Pain the Opioids

8/4/2019 Pain the Opioids

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PAIN

THE OPIOIDS

Prof. H.Y.A. LAUSchool of Biomedical Sciences

March-2011


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Diagram showing

an opium poppy

Papaver somniferum(Opium poppy)

Dried exudate = Raw Opium

Preparation ofopium tincture

Benzylisoquinoline

Phenanthrene

Papaverine & Noscapine

Opium tincture (laudanum)

Unripe seed capsule

Morphine, codeine &thebaine

Opiates :

Synthetic non-peptide morphine-like drugs

Opioids:Effects blocked byNaloxone

Narcosis:Stupor orinsensibility


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Mechanism of Actions

Neuronalexcitability

Hyperpolarisation

Transmitter

releasemk d

G

GG

ATP cAMPCa2+

-K+

OPIOID RECEPTORS mu (m), delta (d) and kappa (k)

G-protein coupled receptors Directly coupled to adenynyl

cyclase or ion channels

[Ca2+]i

+AC-


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Dynorphins [m++ d + k +++] multiple length peptides, first 5 a.a.: Tyr-Gly-Gly-Phe-Leu.

Precursor: preprodynorphin yields > 7 peptides

Endogenous Opioid Peptides

Endorphins [m+++ d +++ k +++] multiple length peptides, 1st 5 a.a. are Tyr-Gly-Gly-Phe-Met.

-Endorphin 1-31 is the most analgesic of opioid peptides.

Precursor: prepro-opiomelanocortin (POMC)

Enkephalins

(4) Met-enkephalin: Tyr-Gly-Gly-Phe-Met[m++ d +++ k O](1) Leu-enkephalin: Tyr-Gly-Gly-Phe-Leu [m+ d +++ k O] Precursor: preproenkephalin


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Receptor specificity / Efficacy at receptors

PURE AGONIST

Typical morphine-likedrugs

High affinity for m -

receptors

Varying affinity for dand k receptors

m d k

Morphine +++ + ++

Methadone +++ O O

Fentanyl +++ + O

Codeine + + +

Pethidine ++ + +

Etorphine +++ +++ +++

AGONISTS & ANTAGONISTS


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m d kPentazocine - (+) (++)

Nalorphine -- O (++)

Buprenorphine (+++) O --

Combine a degree of agonist and antagonist activity ondifferent receptors

Attempt to eliminate abuse potential but not successful Reduction of side effects

Diminish analgesia produced by full agonist

k agonists such as pentazocine cause dysphoria

Partial Agonists / Mixed Agonist-Antagonists


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No effect alone

Blocks the effects of opioids

Precipitate severe abstinence syndrome in addicts

Pure Antagonists

m d k

Naloxone - - -

Naltrexone - - -


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Route of administration

Oral

Pharmacokinetics

100%15-30%

Morphine

Morphine preferred for chronic use

variable bioavailability

Codeine is protected by themethyl group on the aromatic ring

Methadone is slowly metabolizeddue to extensive binding to tissueand plasma protein

more prolonged and smootheffects but slower onset


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Special devices for chronic use Skin patch (Fentanyl);

Rectal suppositories Patient controlled infusion pump

Parenteral

Short term treatment or when oral therapy is impossible.

Subcutaneous: variable absorptionIntramuscular: preferred route

Intravenous: severe acute pain or lung oedema

Intrathecal or epidural infusion:

prolonged post-operation analgesia

Mucosal absorption sublingual (buprenorphine) nasal (heroin)


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Significant level in brain within sec to min after i.v.

Blood Brain Barrier traversing capacity varies

Fast, lipohilic (fentanyl, heroin, codeine)

Slow, hydrophilic (morphine)

Varying degree of plasma protein binding

morphine (30%) pethidine (60%), methadone (85%)

Localized in well-perfused tissues

All traverse the placenta

neonates lack BBB

Distribution


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Metabolism

Opiates with no free -OH at 3 or 6 are metabolized to morphine

Morphine-6-glucuronide is a more active analgesic

Neonates have low level of conjugating enzyme

Hence avoid morphine congeners in neonates and childbirth

CH3

COOC2H5

N

O

N CH3

OH

HO

3

6

Conjugationwith

glucuronides

N-demethylation

Pethidine


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Excretion

Mainly as polar glucuronidated metabolites

Excreted mainly in urine

May be excreted in the bile (small extent)

e.g. Morphine excretion in 24 hr :90% in urine, 10% in faeces.

Half -life

pethidine fentanyl buprenorphine methadonemorphine

2-4 hr 4-8 hr 12 hr >24 hr

Fentanyl duration of action is only 1 hr due to rapid redistribution


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m d k

Analgesia

Supraspinal

Spinal

Peripheral

+++

++

++

-

++

-

-

+

++ Euphoria +++ - -

Dysphoria - - +++

Sedation and drowsiness ++ - ++

Respiratory depression +++ ++ -

Pupil constriction ++ - +

Gastrointestinal effects ++ ++ +

Dependence +++ - +

PHARMACOLOGICAL EFFECTS


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Analgesia *

Selective

Mediated via opioid receptors

Reduce presynaptic release

Hyperpolarization of postsynaptic neurons

Mimic the endogenous analgesic system

Altering the central processing of pain, spinal/ supraspinal

MIDBRAIN

nociceptive afferents

MEDULLA

PAG

NRMNRPG

Thalamus

LC

Dorsal Horn

Opioid

Opioid

Opioid

5-HT ENK NA

MIDBRAIN

nociceptive afferents

MEDULLA

PAG

NRMNRPG

Thalamus

LC

Dorsal Horn

Opioid

Opioid

Opioid

5-HT ENK NA



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Primaryafferent

Presynapticterminal

Postsynapticneuron

m,d,k receptors cause

Ca2+ influx transmitter release

mreceptor cause

K+ efflux

HyperpolarisationSpinal pain-transmissionneuron

Spinal Site


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Pain inhibitoryneuron

Opioid

m receptor

Inhibitory

Interneuron

Brainstem

-

-

Opioid

GABA


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Indirectly by reducing the

inhibition exerted by

GABA on dopamine

neurons

m

DA GABA

Opioid

-Euphoric effects

+

-

Ventral Tegmental Area

Euphoria

Strong feeling of contentment, well being & lack of concern

Activate the mesolimbic dopamine reward system

Reduce pain associated agitation and anxiety

Positive reinforcing Addiction

http://www.physics.uiowa.edu/applied_physics/AP_descriptions.htmlhttp://www.physics.uiowa.edu/applied_physics/AP_descriptions.html


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Euphoria contributes to

overall analgesia

Pain may still be perceivedbut no longer distressful

Less effective for nerve pain

Effective for postoperative &cancer pain

Analgesia Drug Equianalgesic

dose (IM/SQ)Fentanyl 0.15 mg

Buprenorphine 0.4 mg

Morphine 10 mg

Methadone 10 mg

Pentazocine 60 mg

Codeine 60 mg

Pethidine

(Meperidine)

100 mg

Standard: morphine(10mg/70kg im)

Clinical Applications

Careful evaluation: analgesia vs dependence & side effects

Given often enough to provide continuous control of pain
http://www.physics.uiowa.edu/applied_physics/AP_descriptions.html


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Drowsiness and mental clouding

Level of sedation not as deep as CNS depressants

Dozing patient can readily be waken

Inhibition of neuronal activity in the locus ceruleus(m & k mediated)

Useful property for pre-anaesthetic medication

Pethidine causes restlessness instead due tonorpethidine

Sedation



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Morphine, pethidine, fentanyl and derivatives

Premedication for sedative,anxiolytic and analgesic actions

Used intraoperatively as adjuncts to anaesthetic agents

Reduce the dose of general anaesthetics

Regional analgesia by injecting into the epidural orsubarachnoid space

Primary anaesthetic agent in cardiovascular surgery[high doses of morphine or fentanyl & derivatives]

minimal circulatory deterioration

complication: respiratory depression

Anaesthesia

Clinical Applications


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Depress cough reflex and cough center in brain stem

Antitussive at doses lower than analgesia

No correlation with analgesic and respiratory depression

Different type of receptor?

Cough Suppression

Antitussive

Related to increasing substitution on the OH group at position 3

e.g. codeine, pholcodine and dextromethorphan

Pethidine has no antitussive effect

Superseded by effective synthesized non-opioid drugs that areneither analgesic or addictive

NCH3

OOHH3CO

NCH3

OOHH2CH2CONO


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Constriction of pupils (pinpoint pupil) Central effect mediated by m and k receptors

Removal of cortical inhibitory action on the oculomotor(third cranial) nerve

parasympathetic tone

Blocked by muscarinic and opioid antagonists

Characteristic of opioid use

Not obvious with pethidine as it has anti-muscarinic effect

Miosis

Diagnostically important for opioid overdose

Other coma or respiratory depression inducing agents

produce pupil dilation


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Local inhibitory effects on neurons of myenteric plexus (m & d)

Also central actions

Gastrointestinal Tract

Decrease secretion along the G.I. Tract

smooth muscle resting tone but motility of GI tract

Delayed gastric emptying

Reduced acid secretion

intestine spasm (segmental contraction)

peristalsis

Delayed passage of bowel contents

Dehydration of faecal mass hence constipation

Constriction of biliary smooth muscle

intraluminal pressure inside biliary tract biliary colic


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Anti-diarrhea

Symptomatic control of acute non-infectious diarrhea

Diphenoxylate (Lomotil)

Loperamide (Imodium)

Exceedingly effective but not analgesics

No compulsive abuse

Minimal BBB penetration

Distribution and action restricted outside the CNS


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sensitivity of brainstem respiratory center to CO2

Dose dependent and significant at therapeutic level

in arterial pCO2 with in both the rate and volume of

respiration

mediated by & d receptors

Respiratory Depression

major acute side effect

commonest cause of death in acute opioid poisoning

less severe with partial agonists and mixed

agonists/antagonists


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Direct stimulation of receptors in the area postrema

(chemoreceptor trigger zone for emesis) of medulla An area where most chemical stimuli initiate vomiting

Observed in 40% of patients

Disappear with repeated administration

Nausea and Vomiting

Morphine and closely related opioids

Histamine release from mast cell

Unrelated to opioid receptors

Local effects such as urticaria and itching at sites of injection

Systemic effects such as bronchoconstriction and hypotension

Histamine Release


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VASODILATOR ACTION

Central action

Impairs sympathetic vascular reflexes Veno- and Arteriolar dilataionStimulates the vagal center Bradycardia

Histamine release

cardiac preload ( venous tone) andafterload ( peripheral resistance)

Psychological

Reduced fear to impaired

respiratory function

Decreases work of heart

Left ventricular failure

Medical emergency

Treatment with O2, i.v. morphine(10 mg) or diamorphine, a loopdiuretics and vasodilators

Pulmonary oedema


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Substitution therapy

A long acting opioid counteracting the withdrawal effects

Methadone (orally 40 to 100 mg/day)

Initially stabilizes the patient on methadone then graduallywithdraw from it

L-alpha acetylmethadol, a longer acting methadoneanalogue

Only 3 times a week and as safe as methadone

Treatment for Heroin Addicts


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Acute

Extension of acute pharmacological effects

Respiratory depression

Nausea and vomitting

Constipation

Sedation and mental clouding

Itching

ADVERSE EFFECTS

Chronic

Tolerance

Dependence


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An increase in the dose needed to produce a given

pharmacological effect

Cellular compensatory response counteracting theinhibitory effects of chronic opioid use

Develops readily

All opioids

Tolerance

High Degree Minimal

AnalgesiaEuphoria, dysphoria

Mental cloudingSedationRespiratory depressionNausea and vomitingCough suppression

MiosisConstipation


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Psychological Restless and distressed with a strong craving for the drug

Major cause of dependence

Dependence

Physical

Abstinence (withdrawal) syndrome

resembles severe influenza:

yawning, pupillary dilatation, fever, sweating,piloerection (cold turkey), nausea, diarrhoea andinsomnia

Closely related with tolerance


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Pulmonary failure and asthma

Respiratory depression leads to acute respiratory failurein patients with borderline respiratory reserve

CONTRAINDICATION

Severe hepatic and renal diseases

Hepatic metabolism and renal excretion of opioids are

impaired careful titration of dose


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Cranial trauma, increased intracranial pressure

Respiratory depression CO2 retention

Cerebral vasodilatation

Lethal alteration in brain function in patients withelevated cranial pressure

CONTRAINDICATION


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DRUG INTERACTIONS

Sedative-hypnotics antipsychotic tranquilizers

Increased CNS depression, particularly respiratory

depressionAntipsychotic tranquilizers

Increased CNS depression, variable respiratorydepression

Accentuation of cardiovascular effects(antimuscarinic and a-blocking actions)

Central nervous system depressants


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Monoamine oxidase inhibitors

Intensify the effects of morphine and other opioid drugs

anxiety, confusion and significant depression of

respiration, sometimes leading to coma.

MAOI and pethidine

severe excitatory reaction characterised by delirium,hyper-or hypotension, hyperthermia, rigidity,convulsion and coma

DRUG INTERACTIONS


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Symptoms Unconsciousness or coma

Pupillary constriction

Respiratory depression

Treatment

intravenous injection of the specific opioid antagonist,

naloxone (0.2 - 0.4 mg, i.v.) precipitate acute withdrawal syndrome in addicts

shorter half-life than morphine hence recurrence of

respiratory depression may return

ACUTE MORPHINE POISONING:


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First pure opioid antagonist

High binding affinity for all three primiary opioid

receptors No effect when given alone

Rapidly reverse the effects of all types of opioidagonists

Precipitate withdrawal syndrome in addicts Main clinical use is to treat narcotic intoxication

Poor efficacy when given orally but prompt and shortacting (1-2 h) following i.v. administration

OPIOID ANTAGONIST

NALOXONE

NCH2CH = CH2

OHO O


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Orally effective

Long duration of action : t1/2= 10 h

Clinically used as a maintenance drug for opiate

addicts in treatment programs

OPIOID ANTAGONIST

NALTREXONE

N

OHO O

OH

CH2


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MORPHINE ANALOGUES (PHENANTHRENES)

Heroin (Diamorphine)

Lipophilic, strong agonist

Rapidly converted to 6-monoacetylmorphine &

morphine

Rapidly enter CNS to produce a greater rush afteri.v.injection hence greater tendency of dependence

Duration of action ~ 2 hr

NCH3

OOCOCH3

H3COCO

NCH3

OOHHO

NCH3

O OCOCH3HO

PHARMACOLOGY OF OTHER OPIOID ANALGESICS


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Codeine

Weak agonist

Metabolised to morphine to produce weak analgesia

Less likely to produce addiction or respiratory depression

Codeine binds to distinct receptors to suppress cough

Orally active for mild to moderate pain and cough

Often combined with paracetamol in proprietary analgesicpreparation

NCH3

OOHHO

NCH3

OOHH3CO


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Buprenorphine

A partial m receptor agonist

Strong binding to the receptor and hence long duration ofaction

Analgesia and other CNS effects are qualitatively similar tothose of morphine

Effects more resistant to naloxone reversal Very lipid-soluble



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PHENYLPIPERIDINE

Pethidine

Strong agonist with antimuscarinic activities

Less constipation and not antitussive

Preferred during labour as it is cleared more rapidly in

neonates and does not delay labour

Restlessness, hallucination & convulsions in overdose

due to the metabolite norpethidine


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PHENYLPIPERIDINE

Fentanyl

Highly lipophilic strong agonist

Used in anaesthesia

Short duration patient-controlled infusion system

Skin patches for intractable cancer pain.


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PHENYLHEPTYLAMINE

Methadone

Pharmacologically similar to morphine

Orally active with long t1/2of 15-22 h

Suppresses withdrawal symptoms in physically

dependent individuals


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BENZOMORPHAN

Pentazocine

Mixed agonist-antagonist

Analgesia (k receptor) with dysphoria (non-opioid sreceptor)

Withdrawal syndrome in heroin addicts (m recptorantagonist)

Lower tendency to produce dependence and henceused in the control of chronic pain

Documents

Pain the Opioids