A. M.

Takdir Musba

Department of Anesthesiology,
Intensive Care and Pain Management
Faculty of Medicine , Hasanuddin University
 Perception
PAIN PATHWAY
Pain

Modulation
Descending
modulation Dorsal Horn

Ascending
input
Dorsal root
ganglion
Transmission

Transduction
Spinothalamic
Peripheral
tract
nerve

Trauma
Peripheral
nociceptors

Adapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049.
PIB FK UNHAS Makassar, 28 januari 2011
Introduction
 Opioid most commonly used analgesic in clinical
practice
 Easy availability
 Low cost
 Effectiveness
 Opium ( juice ) papaver somniferum contains 20
distinct alkaloids
 Morphine , first isolated in 1803
 Opioid : all substances, natural and synthetic that have
morphine – like properties
Doctor’s problem
 Opiophobia
 Common mis-perception about opioid
 PK/Pd of Drugs
 Regular assessment
Choice of Analgesic Technique
(Analgesic Ladder of WFSA)

Opiate Oral route available – give

And orally
NSAID Oral route unavailable –
Rectal paracetamol & NSAID,
and Opiate: PCA, IM algorithm,
Paracetamol Epidural infusion analgesia

NSAID
and
Paracetamol

Pain Paracetamol
decreases as
time passes
 WHO Analgesic
LADDER
OPIOID ORAL
AVAILABLE IN INDONESIA
“ LOGICAL APPROACH TO PAIN CONTROL “

PIB FK UNHAS Makassar, 28 januari 2011

Using Opioid for pain relief
 Inadequate Dose opioid
 Poor understanding of pain intensity
 Overestimation duration action
 Fear of abuse
 ( Mark RM, et al, 1973 )
 Accessibility and widespread used opioid in postop
pain till now but 60% patient still experience
moderate to severe pain
 ( Apfelbaum JL, et al, 2003 )
Mechanism action of Opioids
Binding to specific membrane receptor ( ORs )

Pharmacology effect as analgesia

 Endogenous opioid peptide ( EOPs ) endorphins,

dynorphins, enkhepalins, binding also to ORs 
Endogenous Opioid System (EOS)  modulate
nociceptive transmission
 Central and Peripheral NS, CV, GI and Immune Cell.
Opioid Receptor
 MOR or OP3 ( µ opioid receptor )
 Cortex, amygdala,hippocampus,thalamus,
mesenchepalon, pons, medulla and spinal cord
 KOR or OP2 ( κ opioid receptor )
 Similar distributed but also in hypothalamus
 DOR or OP1 ( δ opioid receptor )
 Not widely distributed
 Telencephalon and spinal cord
 ORs also identified in peripheral administration
 OP4/ ORL-1 : Nociceptin / Orphanin-FQ
Opioid receptor and mechanism
 G-coupled protein receptors
 Signal via cyclic AMP and ion channel
 Decrease Ca entry  reduce NT release
 Potassium efflux  hyperpolarization  decrease
synaptic transmission
 Modulate inhibition of GABA-ergic in spinal

Activating one or more OR  Analgesic Effect

 Opioid mechanisms
Descending
controls

To the bra

C-fibre
Glutamate

Substance P
etc

Spinal cord neurone

 Opioid mechanisms
Descending
controls

To the bra

C-fibre
Glutamate

Substance P
etc Opioid

Spinal cord neurone

Mechanisms of Action of Opioids
Primary
afferent

, d, k receptors
Presynaptic
terminal {  gCa++
 Transmitter release

 receptors
Postsynaptic
neuron {  gK+
Spinal pain-
transmission
neuron
Basic and Clinical Pharmacology. 8th ed. 2001.
Endogenous opioid
Activation of the Different ORs
Receptor Type Effect
μ ( MOR ) Supraspinal , spinal and peripheral analgesia
Respiratory depression
Gastrointestinal : ileus, constipation, nause, emesis
Pruritus, urinary retention
Cardiovascular depression
Tolerance / dependence
Sedation , euphoria
Miosis
Κ ( KOR ) Spinal analgesia
Dysphoria
Sedation
Diuretion
δ ( DOR ) MOR receptor modulation
Spinal / Supraspinal analgesia
Intrinsic activity
 Agonist : drug bind to and stimulate OR, capable produce
max response from receptor ( intrinsic activity 1 )
 Antagonist : drug bind to but do not stimulate OR and may
reverse effect of opioid agonist ( intrinsic activity 0 )
 Partial agonist : drug bind and stimulate OR but have a
ceiling effect. Produce submaximal response compared
with an agonist ( intrinsic activity > 0 and < 1 )
 Agonis-antagonist : drugs that agonist at one OR and
antagonist at another
Intrinsic Activity Opioid Drugs

Agonist Morphine
Fentanyl
Alfentanyl
Sufentanyl
Pethidine
Oxycodone
Diamorphine
Remifentanyl

Partial agonist Buprenorphine

Agonist-antagonist Butorphanol
Pentazocine

Antagonist Naloxone
Naltrexate
Pharmacokinetics
 Absorption, distribution, metabolism and excretion

 All opioid are well absorpted by all routes adm.

 Distribution
 Lipid solubility : high  early onset
 pKa : lower pKa  larger nonionized form  greater
membrane permeability  rapid onset
 Most opioid similar elimination half lives, but half lifes
does not predict duration effect
 Liver is main site metabolism most opioid
 Opioid metabolite : M6G, M3G, Norphetidine, morphine
Opioids comparative
Opioid Half live Equipotent Equipotent Duration
IV dose PO dose ( hr )
( mg/kg) ( mg/kg )
Morphine 2-4 hrs 0.1 0.3 – 0.5 3-5
Fentanyl 1 – 7 min 0.001 0.001-0.005 0.75 – 1
transmucosal
Pethidine 3 – 4 hrs 1 1.5 – 2 2–3
Alfentanyl 1.4 min 0.05 N/A 0.5
Sufentanyl 1.4 min 0.0001 N/A 1
Codeine 3 hrs 1.2 2 4-6
Oxycodone 2 – 6 hrs N/A 0.1 4–6
Factors influence opioid
pharmacokinetics
 Age
 Sex
 Liver and Renal disease
 Obesity
 Plasma protein binding
Age
 Neonates :
 Immature Cytochrome P450
 Decreased renal clearance
 Immature BBB

 Older patiens :
 lower clearance
 Reduced VD
Sex
 More effective analgesia in males
 Onset and offset analgesic effect later in female

Liver & Renal Disease

 Renal impairment
 Metabolites excreted via kidney
 Bolus Vs Continuous
 Liver impairment no clinical problems if use in
recommended doses for pain relief
 Fentanyl and sufentanyl are not affected in liver and renal
failure
 Alfentanyl not recommended, but remifentanyl good
choice for Liver And renal failure
Obesity
 Dosing remifentanyl due to ideal body weight adequate
for morbidly obese patient
 Actual body weight give overestimates fentanyl dose
requirement
 Dosing should be due to ideal body weight

Plasma Protein Binding

 Α1-acid-glycoprotein bound most opioid
 Decreased after trauma, surgery, chronic inflammatory
disorders, and Cancer
 Greater sensitivity cause higher plasma conc. Free
drugs
Routes of administration
 Intravenuous
 Intramuscular
 Oral
 Buccal
 Transdermal
 Intranasal
 Rectal
 Subcutaneous
 Spinal route : Epidural and Intratechal
Morphine
 Least lipid soluble
 Metabolites M6G and M3G ( longer half lifes )
 M6G more potent than morphine
 M3G ( no analgesic effect ) role in tolerance
 Slow release ( controlled release or sustained release )
use for chronic and cancer pain
 Slow onset, prolonged duration  fast titration its
impossible
Fentanyl and its analogs
 Highly lipid soluble synthetic opioid
 Rapid onset and short duration
 Metabolite inactive ( safe for renal impairment )
 Suitable for transdermal administration
 Alfentanyl and sufentanyl ( highly lipid soluble ) 
more rapid onset and shorter suration  for intra
operatif but limited in postoperative
 Remifentanyl ( very rapid onset )  high dose induce
acute opioid tolerance and hiperalgesia
Pethidine
 Synthetized as a potential substitute for atropine 
( atropine like effect )
 Weak affinity for NMDA receptor
 Pethidine superior in renal and biliary colic but
evidenced show that all opioids are equally effective
 Metabolite is norphetidine ( normeperidine ) with
long half-life ( 15-20 hrs )  analgesia ( µ receptors )
but neurotoxicity ( CNS excitation : anxiety, mood
changes, tremors, twitching, myoclonic , convulsion )
Norpethidine toxicity
 Treatment
 Discontinue pethidine
 Substitue to alternative opioid
 Symptomatic treatment
 DO NOT administer naloxone
 Suggest
 Dose limit : 1000 mg in first 24 hrs and 600-700 mg/day
thereafter, Reduced in elderly
 Should be avoided in renal impairment
Tramadol
 Centrally acting synthetic analgesia
 µ receptors activity ( by main metabolite M1 ( O-
desmethyl-tramadol ))
 Inhibit reuptake NE and serotonine (5HT ) in nerve
terminal
 Advantages of equianalgesic dose opioid
 Less sedation
 Less repiratory depression
 Less constipation
 Nausea and vomiting similar
 Not a controlled drug
 Epilepsy was relatively contra indication
 Seizure have been reported but probably similar with
other opioid
 Accumulation M1 in renal failure can cause respiratory
depression
 Total daily dose : 600 mg
Codeine
 Naturally alkaloid like morphine
 Metabolized in liver by CYP 2D6  converted to
morphine (2-10%)  analgesic effect of Codeine
( ineffective prodrug of morphine )
 Usually for mild to moderate pain
 Combine with non-opioid agents like acetominophen
or aspirin  increased analgesic efficacy but also
opioid relate adverse effect
Equianalgesic doses Opioids
Oral dose Opioid Parenteral iv/sc/im
( mg ) ( mg )
400 Meperidine 100
100 Tramadol 100
200 Codeine 130
30 Morphine 10
- Fentanyl 0.15 – 0.20
- Sufentanyl 0.02
Morphine 50 mg PO in 24 hrs = fentanyl patch 25 mcg/hr
Comparative Onset of Opioid Drug Effect

100 Hydromorphone
Methadone
Meperidine
Percent of peak effect

80 Morphine
site concentration

Sufentanil

60
Fentanyl

40

Alfentanil
20

Remifentanil
0
0 5 10 15 20
Minutes since bolus injection
Opioid-induced adverse effect
 Respiratory depression
 Pruritus
 Gastrointestinal effect
 Urinary effects
 Nausea and Vomiting
Respiratory depression
 Less than 0.1 %
 Activation of MORs
 Decrease MV : RR and TV
 Decrease responsiveness of respiratory center in CO2
 Decrease RR to late for RD sign
 Nociceptive input Vs respiratory depression
 R/ naloxone iv 100 – 400 µg titration and maybe
continuous 2 – 5 µg/kg/hr
Pruritus
 Histamine release due to iv administration Morphine
and Fentanyl
 Neuraxial opioid – induced pruritus
 R/ antihistamine, 5-HT receptor antagonist, opioid
antagonist, propofol, NSAIDs, droperidol
 R/ ondansentron iv 2 – 4 mg
Gastrointestinal
 Delay gastric emptying, increase small and large bowel
transit times, inhibit fluid secretion and permeability
 Oral, parenteral, also neuraxial delivery
 MORs located in gut and CNS
 Side effect – dose related
 Partially reversed with naltrexon

Nausea and vomiting

 Opioid receptor located in CTZ
 No difference in route administration
 Cephalad migration after spinal opioid
Cardiovascular Effect
 Analgesic dose have minimal effect on BP,HR,and
Rhytm
 Effect on patient with CAD : decrease O2 cons, cardiac
work, LVP and Diastolic pressure
 Hypotension due to histamine release after morphine
 Fentanyl and ultra short acting cause bradycardia
Urinary effect
 Increase tone and amplitude of contraction ureter and
bladder
 EOS via modulation parasympathetic outflow in
sacral spinal cord
 Urine retention higher in neuraxial
 Relaxation muscle detrusor
Opioids - Principles of Dosing
n Individualize dose by gradual escalation until
development of adequate analgesia or intolerable
and unmanageable side effects.
 No therapeutic ceiling effect.
n “Around the clock dosing” for continuous or
frequently recurring pain.
n As needed (“prn”) dosing for dose finding and for
“rescue doses”.
Opioid Titration Guidelines
 Titrate with short –acting hydrophilic opioid; can be given
at interval based on the time to peak serum level ( Cmax )
as needed; oral ~ 1 hour , sc ~ 30 min, iv ~ 10 min.
 Calculate 24 hrs requirements and convert to long-acting
opioid; if pain persist at steady state, adjust as follow :
 Mild to moderate pain, increase daily dose 25 – 50 %
 Moderate to severe , increase daily dose 50 – 100 %
 For breakthrough pain, give 5 – 15% of total daily dose at
intervals based on the time to Cmax as needed as above
with short-acting opioid
Breakthrough Pain
n Transitory exacerbations of severe pain over a baseline
of moderate to mild pain
n Reported by 2/3 of cancer patients with controlled
baseline pain
n Often due to: incident pain or end-of-dose failure
(important to distinguish)
Opioid Rescue Doses
n Used for breakthrough pain.
n Dose:
 Approximately 10% of daily dose equivalent.
n Frequency:
 Oral every 1 - 2 hours
 Parenteral every 15 - 30 minutes
Opioid Dose Adjustment
n Gradual dose escalation until development of
adequate analgesia or intolerable and unmanageable
side effects.
n No ceiling to analgesia and doses may become very
large.
n Rate of escalation depends on severity of pain.
Increase dose by 30 -50 % for mild to moderate pain,
50-100% for severe pain.
n Increase rescue dose as baseline dose is increased
When dose-limiting side effects occur
with opioid pharmacotherapy...
• More aggressive treatment of adverse effect(s)
• Opioid-sparing strategies
• Analgesic adjuvants
• Alternate route (e.g. intraspinal)
• Anaesthetic/Neurolytic procedures
• PM&R approaches
• Cognitive therapy
• Complementary therapies
• e.g., acupuncture, massage, music therapy

• Opioid rotation
Opioid rotation
 When changing from one opioid to another :
“ incomplete cross opioid tolerance “
 Start with 50 – 75% of the calculated equianalgesic dose
 Use more, if pain uncontrolled
 Use less, if adverse effect are present
Tolerance
Definition: A change in the dose-response relationship
induced by exposure to the drug and manifest as a need for
a higher dose to maintain an effect.
Develops at different rates to these varying effects:
 respiratory depression, somnolence, nausea >> analgesia >
constipation.
Analgesic tolerance is rarely a problem.
 Opioid doses remain relatively stable in the absence of worsening
pathology and increased opioid requirements after stable periods is
often a signal of disease progression.
Dependence
Definition: The development of a withdrawal syndrome
following dose reduction or administration of an
antagonist.
• Often develops after only a few days of opioid therapy.
• Not a clinical problem if drug is tapered before
discontinuation.
• Taper by no more than 50% of the dose/day
THANKS FOR YOUR ATTENTION

ALWAYS TRY ……
TO BE A GOOD DOCTOR