OPIOID ANALGESICS

Dr. G.vishnupriya M.D

1

Pain –

Unpleasant & emotional experience associated with tissue

damage such as injury , inflammation or cancer.

Analgesics – Opioid/narcotic/Morphine like analgesics. Non opioid/non narcotic/Aspirin like antipyretics/analgesics.

Pathophysiology of pain -

1- Nociceptive component - ascending pathway

2- Affective component - descending pathway

2

CLASSIFICATION OF PAIN - Somatic Visceral Superficial Vascular Referred Neuropathic Phantom Cancer Psychogenic Central

3

Peripheral and Central Pathways for PainAscending TractsAscending TractsDescending TractsDescending Tracts

Cortex

Midbrain

Medulla

Spinal Cord

Thalamus

Pons

Ascending pathway – From primary afferent neurons relays impulses to the cortex

from cortex it relays signals to the organ ,it alerts the person to

Use withdrawal reflexes to avoid noxious stimuli. This is called

sensory discriminative component via A delta fibres C fibres causes motivational affective response These nociceptors are present in lamina I & II

Descending pathway – It possess inhibitory effect on dorsal horn transmission.

PAG → RVM & NRM → SG Inhibits ascending pain transmission via STT neurons Met encephalins are released to inhibit pain .

5

described by Melzack and Wall in 1965

Gate control Mechanism.

• Stimulation of the large fibers inhibits the transmission of pain, thus “closing the gate.” Whereas, when smaller fibers are stimulated, the gate is opened.

• When the gate is closed signals from small diameter pain fibres do not excite the dorsal horn transmission neurons.

• When the gate is open pain signals excite dorsal horn transmission cells.

• The gating mechanism is influenced by nerve impulses that descend from the brain.

Wind up – in event of repeated firing synaptic potential

increases amplitude & results in wind up shows activity

dependent facilitation .

NMDA, substance P, Nitric oxide, ↑ NGF causes

facilitation by tissue damage results in hyperalgesia. 6

MODULATION OF PAIN –

Peripheral modulators & neuromodulators- capsacin →TRPV1→Depolarisation → initiation of action

potential. Capsacin is obtained from bell peppers it irritates skin on

applying used in incontinence of bladder in patients with spinal

injury & stroke.

TRPV1- Polymodal, closely matches nociceptive neurons Modulated by phosphorylation, TRPV1-4 are thermosensitive, non-selective cation channels that exist as tetrameric

complexes7

They are activated by a range of stimuli including heat, protons, lipids and changes in osmolarity or pressure.

TRPV5-6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and renal epithelia.

cannabinoids are endogenous ligands for vanilloid receptors. adenosine has been shown to be an endogenous TRPV1

ligand and TRPV4 is activated by anandamide and arachidonic acid.

Kinins – Bradykinins & kallidin produced during tissue injury. Potent pain producing substance Releases prostaglandins

8

Kinins contd… Act on B2 receptors on nonciceptive neurons Opens TRPV1 channels

Prostaglandins- Enhances 5HT& bradykinins Sensitizes nerve terminal by inhibiting k channels

Other peripheral mediators –ATP, Protons, 5HT, Histamine, K ions, Substance P, Glutamate,

GABA, Noradrenaline, Adenosine

9

10

History of opioids – First reference of opium by Theophrastus 3rd century BC.

Arab physician used it for control of dysentry

1806, Frederich Serturner a pharmacist assistant isolated by

crystallization of pure substance in opium named Morphine

after Morpheus – Greek god of dreams.

middle of 19th century – use of pure alkaloids coincided with

development of hypodermic syringe and hollow needle.

11

They used in a civil war in U.S named as soldiers disease.

C.R Alder Wright in 1874 – heroin

Early 1970 – effect of Morphine, Heroin and other opioids as anti nociceptive and addictive agents were well described.

Martin and Goldstein discovered receptors.

12

F. SERTURNER (1783–1841)

Morphine

Papaver somniferumL.•Opium-morphine (1806)-codeine-papaverine

..Afghanistan PakistanThailand

13

14

ENDOGENOUS OPIOID PEPTIDES –

In 1973 researchers determined the existence of opiate binding

sites in the brain through the use of radioligand-binding assays

Have Morphin like actions & μ receptor binding activity

– Endorphins,

Encephalin

Dynorphins &

Nociceptin

share a common terminal amino acid sequence of five amino

acids joined to MET/LEU

15

β Endorphins It has Met at the last +26 amino acids Has greater affinity to μ Derived from POMC found in Pituitary, Hypothalamus, Limbic area & Medulla These project from Hypothalamus, Thalamus, Arcuate

Nucleus & brain stem

16

ENCEPHALINS- 2 encephalins (Leu/Met) derived from preproencephalin Both have high affinity to δ Present- Hypothalamus, cortex, limbic system , PAG &Pain

areas of spinal cord.

DYNORPHINS- It has Leu terminal amino acid sequence Dynorphin A,B,α neo endorphin & β neo endorphin possess

extension of additional amino acids. Greater affinity to κ

17

Dynorphins contd… Derived from preprodynorphin Present in dorsal horn of spinal cord Binds to activate NMDA receptors.

ENDOMORPHINS - Endomorphin 1&2 found in brain during stress High affinity μ receptors Precursors not known Short amino acid sequence.

18

NOCICEPTIN – Orphan receptors Derived from pro orphanin Found in hippocampus, cortex, many sensory neurons 17 amino acid sequence it is termed as ORL-1 In reward , reinforcement, learning, memory & parkinsons

Disease It causes hyperalgesia.

19

Opioid Receptors-

types of receptors - μ, δ, κ & NOP. μ- μ1, μ2 Delta- δ1, δ2 κ-κ1, κ2, κ3.

20

Functional effects and opioid receptorsMu Delta Kappa

Analgesia

Supraspinal +++ - -

Spinal ++ ++ ++

Peripheral ++ - ++

Resp. depression

+++ ++ -

Miosis ++ - +

GI motility ++ ++ +

Euphoria +++ - -

Dysphoria - - +++

Sedation ++ - ++

Dependence

+++ - +21

22

Selectivity of Opioid Drugs for receptor subtypes

Mu Delta Kappa

Morphine, Codeine

+++ + +

Methadone ++ - -Pethidine ++ + +Pentazocine + + ++Buprenorphine

+++ - ++

Naloxone +++ + ++Naltrexone +++ + +++

Agonist + Antagonist + 23

MECHANISM OF ACTION OF OPIOID

RECEPTORS-

STRUCTURE OF RECEPTOR

These are G protien coupled receptorsSeven hydrophobic regionThree intracellular loopsThree extracellular loopsIntracellular carboxy-terminal tailExtracellular amino-terminal tail

24

25

MECHANISM OF ACTION OF OPIOID

RECEPTORS-The mu-receptor opens ion channel allowing K ions to

flow

out of the cell → hyperpolarisation. it become extremely difficult

for an action potential to be reached and the neurons excitability

decreases.

also causes less calcium ions to enter the terminal end of the

neuron where neurotransmitters are stored and as a result this

significantly reduces neurotransmitter release26

MOA of opioid recep Contd…

It inhibits the membrane bound enzyme adenyl cyclase and

prevents the synthesis of cAMP.

Action at supra spinal level –

Opioids binds at μ opioid receptor & blocks pain which is

Naloxone reversible

27

Action at supra spinal level Cont…

Action at spinal level – Opioids depress discharge from spinal dorsal horn neurons by

C Fibers. Prevents opening of Ca, preventing transmitter release.

28

Action at spinal cord level Cont… Post synaptic action is demonstrated by ability of opioids to block

excitation of dorsal horns evoked by Glutamate..

Peripheral actions-These agents acts centrally

Direct application produces Local anesthetic like action at high

conc. which is not Naloxone reversible

29

OPIOID ANALGESICS Opioids are drugs derived from or related to the Opium Opium is derived from the juice of the opium poppy, Papaver

somniferum Opium contains over twenty distinct alkaloids (morphine was the

first alkaloid of opium to be isolated in 1806). The unripe seed capsule of poppy plant

are incised ,milky exudates collected, dried

& powdered

30

Based on the chemical structure opium alkaloid are

classified into two types:

Phenanthrene derivatives

Morphine

Codeine

Thebaine

Benzoisoquinoline derivatives

Papaverine, Noscapine, Narcine

31

CLASSIFICATION:

NATURAL-Morphine, Codeine

SEMI SYNTHETIC-Diacetyl Morphine, Pholcodeine, Hydromorphone, oxymorphone,

SYNTHETIC –

Pethidine , Fentanyl, Methadone, Dextropropoxyphene, Tramadol

Levorphanol, Dextromoramide, Alfentanyl, Sufentanyl, Remifentanil 32

Phenanthrene group –

8%- 20% of morphine

0.5 – 2.5% of codeine along with thebaine(0.2 – 0.4).

MORPHINE – Phenanthrene derivative with 2 planar ring & 2 aliphatic ring

Prototype analgesic used as sulfate or hydrochloride, both salts are soluble in water

Acts on μ receptors ,↓ release of glutamate from nociceptive

nerve terminals & also acetylcholine,NA,5HT& Substance P

33

Pharmacokinetics – Oral morphine extensive first pass effect hence bioavailability

is 20-40%,sustained release have a longer duration of action.

various routes of administration are -

Oral, intrathecal ,epidural, rectal, I.V, I.M & S.C- effect within 15-20 mins, persist 3-5hrs.

It circulates in plasma partly protein bound &

partly in free Form.

34

Morphine Cont.. It enters the blood brain barrier, placental barrier, secreted in

breast milk

It metabolized by liver & kidney

Conjugated with Glucuronic acid to form morphine-6-

Glucuronide active and more potent than morphine,t1/2 is longer

Eliminated in urine 90% of the dose, biliary excretion

accounts for 7-10% of dose

35

EFFECTS OF MORPHINE –

Analgesia- Acts on μ receptor Acute & chronic pain ↓ affective component of pain – reflects supra spinal

level at limbic system involved in euphoria producing action

Euphoria,sedation,convulsion – With therapeutic doses causes sense of well being ,

Agitation & anxiety associated with pain ↓ - acts on μ

receptors

36

Actions Cont.. κ receptors activation produces dysphoria & hallucinations

even in the absence of pain. Causes drowsiness, difficulty in concentration & mental

apathy, thoughts lack logic produces vivid & daydreams Large dose induces sleep, normal NREM & REM cycle

disrupted ↑ monosynaptic responses via supra spinal stimulation causes

convulsions.

Respiratory depression- Due to↑ PCO2 with normal analgesic doses mediated by μ

receptors

37

Actions CONT.. This effect is due to ↓ sensitivity of respiratory centers to ↑

plasma CO2 concentration. Direct depressant action on respiratory center (μ2). In later stages hypoxic drive tends to maintain minute volume

despite ↓ sensitivity of respiratory center to accumulate CO2. broncho constriction → Histamine Toxic doses breathing is maintained by hypoxic drive

mediated through carotid & aortic body chemoreceptors results

in cheyne stokes respiration - in this case, controlled assisted

Ventilation & O2 induced tolerance can develop.

38

cough suppression – Direct depressant at cough center, causes this action at lower

than the doses required to produce analgesia, tolerance will

develop Codeine & pholcodeine suppress cough but causes

constipation.

Nausea & vomiting – Directly stimulates CTZ produces emesis, later depresses

vomiting center abolished by Nalorphine& Prochlorperazine &

Haloperidol. In case of poisoning vomiting is absent.

39

Pupillary constriction- μ & κ receptor mediated stimulation of occulomotor nucleus. Pin point pupils is important diagnostic feature in opioid

Poisoning. tolerance does not develop.

Vagus stimulation –

Bradycardia & hypotension occurs due to action on medulla

Spinal cord-

depression of higher centers in

CNS → significant ↑ CSF pressure .

40

Miscellaneous actions – Release of ADH with resultant ↓ in urinary output, Morphine reduces the efficacy of diuretics in CHF patients ↓ body temperature in larger doses by central actions.

GIT – Induces spasm of smooth muscle of gut,ileocolic & anal

sphincter ↓ propulsive peristaltic movement,spasmogenic action in

duodenum & large intestine ↓ in saliva, gastric acid & intestinal secretion, spasm of

sphincters.

41

Action Cont… Inattention to normal sensory stimuli from loaded rectum

causes constipation Atropine antagonizes the action in biliary spasm, patient

should receive laxatives Senna regularly. In mice morphine produces severe spasm of anal sphincter

causes erection of tail- straub’s test formerly employed to detect morphine in biological fluids.

It can be used in treatment of diarrhoea

Smooth muscles – ↑ tone of ureter & detrusor muscle of the bladder Vesical sphincter is contracted ,effects are augmented by

inattention to stimuli arising from bladder -urinary retention ↑ tone of bronchi & bronchioles – bronchoconstriction

42

Actions Cont..

Inhibitory release of GnRH ↓ plasma concentration FSH, LH

& ACTH, plasma Prolactin ↑. Suppress the various immune function -↑ susceptibility to

infection in experimental animals . Release of Histamine causes urticaria , Asthmatics should not

be given morphine.

TOLERANCE/DEPENDENCE/ADDICTION –

Tolerance – it develops when large amount of dose of drug is

needed to produce the effect ordinarily produced by its normal

therapeutic dose.

43

Mechanism of development of tolerance Tolerance to opioids is cellular adaptive type – long term

desensitisation of receptor effector coupling mechanism

Or it may be due to ↑ Ca levels in the cells,↑ production of

cAMP, ↓efflux of k and resultant release of neurotransmitters to

normal levels

Development of tolerance begins with first dose of

opioids, repeated administration at shorter interval results in loss

of effectiveness with intermittent use of morphine.

Tolerance develops to respiration, depression, emetic,

hypotensive, euphoriant & urinary retention action but not to

miotic & constipation.

44

Tolerance cont.. Cross tolerance can occur with other opioid analgesic to

prevent this opioid rotation should be done another approach is to

recouple opioid receptor function via use of adjunctive non

opioid agents. Does not develop tolerance to antagonist action of mixed

agonist antagonist. Remifentanyl induces tolerance within hours

ketamine prevents or reverses opioids induced tolerance

Novel use of δ receptor antagonist with μ receptor agonist –

Useful in emergency condition.

45

Dependence –

WHO definition- A state of psychic & sometimes also physical, resulting from the interaction between a living organism & a drug, charecterized by behavioural & other responses that always include a compulsion to take the drug on continuous or periodic basis in order to experience its psychic effect and sometimes to avoid the discomfort of its absence. Tolerance may or not be present. A person may be dependent on more than one drug.

Morphine produces physical dependences, life threatening

withdrawal symptoms are produced with exaggerated rebound

from acute effects of the drug.There is some psychological

dependence also46

Signs &Symptoms –morphine & heroin signs starts within 6-10hrs of last dose, by 5 days most of signs & symptoms disappear some persists for months. Increased craving for drug, lethargy & weakness Weight loss Pupil dilation Chills,rhinorrhea Excessive sweating Abdominal cramps Muscle spasms Hyperirritability Lacrimation Tremor Increased heart rate Increased blood pressure

47

Dependence cont.. Buprenorphine & Clonidine are treatments for opioid

detoxification. Babies born to opioid addicted women also exhibit withdrawl

signs because of slower metabolism of opioids in newborn. It facilitate DA transmission in mesocortical or mesolimbic

Pathways and thus activate endogenous reward pathway in the

brain. In order to prevent morphine dependence , morphine should

not be prescribed readily for chronic pain except in terminal

Cancer pain

48

Treatment – gradual withdrawal of morphine with substitution of

another opioid analgesic to ↓ severity of withdrawal syndrome. Methadone orally is often used for replacement as it has longer

duration of action than Morphine.

1mg of Methadone will substitute for 4mg of Morphine. Once

it is stabilized, dose is gradually ↓ by 10-20% daily. Drug can be

completely stopped from 6-10th day.

Acute opiate withdrawal symptoms & signs can be controlled

to certain extent by drugs like Chlorpromazine, Propranolol &

clonidine which counter non adrenergic activity49

Morphine poisoning – Due to overdosage, accidental overingestion in an addict or

From suicidal or homicidal intention.

60mg is usually toxic but rarely fatal in normal adult who is

not in pain. Doses 250mg usually fatal.

Larger doses are generally required to produce toxicity in

individuals with pain, whereas in addicts the toxic as well as the

fatal doses are much higher.

50

Pin point pupils

51

Characterized by – Respiratory depression, pin point pupils, Cyanosis, Reduced body temperature & urinary output, Hypotension, Shock & coma.

Convulsions may occur in infants, Death due to respiratory

depression or shock & pulmonary embolism

52

Treatment Naloxone & Nalorphine are specific morphine antagonists

should be administered since they produce severe withdrawal

syndrome.

Drug interactions :

CNS depressants, Phenothiazines, MOA inhibitors & Tricyclic

antidepressants enhances the sedative effects of Morphine &↑

respiratory depression

53

Therapeutic uses of Morphine –

Pain relief – Acute MI, fracture of long bones, burns, terminal

stage of malignancy, pulmonary embolism, acute pericarditis &

spontaneous pneumothorax, renal & biliary colic Morphine is administered I.V to↓ shock ,S.C not

advocated because absorption is hampered. If repeated S.C may

result in sudden absorption of toxic quantities into systemic

circulation . Parentral morphine ↓ Post operative pain it ↓ coughing and

Mask signs of recovery & of its complication.

54

Pain relief cont.. morphine produces long lasting analgesia -segmental Used following thoracic & upper abdominal surgery

Actions in acute LVF & pulmonary edema –

Morphine induced peripheral vasodilatation → shunting of

Blood to dilated peripheral vasculature - ↓preload thus it ↓

cardiac work load & relieves dyspnoea, provided oxygenation is

Maintained.

55

presence of severe pain

Morphine routinely for sedating patients in haematemesis,

Diazepam is safer. Preanesthetic medication Control diarrhoea Anaesthetic – morphine I.V produce general anaesthesia

56

DOSAGE.

10 mg / ml inj.

10,30,60,100 mg CR Tabs; 60 mg SR Tabs, 10,20 mg Tab.

2-3 mg epidural / intrathecal

10-15 mg IM or SC

0.1 – 0.2 mg / kg – children.

2-6 mg IV

57

Precautions & Contraindications

Infants & elderly

Respiratory insufficiency

Bronchial asthma

Head injury

Hypotension / hypovolemia

Undiagnosed acute abdominal pain

Hypothyroidism, liver & kidney disease

Unstable personalities.

58

59

60

61

Other drugs

Oxycodone - acts on κ receptors

Alphaprodine –

Relief of pain in first stage of labour.

Diphenoxylate, Difenoxin, Loperamide- treatment of diarrhoea

62

FENTANYL -

1959-Fentanyl first synthesized by Paul Janssen under Janssen

Pharmaceuticals 1960s-Introduced as intravenous anesthetic 1990’s-same company produced Duragesic patch Next came flavored lollipop of fentanyl citrate Present-Effervescent tab for buccal absorption and buccal

spray device patient controlled infusion systems, Advantage in

breakthrough pain Causes Post operative muscle rigidity

63

NEUROLEPTANALGESIA•Fentanyl 100 mcg +•Droperidol 5 mg i.m.

64

Alfentanil - an ultra-short acting (5-10 minutes) analgesic

Sufentanil – a most potent analgesic (5 to 10 times more potent than fentanyl) for use in heart surgery

Remifentanil - currently the shortest acting opioid, has the benefit of rapid offset, even after prolonged infusions

Carfentanil - is an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals such as elephants

Fentanyl, Sufentanil, Alfentanyl –truncal rigidity on rapid I.V

65

Apomorphine-

Obtained from acid catalyzed rearrangement

Of Morphine, stimulates CTZ –potent emetic-

activation of DA receptors-

blocked by Chlorpromazine Produces a variety of behavioural,

neuro- pharmacological & endocrine effects.

In larger doses in rats causes stereotyped behaviour

syndrome

66

Apomorphin cont.. It is used to evaluate actions of psychotropic drug actions in

experimental animals. Dose- 0.1mg/kg S.C – causes vomiting Other effects- nausea, dizziness, hypotension & bradycardia.

Pethidine : 25-100mg oral, I.M/S.C 25-100mg I.V Potent as morphine as analgesic Not suitable in Asthmatics ↑ heart rate, ↓B.P –depression vasomotor system &release

Histamine anti cholinergic property – tachycardia, C/I – M.I

67

Pethidine contd.. Preferred in labour does not reduce the force of uterine

Contraction

Naloxone is needed to reverse respiratory depression

50% bioavailability, analgesic effect occur within 10-15 mins,

crosses placental barrier, secreted in milk, metabolized by liver , product Norpethidine shows excitatory effects on CNS.

Treatment to Pethidine addiction is similar to morphine ,Methadone 1mg for 20 mg Pethidine 68

Drug Interactions- Phenytoin ↑ biodegradation of pethidine Cemetidine ↓ clearance of pethidine /morphine is given as

alternative Administered in patient with MAOI → Confusion, excitement,

collapse, Causes seizure in renal failure patient due to accumulation of

Norpethidine

Methadone -5-10 mg/ml oral/ I.M/S.C/rectal

In chronic visceral pain can be given, substitute for Morphine &

Pethidine & used in opioid abstinence.

69

Methadone contd… Acts on inhibiting Noradrenaline & 5HT reuptake Blocks NMDA receptors that modulate pain – in neuropathic

& cancer pain Long t1/2 24-36hrs ,bioavailability 80% ,high protein & tissue

bound. Development of tolerance & dependence is slow- useful

for opioid rotation therapy. causes cumulative toxicity Crosses placental barrier Codeine is used as a substitute – Methadone addiction.

Methadone congeners –

Levomethadyl acetate – slow onset ,prolong action in long term

management of heroin addicts to prevent withdrawal syndrome

70

d-propoxyphene – Few G.I side effect less respiratory depression, analgesic Potentiates action of Warfarin Dose- 65mg t.i.d .

Morphinan compounds –

Levorphanol - More potent analgesic than Morphine Cause drug dependence Oral/I,M/I.V – 2mg ,intranasally

Butorphanol- Partial agonist I.M/I.V- 2mg, intranasal. Psychomimetic effects

71

Pentazocine – Action at κ receptors in spinal cord ,weak opioid

antagonist activity in μ receptor- dysphoria. ↑ systemic & pulmunory arterial blood pressure -↑cardiac

load ,C/I – M.I Dose-25mg-30mg ,Given orally, rectally, S.C, I.M & I.V. Causes hallucinations & unpleasant dreams, precipitates withdrawal syndrome in morphine addicts –

antagonist action μ receptors Naloxone is useful antidote to Pentazocine

72

Nalbuphine – Related to Oxymorphone & Naloxone Both agonist & antagonist property Causes psychomimetic effects S.C,I.M,I.V, dose 10 – 20mg every 3-6hrs Ceiling effect to its respiratory depressant action

Meptazinol –

Partial agonist ,Oral or by injection

Buprenorhine – High lipophilic,synthetic derivative of Thebaine Mainly partial μ agonist weak antagonist at κ receptors Dissociates slowly from μ receptors resistant to Naloxone reversal

73

Buprenorphin cont..

Not precipitate withdrawal symptoms in morphine addicts

cause respiratory depression , can be used in M.I

Given during induction of anesthesia with nitrous oxide &

Fentanyl, it reverses anaesthetic and respiratory depressant

effects of Fentanyl prolongs analgesia.

74

Buprenorphin cont..

Adverse Effects -

drowsiness, nausea, vomiting, constipation, miosis, bradycardia available 0.2mg tablets, 0.3 mg/ml inj & transdermal patches

0.2-0.4 mg sublingually every 8hrs & 0.3-0.6 mg I.M or slow I.V

Every 6-8hrs

Tapentadol-μ receptor agonist NA reuptake inhibiting action

Ziconotide -for intrathecal analgesia,blocks voltage gated N type

Ca channels

OPIOID ANTAGONISTS –

Competitive antagonism

Pure antagonist – Naloxone

- Naltrexone75

Partial agonist of Nalorphine type-

Nalorphine

Levallorphan

Cyclazocine

Partial agonist of morphine type-

Propiram & Profadol

Naloxone- Pure antagonists Antagonizes respiratory depressant effect of opioids D.O.A :3 -4 hrs, Given parenterally ,short acting

76

Naloxone cont… treatment of opioid poisoning – I.V bolus 0.8-2.0mg every 2-

3mins – max of 10mg children – 10 mcg/kg bolus

If no response inject 100 mcg/kg bolus Reverses respiratory depression of opioid analgesic post

Operatively Naloxone I.V given correct hypotension in septic shock, Treat adverse drug reactions of epidural opioids Used in neonatal resuscitation to reverse effect of opioids if

used during labour, but should not be used if mother is dependent

on opioids since baby is also dependent in utero Naloxone can

precipitate withdrawal77

Naltrexone – effective opioid antagonist Maintenance drug for opioid poisoning repeatedly given Decreases craving in chronic alcoholics Prevents relapse after opioid deaddiction Long acting well tolerated no euphoric effect No physical dependence Blocks heroin and other opiates upto 4 days, 25mg is used

50mg available ,drug causes difficulty in sleeping, muscular pain

Methylnaltrexone –

Used S.C treat morphine induced constipation

78

Nalmefene –

Pure μ receptor antagonist, more potent than naltrexon

Given parenterally longer1/2 life

Nalorphine – 10mg/ml S.C or I.V Semisynthetic compound of morphine Treat acute morphine poisoning It acts as partial agonist produce analgesia & respiratory

Depression,displaces Morphine from receptor site & abolishes its

effects

79

Nalorphin contd…

Dysphoric symptoms may be present

Do not produce dependence, less effective against Pethidine

When 1-3 mg given to morphine addict it precipitates

Withdrawal syndrome within 3-5min lasting 2 hrs, pupil dilates

or fail to produce effects

Withdrawal syndrome is precipitated in Heroin & Methadone

80

Nalorphine cont… Diagnosis of morphine addiction Given to morphine addicts.

Levallorphan- More potent than Nalorphine I.V - 0.2mg, fails to reverse Pethidine induced respiratory

depression.

Alvimopan – Selective opioid μ receptor antagonist Blocks G.I effects of opioids Treating post operative ileus after bowel resection Given 30 min -5 hrs before surgery continued for 7 days Does not be useful unless started before paralytic ileus

81

SCREENING METHODS-

Principle: record the response of animal to a painful stimulus before & after administration of analgesic

CLASSIFICATION

In Vivo Studies

In Vitro Studies

Neuropathic Pain Models

In Vivo screening methods

Chemical Stimulation Methods

Electrical Stimulation Methods

Mechanical Stimulation Methods

Thermal Stimulation Methods

82

Thermal –Tail flick test

hot-plate test

Mechanical-Haffner’s tail clip method

Randall & selitto test

Chemical –Formalin test (intradermal injection)

writhing test (intraperitoneal injection)

chemical stimulation of visceral organs

Electrical – Tail stimulation

Tooth pulp test

Monkey shock titration test

83

Hot plate method

Principle-

Animals should be individually placed on hot plate at constant

temperature (55ºc)reaction of animal such as paw licking or

Jumping response is taken as end point. analgesic ↑ reaction time

Drugs:

• Morphine -5mg/kg s.c

• Unknown

– Instruments: Cages Stop watches Thermostatically controlled hot plate Thermometer

– Animals: 30 mice84

Method-

Group I, 6 mice (20-25 g) should be taken

Test sensitivity of animal to heat (not exceed 10 sec.)

Morphine (IP) 0.2ml/10 gm should be given

Test sensitivity of animal to heat every 10 min for 60 min

results should be recorded in table.

Procedure

Mouse should be weighed and numbered

Basal reaction time observing hind paw licking noted

Normal response 6-8 sec,cut off 15 sec observed

Drug should be given react. time of 15,30,60&120 min

Calculate % ↑ in reac time as index of analgesia at each interval

85

Table 1 Change in the reaction time (sec.) over 60 min. in group injected with morphine using hot-plate method

Animal #

0 min.

10 min.

20 min.

30 min.

40 min.

50 min.

60 min.

1

2

3

4

5

6

Mean

86

Tail flick method

Material

• Animal: Mouse

Instrument: Tail-flick analgesiometer

Drug used: 5mg/kg Morphine hydrochloride via s.c route

Procedure-

mouse should be weighed and number

Basal reaction time gap of 5mins should be taken to radiant heat by

placing the tip of tail on heat source, tail withdrawal from heat is end

point. Normal withdrawal time 3-5 sec,cut off 10-12 sec noted

Inj morphine should be given & reaction time of 5,15,30 & 60min is

Noted %↑ in reaction time at each interval is noted

87

88

in vitroμ opiate receptor binding assayAssay to study Cannabinoids activityRole of vasoactive intestinal polypeptide &

pituitary adenylate cyclase activating peptide&

nociceptin in analgesia

89

Newer drug in clinical trials NKTR-192, A New Short-Acting Mu-Opioid Analgesic

Molecule, Achieves Desired Pharmacokinetic Profile in First

Phase 1a Clinical Study NKTR-192 is a new mu-opioid agonist molecule designed to

have a short-acting profile and onset of pain relief suitable for

the treatment of acute pain, but with a reduced rate of entry into

the CNS as compared to other fast-acting opioids used to treat

acute pain. Reduce the euphoria, or rush, that can drive opioid abuse and

dependence, while at the same time reducing other unwanted

CNS side effects, such as sedation

90

H.L Sharma & K.K Sharma – The Principles of Pharmacology

second Edition.

Goodman & Gilman- pharmacological basis of therapeutics -12th edition

R.S.Satoskar - Pharmacology &Therapeutics

-Twentieth Edition. Rang & Dale - Pharmacology –sixthEdition

H.L Sharma & K.K Sharma – The Principles of Pharmacology

second Edition.

Goodman & Gilman- pharmacological basis of therapeutics -12th edition

R.S.Satoskar - Pharmacology &Therapeutics

-Twentieth Edition. Rang & Dale - Pharmacology –sixthEdition

91

92