0pioid

7/31/2019 0PIOID

1/77

DR. SIDDHARTH

POST GRADU

ORAL & MAXILLO

7/31/2019 0PIOID

2/77

7/31/2019 0PIOID

3/77

BRIEF INTRODUCTION TO PAIN MECHANISM

OPIOID ANALGESICS

oCLASSIFICATION

oPHARMACOLOGY OF INDIVIDUAL DRUGS

oPRINCIPLES OF OPIOID PHARMACOLOGY

oINDICATIONS OF OPIOIDS FOR DENTISTRY

oOPIOIDS IN CANCER THERAPY

7/31/2019 0PIOID

4/77

NSAIDs

History of NSAIDs

Classification of NSAIDs

Mechanism of action (PG synthesis inhibition)

Adverse effects

Individual drugs

Analgesic combinations

7/31/2019 0PIOID

5/77

WEBSTERS dictionary describes pain as a basensation induced by a harmful stimulus chara

by physical discomfort.

Arbitrarily one may define pain as an unpleasaemotional experience usually initiated by a noxstimulus & transmitted over a specialized neurto the central nervous system where it is intesuch .

(Monheims local anesthesia & pain control in dental pra

7/31/2019 0PIOID

6/77

ANALGESICS

Analgesics are a class of drugs which obtundperception of pain without producingunconsciousness

Analgesics are drugs that selectively relieve acting in the CNS or on the peripheral painmechanisms, without significantly alteringconsciousness

7/31/2019 0PIOID

7/77

ACUTE PAIN MECHNANISM

7/31/2019 0PIOID

8/77

FUNCTIONAL NEUROANATOMY

7/31/2019 0PIOID

9/77

FIRST ORDER NEURON

Each sensory receptor is attached to first order or primary afferent

A general classification of neurons divides the larger fibres from thone, on the basis of thickness.

7/31/2019 0PIOID

10/77

CLASSIFICATION OF FIRST ORDER NE

TYPE A FIBERS

1. Alpha fibers : size, 13 to 20 micro.m indiameter; velocity, 70 to 120m/s

2. Beta fibers: size 6 to 13 micro.m indiameter; velocity, 15 to 40 m/s

3. Gamma fibers: size, 3 to 8 micro.m indiameter; velocity, 5 to 15 m/s

: size, 1 to 5 micro.m in

diameter velocity, 5 to 15 m/s

Size 0.5 to 1 micro.

.5m/s

7/31/2019 0PIOID

11/77

SECOND ORDER NEURONS

There appears to be three specific type of second order neurtransfer impulses to the higher center.

These neurons are named according to the impulses theypredominantly carry LTM low threshold mechanosensitive neuron

NS Nocioceptive specific neurons

WDR wide dynamic range neuron

7/31/2019 0PIOID

12/77

Once the impulses have transferred from the primary

most of the second order neurons cross to the oppos

the spinal cord & enter the -

which ascends to the higher centers

Some second order neurons remain on the same sid

column & ascend by the way of

7/31/2019 0PIOID

13/77

LATERAL SPINOTHALMIC TRACT( composed of small unmylinated fibers

that transmit signal at 40 m/s)

LEMINISCAL SYSTE

Composed of large &nerve fibre transmbrain at velocity of 3

NeospinothalmicTract

(A Delta fibres )

PaleospinothalmicTract

(C fibres)

7/31/2019 0PIOID

14/77

THE SPINAL CORD

The spinal cord is subsiddifferent layers or lamina

Studies suggest that nociinput enters the dorsal hNS & WDR neurons in thlaminae 1, 2, 5

7/31/2019 0PIOID

15/77

SUBSTANTIA GELATINOSA

Within the dorsal horn there are inter neurons that transfer iminter neurons or to ascending neurons

These neurons can be either inhibitory or excitory

Excitory interneuron in laminae 2 & 3 of spinal cord are colle

as substantia gelatinosa

7/31/2019 0PIOID

16/77

THEORIES FOR PAIN MECHANISM

SPECIFICITY THEORY- DESCARTES 1664 MULLERS postulated the theory of information transmission on

sensory nerves

VON FREY developed the concept of cutaneous receptors

PATTERN THEORY GOLDSCHEIDER in 1894 was the first t

stimulus intensity and central summation are the critical deterpain.

GATE CONTROL THEORY 1965 PROPOSED BY MELZAC

7/31/2019 0PIOID

17/77

GATE CONTROL THEORY

Briefly stated the gate control theorypostulates that brain receives themessage about injury by the way of thegate control system, which isinfluenced by

INJURY SIGNALS

OTHER TYPE S OF AFFERENTIMPULSES

DESCENDING CONTROL

7/31/2019 0PIOID

18/77

In contrast to pain centreproposed by specificity theory, thegate control mechanism postulatesthe existence of action systems

7/31/2019 0PIOID

19/77

PAIN MODULATION OF THE DESCENDING INHIBITOR

In 1983, while studying nerve injuries in rat, WALL AND DEVOR determined thareceptor is not the only region of the neuron that can initiate sensory impulse

The DRG can also initiate sensory impulse

The source of afferent input may account for persisting pain after peripheral ane

The neural mechanism that appears to balance this continuous barrage of senso

called Descending inhibitory system

Several neurotransmitters are imp in descending inhibitory system like serotonendorphins.

7/31/2019 0PIOID

20/77

7/31/2019 0PIOID

21/77

DISTRIBUTION OF RECEPTORS High density of opioid

receptors are presentin five general areas of

the CNS known to be

involved in integrating

information about pain

These pathwaysdescend from the

periaquedectel grey

through the dorsal

horn of the spinal

cord.

7/31/2019 0PIOID

22/77

PAIN PATHWAY

7/31/2019 0PIOID

23/77

OPIOID ANALGESICS

THE TERM OPIOID ANALGESICS REFTHOSE ANALGESICS THAT APPEAR HAVE PHARMACOLOGICAL PROPERTIESIMILAR TO MORPHINE.(DENTAL CLINICS OF NORTH AMERICA

VOL 28, NO 3,JULY 1984)

7/31/2019 0PIOID

24/77

History Of Opium Opiates are one of the oldest types of drugs in history

Opium is extracted from poppy seeds (Papaver somniferum)

Undisputed reference to opium found in writings (Theophrastus) frthird century BC

Use of Opium recorded in China and Mesopotamia over 2000 years a

Greeks dedicated the Opium poppy to the Gods of Death (Thanatos),(Hypnos), and Dreams (Morpheus)

Sixteenth Century is the first reported use of Opium for itsAnalgesicqualities

7/31/2019 0PIOID

25/77

CLASSIFICATION

NATURAL OPIUMALKALOIDS

SEMISYNTHETICOPIATES

SYNTHETIC O

MORPHINECODIENE

DIACETYL MORPHINEPHOLCODIENE

PETHIDINEFENTANYLMETHADONETRAMADOL

ETHOHEPTAZINEDEXTROPROPOXPENTAZOCINE

7/31/2019 0PIOID

26/77

CLASSIFICATION ON THE BASIS OF CHEMICAL STRPhenanthrenes Phenylpiperidines Phenylhepylamines Morphinans Be

MorphineCodeineOxycodoneNalbuphineHydromorphone

MeperidineFentanylAlfentanilSufentanilRemifentanyl

PropoxypheneMethadone

Butorphanol Pe

7/31/2019 0PIOID

27/77

CLASSIFICATION OF OPIOIDS BY ACTION ON REC

STRONGAGONISTS

MODERATE AGONISTSMIXED AGONISTSANTAGONISTS

FENTANYLHEROINMEPERIDINEMETHADONEMORPHINESUFENTANIL

CODIENEPROPOXYPHENE

BUPERINORPHINEPENTAZOCINE

7/31/2019 0PIOID

28/77

7/31/2019 0PIOID

29/77

MORPHINE( STRONG AGONISTS) It is the major analgesic contained in crude opium & is prototype

used as sulphate or hydrochloride.

Shows high affinity for mu receptors, varying affinity for delta & kreceptors & low affinity for sigma receptors

7/31/2019 0PIOID

30/77

MECHANISM OF ACTION

Major effects by interacting with opioid receptors in the CN Causes hyperpolarisation of nerve cells , inhibition of nerve

presynaptic inhibition of transmitter release

Acts at mu receptors in lamina 1 & 2 of substantia gelatinosacord & decreases the release of substance P .

Also inhibits the release of many excitory transmitters from terminals carrying nocioceptive stimuli

7/31/2019 0PIOID

31/77

ACTIONS

ANALGESIA EUPHORIA

RESPIRATION

DEPRESSIONS OF COUGH REFLEX

MIOSIS

EMESIS GASTROINTESTINAL TRACT

CARDIOVASCULAR

HISTAMINE RELEASE

HORMONAL ACTIONS

7/31/2019 0PIOID

32/77

ANALGESIA

Opioids relieve pain by both raising the pain threshold at the spinaby altering the brains perception of pain

EUPHORIA

May be caused by stimulation of the ventral tegmentum

RESPIRATORY DEPRESSION

By direct action on the brain stem respiratory centre

By reducing the sensitivity to increased CO2 concentration

MIOSIS

Morphine excites the Edinger westphal nucleus of the occulomotorenhanced parasympathetic stimulation

NAUSEA AND EMESIS Morphine produces vomiting by the stimulation of the CTZ in the area post trem

7/31/2019 0PIOID

33/77

EFFECT ON GIT

Morphine relieves diarrhea

Decreases motility of smooth muscles and increases tone

Increases the intrabiliary pressure

CARDIOVASCULAR EFFECTS

No major effects on blood vessels , large doses bradycardia & hypote

Contraindicated in severe brain injury

HISTAMINE RELEASE Morphine releases histamine from mast cells which can lead to

bronchoconstriction, hence should be avoided in asthmatics

HARMONAL ACTIONS

Morphine increases ADH and hence leads to urinary retention

7/31/2019 0PIOID

34/77

THEREPEUTIC USESANALGESIA

To alleviate severe pain in conditions such as MI, fractures of long burns,terminal stage of malignancy etc

TREATMENT OF DIARRHEA

RELIEF OF COUGH

AS PREANESTHETIC MEDICATION IN ACUTE LEFT VENTRICULAR FAILURE

SEDATION AND SLEEP

7/31/2019 0PIOID

35/77

PHARMACOKINETICS

ADMINISTRATION- absorption ofmorphine from gastrointestinal tract is slowand erratic , therefore , intramascular,subcutaneous, or intravenous injectionproduces most reliable response

7/31/2019 0PIOID

36/77

DISTRIBUTION Morphine rapidly enters all the body tissues, including fetuses of

women .

Infant born of addicted mothers show physical dependence on oexhibit withdrawal symptoms if opioids are not administered.

FATE - Morphine is metabolized in the liver to glucoronides

7/31/2019 0PIOID

37/77

ADVERSE EFFECTS

7/31/2019 0PIOID

38/77

DRUG INTERACTIONS

7/31/2019 0PIOID

39/77

PRECAUTIONS AND CONTRAINDICAT

7/31/2019 0PIOID

40/77

MEPERIDINE

It is a synthetic opioid with structure unrelated to mo

MOA- binds to opioid receptors particularly kuppa re

Important differences in comparison to morphine are Dose to dose 1/8 1/10 in analgesic potency

Does not effectively suppress cough

Spasmodic action on smooth muscle is less marked

It causes less histamine release and is safer in asthamatics

It has local anesthetic action ; corneal anesthesia is seen aftedose

It is well absorbed orally

7/31/2019 0PIOID

41/77

(Oral maxillofacial surgery clinics of N AM 14 2002 ; 137-

7/31/2019 0PIOID

42/77

METHADONE

MECHNAISM OF ACTION- greatest action on mu receptorsACTIONS

Strong analgesic action when administered orally

analgesic action is equivalent to that of morphine when given

The miotic and respiratory depressant action have average ha

hrs

7/31/2019 0PIOID

43/77

THEREPEUTIC USES Used in controlled withdrawal of addicts from heroin and mo

Orally administered methadone is substituted for the injecte Causes moderate withdrawal symptoms

PHARMACOKINETICS Readily absorbed following oral administration

Accumulates in tissue where it remains bound to proteins &

released Drug is biotransformed in the liver and excreted in urine

ADVERSE EFFECTS Can produce dependence like morphine

7/31/2019 0PIOID

44/77

FENTANYL Chemically related to meperidine

Has 80 times the analgesic potency of morphine

Has a rapid onset and short duration of anesthesia

Combined with Droperidol it produces dissociative anes

7/31/2019 0PIOID

45/77

4 hrs

2 hrs

45 min

Morphine

MEPERIDINE

FENTANYLTime

Dura

20 min

15 min

5 min

7/31/2019 0PIOID

46/77

HEROIN( di acetyl morphine, brown sugar)

7/31/2019 0PIOID

47/77

MODERATE AGONISTS CODIENE (Oral Maxillofacial Surg Clin N Am 14; 2002)

Closely related in structure to morphine, possessing a methyl

One third as potent as morphine, but ha s a higher oral efficac

Has a lower abuse potential and rarely produces dependence

Studies assessing codeins ability to relieve post operative ora

have indicated that 60 mg of codeine is required to achieve thbenefit in dental pain.

7/31/2019 0PIOID

48/77

7/31/2019 0PIOID

49/77

HYDROCODONE

7/31/2019 0PIOID

50/77

MIXED AGONIST AND ANTAGONISTS PENTAZOCINE

Acts as an agonist at kuppa receptor and is a weak antagonistsigma receptors

Promotes analgesia by activating receptors in the spinal cord

At therapeutic doses , pentazocine has less respiratory depremorphine

Not recommended in myocardial infarction patient.

Should not be used with agonists such as morphine, since thaction of pentazocine may block the analgesic effects of mor

Given orally , pareneterally, or intramascularily.

7/31/2019 0PIOID

51/77

BUTORPHANOL

7/31/2019 0PIOID

52/77

ANTAGONISTS Bind with high affinity to opioid

receptors but fail to activate thereceptor mediated response

Produces no profound effects innormal individuals

In patients addicted to opioid

rapidly reverse the effect ofagonists.

7/31/2019 0PIOID

53/77

NALOXONE

7/31/2019 0PIOID

54/77

PRINCIPLES OF OPIOID PHARMACOL

1. The analgesic property of

morphine and all otheropioids is dose related

The customary doses formorphine & codeine do notrepresent the maximally

effective dose but the pointabove which toxicities & sideeffects are first noted

They do not have a plateau intheir response curve.

(DENTAL CLINICS OF NORTH AMERICA-VOL 28,NO 3,JULY 19

7/31/2019 0PIOID

55/77

2.ORAL VERSUS PARNATERAL POTEAnalgesic efficacy is dependent on route of administration

AGENT INTRAMASCULAR ORAL RELATIVE PO

MORPHINE

METHADONECODIENEOXYCODONEMEPERIDINE

5- 15

5-10__

50- 100

_

5-1530-605100

1/6

1/ 26/101/ 22/3

USUAL ADULT DOSE (mg)

OPIOID ANALGESIC POTENCY : ORAL VERSUS PARNETRAL

7/31/2019 0PIOID

56/77

3.AGONISTS VERSUS ANTAGONISTS

One of the unique

properties of opiates isthat their pharmacologicand toxicologic propertiescan be inhibited orreversed

7/31/2019 0PIOID

57/77

INDICATIONS FOR DENTISTRY(DENTAL CLINICS OF NORTH AMERICA-VOL 28,NO 3,JULY 1984)

1. Relief of severe pain in hospitalized patient In this controlled setting , patient can be administered larg

narcotics , as the possible adverse reactions can be recognizmanaged

Nausea & vomiting problems seen in ambulatory patientsminimized because the patient remain recumbent.

Agents with longer duration can be used as these patients cmonitored through out the day

7/31/2019 0PIOID

58/77

ANALGESICS FOR HOSPITALIZED PATIENT WITH S

PAIN

AGENT ROUTE ADULT DOSE(mg)

DURAT(hr

Morphine sulphateMeperidine

OxymorphoneButorphanolNalbuphine

i.mi.m

i.mi.mi.m

10- 1510 -80

1.0- 1.52- 310

4 52- 4

4- 544

7/31/2019 0PIOID

59/77

2.Relief of severe pain in dental out patient

ANALGESICS FOR DENTAL OUT PATIENTS WITH SEVERE


DURATION(hr)

CODEINOXYCODONEHYDROCODONEDIHYDROCODEINEMEPERIDINE

ORALLYORALLYORALLYORALLYORALLY

605- 10532

50 - 100

4-54- 54 -643- 4

7/31/2019 0PIOID

60/77

The list includes agents that can be administered orally a

slight low potential for abuse

Codeine and codeine derivatives are not extensively metatherefore they maintain their analgesic activity

The agents at recommended doses are generally well tole

These agents are almost always marketed in combinationNSAID

7/31/2019 0PIOID

61/77

3.MODERATE PAIN IN DENTAL OUTPATIEN

4 ADULT SEDATION AND GENERAL ANESTHESIA

7/31/2019 0PIOID

62/77

4.ADULT SEDATION AND GENERAL ANESTHESIA These agents are administered in incremental dose s, usually in

with nitrous oxide

Short acting agents are preferred so that recovery is not unneceprolonged

These provide added sedation and some analgesia during the d


DURATI(hr)

FENTANYL

MEPERIDINE

MORPHINESULPHATE

IV

IV

IV

.01*

10*

1*

- 1

1 1

2-4

7/31/2019 0PIOID

63/77

5.EMERGENCY DRUGSAGENT ROUTE ADULT DOSE

(mg)

DUR

NALAXONE

MORPHINE SULPHATE

IV

IV

0.4

10

7/31/2019 0PIOID

64/77

PHARMACOTHERAPY FOR CANCER PAIN Emphasizing that the intensity of pain, rather than its specific

mechanism should be the prime consideration in analgesic selcancer unit of theWHO has developed an approach to drug secancer pain, which has become known as the three step analadder

( Hematology/Oncology clinics of north America vol 10 number 1 feb 1996)

7/31/2019 0PIOID

65/77

OPIOID ANALGESICS PRINCIPLES OF ADMINISTRATION FOR C

7/31/2019 0PIOID

66/77

OPIOID ANALGESICS- PRINCIPLES OF ADMINISTRATION FOR C

PATIENTS( Hematology/Oncology clinics of north America vol 10 number 1 feb 1996)

DRUG SELECTION Pain intensity

Pharmacokinetic & formulatory consideration

Response to previous trials of opioid therapy

Coexisting disease

ROUTES OF ADMINISTRATION

Oral Rectal

Transdermal

Sublingual

Parneteral

7/31/2019 0PIOID

67/77

ROUTES OF ADMINISTRATION Opioids should be administered by the least invasive and safes

capable of producing analgesia During long term treatment , it is often necessary to switch RO

ORAL orally administered drugs have slower onset ofaction and more delayed peak time effect

RECTALNoninvasive alternative for patients unable touse oral opioidsThe potency of rectally administered opioids isapproximately equal to oral dosing

TRANSDERMAL-A transdermal formulation of fentanyl t,50,75 or 100 micro gram/ hour is comm

INDICATIONS Intolerance of oral medicationPoor compliance with oral medication

7/31/2019 0PIOID

68/77

ROUTES OF ADMINISTRATION . . . . . PARENTRAL ( INDICATIONS)

Patients who require the rapid onset of analgesia

Or who require very high dose

Patients with impaired swallowing or gastrointestinal obstruct

Repeated parentral bolus injections may be complicated by th

occurrence of untoward bolus effects( toxicity at peak concor pain break through at the trough). Indwelling IV lines should be used

SC device can be used

SCHEDULING OPIOD ADMINISTRATION

7/31/2019 0PIOID

69/77

SCHEDULING OPIOD ADMINISTRATION

AROUND THE CLOCK dosing to prevent the pain from recurprovide continuous relief.

Controlled release oral morphine sulphate transdermal fentanyl arfor this purpose

These typically acheives peak plasma levels 3 to 4 hours after a dosduration of effect of 8 to 12 hrs

RESCUE DOSE

All patients who receive an around the clock opioid regimen shooffered a rescue dose given on an as needed basis to treat pain ththrough the regular schedule.

PATIENT CONTROLLED ANALGESIA (PCA)

7/31/2019 0PIOID

70/77

PATIENT CONTROLLED ANALGESIA (PCA)

PCA is a technique of parentral drug administration in wpatient controls a pump that delivers bolus doses of an aaccording to parameters set by the physician

Use of PCA device allows the patient to carefully titrate tdose to his or her analgesic need

DOSING

7/31/2019 0PIOID

71/77

DOSING INITIAL DOSE SELECTION

A patient with severe pain who is relatively non tolerant should genone of the opioid agonist at a dose equivalent to 5 to 10 mg im morhrs.

If a switch of one opoid to another is required because of unaccept, the equianalgesic dose table is used as guide.

DOSE TITRATION

Inadequate pain relief should be addressed through gradual escalatdose .

Gradual dose escalation should achieve a favorable balance bet anaeffects that remains stable for long period

EQUI ANALGESIC DOSE

7/31/2019 0PIOID

72/77

EQUI ANALGESIC DOSE

7/31/2019 0PIOID

73/77

DOSING . . . . RATE OF DOSE TITRATION

Severity of pain should determine the rate of dose titration

Patients with severe pain who need rapid relief can be managed bdosing every 15 to 30 min until pain is partially relieved

After parentrally loading with a short half life opioid, an approximmaintenance dose can be calculated bydividing the total load

twice the elimination half life of the drug.

REFERENCES

7/31/2019 0PIOID

74/77

REFERENCES PHARMACOLOGY- LIPPINCOTTS

ESSENTIALS OF MEDICAL PHARMACOLOGY- K.D. TRIPA

BELLS OROFACIAL PAIN

MONHEIMS LA & PAIN CONTROL IN DENTAL PRACTICE

ORAL & MAXILOFACIAL SURGERY CLINICS OF NORTH A

(2001

DENTAL CLINICS OF NORTH AMERICA (VOL 28 NO 3 J

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERIC

(VOL 10 NO 1 FEB 199

THANK YOU

7/31/2019 0PIOID

75/77

THANK YOU

7/31/2019 0PIOID

76/77

MEMBRANE PHOSPHOLIPIDS

FREE ARACHIDONIC ACID

PHOSPHOLIPASE

PROSTAGLANDINSPROSTACYCLINESTHROMBOXANES

7/31/2019 0PIOID

77/77

COX 1(CONSTITUTIVE)

PGE2 (RENAL FUNCTION)

PROSTACYCLIN(GASTRIC PROTECTION)

THROMBOXANE A2(PLATELET FUNCTION)

0pioid

Documents