Opioid pharmacology an overview with emphasis on clinical relevance

Opioid Pharmacology: an overview
with emphasis on clinical relevance
Dr. Dhrubajyoti Bhuyan
Assistant Professor
Department of Psychiatry
Assam Medical College, Dibrugarh
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Plan of presentation
• Introduction
• Basic Overview
• Opioid Receptors
• Classification of Opioids
• Pharmacokinetics & Pharmacodynamics
• Etiological basis & Treatment Implication
• Treatment options
• Summary

Introduction
“Among the remedies which it has pleased
Almighty God to give to man to relieve his
sufferings, none is so universal and so
efficacious as opium”
Sydenham (1680)

Introduction
• The word opium is derived from opos, (juice)
• Derived from the Papaver somniferum.
• Opioid refers broadly to all compounds related to
opium
• Opiates refers to synthetic opioids.
(Baltieri DA 2001)
• Endogenous opioid peptides are the naturally
occurring ligands for opioid receptors

Introduction
• The term narcotic was derived from the
Greek word for "stupor."
• At one time, the term referred to any drug
that induced sleep, but then it became
associated with opioids.
• It often is used in a legal context to refer to a
variety of substances with abuse or addictive
potential.

Opioid Receptors
• Classical Receptors
µ (Mu) receptor
δ (Delta)
κ (Kappa)
• Non-Classical
opioid-receptor-like 1 (ORL-1) receptor or
"orphan" opioid receptor

Opioid Receptors
Receptor IUPHAR* Origin of name
δ (DOP) OP 1 first isolated from, vas Deferens
κ (KOP) OP 2 first ligand, Ketocyclazine
μ (MOP) OP 3 Morphine, proposed 1976,cloned
1993
(IUPHAR = International Union Of Pharmacology

Opioid Receptors
Receptor CNS Location Response on activation
μ Brain (laminae III and
IV of the cortex,
thalamus, periqueductal
gray), spinal cord
(substantia gelatinosa)
μ1 supraspinal analgesia,
physical dependence; μ2-
Respiratory depression, miosis,
euphoria, reduced
gastrointestinal motility,
physical dependence
κ Brain (hypothalamus,
peri-aqueductal gray,
claustrum), spinal cord
(substantia gelatinosa)
Spinal analgesia,.diuresis,,
dysphoria, sedation, miosis,
depersonalization and
derealization
δ Brain (pontine nucleus,
amygdala, olfactory
bulbs, deep cortex
Analgesia, may be associated
with mood change

Affinity, Intrinsic Activity & Dissociation
• Affinity: strength of drug binding to receptor
• Intrinsic activity: The degree to which a drug
activates its receptors.
• Dissociation : measure of the uncoupling of
the drug from the receptor

Affinity, Intrinsic Activity,& Dissociation
• Affinity for a receptor and activation of the
receptor are two different qualities of a drug.
• A drug can have high affinity for a receptor
but not activate the receptor (e.g.antagonist).
• agonists, partial agonists, and antagonists
can vary in their affinity
• In addition to variations in affinity and
intrinsic activity, drugs also vary in their rate
of dissociation from receptors..Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

• Dissociation is not the same as affinity—a
drug can have high affinity for a receptor,
but it still dissociates or uncouples from
the receptor with some regularity.
Buprenorphine’s slow dissociation
contributes to its long duration of action.
Affinity, Intrinsic Activity,& Dissociation

• Most of the clinically used opioids are
relatively selective for µ receptors,
reflecting their similarity to morphine
However, it is important to note that drugs
that are relatively selective at standard
doses will interact with additional receptor
subtypes when given at sufficiently high
doses, leading to possible changes in their
pharmacological profile.

Classification of opioids
• Traditional: based upon analgesic potency
• Origin of drug: i.e naturally occurring or
manufactured
• Function: their action at the opioid receptor

Traditional
Strong
1. Morphine
2. Pethidine
3. Fentanyl
4. Alfentanil
5. Remifentanil
6. Sufentanil
Intermediate
1. Buprenorphine
2. Pentazocine
3. Butorphanol
4. Nalbuphine
Weak
1. Codeine
Origin
Naturally occurring
1. Morphine
2. Codeine
3. Papavarine
4. Thebaine
Semisynthetic
1. Diamorphine
2. Dihydrocodeine
3. Buprenorphine
Synthetic
1. Phenylpyperidines:
pethidine, fentanyl,
alfentanil, sufentanil
2. Diphenylpropylamines:
methadone,
dextropropoxyphene
3. Morphinans: butorphanol,
levorphanol
4. Benzomorphans:
pentazocine
Function
Pure agonists
1. Morphine
2. Fentanyl
3. Alfentanil
4. Remifentanil
5. Sufentanil
Partial agonist
1. Buprenorphine
Agonists-antagonists
1. Pentazocine
2. Nalbuphine
3. Nalorphine
Pure Antagonists
1. Naloxone
2. Naltrexone
Classification

Opioids with their selectivity for different
opioid receptors
RECEPTOR TYPE
Opioid MOP KOP DOP NOP
Endogenous
Beta-endorphin +++ +++ +++ -
Leu-enkaphalin + - +++ -
Dynorphin A& B ++ +++ + +
N/OFQ - - - +++
+ = low affinity; ++ = moderate affinity; +++ = high affinity; -
= no affinity

Opioids with their selectivity for different
opioid receptors
RECEPTOR TYPE
Opioid MOP KOP DOP NOP
Clinical drugs
Agonists
Morphine +++ + + -
Pethidine +++ + + -
Diamorphine +++ + + -
Fentanyl +++ + - -
Partial agonists
Buprenorphine ++ + - -
Pentazocine - ++ - -
Antagonists
Naloxone +++ ++ ++ -
Naltrexone +++ ++ ++ -
+ = low affinity; ++ = moderate affinity; +++ = high affinity; - = no affinity

Partial vs. Full Opioid Agonist
Dose of Opiate
Opiate
Effect
death
Full Agonist
(e.g., methadone)
(e.g. Naloxone)
Antagonist
Partial Agonist
(e.g. buprenorphine)

© AMSP 18
Pharmacodynamics: CNS
Undesirable:
• Euphoria
• Respiration
• Sedation
• Endocrine effects
Desirable:
• Analgesia
• Cough suppression

© AMSP 19
Pharmacodynamics: GI
Undesirable:
• Nausea, vomiting
• Constipation
Desirable:
• Antidiarrheal
• Inhibit peristalsis

Effects of Opiates in Body

Pharmacokinetics
• absorbed readily from GIT;
• absorption through the rectal mucosa is adequate.
• lipophilic opioids also are absorbed readily through
the nasal or buccal mucosa (Weinberg et al., 1988).
• Those with the greatest lipid solubility also can be
absorbed transdermally (Portenoy et al., 1993).
• Opioids are absorbed readily after subcutaneous or
intramuscular injection
• Biotransformation: liver
• Excretion: kidney and GI (bile)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Opiates And Opioid Metabolism

Pharmacokinetics
• With most opioids, including morphine, the
effect of a given dose is less after oral
than after parenteral administration
because of variable but significant first-
pass metabolism in the liver.

Opioids: Pharmacokinetic Aspects
Drug Dosing Route PharmacokineticAspects
Morphine Oral (including slow release
form), IV, IM intrathecal
t½ = 3 -4hr. Converted to active
metabolite ( morphine6 –
glucuronide)
Heroin IV,IM, smoked, oral chasing ½ = <1 hr. Partly metabolized to
morphine
Methadone Oral, IV, IM ½ = >24 hr. No active
metabolite
Pethidine Oral, IM ½ = 2 – 4hr. Active metabolite
(norpethidine)
Buprenorphine Sublingual, Intratheacl, sc, iv, im ½ = 40 hr
Fentanyl IV, epidural, transdermal ½ = 1- 2 hr
Codeine Oral Acts as pro-drug. Metabolized
to morphine & other active
opioids
Crude opium Oral Varies according to concPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Pharmacologic & physiochemical
properties and addiction
• Liposolubility increases the passage through
the blood-brain barrier
• Water solubility facilitates injection
• Heat resistance favours smoking
• Rapid onset and intensity of effect increase
the potential for abuse
• A short half-life produces abrupt & intense
syndromes of withdrawal

Etiological Basis & Treatment
Implication
Pre Frontal Cortex
Regulates judgement,
planning and other
executive functions
Helps to overcome some
of our impulses for
immediate gratification
Ventral Tegmental area
Release of Dopamine
Feeling of pleasure
Opiates
- ve
+ ve

Implication
DA neurons become dysfunctional
Alteration in baseline level of electrical activity and DA release
Grace 2000

Resting Dopamine release in Nucleus accumbens
Cortical excitatory
neurons (Glutamate)
Autoreceptors
Opiates
Bypasses
Increases release of Dopamine
Pleasure
Activation
When drug is stopped there is low DA
level leading to dysphoria

• Increased sensitivity to environmental cues lead to
craving rather than just reinforcement and withdrawal
Breiter et al 1997)
• When drug is not available, brain can remember the
drug and there is increased cortical glutamate secretion
which leads to increased Dopamine level (Craving) and
this inturn leads to increased NA from LC (withdrawal)
• Inhibition of glutamate (excitatory amino acid
antagonists) a major area of research
Implication

Etiopathogenesis & Treatment
Basis
Locus ceruleus
Release of NA
Widely distributed in cerebral
cortex, brain stem and various
sub cortical areas
wakefulness breathing Blood pressure General
alertness

Implication
Opiates binds to mu receptors
adenyl cyclase
ATP
C AMP
Locus ceruleus
Noradrenergic secretion
On repeated use of opiates there is compensatory up regulation of c AMP
Inhibits
Sudden
stoppage of
opiate leads to
un opposed
action of NA
Intoxication
leads to
drowsiness,
slowed
respiration and
low BP

Current Pharmacotherapy Treatment
Options for Opioid Addiction
• Three traditional types of pharmacotherapy
agonist treatment (e.g. methadone)
antagonist treatment (e.g., naltrexone), and
use of these and other agents (e.g., clonidine)
• Newer Option:
Partial agonist treatment: Buprenorphine

Heroin (opiate) addiction is a disease – a “metabolic disease”
– of the brain with resultant behaviors of “drug hunger” and
drug self-administration, despite negative consequences to self
and others. Heroin addiction is not simply a criminal behavior
or due alone to antisocial personality or some other
personality disorder.
Hypothesis (1964)
Leading to Development of Methadone
Maintenance Treatment
Dole, V.P., Nyswander, M.E. and Kreek, M.J.: Narcotic blockade. Arch. Intern. Med., 118:304-309, 1966; 2006

Agonist Pharmacotherapy
• Methadone is the most commonly used
medication for opioid addiction treatment
• Demonstrated to
decrease heroin use and related crime, increase
employment, improve physical and mental health
(McLellan et al. 1993),
incidence of needle sharing (Metzger et al. 1991) and
HIV transmission (Metzger et al. 1993).
• Methadone suppresses opioid withdrawal, blocks
the effects of other opioids, and decreases
craving for opioids.Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Methadone
 Long-acting µ-receptor agonist with
pharmacological properties qualitatively
similar to those of morphine.
The outstanding properties of methadone
analgesic activity,
efficacy by the oral route,
extended duration of action in suppressing
withdrawal symptoms in physically dependent
individuals, and
 its tendency to show persistent effects with
repeated administration

Antagonist Pharmacotherapy
• Naltrexone - blocks the effects of heroin and
other opioids.
• No addictive properties no physical dependence,
and tolerance
• long t½, and its therapeutic effects can last up to
3 days
• Not a stigmatized treatment.
• Decreases the likelihood of alcohol relapse
when used to treat alcohol dependence

Antagonist Therapy

Antagonist Pharmacotherapy
• From a purely pharmacological point of
view, naltrexone would appear to have the
properties of a useful medication for the
treatment of opioid addiction.
• Its usefulness in the treatment of opioid
addiction, however, has been limited
because of certain disadvantages.

Agents Used To Assist With
Withdrawal From Opioid Drugs
• Medically supervised withdrawal from
opioids is an initial component of certain
treatment programs but, by itself, does not
constitute treatment of addiction

Agents Used To Assist With
Withdrawal From Opioid Drugs
• These include methadone dose reduction,
the use of clonidine (0.1 -0.3 mg/d) and
other alpha-adrenergic agonists to suppress
withdrawal signs and symptoms, and rapid
detoxification procedures (e.g., with a
combination of naltrexone or naloxone and
clonidine and, more recently,
buprenorphine).

Buprenorphine
• Synthetic Thebaine coneger
• Highly lipid soluble µ analgesic
• High affinity/occupancy (95% at 16mg)
• 25 to 50 times more potent than morphine
• t½ ≈ 40 hours
• relatively well absorbed by most routes.
• Peak plasma level at 5 mins following i.m & 1 –
2 hr following sublingual administration

Properties of Buprenorphine
• Partial mu – opioid agonist
• Moderate Intrinsic Activity
• Kappa antagonist
Greenwald et al, 2003

Buprenorphine

Effect of Buprenorphine

Buprenorphine Vs Methadone

Naloxone:
• Competitive antagonist on all types of opioid
receptors
• Blocks mu receptors at much lower doses
than those needed to block κ and δ receptors
• Devoid of any kind of agonist action

Naloxone:
• No dependence or withdrawal syndrome
• i.v .04 - .08 mg promptly antagonizes all
actions of morphine
• At 4 – 10 mg doses antagonises agonist actions
of nalophine, pentazocine but the dysphoric
and psychomimetic effects are not completely
suppressed
• Naloxone insenitive component is through
sigma receptorPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Naltrexone
• Chemically related to naloxone
• Pure opioid antagonist
• More potent than naloxone
• Orally active and long duration of action (1
– 2 days)

Nalorphine
• First antagonist introduced in 1951 which
could reverse morphine action.
• Later on found to have agonist action
• Agonist action at k receptor
• At low doses approx equipotent to Morphine.
• With increasing dose this relation is not
mainained
• Nalorphine 15 mg = morphine 10 mg

Comparison of various Treatment Modalities
TYPE OF
TREATMENT
ADVANTAGES DISADVANTAGES
Substitution
Treatment
Strong evidence of capacity to
reduce opioid use
decrease mortality
improve quality of life
Capacity to retain patients in Rx
Expense to patient (daily travel
dispensing fees)
Side effects, Stigma
Prolonged withdrawal on
cessation
Detoxification Short-term commitment
Attractive to consumer
Low threshold easy access
Entry point to treatment
Poor long-term outcomes if
stand-alone treatment
Increased overdose risk
following withdrawal
Can lead to destabilisation of
other health conditions
Antagonist
treatment
(naltrexone)
Effective in decreasing opioid use
in highly motivated well-supported
people
Opioid-free’ medication
Poor retention for most people
Limited acceptance
Complicates pain management
Cost to patient
Requires detoxification prior to
initiating naltrexone
Increased overdose risk
following cessation due to loss
of tolerance

Opioid Receptor system & Related Pharmacological Treatment
Neurotransmitter Dopamine, Noradrenaline and 5HT
Receptor types µ, κ, δ
Role in addiction µ, & possibly δ receptor
Opioid
Medication
Mechanism of
action
Therapeutic dosage
Buprenorphine Partial opioid
agonist
FDA labeled indication for opioid
dependence. Dosage: 4 – 24 mg/d
Methadone Opioid agonist FDA labeled indication for detoxification &
maintenance opioid abuse, 15 – 40 mg/d
Naloxone µ antagonist FDA labeled indication for opioid
dependence, overdose of opiates and
reversal of opiate activity, 0.1 – 0.2 mg/day
Naltrexone µ antagonist FDA labeled indication for opioid
dependence, overdose and reversal of
opiate activity, reduction alcohol
consumption & craving, 50 mg/d
Nalmefen Opioid antagonist Experimental agent alcohol relapsePresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Pharmacologic Agents Used to
Treat Opioid Dependance

Name Onset Duration t1/2 of
parent drug
Dose range morphine
equivalent
PO mg/d
Methdone
equivalent
PO mg/d
Fentanyl
patch
12-24 h 60- 72 h 7 h 25 – 300
mcg
150 - 200 60 – 80
Fentanyl
Transmucosal
5 – 15 min 4 – 8 h 17 hr 200 – 1600
mcg
45 – 60 18 – 24
Hydromorpho
ne oral
15 – 30 min 4 – 6 h 2- 4 h 2 – 8 mg 64 26
Meperidine
oral
10 – 15 min 2 – 4 h 3 – 4h 50 – 100 mg 40 16
Methadone
oral
30 – 60 min 4 – 8 h 15-29 h 10 – 100 mg 150 60
Morphine oral 15- 60 min 3- 6 h 2 – 4 h 5 – 20 mg 60 24
Morphine oral
LA
2 – 3 h 8 – 14 h 2 – 4h 15 – 100 mg 120 48
Codeine oral 30 -60 min 4 – 8 h 3 – 4 h 15 – 60 mg 20 8
Propoxyphen
e oral
30 – 60 min 4 – 6 h 3 – 15 h 50 – 100 mg 60 24
Opioid Conversion Data

Summary:
Successful Pharmacotherapy
• Clinical efficacy and safety
• Patient and provider acceptance
• Public health significance
• Powerful advocacy and strong leadership
• Favorable societal attitude
– The role of the clinicians; we must change
before our patients’ lives can change.

Opioid pharmacology an overview with emphasis on clinical relevance

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