and growth hormone levels are increased.

Secretion of thyrotropin is relatively unaffected.

Effects on GITEffects on GIT

increase in tone and decrease in mobilityincrease in tone and decrease in mobility leads to leads to constipation constipation

increased tone in stomach, small intestine, and large increased tone in stomach, small intestine, and large intestineintestine

delay of passage of food (gastric contents) so more delay of passage of food (gastric contents) so more reabsorption of waterreabsorption of water

tolerance does not develop to this constipation effecttolerance does not develop to this constipation effect

Cardiovascular effectsCardiovascular effects

Cardiovascular effects of morphine lead to Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure vasodilation, thus a decrease in blood pressure esp orthostatic hypotensionesp orthostatic hypotension

release of histaminerelease of histamine suppression of central adrenergic tone andsuppression of central adrenergic tone and suppression of reflex vasoconstriction suppression of reflex vasoconstriction

Effects on other smooth musclesEffects on other smooth muscles biliary tractbiliary tract

marked increase in the pressure in the biliary tract marked increase in the pressure in the biliary tract increase due to contraction of Sphincter of Oddi increase due to contraction of Sphincter of Oddi

urinary bladderurinary bladder tone of detrusor muscle and sphincter is increased tone of detrusor muscle and sphincter is increased urinary urgency, urinary retentionurinary urgency, urinary retention

bronchial musclebronchial muscle bronchoconstrictionbronchoconstrictioncontraindicated in asthmatics, particularly before contraindicated in asthmatics, particularly before

surgery surgery uterusuterus

contraction of uterus can prolong labor contraction of uterus can prolong labor

ANSANS

Mild hyperglycaemiaMild hyperglycaemia

SKINSKIN

Skin appears flushed Skin appears flushed

UrticariaUrticaria

Immune systemImmune system

Suppression of immune systemSuppression of immune system

PHARMACOKINETICSPHARMACOKINETICS

Routes of administration Routes of administration Oral (preferred)Oral (preferred) latency to onset –15 – 60 minslatency to onset –15 – 60 mins it is also sniffed, swallowed and injected. it is also sniffed, swallowed and injected. duration of action – 3 – 6 hoursduration of action – 3 – 6 hours First-pass metabolism results in poor availability from First-pass metabolism results in poor availability from

oral dosing.oral dosing. 30% is plasma protein bound30% is plasma protein bound

Metabolism conjugation with glucoronic acidMorphine-3ß-glucuronideMorphine-6ß-glucuronideExcretion by kidney 90% in 1st day

Side effectsSide effects Idiosyncrasy and allergyIdiosyncrasy and allergy Apnea and respiratory depressionApnea and respiratory depression Constipation and urinary retentionConstipation and urinary retention Acute morphine poisoning Acute morphine poisoning due to respiratory depression due to respiratory depression

50mg severe toxicity 250mg lethal.50mg severe toxicity 250mg lethal.

Rx naloxone 0.4-0.8mgRx naloxone 0.4-0.8mg

Tolerance Tolerance Dependence Dependence

Tolerance Tolerance is a diminished responsiveness to the drug’s action is a diminished responsiveness to the drug’s action

Tolerance can be demonstrated by a decreased effect Tolerance can be demonstrated by a decreased effect from a constant dose of drug or by an increase in the from a constant dose of drug or by an increase in the minimum drug dose required to produce a given level of minimum drug dose required to produce a given level of effecteffect

Physiological tolerance involves changes in the binding Physiological tolerance involves changes in the binding of a drug to receptors or changes in receptor of a drug to receptors or changes in receptor transductional processes related to the drug of actiontransductional processes related to the drug of action

This type of tolerance occurs in opioidsThis type of tolerance occurs in opioids

1997, Gies and colleagues stated that activation of 1997, Gies and colleagues stated that activation of glutamate NMDA receptors correlates with development glutamate NMDA receptors correlates with development of toleranceof tolerance

No tolerance to its effect on GIT and miotic effect on No tolerance to its effect on GIT and miotic effect on pupilpupil

Cross-tolerance– person who is tolerant to morphine will also be tolerant to the analgesic effect of fentanyl, heroin, and other opioids

DEPENDENCEDEPENDENCE

DependenceDependence

Physiological dependencePhysiological dependence Psychological dependencePsychological dependence Withdrawal reactions are usually the opposite of the Withdrawal reactions are usually the opposite of the

physiological effects produced by the drugphysiological effects produced by the drug Treatment use of methadone 20-30 mgTreatment use of methadone 20-30 mg antagonist naltrexone antagonist naltrexone

OPIOID WITHDRAWALOPIOID WITHDRAWAL

Pain and irritabilityPain and irritability HyperventilationHyperventilation Dysphoria and depressionDysphoria and depression Restlessness and insomniaRestlessness and insomnia Fearfulness and hostilityFearfulness and hostility Increased blood pressureIncreased blood pressure DiarrheaDiarrhea Pupillary dilationPupillary dilation HyperthermiaHyperthermia Lacrimation, runny noseLacrimation, runny nose Severe craving for drugSevere craving for drug

PRECAUTIONS AND PRECAUTIONS AND CONTRAINDICATIONCONTRAINDICATION

In infants and elderly more respiratory In infants and elderly more respiratory depression depression

Contraindicated inContraindicated in

bronchial asthma bronchial asthma

Head injuryHead injury Unstable personalities are liable to continue and Unstable personalities are liable to continue and

become addictsbecome addicts

DRUG INTERACTIONS WITH OPIOIDSDRUG INTERACTIONS WITH OPIOIDS

Phenothiazines, tricyclic antidepressants, MAO Phenothiazines, tricyclic antidepressants, MAO inhibitors amphetamine, neostigmine, potentiate inhibitors amphetamine, neostigmine, potentiate morphine and other opioids.morphine and other opioids.

Delays absorption of many orally administered drugs.Delays absorption of many orally administered drugs.

OTHER RELATED OPIOID AGONISTSOTHER RELATED OPIOID AGONISTS

CodeineCodeine Methyl morphineMethyl morphine one tenth the potency of morphine one tenth the potency of morphine absorbed readily from GI tract absorbed readily from GI tract the absorption is more regular and more predictable the absorption is more regular and more predictable less first pass metabolismless first pass metabolism metabolized through glucuronic acid metabolized through glucuronic acid about 10% converted to morphine about 10% converted to morphine antitussive drug for cough antitussive drug for cough

Heroin (diacetylmorphine)Heroin (diacetylmorphine) at 3 and 6 hydroxy positions, there are acetyl at 3 and 6 hydroxy positions, there are acetyl

groups instead of hydroxyl groups groups instead of hydroxyl groups it is 3 to 4 times the analgesic potency of it is 3 to 4 times the analgesic potency of

morphine morphine heroin is the most lipophilic of all the OPIOID heroin is the most lipophilic of all the OPIOID morphine is the least lipophilic of all the OPIOID morphine is the least lipophilic of all the OPIOID OPIOID withdrawal is NOT fatalOPIOID withdrawal is NOT fatal Used as ‘brown sugar’ as a drug of abuseUsed as ‘brown sugar’ as a drug of abuse

Meperidine Semisynthetic phenylpiperidine same CNS actions as morphine sedation, analgesia, respiratory depression Dose 50 -100mg im/sc Dose to dose1/8 to1/10 in analgesic potency however analgesic

efficacy is near to morphine Plasma half life3 hrs

Pethidine hydrolysis meperidinic acid

norpethidine

unlike morphine:unlike morphine: less constipation less constipation no antitussive activity no antitussive activity it causes mydriasisit causes mydriasis drug absorbed orally drug absorbed orally drug most abused by health care professionals due to its drug most abused by health care professionals due to its

availability availability withdrawal similar to morphine toxic effects similar to withdrawal similar to morphine toxic effects similar to

atropine atropine Side effects overdose produces excitatorySide effects overdose produces excitatory

used as analgesicused as analgesic

Trade name Dolotram Trade name Dolotram Synthetic codeine analog Synthetic codeine analog Opioid receptor agonist (mu and delta)Opioid receptor agonist (mu and delta) NE and 5-HT reuptake blocker (antidepressant)NE and 5-HT reuptake blocker (antidepressant) These actions are synergistic for analgesiaThese actions are synergistic for analgesia Dose 50-100mg orally/imDose 50-100mg orally/im

Tramadol

Fentanyl Fentanyl Trade names Durogesic patch, SublimazeTrade names Durogesic patch, Sublimaze synthetic drug related to phenylepiperidinesynthetic drug related to phenylepiperidine 80 to 100 times more potent than morphine 80 to 100 times more potent than morphine rapidly acting drug due to high lipid solubilityrapidly acting drug due to high lipid solubility used as iv supplement during GAused as iv supplement during GA short acting (30-45 min) short acting (30-45 min) onset of action is 5 minutes onset of action is 5 minutes Patch delivers 25ug,50ug/75ug /hrPatch delivers 25ug,50ug/75ug /hr highly abused ,known as highly abused ,known as china whitechina white . .

MethadoneMethadone Trade name PhyseptoneTrade name Physeptone pharmacologically similar to morphine, long pharmacologically similar to morphine, long

duration of activity duration of activity absorbed well orally(1:2)absorbed well orally(1:2) 24 to 36 hrs duration of action on chronic use24 to 36 hrs duration of action on chronic use powerful pain reliever powerful pain reliever used in maintenance program for narcotic used in maintenance program for narcotic

treatment treatment

Complex action opioidsComplex action opioids

Mixed agonist-antagonistsMixed agonist-antagonists

Nalorphine and cyclazocine not used as analgesic Nalorphine and cyclazocine not used as analgesic

PentazocinePentazocine

Butorphanol has analgesic action Butorphanol has analgesic action

NalbuphineNalbuphine

Pentazocine Pentazocine Trade name Fortwin ,PentawinTrade name Fortwin ,Pentawin mostly spinal analgesia obtained but efficiency lower.mostly spinal analgesia obtained but efficiency lower. sedation ,respiratory depression – sedation ,respiratory depression – 1/3-1/21/3-1/2 of morphine. of morphine. less vomiting, biliary spasms and constipationless vomiting, biliary spasms and constipation Dose 25-100mg 4 times daily.Dose 25-100mg 4 times daily.

ButorphenolButorphenol Trade name Butrum Trade name Butrum More potent analgesic than pentozocineMore potent analgesic than pentozocine

Partial agonist: BuprenorphinePartial agonist: Buprenorphine

Trade names Norphin, Tidigesic inj or sl Trade names Norphin, Tidigesic inj or sl tabletstablets

25 times more potent than morphine25 times more potent than morphinePartial agonist at mu receptorsPartial agonist at mu receptors6-8 hrs action 6-8 hrs action Lower efficacy analgesic than morphineLower efficacy analgesic than morphine

NaloxoneNaloxone

Trade nameTrade name Narcotan,NaloxNarcotan,Nalox

competitive antagonist at mu, kappa, and competitive antagonist at mu, kappa, and delta receptordelta receptor

Short half-life ,not effective orallyShort half-life ,not effective orallyAntagonizes all action of Antagonizes all action of

morphine,nalorphine pentazocine even morphine,nalorphine pentazocine even endogenous opioids.endogenous opioids.

it will precipitate withdrawal it will precipitate withdrawal Drug of choice for morphine poisoningDrug of choice for morphine poisoning

NaltrexoneNaltrexone Trade name NaltremaTrade name Naltrema same effect of naloxone except it is used orally so can't same effect of naloxone except it is used orally so can't

use it if for person with acute toxicity use it if for person with acute toxicity long duration of activity 1-2 dayslong duration of activity 1-2 days Used for opioid blockade therapy Dose 50mg per day Used for opioid blockade therapy Dose 50mg per day also used for treatment of alcoholism  also used for treatment of alcoholism 

NalmefeneNalmefene Intermediate duration (4-6 hr)Intermediate duration (4-6 hr) orally activeorally active no hepatotoxicity with long term useno hepatotoxicity with long term use

Opioid therapy is the mainstay approach Opioid therapy is the mainstay approach for for

• Acute pain Acute pain • Cancer painCancer pain• Pain in advanced illnessesPain in advanced illnesses

But under treatment is a major problemBut under treatment is a major problem

opiphobiaopiphobia

ALTERNATIVE ROUTES OF ADMINISTRATIONALTERNATIVE ROUTES OF ADMINISTRATION

Patient controlled analgesiaPatient controlled analgesia TransdermalTransdermal Iontophoresis Iontophoresis Oral Tran mucosalOral Tran mucosal Rectal routeRectal route Inhalation Inhalation computer assisted computer assisted continuous infusioncontinuous infusion Intraspinal intrathecalIntraspinal intrathecal

NSAIDSNSAIDS

Non steroidal anti inflammatory drugs

4 Major actions4 Major actions analgesic analgesic antipyreticantipyretic anti-coagulantanti-coagulant anti-inflammatory anti-inflammatory

MOA OF NSAIDSMOA OF NSAIDS

inhibit prostaglandin production

reduction of activation of T lymphocytes

stabilizing the mast cell

inhibits bradykinin from stimulating pain receptors

May unmask T cell suppressing activity thus decrease production of rheumatoid factor

The anti-inflammatory properties of the The anti-inflammatory properties of the NSAIDs insure that the release of the NSAIDs insure that the release of the prostaglandins, histamines, thromboxanes prostaglandins, histamines, thromboxanes and leukotrienes is inhibited and leukotrienes is inhibited ..

Do not produce toleranceDo not produce tolerance

Has ceiling effectHas ceiling effect

CLASSIFICATIONCLASSIFICATION NON SELECTIVE COX INHIBITORSNON SELECTIVE COX INHIBITORS Salicylates :aspirinSalicylates :aspirin

pyrazolone derivatives : phenylbutazones,pyrazolone derivatives : phenylbutazones, Indole : indomethacinIndole : indomethacin

Propionic acid : ibuprofen ,Ketoprofen Propionic acid : ibuprofen ,Ketoprofen Anthranilic acid : mephanamic acidAnthranilic acid : mephanamic acid

Aryl acetic acid : diclofenacAryl acetic acid : diclofenac

Oxicam : piroxicamOxicam : piroxicam

Pyrolo-pyrole :ketorolacPyrolo-pyrole :ketorolac

PREFERENTIAL COX2 INHIBITORS

Nimesulide

meloxicam

nabumetone SELECTIVE COX2 INHIBITORS

celecoxib

rofecoxib

valdecoxib

WITH POOR ANTIINFLAMMATORY PROPERTY

Paracetamol

Metamizol

Nefopam

NSAIDS AND COXNSAIDS AND COX

Inhibits COX

COX1

COX2

Beneficial action due to inhibition of PG Analgesia Antipyretic Anti-inflammatory Antithrombotic

Adverse effect due to inhibitionGI mucosal damageBleedingDecreased renal blood flow ANALGESIC HYPERSENSITIVITY

NSAIDs... A Host Of DrugsNSAIDs... A Host Of Drugs

ASPIRIN

Trade name ASPIRIN, ECOSPIRIN,DISPIRINAcetylsalicylic acid

MOA inactivates COX by irreversibly acetylating the enzyme.

May inhibit cell migration and formation of rheumatoid factor.

decreased capillary permeability,

decreased antibody response

PHARMACOLOGICAL PROPERTIESPHARMACOLOGICAL PROPERTIES

ANALGESIAANALGESIA

Mainly peripheral but central action of raising Mainly peripheral but central action of raising subcortical action also cotributes.subcortical action also cotributes.

Shows ceiling effectShows ceiling effect

Do not affect emotional reaction to painDo not affect emotional reaction to pain

Difficult to separate analgesic and anti-Difficult to separate analgesic and anti-inflammatory action. inflammatory action.

ANTIPYRETIC EFFECTANTIPYRETIC EFFECT

resets hypothalamic thermal setresets hypothalamic thermal set

Promotes heat loss by sweating and vasodilatationPromotes heat loss by sweating and vasodilatation

But does not reduce heat production.But does not reduce heat production.

ANTI INFLAMMATORY EFFECT AND ANTI INFLAMMATORY EFFECT AND ANTIRHEUMATOID EFFECTANTIRHEUMATOID EFFECT

Exerted at a higher dose 3-6gm/dayExerted at a higher dose 3-6gm/day

Inhibit PG synthesisInhibit PG synthesis

Reduce capillary permeabilityReduce capillary permeability

So decreased fluid exudation and edemaSo decreased fluid exudation and edema

Inhibition neutrophil aggregationInhibition neutrophil aggregation

Suppression of antigen-antibody reactionSuppression of antigen-antibody reaction

Inhibit mucopolysaccharide biosynthesisInhibit mucopolysaccharide biosynthesis

EFFECT ON RESPIRATIONEFFECT ON RESPIRATION1.1. Increase O2 consumption→ ↑ COIncrease O2 consumption→ ↑ CO2 2 → stimulates → stimulates

respiration. respiration.

2.2. Direct stimulation of respiratory center → Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal Hyperventilation → resp. alkalosis → renal compensationcompensation

Plasma conc of 350ug/ml hyperventilationPlasma conc of 350ug/ml hyperventilation

500ug/ml hyperpnea.500ug/ml hyperpnea.

ACID BASE AND ELECTROLYTE ACID BASE AND ELECTROLYTE BALANCEBALANCE

RESPIRATORY ALKALOSISRESPIRATORY ALKALOSIS

RESPIRATORY ACIDOSISRESPIRATORY ACIDOSIS

UNCOMPENSATEDUNCOMPENSATED METABOLIC ACIDOSISMETABOLIC ACIDOSIS

GITGIT

Epigastric distress, due toEpigastric distress, due to

Loss of protective mucosal barrierLoss of protective mucosal barrier

‘‘Ion trappingIon trapping’ in gastric mucosal cell’ in gastric mucosal cell

Back diffusion of acidBack diffusion of acid

URATE EFFECTSURATE EFFECTS<2gm/day- urate retention<2gm/day- urate retention

2-5gm/day variable effect2-5gm/day variable effect

>5gm/day –increase urate excretion>5gm/day –increase urate excretion

BLOODBLOOD

inhibits platelet aggregationinhibits platelet aggregation

platelet COX acetylation occurs presystemically.so platelet COX acetylation occurs presystemically.so selective TXA2 suppressed,no effect on selective TXA2 suppressed,no effect on

antiaggregatoryantiaggregatory PGI2. PGI2.

Also lowers leucocytosis and high ESR in acute Also lowers leucocytosis and high ESR in acute rheumatic fever.rheumatic fever.

CVSCVSAt toxic dose depress vasomotor centre BP fallsAt toxic dose depress vasomotor centre BP falls..

METABOLIC EFFECTS

Cellular metabolism increased

Large dose cause hyperglycaemia

Cause negative nitrogen balance

Decrease free plasma FFA

ENDOCRINEInduce release of adrenaline

Interferes with binding of thyroxine to their binding proteins

SALICYLATE AND PREGNANCYSALICYLATE AND PREGNANCY premature closure of ductus arteriosuspremature closure of ductus arteriosus

Low birth weight babiesLow birth weight babies

Prolongs labourProlongs labour

Greater postpartum blood lossGreater postpartum blood loss

LOCAL ACTIONLOCAL ACTION

salicylic acid and methyl salicylate are irritantssalicylic acid and methyl salicylate are irritants

Salicylic acid is keratinolytic used in the treatment of Salicylic acid is keratinolytic used in the treatment of warts.warts.

PHARMACOKINETICSPHARMACOKINETICS taken orally rapidly absorbed from stomach and taken orally rapidly absorbed from stomach and

small intestine.small intestine. Rate limiting step is disintegration and dissolutionRate limiting step is disintegration and dissolution 80% is plasma protein bound 80% is plasma protein bound

Plasma t1/2 is 15 – 20 min,together with salicylic Plasma t1/2 is 15 – 20 min,together with salicylic acid is 3 – 4 hrs.t1/2 anti-inflammatory dose 8 – acid is 3 – 4 hrs.t1/2 anti-inflammatory dose 8 – 12hrs.12hrs.

Conjugated in liver with glycine and with glucoronic Conjugated in liver with glycine and with glucoronic acidacid

Excreted by glomerular filtration and tubular Excreted by glomerular filtration and tubular secretion Elimination dose dependentsecretion Elimination dose dependent

ADVERSE EFFECTSADVERSE EFFECTS Side effectsSide effects - nausea ,vomiting, epigastric - nausea ,vomiting, epigastric

distress, peptic ulcerations distress, peptic ulcerations

Hypersensitivity and idiosyncrasyHypersensitivity and idiosyncrasy

Salicylism Salicylism prolonged use of salicylates develops prolonged use of salicylates develops

when plasma conc.>25mg%when plasma conc.>25mg% On kidneysOn kidneys – dose dependent water and sodium – dose dependent water and sodium

retention retention renal artery vasoconstrictionrenal artery vasoconstriction Analgesic associated nephropathyAnalgesic associated nephropathy

Reyes Syndrome

is associated use of aspirin in children recovering from viral infections

Signs/Symptomscerebral edemaencephalopathydisorientation & confusionliver damageliver failurefatty infiltration of the brainfatty infiltration of the liver

ACUTE SALICYLATE POISONINGSeen more in childrenFatal adult dose 15 – 30 gm

Headache - tinnitus - dizziness – hearing impairment – dim vision

Confusion and drowsiness Sweating and hyperventilation Nausea, vomiting Marked acid-base disturbances Hyperpyrexia Dehydration Cardiovascular and respiratory collapse, coma

convulsions and death

Enhance excretion - alkalinize urine, forced diuresis, hemodialysis

Decrease absorption - activated charcoal, emetics, gastric lavage

Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…

Aspirin Toxicity - TreatmentAspirin Toxicity - Treatment

CONTRAINDICATIONS AND CONTRAINDICATIONS AND PRECAUTIONSPRECAUTIONS

Peptic ulcer Asthma Diabetes Gout Chronic liver disease G6PD deficient individual In children Hypo coagulation state Aspirin should be stopped 1 wk before elective

surgery

DRUG INTERACTIONSDRUG INTERACTIONS Warfarin, heparin , ethanol – increase internal Warfarin, heparin , ethanol – increase internal bleedingbleeding

Phenytoin, methetrexate - plasma conc. increases Phenytoin, methetrexate - plasma conc. increases

Probencid, silfinpyrazone – decreased uricosuric Probencid, silfinpyrazone – decreased uricosuric effecteffect

Sulfonylureas, insulin – unpredictable effectSulfonylureas, insulin – unpredictable effect

Diuretics action of furosimide and thiazide is Diuretics action of furosimide and thiazide is bluntedblunted

USESUSES

AnalgesicAnalgesic AntipyreticAntipyretic In acute rheumatic feverIn acute rheumatic fever Rheumatoid arthritis and osteoarthritisRheumatoid arthritis and osteoarthritis Post myocardial infarction patientsPost myocardial infarction patients Closure of ductus arteriosusClosure of ductus arteriosus pregnancy induced hypertension etcpregnancy induced hypertension etc

DIFLUNISALDIFLUNISAL

Trade name – Trade name – DOLOBIDDOLOBID

More potent and longer duration than aspirinMore potent and longer duration than aspirin

No antipyretic actionNo antipyretic action

PYRAZOLONESPYRAZOLONES

include phenylbutazone, oxybutazone antipypyrine, include phenylbutazone, oxybutazone antipypyrine, aminopyrine etc.aminopyrine etc.

High chances of bone marrow depression, agranulocytosisHigh chances of bone marrow depression, agranulocytosis

Recently 2 other pyrazolones available in IndiaRecently 2 other pyrazolones available in India

Trade nameTrade name

Metamizol Metamizol NOVALGIN,ANALGINNOVALGIN,ANALGIN

Propophenazone Propophenazone SARIDON,(SARIDON,(in combination with in combination with paracatamol)paracatamol)

INDOMETHACININDOMETHACIN

Trade name Trade name INDICIN, ARTICIDINDICIN, ARTICID ETC ETC

Use closure of patent ductus arteriosusUse closure of patent ductus arteriosus

Malignancy associated fever Malignancy associated fever

Rheumatoid arthritis.Rheumatoid arthritis.

Use in dentistry not known.Use in dentistry not known. SULINDACSULINDAC

Prodrug of indomethacinProdrug of indomethacin ETODOLACETODOLAC

3 times more selective COX2 inhibitor3 times more selective COX2 inhibitor

t1/2 7hrst1/2 7hrs

PROPIONIC ACID DERIVATIVESIbuprofen BRUFEN, EMFLAM

Dose 400 – 800 mg thrice daily

Naproxen

Ketoprofen

Flurbiprofen

Better tolerated than aspirin side effects similar but milder ppt of asthma occurs .

Special features:

Naproxen inhibit leucocyte migration

Ketoprofen stabilizes lysosomes

Fluriprofen used as occular anti inflammatory.

MEPHANEMIC ACID MEPHANEMIC ACID

MEFTALMEFTAL

Exerts peripheral as well central analgesic actionExerts peripheral as well central analgesic action

Adverse effect severe diarrhoea,this limits its use Adverse effect severe diarrhoea,this limits its use in dental pain managementin dental pain management

Use – analgesic in muscle ,joint ,soft tissue pain Use – analgesic in muscle ,joint ,soft tissue pain where stong anti inflammatory action not where stong anti inflammatory action not required.required.

DICLOFENAC SODIUM DICLOFENAC SODIUM DICLONAC ,VOVERANDICLONAC ,VOVERAN Dose 100 – 150 mg in 2-3 divided doseDose 100 – 150 mg in 2-3 divided doseInhibits COX, short lasting antiplatelate action, Inhibits COX, short lasting antiplatelate action,

may reduce intracellular concentration of free may reduce intracellular concentration of free arachidonic acid, arachidonic acid,

T1/2 1 -2 hrsT1/2 1 -2 hrsGood tissue permeabilityGood tissue permeabilityAdverse effect increase chance of hepatotoxicity Adverse effect increase chance of hepatotoxicity

DICLOFENAC POTASSIUMDICLOFENAC POTASSIUMVOLINI,VOLTAFLAM VOLINI,VOLTAFLAM

suited for patients on sodium free diet, suited for patients on sodium free diet, hypertensives hypertensives

OXICAM DERIVATIVESOXICAM DERIVATIVESPIROXICAM MELOXICAMPIROXICAM MELOXICAM

MICROPEC PIRICAM OXYCAMMICROPEC PIRICAM OXYCAM

long acting potent analgesiclong acting potent analgesic

T ½ is 50 hrs T ½ is 50 hrs

Single daily dosing used for long term therapySingle daily dosing used for long term therapy

KETOROLACKETOROLAC KETOROL, ZOROVONKETOROL, ZOROVON

Given im or orally Given im or orally

Potent analgesic and modest anti inflammatory equal Potent analgesic and modest anti inflammatory equal efficincy as morphine in management of post operative efficincy as morphine in management of post operative painpain

Adverse effects high incidence of GI ulcerations and Adverse effects high incidence of GI ulcerations and postoperative bleedingspostoperative bleedings

Not to be used more than 5 daysNot to be used more than 5 days

COX-2 COX-2 SelectivitySelectivity

PREFERENTIAL COX2 INHIBITOR NIMESULIDE, MELOXICAM, NABUMETONE

NIMESULIDE Nimulid , Dose 100mg BD

inhibits cyclooxygenase inhibits neutrophil activation,exhibits

antioxidant properties

Adverse effect hepatc toxicity so banned in some countries

Usefulness lies in patients whoare asthmatics and those who are intolerant to aspirin and other NSAIDs,

MELOXICAM Melflam

Newer congener of piroxicam

NABUMETONE Nabuflame

Selective COX-II InhibitorsSelective COX-II Inhibitors

Celecoxib CELECT rofecoxib ROFIBAX Valdecoxib VALUS

Anti-inflammatory with less adverse effects, especially GI events.

Potential toxicities: kidney and platelets increased risk of thrombotic events due to reduction ofPGI2

JUXTAGLOMERULAR cox2 inhibition salt and water retention, pedal edema, rise in BP ,ppt CHF

PARACETAMOL(ACETOMINOPHEN) Crocin, metacin,calpol equal efficacy as aspirin for noninflammatory conditionsPoor anti-inflammatory effect due to poor ability to inhibit

COX in presence of peroxides ,has central analgesic action raises pain threshold.

Does not stimulate respiration, affect acid base balance, or cause GI ulcerations. do not effect platelet function .

Adverse effect: occasional nausea and rashesanalgesic nephropathyAcute paracetamol poisoning

ACUTE PARACETAMOL POISONINGACUTE PARACETAMOL POISONING

occurs mostly in children with low glucuronide conjugation. Serious toxicity in adults at dose>10gm

Features Nausea, vomitingAbdominal pain 12 – 18 hrs laterCentrolobular hepatic necrosisHypoglycemiaComaJaundiceHepatic failure and death

Mechanism of toxicityMechanism of toxicity due to formation of NABQIdue to formation of NABQI

binds to hepatic cells and renal tubules and cause binds to hepatic cells and renal tubules and cause necrosis.necrosis.

Treatment Treatment induce vomiting give gastric lavageinduce vomiting give gastric lavage

Activated charcoal is given Activated charcoal is given

Specific antidote N acetylcysteineSpecific antidote N acetylcysteine

ContraindicatedContraindicated in alcoholicsin alcoholics

In premature childrenIn premature children

ADJUVANT ANALGESICSADJUVANT ANALGESICS

ANESTHETIC AGENT topical anesthetic mainly used as

solutions sprays ointments or lozenges. injectable local anesthetic

mainly used to control surgical pain, as

analgesic agent has 4 facets :

to arrest primary pain

to interrupt pain cycle

to resolve myofascial trigger point activity

to induce a sympathetic block

ANTI INFLAMMATORY AGENT

use of corticosteroids esp useful for infalmmatory pain, suppress the symptoms

Induce lipocortin thus blocks phospholipaseA2

Suppress synthesis of cyclooxygenase in e

Inhibit synthesis of endothelial adhesion molecules

MUSCLE RELAXANTS drugs such as Diclomine ,methacarbamol used Used for myogenous pain Depress spinal and sopraspinal reflexes needed

to maintain muscle tone.

ANTIDEPRESSANTS

Tricyclic antidepressants like amitriptyline is used.

they increase availability of 5HT and norepinephrine.

SSRI used.

ANTIANXIETY AGENTS

Phenothiazines,

Diazepam

Clonazepam for neuropathic pain

Useful in pain control by reducing the modulating effect of anxiety and apprehension

Their muscle relaxation action is also useful

Precaution

Long term use may cause dependence and tolerance

ANTICONVULSIVE

Carbamazepine Tegretal

Gabapentin

topiramide

Oxycarbamazepine

Useful in neuralgic pain

Side effects bone marrow suppression

Blood dyscrasia

NEUROLYTIC AGENTS

95% ETHYL ALCOHOL

GLYCEROL

Others

VASOACTIVE AGENTS

ANTIHISTAMINICS

ANTIMICROBIALS

ANTIVIRALS

URICOSURIC AGENTS

DIETARY CONSIDERATIONS tryptophan

PHYSICAL THERAPYPHYSICAL THERAPY

Sensory stimulation Cutaneous- rubbing the skin

counterirritants, vapocoolants, hydrotherapy

Transcutaneous- TENS, Acupuncture

Percutaneous

Cutaneous- rubbing the skin Cutaneous- rubbing the skin

counterirritants, counterirritants,

hydrotherapy,hydrotherapy,

vapocoolants vapocoolants

VAPOCOOLANT VAPOCOOLANT SPRAYSPRAY

TENSTENS Kane & Tub reviewed history of electric fish to Kane & Tub reviewed history of electric fish to

minimize painminimize pain Current of low intensity at frequency of 50 to 100 Current of low intensity at frequency of 50 to 100

HzHz Stimulation of thick A- beta fibersStimulation of thick A- beta fibers Release of serotonin & dynorphinsRelease of serotonin & dynorphins

ACUPUNCTUREACUPUNCTURE

Utilizes a low frequency 2hz but high intensity Utilizes a low frequency 2hz but high intensity electric current.electric current.

Applied at ‘acupoints’ infraorbital acupoint ,Hoku Applied at ‘acupoints’ infraorbital acupoint ,Hoku acupoint.acupoint.

Activation of endogenous antinociceptionActivation of endogenous antinociception Release of B endorphin. Release of B endorphin.

UltrasoundUltrasound

increases temperature at deeper increases temperature at deeper tissue interface thus increases tissue interface thus increases blood flow.blood flow.

Heat therapy - Short wave Heat therapy - Short wave diathermydiathermy

Indicated in patient with Indicated in patient with pain in masticatory pain in masticatory musclesmuscles

mechanical vibration and mechanical vibration and partly by deeply partly by deeply penetrating thermal penetrating thermal energy this increases energy this increases blood flow blood flow

Manual techniquesManual techniques

MASSAGE CAN MAKE AMASSAGE CAN MAKE A DIFFERENCEDIFFERENCE

EXERCISE AND PHYSICAL EXERCISE AND PHYSICAL ACTIVITYACTIVITY

PSYCOLOGICAL THERAPYPSYCOLOGICAL THERAPY

Counseling Counseling

Behavioral modificationBehavioral modification

CHOICE OF ANALGESICS

Cause of pain Past h/o pain Anticipation of degree of pain

HIERCHY OF ANALGESIC PRESCRIPTION

The most important concept in pain management…..

References References

Goodman and Gilman’s The pharmacological basis of Goodman and Gilman’s The pharmacological basis of

therapeutics,10therapeutics,10thth edition. edition. K D Tripathi ,Essentials of medical pharmacology, 5K D Tripathi ,Essentials of medical pharmacology, 5thth edition. edition. Satoskar, Bhandarkar, Ainapure, Pharmacology and Satoskar, Bhandarkar, Ainapure, Pharmacology and

pharmacotherapeutics, 18pharmacotherapeutics, 18thth edition. edition.

Okesson JP,Bells orofacial pains, 6Okesson JP,Bells orofacial pains, 6thth edition edition

Yagiela, Dowd, Neidle,Pharmacology and therapeutics for Yagiela, Dowd, Neidle,Pharmacology and therapeutics for dentistry,5dentistry,5thth edition . edition .

THANK YOU