BSC 2017

Opioids
- with special emphasis on its
pharmacology -

Paulo Sá Rodrigues
Consultant Anaesthesiologist, Lisbon, Portugal
ESA OLA Subcommittee member, EDAIC examiner and translator
paulosarodrigues@Hotmail.com
Conflict of interest declaration
WHAT DECLARATION
Grants/research support/P.I. No conflict
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BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 • Introduction
• Structure, receptors, mechanisms of action
• Classification, potency, affinity, Emax curves
• Pharmacokinetics – global aspects
Outline • Pharmacodynamics – CNS effects
• Pharmacodynamics – peripheral effects
• Clinical Pharmacology of some selected drugs
• References

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 Short history and etymology
• OPIUM:
• Word derived from opos,
the Greek word for juice,
• The drug is derived from
the juice of the opium
poppy Papaver
somniferum.
• OPIATES:
• are drugs derived from
opium
• include the natural
products morphine,
codeine, and thebaine,
• Include many semisynthetic
drugs derived from them.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

Chemical structures of common opioids

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 OPIOIDS act on RECEPTORS
• Distributed throughout
• the brain & spinal cord;
• and also outside the CNS – vascular tissues, cardia, airway/lung,
gut and cells of the immune system.
• Rhodopsin family of GPCRs
• μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid
receptor (DOR), and orphanin FQ /nociception (NOP)
receptor

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

OPIOID RECEPTORS (contd.)
• Upon activation of the
receptors , Gi/Gs
coupling causing:
• Inhibition of
adenylyl cyclase
activity
• Reduced opening of
voltage-gated Ca2+
channels
• Stimulation of K+
current through
GIRKs (G protein-activated
inwardly rectifying K+ channels)
• Activation of PKC
(phosphokinase C) & PLCβ
(phospholipase C-β)

From Millers-anesthesia-7th/chapter-27/figure-27-3

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 Classification of Opioid Receptors

Adapted from Atcheson R, Lambert DG. Update on opioid receptors. Br J Anaesth 1994;73:132–134.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

Opioids: mechanisms of analgesia
• Directly inhibit ascending
transmission of nociceptive
information from the spinal
cord dorsal horn
• Activate pain control
circuits that descend from
the midbrain, via the rostral
ventromedial medulla
(RVM), to the spinal cord
dorsal horn.
• The actions of opioids in the
bulbospinal pathways are
critical to their analgesic
efficacy.
From: Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior
Anesthes. 2011;115(6):1363-1381. doi:10.1097/ALN.0b013e318238bba6

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

Opioids: mechanisms of analgesia

• May also produce analgesia

through a peripheral
mechanism.
• Immune cells infiltrating an
inflammatory site may
release endogenous opioid-
like substances that act on
opioid receptors located on
the primary sensory neuron
(disputed).

From: Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior

Anesthes. 2011;115(6):1363-1381. doi:10.1097/ALN.0b013e318238bba6

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 • Agents found throughout the
body that act on an opioid
receptor
• All are peptides derived from
distinct large precursor proteins -
POMC, preproenkephalin,
Endogenous preprodynorphin
Opioids • Common amino terminal
sequence: TYR-GLY-GLY-PHE-
(MET OR LEU)
• Principally three classes –
enkephalins, endorphins,
dynorphins

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 Exogenous Opioids

• Classified according to
• Synthesis
• Chemical structure
• Potency
• Receptor binding
• Effect at opioid receptors

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 A. Opioid Agonists: Morphine, Codeine,
Classification Meperidine, Fentanyl, Sufentanil,
Remifentanil, Methadone, Tramadol
by B. Opioid Agonist/Antagonist & Partial
receptor Agonist: Pentazocine, Nalbuphine,
Butorphanol, Buprenorphine
affinity C. Opioid Antagonists: Nalorphine,
Naloxone, Naltrexone, Naltrindole,
Nalmefene

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

 • According to the strength or
potency based on the plasma
concentrations at which they
Classification exert their effects (C 50 or the plasma
of Exogenous concentration causing a 50% effect)
• Strong opioids include fentanyl,
Opioids sufentanil, and remifentanil.
- Strength - • Weak opioids include codeine and
tramadol.
• An intermediate group includes
morphine, methadone, oxycodone, and
buprenorphine.

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

Opioid potency comparison

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

Opioids sigmoid Emax relationships

From clinical-anesthesia-paul-barash-7th/chapter-19/figure-19-4:

BSC 2017 – Pharmacology of Opioids – Paulo Sá Rodrigues www.esahq.org

Opioid Pharmacokinetics (PK)
ESA Basic Sciences Course resume
Opioids: Physicochemical Properties

• Ionized fraction
• Less lipid soluble
• Attached to plasma proteins and not available to
diffuse to the action site (the receptor)
• However - it is the “effective” form of the
molecule – the receptor recognizes the ionized
form
• Base (free) fraction
• More lipid soluble – free to diffuse to the action site
Physicochemical and Pharmacokinetic Data
for Commonly Used Opioid Agonists

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p
312. t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the central compartment; Vdss volume of distribution at steady state
 • Modestly absorbed through
GI tract -oral, rectal,
• Depends on lipophilicity
• High first pass metabolism (FPM)
• Morphine - ~25% bioavailability by
oral route
PK: • Codeine & oxycodone – low FPM
Absorption • Well absorbed through SC &
IM routes
• Nasal route – rapid
absorption
 • High concentrations in
highly perfused tissues –
brain, liver, kidneys & spleen
PK: • In chronic administration –
Distribution accumulation can take place
& opioids are found in the
plasma long after their
dosage has been stopped
 PK: Metabolism

• In liver
Morphine  morphine-6-glucuronide, morphine-3-
glucuronide
These have significant activity themselves.
• CYP3A4 & CYP2D6 are involved in biotransformation of
morphine congeners like heroin, codeine, fentanyl etc
Ex: Increased & Decreased activity of CYP2D6
• Remifentanil metabolized within erythrocyte and tissue
nonspecific esterases
 • In kidneys, M6G & M3G are
excreted by glomerular
filtration.
PK: • Chronic renal failure can
cause elevated levels of
Excretion these metabolites & lead to
adverse effects
• Seizures
• CNS depression
Context-sensitive half-times for fentanyl, alfentanil,
sufentanil and remifentanil
Decline of effect site concentrations of different
opioids (simulation)
Pharmacodynamics (PD)
Central Nervous System effects
PD: Variability in opioid effects

• Related to
• variability in PK-related parameters
• Age, weight, body fat, muscle content, renal/liver
function, cardiac output, genetic polymorphism, co-
medication
• Variability in PD parameters
• Different opioid sensitivity
• Different pain perception
 PD: Analgesia
• When given to patients in pain
• less intense, tolerable, feel more comfortable with relief of distress
• Neuropathic pain responds poorly to opioids
• Remifentanil may have a sedative and hypnotic effect*
• When given to normal patients
• Analgesia
• Drowsiness
• Changes in mood
• Mental clouding
 PD: Opioids as anesthetics

• EEG
• High doses produce high-voltage slow (δ) waves that are suggestive
of a state consistent with anesthesia
• Similar for fentanyl, alfentanil, sufentanil, and remifentanil
• Ceiling effect not leading to burst suppression and flat EEG
• Evoked potentials
• opioids do not appreciably alter sensory evoked potentials (SEPs)
elicited at the posterior tibial or median nerve,
• SEPs can be used to monitor spinal cord function during anesthesia with
opioids.
PD: Cerebral Blood Flow and Cerebral
Metabolic Rate
• modest decreases in the cerebral metabolic rate
(CMR) and intracranial pressure
• Opioids also decrease cerebral blood flow (CBF)
when combined with N2O
• However, opioid-induced neuroexcitation and focal
seizure activity can cause regional increases in brain
metabolism.
 • Respiratory depression: primary cause
of morbidity secondary to opioid
therapy

PD: CNS 1. Direct depression of rhythm

generation in ventrolateral medulla
depression 2. Desensitization of brainstem
- Respiration - chemoreceptors which normally
respond to rising PCO 2
3. Also desensitize the carotid & aortic
chemo sensors which usually respond
to hypoxia.
 • Direct inhibitory effect on
the cough centre of medulla
• No loss protective glottic
PD: Effect on function
Cough • Centrally acting antitussives:
• Dextromethorphan
• codeine,
• pholcodeine
 Some opioids at a slightly higher
doses can produce epileptogenic
activity
PD: Seizure • Meperidine (pethidine)
• Frank seizures & myoclonus
& • Several mechanisms
• Inhibition of inhibitory
Convulsions interneurons
• Direct stimulatory effects
• Actions mediated by non-opioid
receptors by their metabolites
Pharmacodynamics (PD)
Peripheral effects
Other opioid-related side effects

a) Nausea and vomiting

b) Smooth muscle effects
c) Skeletal muscle effects
d) Histamine release
e) Puritus
f) Pupil effects
g) Diffuse CNS effects
h) Cardiovascular effects
Clinical Pharmacology
Of some selected drugs
Morphine
• Multiple routes of
administration
• Slow rise to peak effect
• Active metabolite
• Morphine-6-glucuronide is
Will contribute to effects
with chronic dosing
especially in renal failure

Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In
Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312.
t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the
central compartment; Vdss volume of distribution at steady state
Remifentanil
• Potency 50 to 100X
morphine
• Main features
• Rapid onset and offset
• Brevity of action (3’ to 5’)
• Total metabolism
• Rapid recovery
• Metabolism by tissue and
plasma esterases to inactive
metabolites.
Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In
Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312.
t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the
central compartment; Vdss volume of distribution at steady state
Remifentanil
• Pharmacokinetics
• small Vd
• rapid clearance
(3l/min), and
• low interindividual
variability
• will accumulate less than
other opioids.
• context-sensitive half-
time) nearly
independent of the
infusion duration Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In
Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312.
t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the
central compartment; Vdss volume of distribution at steady state
Alfentanil
• More rapid onset (effect-
site equilibration of 1.4
min) – low pKa
• Short elim halt-time but
long context sensitive half-
time
• High interindividual
variability in metabolism
• Elimination prolonged by
liver cirrhosis
Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In
Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312.
t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the
central compartment; Vdss volume of distribution at steady state
Fentanil
• High potency 100x
morphine – due to lipid
solubility
• Large Vdss 3-5 L
• Significant first pass
pulmonar uptake 75%
• Potential for
accumulation
Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In
Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312.
t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the
central compartment; Vdss volume of distribution at steady state
Sufentanil

• High potency 1000x

morphine
• Large Vd
• Significant first pass
pulmonar uptake 60%
• Potential for
accumulation in obese
patients (higher Vd) Table from From Bailey PL, Egan TD, Stanley TH: Intravenous opioid anesthetics. In
Miller RD (ed): Anesthesia, 5th ed. New York, Churchill Livingstone, 2000, p 312.
t1/2a,b,d are half-lives of a 3 compartment model; Vdc volume of distribution on the
central compartment; Vdss volume of distribution at steady state
 Pethidine (Meperidine)

• Potent MOR agonist

• Used in post op pain, chronic
pain of severe degree & post
anesthetic shivering
• Its metabolite normeperidine is
epileptogenic
• It can block neuronal uptake of
5HT3 – can cause serotonin
syndrome if used with MAO
inhibitors & SSRIs
• Concurrent use of
Antihistaminics & TCAs can cause
additive CNS depression
 Effect in the presence of Agonists
• Effect on Acute opioid actions:
• Increase in respiratory rate &
depth
• Reversal of dysphoric &
Opioid psychotomimetic effects
Antagonists • Overshoot phenomenon
• Rebound release of
catecholamines  tachycardia,
hypertension, ventricular
arrhythmias
 Effect in the presence of Agonists
• Effect on Opioid dependant patients:
• Moderate to severe withdrawal
Opioid • Depends on the dose of the
antagonist and also on the degree
Antagonists and duration of dependence
• Methylnaltrexone & Alvimopan
can reverse the GI effects of opioid
dependence without making
central withdrawal syndrome.
References
• Opioids in Medicine– A comprehensive Review on the mode of action
and the use of analgesia in different pain states; Enno Freye, Spinger,
1997
• Miller’s Anesthesia, 7th edition
• Barash Clinical Anesthesia, 7th edition
• Stoelting Pharmacology and Physiology in Clinical Practice, 4th edition
• http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1934470#6
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