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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
PHARMACOLOGICAL EFFECTS
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Mechanism of Actions
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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Mechanism of Actions
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
PHARMACOLOGICAL EFFECTS
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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
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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
PHARMACOLOGICAL EFFECTS
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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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MORPHINE ANALOGUES (PHENANTHRENES)
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
MORPHINE ANALOGUES (PHENANTHRENES)
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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