DR.

SIDDHARTHA CHANDEL
POST GRADUATE STUDENT
ORAL & MAXILLOFACIAL SURGERY

ANALGESICS CAN BE BROADLY CLASSIFIED AS

OPIOIDS
NONOPIOIDS

 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

NSAIDs
History of NSAIDs
Classification of NSAIDs Mechanism of action (PG synthesis inhibition) Adverse effects Individual drugs

Analgesic combinations

 WEBSTERS dictionary describes pain as a basic bodily

sensation induced by a harmful stimulus characterized by physical discomfort.

Arbitrarily one may define pain as an unpleasant

emotional experience usually initiated by a noxious stimulus & transmitted over a specialized neural network to the central nervous system where it is interpreted as such .
(Monheims local anesthesia & pain control in dental practice)

ANALGESICS
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

 Peripheral pain stimuli are initially

ACUTE PAIN MECHNANISM

encountered at the nocioceptor level on skin, joint, or end organ surfaces, where they are processed and transmitted via first order neuron to the dorsal neurons of spinal cord.
dorsal horn to synapse with the second order neuron

The first order neuron carry input into the

The second order neurons then crosses

over & ascends on to the higher centers.

Small interneurons connect the primary

afferent with the primary efferent neurons

FUNCTIONAL NEUROANATOMY

FIRST ORDER NEURON

Each sensory receptor is attached to first order or primary afferent neuron A general classification of neurons divides the larger fibres from the smaller

one, on the basis of thickness.

CLASSIFICATION OF FIRST ORDER NEURONS

1.
2. 3. 4.

TYPE A FIBERS Alpha fibers : size, 13 to 20 micro.m in diameter; velocity, 70 to 120m/s Beta fibers: size 6 to 13 micro.m in diameter; velocity, 15 to 40 m/s Gamma fibers: size, 3 to 8 micro.m in diameter; velocity, 5 to 15 m/s Delta fibres: size, 1 to 5 micro.m in diameter velocity, 5 to 15 m/s

TYPE C FIBERS
Size 0.5 to 1 micro.m ; velocity

.5m/s

SECOND ORDER NEURONS

There appears to be three specific type of second order neuron that transfer impulses to the higher center. These neurons are named according to the impulses they predominantly carry
LTM low threshold mechanosensitive neuron
NS Nocioceptive specific neurons WDR wide dynamic range neuron

 Once the impulses have transferred from the primary afferents

most of the second order neurons cross to the opposite side of the spinal cord & enter the ANTRO -LATERAL SPINOTHALMIC TRACT- which ascends to the higher centers Some second order neurons remain on the same side of dorsal column & ascend by the way of LEMNISCAL SYSTEM

 LATERAL SPINOTHALMIC TRACT

LEMINISCAL SYSTEM
Composed of large & myelinated

( composed of small unmylinated fibers that transmit signal at 40 m/s)

nerve fibre transmit signal to brain at velocity of 30 to 110 m/s)

Neospinothalmic Tract (A Delta fibres )

Paleospinothalmic Tract (C fibres)

THE SPINAL CORD

The spinal cord is subsided into different layers or laminae Studies suggest that nocioceptive input enters the dorsal horn by way of

NS & WDR neurons in the area of laminae 1, 2, 5

SUBSTANTIA GELATINOSA
Within the dorsal horn there are inter neurons that transfer impulse to other

inter neurons or to ascending neurons These neurons can be either inhibitory or excitory Excitory interneuron in laminae 2 & 3 of spinal cord are collectively called as substantia gelatinosa

THEORIES FOR PAIN MECHANISM

SPECIFICITY THEORY- DESCARTES 1664 MULLERS postulated the theory of information transmission only by the way of sensory nerves VON FREY developed the concept of cutaneous receptors PATTERN THEORY GOLDSCHEIDER in 1894 was the first to propose that

stimulus intensity and central summation are the critical determinants of the pain. GATE CONTROL THEORY 1965 PROPOSED BY MELZACK AND WALL

GATE CONTROL THEORY

Briefly stated the gate control theory

postulates that brain receives the message about injury by the way of the gate control system, which is influenced by
INJURY SIGNALS OTHER TYPE S OF AFFERENT

IMPULSES DESCENDING CONTROL

 In contrast to pain centre

proposed by specificity theory, the gate control mechanism postulates the existence of action systems

PAIN MODULATION OF THE DESCENDING INHIBITORY SYSTEM

In 1983, while studying nerve injuries in rat, WALL AND DEVOR determined that the peripheral receptor 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 anesthesia
The neural mechanism that appears to balance this continuous barrage of sensory input is called Descending inhibitory system Several neurotransmitters are imp in descending inhibitory system like serotonin & endorphins.

DISTRIBUTION OF RECEPTORS
High density of opioid

receptors are present in five general areas of the CNS known to be involved in integrating information about pain These pathways descend from the periaquedectel grey through the dorsal horn of the spinal cord.

PAIN PATHWAY

OPIOID ANALGESICS
THE TERM OPIOID ANALGESICS REFERS TO THOSE ANALGESICS THAT APPEAR TO HAVE PHARMACOLOGICAL PROPERTIES SIMILAR TO MORPHINE.
(DENTAL CLINICS OF NORTH AMERICA VOL 28, NO 3,JULY 1984)

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) from the

third century BC

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

Greeks dedicated the Opium poppy to the Gods of Death (Thanatos), Sleep

(Hypnos), and Dreams (Morpheus) qualities

Sixteenth Century is the first reported use of Opium for its Analgesic

CLASSIFICATION
NATURAL OPIUM ALKALOIDS MORPHINE CODIENE SEMISYNTHETIC OPIATES DIACETYL MORPHINE PHOLCODIENE SYNTHETIC OPIOIDS PETHIDINE FENTANYL METHADONE TRAMADOL ETHOHEPTAZINE DEXTROPROPOXYPHENE PENTAZOCINE

CLASSIFICATION ON THE BASIS OF CHEMICAL STRUCTURE

Phenanthrenes Morphine Codeine Oxycodone Nalbuphine Hydromorphone Phenylpiperidines Meperidine Fentanyl Alfentanil Sufentanil Remifentanyl Phenylhepylamines Propoxyphene Methadone Morphinans Butorphanol Benzomorphans Pentazocine

CLASSIFICATION OF OPIOIDS BY ACTION ON RECEPTORS

STRONG AGONISTS FENTANYL HEROIN MEPERIDINE METHADONE MORPHINE SUFENTANIL MODERATE AGONISTS CODIENE PROPOXYPHENE MIXED AGONISTS ANTAGONISTS BUPERINORPHINE PENTAZOCINE ANTAGONISTS NALOXONE NALTRAXONE

MORPHINE( STRONG AGONISTS)

It is the major analgesic contained in crude opium & is prototype agonist & is

used as sulphate or hydrochloride. Shows high affinity for mu receptors, varying affinity for delta & kuppa receptors & low affinity for sigma receptors

MECHANISM OF ACTION
Major effects by interacting with opioid receptors in the CNS & GIT Causes hyperpolarisation of nerve cells , inhibition of nerve firing, presynaptic inhibition of transmitter release Acts at mu receptors in lamina 1 & 2 of substantia gelatinosa of the spinal cord & decreases the release of substance P . Also inhibits the release of many excitory transmitters from nerve terminals carrying nocioceptive stimuli

ACTIONS
ANALGESIA EUPHORIA RESPIRATION DEPRESSIONS OF COUGH REFLEX MIOSIS EMESIS GASTROINTESTINAL TRACT CARDIOVASCULAR HISTAMINE RELEASE HORMONAL ACTIONS

 ANALGESIA Opioids relieve pain by both raising the pain threshold at the spinal cord level, and by 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 occulomotor nerve , causing enhanced parasympathetic stimulation NAUSEA AND EMESIS
Morphine produces vomiting by the stimulation of the CTZ in the area post trema of the medulla

 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 & hypotension may occur 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

THEREPEUTIC USES
ANALGESIA To alleviate severe pain in conditions such as MI, fractures of long bone, burns,terminal stage of malignancy etc TREATMENT OF DIARRHEA RELIEF OF COUGH AS PREANESTHETIC MEDICATION IN ACUTE LEFT VENTRICULAR FAILURE SEDATION AND SLEEP

PHARMACOKINETICS
ADMINISTRATION- absorption of morphine from gastrointestinal tract is slow and erratic , therefore , intramascular, subcutaneous, or intravenous injection

produces most reliable response

 DISTRIBUTION Morphine rapidly enters all the body tissues, including fetuses of pregnant women . Infant born of addicted mothers show physical dependence on opiates and exhibit withdrawal symptoms if opioids are not administered. FATE - Morphine is metabolized in the liver to glucoronides

ADVERSE EFFECTS

 DRUG INTERACTIONS

PRECAUTIONS AND CONTRAINDICATIONS

Infants and elderly are more susceptible to the respiratory depressant action

of morphine Dangerous in patient with respiratory insufficiency Bronchial asthma Head injury Undiagnosed acute abdominal pain Unstable personalities

MEPERIDINE
It is a synthetic opioid with structure unrelated to morphine. MOA- binds to opioid receptors particularly kuppa receptors 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 after systemic

dose It is well absorbed orally

 Meperidine is a reasonable alternative for the patients who have been

determined to be non respondent to codiene derived analgesics or those with a true allergy to the codiene class Its use should be limited to 10 to 14 days It is the preferred analgesic in biliary colic and and during labour Strictly contraindicated in patients taking MAO inhibitors (Oral maxillofacial surgery clinics of N AM 14 2002 ; 137-151)

METHADONE
MECHNAISM OF ACTION- greatest action on mu receptors ACTIONS Strong analgesic action when administered orally analgesic action is equivalent to that of morphine when given iv The miotic and respiratory depressant action have average half lives of 24 hrs

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

Orally administered methadone is substituted for the injected opioid

Causes moderate withdrawal symptoms

PHARMACOKINETICS
Readily absorbed following oral administration Accumulates in tissue where it remains bound to proteins & is slowly

released Drug is biotransformed in the liver and excreted in urine

ADVERSE EFFECTS
Can produce dependence like morphine

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 anesthesia

Morphine

20 min

4 hrs

MEPERIDINE

15 min 2 hrs
5 min 45 min Time to peak effect Duration of action

FENTANYL

HEROIN ( di acetyl morphine, brown sugar)

Does not occur naturally but is produced by acetylation of morphine , which

leads to three fold increase in its potency Lipid solubility greater than morphine; crosses BBS more rapidly thus more exaggerated euphoria Converted to morphine in the body No accepted medical use

MODERATE AGONISTS
CODIENE (Oral Maxillofacial Surg Clin N Am 14; 2002 )
Closely related in structure to morphine, possessing a methyl group One third as potent as morphine, but ha s a higher oral efficacy Has a lower abuse potential and rarely produces dependence Studies assessing codeins ability to relieve post operative oral surgical pain

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

 Often used in combination with aspirin or acetominophen. It decreases the sensitivity of CNS cough centers to peripheral stimulii, and

decreases mucosal secretions hence used as antitussive. Most common side effects are nausea , constipation , vomiting and sedation.

HYDROCODONE
Derived from opium alkaloid thebaine.Structurally it is a ketone derivative of

codiene. It is an oral, semi synthetic mu opiate receptor agonist It has antitussive and analgesic properties , approximately six times more potent than codiene. Equipotent doses of codiene and hydrocodone have similar efficacy and severity of adverse side effect

MIXED AGONIST AND ANTAGONISTS

PENTAZOCINE
Acts as an agonist at kuppa receptor and is a weak antagonist at mu and sigma receptors Promotes analgesia by activating receptors in the spinal cord At therapeutic doses , pentazocine has less respiratory depression than morphine Not recommended in myocardial infarction patient. Should not be used with agonists such as morphine, since the antagonist action of pentazocine may block the analgesic effects of morphine Given orally , pareneterally, or intramascularily.

BUTORPHANOL
Butorphanol tartrate is a synthetic parnetral and intranasal opiate agonist- antagonist It is agonist at the kuppa receptor but is aweak antagonist at the mu receptor . Undergoes extensive first pass metabolism , making its bioavailability low. Studies indicate that it is an effective analgesic for when administered transnasally , for PO pain Administered trannasally by spraying once in one nostril.Each spray is equivalent to 1 mg.

ANTAGONISTS
Bind with high affinity to opioid

receptors but fail to activate the receptor mediated response Produces no profound effects in normal individuals In patients addicted to opioid rapidly reverse the effect of agonists.

NALOXONE
Used to reverse the coma and respiratory depression of opioid overdose Acts within 30 seconds of IV administration It is a competitive antagonist at mu kappa and delta receptors, with 10 fold higher

affinity for mu receptors than for kuppa Produces no pharmacological in normal individuals, but precipitates withdrawal symptoms in morphine or heroin users 1 mg of naloxane given IV completely blocks the effect of 25 mg of heroin Available in 1 ml vials containing 0.4 mg/ml It has also been used to correct the hypotension in septicemic shock

PRINCIPLES OF OPIOID PHARMACOLOGY

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

1. The analgesic property of morphine and all other opioids is dose related
The customary doses for

morphine & codeine do not represent the maximally effective dose but the point above which toxicities & side effects are first noted They do not have a plateau in their response curve.

2.ORAL VERSUS PARNATERAL POTENCY

Analgesic efficacy is dependent on route of administration
USUAL ADULT DOSE (mg) AGENT INTRAMASCULAR ORAL RELATIVE POTENCY

MORPHINE METHADONE CODIENE OXYCODONE MEPERIDINE

5- 15 5-10 _ _ 50- 100

_ 5-15 30-60 5 100

1/6 1/ 2 6/10 1/ 2 2/3

OPIOID ANALGESIC POTENCY : ORAL VERSUS PARNETRAL

3.AGONISTS VERSUS ANTAGONISTS

One of the unique

properties of opiates is that their pharmacologic and toxicologic properties can be inhibited or reversed

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 large doses of

narcotics , as the possible adverse reactions can be recognized & managed Nausea & vomiting problems seen in ambulatory patients are minimized because the patient remain recumbent. Agents with longer duration can be used as these patients can be monitored through out the day

ANALGESICS FOR HOSPITALIZED PATIENT WITH SEVERE PAIN

ROUTE
i.m i.m i.m i.m i.m

AGENT Morphine sulphate Meperidine Oxymorphone Butorphanol Nalbuphine

ADULT DOSE (mg)

10- 15 10 -80 1.0- 1.5 2- 3 10

DURATION (hr)
45 2- 4 4- 5 4 4

2.Relief of severe pain in dental out patients

ANALGESICS FOR DENTAL OUT PATIENTS WITH SEVERE PAIN
ROUTE ADULT DOSE (mg) 60 5- 10 5 32 50 - 100 DURATION (hr) 4-5 4- 5 4 -6 4 3- 4

AGENT

CODEIN OXYCODONE HYDROCODONE DIHYDROCODEINE MEPERIDINE

ORALLY ORALLY ORALLY ORALLY ORALLY

 The list includes agents that can be administered orally and have

slight low potential for abuse Codeine and codeine derivatives are not extensively metabolized therefore they maintain their analgesic activity The agents at recommended doses are generally well tolerated These agents are almost always marketed in combination with a NSAID

3.MODERATE PAIN IN DENTAL OUTPATIENT

4.ADULT SEDATION AND GENERAL ANESTHESIA

These agents are administered in incremental dose s, usually in combination

with nitrous oxide Short acting agents are preferred so that recovery is not unnecessarily prolonged These provide added sedation and some analgesia during the dental procedures
AGENT FENTANYL IV ROUTE ADULT DOSE (mg) .01* DURATION (hr) -1

MEPERIDINE
MORPHINE SULPHATE

IV
IV

10*
1*

11
2-4

5.EMERGENCY DRUGS
AGENT
NALAXONE IV

ROUTE

ADULT DOSE (mg) 0.4

DURATION (hr) 1-2

MORPHINE SULPHATE

IV

10

4-5

PHARMACOTHERAPY FOR CANCER PAIN

Emphasizing that the intensity of pain, rather than its specific etiology or

mechanism should be the prime consideration in analgesic selection, the cancer unit of the WHO has developed an approach to drug selection for cancer pain, which has become known as the three step analgesic ladder ( Hematology/Oncology clinics of north America vol 10 number 1 feb 1996)

OPIOID ANALGESICS- PRINCIPLES OF ADMINISTRATION FOR CANCER 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

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

capable of producing analgesia During long term treatment , it is often necessary to switch ROA.
ORAL orally administered drugs have slower onset of action and more delayed peak time effect RECTAL Noninvasive alternative for patients unable to use oral opioids The potency of rectally administered opioids is approximately equal to oral dosing TRANSDERMALA transdermal formulation of fentanyl that delivers 25 ,50,75 or 100 micro gram/ hour is commercially available INDICATIONS Intolerance of oral medication Poor compliance with oral medication

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 obstruction Repeated parentral bolus injections may be complicated by the occurrence of untoward bolus effects( toxicity at peak concentrations/ or pain break through at the trough).

Indwelling IV lines should be used SC device can be used

SCHEDULING OPIOD ADMINISTRATION

AROUND THE CLOCK dosing to prevent the pain from recurring and to

provide continuous relief.

Controlled release oral morphine sulphate transdermal fentanyl are widely used

for this purpose These typically acheives peak plasma levels 3 to 4 hours after a dose and have a duration of effect of 8 to 12 hrs

RESCUE DOSE All patients who receive an around the clock opioid regimen should also be offered a rescue dose given on an as needed basis to treat pain that breaks through the regular schedule.

PATIENT CONTROLLED ANALGESIA (PCA)

PCA is a technique of parentral drug administration in which the

patient controls a pump that delivers bolus doses of an analgesic according to parameters set by the physician

Use of PCA device allows the patient to carefully titrate the opioids

dose to his or her analgesic need

DOSING
INITIAL DOSE SELECTION A patient with severe pain who is relatively non tolerant should generally begin one of the opioid agonist at a dose equivalent to 5 to 10 mg im morphine every 4 hrs. If a switch of one opoid to another is required because of unacceptable side effects , the equianalgesic dose table is used as guide. DOSE TITRATION Inadequate pain relief should be addressed through gradual escalation of the opiod dose . Gradual dose escalation should achieve a favorable balance bet analgesia and side effects that remains stable for long period

EQUI ANALGESIC DOSE

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 by parentral dosing every 15 to 30 min until pain is partially relieved After parentrally loading with a short half life opioid, an approximate hourly maintenance dose can be calculated by dividing the total loading dose by twice the elimination half life of the drug.

REFERENCES
PHARMACOLOGY- LIPPINCOTTS ESSENTIALS OF MEDICAL PHARMACOLOGY- K.D. TRIPATHI BELLS OROFACIAL PAIN MONHEIMS LA & PAIN CONTROL IN DENTAL PRACTICE ORAL & MAXILOFACIAL SURGERY CLINICS OF NORTH AMERICA (2001 & 2002) DENTAL CLINICS OF NORTH AMERICA (VOL 28 NO 3 JULY 1984) HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA (VOL 10 NO 1 FEB 1996)

THANK YOU

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