Opioid --> are important drugs used in the pain management. Employ appropriate pharmacological choice by knowing the pharmacology of the drugs --> both pharmaco dynamic and pharmaco kinetics. Provide optimal effect and minimize side effects

1. Curriculum Vitae
Nama : Dr. Ike Sri Redjeki, dr., SpAnKIC,KMN,M.Kes
Jabatan : Kepala Departemen Anestesiologi & Terapi Intensif Fakultas
Kedokteran Universitas Padjadjaran Bandung
Ketua Program Studi Pendidikan Konsultan Intensive Care (KIC)
Fakultas Kedokteran Universitas Padjadjaran Bandung
Alamat : Departemen Anestesiologi & Terapi Intensif Fakultas Kedokteran
Universitas Padjadjaran/RS. Hasan Sadikin
Jalan Pasteur no. 38 Bandung 40161
Telp : 022-2038285/0811230514
Fax : 022-2038306
E-mail : ikesriredjeki@yahoo.co.id

2. Update on Opioid Pharmacology
Ike Sri Redjeki
Department of Anesthesiology and Intensive Care Unit
Hasan Sadikin Hospital/Medical Faculty of Padjadjaran University
BANDUNG

3. Introduction
Opioid
• The most effective analgesics are the opioid
analgesics
• The opioids  interact with opioid receptors in
the nervous system
• These receptors are the sites of action for the
endorphins, compounds that already exist in the
body  also site of action for the external
opioid drugs
• Pharmakokinetics of this specific drugs also
influence its efficacy

4. Ascending fast -
Ascending slow –
Descending
*Opioid Receptor
↓
Site of action of
Endorphine and
other mediator 
Opioid
*
*
*
*
*
*

5. FSC MO P MID DI
C
SC Spinal Cord
MO Medulla (oblongata)
P Pons
C Cerebellum
MID Midbrain (Mesencephalon)
DI Diencephalon (Thalamus + Hypothalamus)
F
NRPG
RVM
Forebrain (Cerebral Cortex + Deep nuclei, e.g. amygdala)
nucleus reticularis paragigantocellularis
Rostral Ventral Medulla
PAGRVM
NRPG
Amygdala
Thalamus
Hypothalamus
Nociceptive
Input

6. Example of physiological control of
descending inhibition
Stress produced analgesia (SPA)
• Many accounts of people ignoring injuries when
stressed, e.g. during sports contests, in battle
• Animal studies show at least partly due to activation
of PAG/RVM system
• Possible role for amygdala, hypothalamus, some
cortical regions (insula) that are also involved in
other aspects of stress responses (hormonal,
cardiovascular)
• Note that PAG/RVM system is also part of
cardiovascular control system for stress responses

7. Enkephalins are
derived from pro-
enkephalin
relatively selective δ
ligands
Endorphins are derived from
pro-opiomelanocortin
(also the precursor for ACTH
and MSH)
bind to the µ receptor
Dynorphins are derived from
pro-dynorphins and are
highly selective at the µ receptor
Presynaptic
Postsynaptic
Opioid
Nociceptins (nociceptin/orphaninFQ
[N/OFQ]) (orphanin),
have potent hyperalgesic effects
Little affinity for the µ, d, κ receptors,
(“opioid-receptor-like”)
Nociceptin antagonists may be
antidepressants and analgesics
Kappa receptor 
only analgesia and
sedation no other
side effect

8. The ORL-1 receptor
• the ORL-1 receptor or the “orphan” receptor
was very recently discovered
• The natural opioid peptide that is a ligand for
this receptor is nociceptin which is also
called orphanin
• The ORL-1 receptor is associated with many
different biological effects such as memory
processes, cardiovascular function, and renal
function
• It is thought to have effects on dopamine
levels and is associated with neurotransmitter
release during anxiety

9. Opioid Receptor
Primary
afferent
nociceptor
terminal
Secondary
ascending
neuron
Ca2+ Ca2+
K+
K+
Neurotransmitter
glutamate
 opioid
receptor
 opioid
receptor
Noxious stimulus
ATP  cAMP

10. Opioid Receptor  placed by opioid
Secondary
ascending
neuron
Primary
afferent
nociceptor
terminal
Ca2+ Ca2+
K+ K+
Neurotransmitter
glutamate
 opioid
receptor
 opioid
receptor
Opioid
Opioid
x x
Noxious stimulus
ATP  cAMPX

11. Classification based on degree of affinity and
efficacy at various receptor
• Opioid Agonist
• Opioid Partial Agonist ( high affinity but low
efficacy at the μ receptor)
• Opioid Agonist / Antagonist ( poor μ opioid
receptor efficacy or μ opioid receptor
antagonist and have κ agonist )
• Opioid Antagonist

12. Analgesic effects at opioid receptors.
in the brainstem and medial
thalamus
in the limbic and other diencephalic
areas, brain stem, and spinal cord

13. Future of Opioid Analgesics
• The future of Opioid Analgesics seems to be
linked to the study of the Kappa Receptor
– The kappa receptor induces analgesia without
the dangerous and unwanted side effects that
the mu and delta receptors are associated with
– However there are not any selectively strong
agonists to this receptor as of now
• As similar as endogenous morphine  non toxic
metabolite

14. Chemical Structure of Opioid
Morphine
Phenolic
hydroxyl group
Alcohol
hydroxyl group
> Nausea and
hallucination
Nitrogen Atom
Changes to the methyl
group  will decrease
analgesia and creating
antagonists ( nalorphine )

15. Prototype of
opioid
Pentazocine
High incidence of
dysporia
Fentanyl,
Meperidine
Hihgest affinity for
the mu receptor
Include
propoxyphene
and metadone
Tramadol does not fit in the
standard opioid classes 
unique analgesic , an atypical
opioid  4-phenyl – piperidine
analogue of codein
Has partial μ agonist, in
addition to central GABA
catecholamine and
serotonergic activity

16. Pharmacology of opioid
Side effect of opioid
Drug interaction
Morphine ( prototype μ receptor, phenanthrene deriative )
• After oral administration  only 40 – 50% reaches the
CNS within 30 minute  other extended release  90
min
• Poor penetration  poor lipid solubility
• Respiratory acidosis increase brain concentration of
morphine caused by increase in CBF
• Elimination half life  120 min
• Drug inhibit morphine degradation : tamoxifen,
diclofenac, naloxone, carbamazepin, tryciclic and
heterocyclic antidepressants, benzodiazepine
Side Effect :
• Decrease sympathetic nervous system
tone
• Decreased intestinal motility
• Spasm of biliary smooth muscle and
sphincter Oddi spasm
• Induce nausea and vomiting  direct
stimulation of CTZ in the floor of 4th
ventricle
• Skin sign  urticaria ( histamine release)

17. Pharmacology of opioid
Side effect of opioid
Drug interaction
Codein
• Weak affinity to μ receptor
• Potency  50% of morphine
• Half life 2.5 – 3 hours
• Analgesic activity  occurs from metabolism of codein
to morphine
• Inhibitor  metabolit : celecoxib, cimetidine, cocaine
• Inducers : dexamethasone, rifampin
• Doses > 65 mg  not well tolerated
• Low dose  paradoxically more emetic than higher
dose  competing effect in CTZ
Side effect :
A very rare but serious side effect
in nursing infants whose mothers are
taking codeine,
and are apparent ultra-rapid metabolizers
of codeine,
resulting in rapid and higher levels of
morphine in
the breast milk, and the subsequent
potentially
fatal neonate respiratory depression

18. Pharmacology of opioid
Side effect of opioid
Drug interaction
Meperidine
• Relatively weak opioid μ agonist  only 10% of morphine
• Have a significant anticholinergic and local anesthetic
properties
• Half life 3 hours  half life the metabolite 
normeperidine 15 – 30 hour
• Must not be given with MAO inhibitor  may produce
severe respiratory depression, hyperpyrexia, CNS
excitation, delirium, and seizures
• side effect : anxiety, tremors, multifocal myoclonus,
seizures  especially in patients with renal disease,
following repeated administration

19. Pharmacology of opioid
Side effect of opioid
Drug interaction
Fentanyl
• Strong opioid agonist
• Available in parenteral, transdermal, transbuccal
preparation
• Synthetic piperidine opioid agonist
• 80x more potent than morphine
• Highly lipophylic
• Binds strongly to plasma protetin
• Transdermal formulation  a lag time 6 – 12
hour to onset of action, reach 3 – 6 days steady
state

20. Notes about the Fentanyl patch
• Takes 12 hours for onset of analgesia
• Need adequate subcutaneous tissue for
absorption
• Takes 24 hours to reach maximum effect
• Change patch every 72 hours
• Dosage change after six days on patch
• Suitable for stable pain only

21. Pharmacology of opioid
Side effect of opioid
Drug interaction
Tramadol
• Unique analgesic
• An atypical opioid, has a higher affinity to μ receptor
than the parent compound
• Max doses  400 mg/day
• Toxic dose cause CNS excitation
• Oral tramadol absorbed rapidly  analgesic potency
the same with codein

22. Addiction
• A single exposure to morphine could induce
tolerance and dependence
• Recent study shows that prolonged ventral
tegmental area (VTA), dopamine neuron
activities (DA) and opiate receptor
desensitization followed single morphine
exposure
• Cause  the development of dependence and
tolerance  cause acute analgesic tolerance
and acute addiction of morphine

23. Withdrawal Sign
( after Physiological Dependence )
Acute Action
• Analgesia
• Respiratory Depression
• Euphoria
• Relaxation and sleep
• Tranquilization
• Decreased blood pressure
• Constipation
• Pupillary constriction
• Hypothermia
• Drying of secretions
• Reduced sex drive
• Flushed and warm skin
Withdrawl Sign
• Pain and irritability
• Hyperventilation
• Dysphoria and depression
• Restlessness and insomnia
• Fearfulness and hostility
• Increased blood pressure
• Diarrhea
• Pupillary dilation
• Hyperthermia
• Lacrimation, runny nose
• Spontaneous ejaculation
• Chilliness and “gooseflesh”

24. Potential problem in  Opioid Therapy
• Opioid induced hyperalgesia : hyperalgesia syndrome
occur following effective opioid administration  the
phenomenon of pharmacological tolerance or may be
mediated through mechanism :
– Central glutamatergic mechanism
– Increase in the synthesis of excitatory neuropeptides such
as dynorphine
– Descending facilitatory mechanism arising in the medula
• Medication overuse headache

25. Pharmakokinetics Aspect of opioid

26. Percent of peak effect
Site Concentration after bolus injection
Minutes since bolus injection
0 5 10 15 20
Percentofpeakeffect
siteconcentration
0
20
40
60
80
100
Methadone
Remifentanil
Fentanyl
Sufentanil
Alfentanil
Hydromorphone
Morphine
Meperidine

27. Pharmacokinetic of opioid

28. Therapeutic Window

29. Blood levels in Therapeutic Window
PCA

30. Conclusions
• Opioid  are important drugs used in the
pain management
• Employ appropriate pharmacological choice
by knowing the pharmacology of the drugs
 both pharmaco dynamic and pharmaco
kinetics
• Provide optimal effect and minimize side
effects