OPIOID

ANALGESICS

dr. Isngadi, M.Kes., SpAn.

Departement of Pharmacology
Departement of Anesthesiology
Dr Saiful Anwar Hospital, Brawijaya University
Malang
 Analgesia
An : without
Algesia (algos) : pain

Pain
an unpleasant sensory and emotional
experience associated with actual or
potential tissue
damage or described in terms of such
damage.
Analgesics : Drugs for the
Suppression of Pain
Morphine, the prototypical opioid agonist,
has long been known to relieve severe pain
with remarkable efficacy.

The opium poppy is the source of crude

opium from which Serturner in 1803
isolated the pure alkaloid morphine
named after Morpheus, the Greek god of
dreams. It remains the standard against
which all drugs that have strong analgesic
action are compared. These drugs are
collectively known as :
Nociception : Basic Process of Pain
Transmission
nociceptors (antipyretic
analgesics, local anesthetics)
3. Interrupting nociceptive conduction in
sensory nerves
(local anesthetics)
4. Suppression of transmission of
nociceptive impulses
in the spinal medulla (opioids)
5. Inhibition of pain perception (opioids,
general
anesthetics)
6. Altering emotional responses to pain,
i.e., pain
behavior (antidepressants as co-
analgesics )
D

E
 Pharmacokinetics Of opioids
Absorption
Morphine and Meperidine
-Rapidandcompleteabsorptionfollowstheintramuscularinjection
-Peakplasmalevelsusuallyreachedafter2060min(im).

Fentanyl
-Oraltransmucosalfentanylcitrateabsorption(fentanyl "lollipop") is an
effective&rapidonset(10min)ofanalgesiaandsedation:
-inchildren(1520ug/kg)
-adults(200800ug)
-Thelowmolecularweightandhighlipidsolubilityoffentanylalsoallow
transdermalabsorption(thefentanylpatch).
-Serumconcentrationsoffentanylreachaplateauwithin1424hofpatch
application(peaklevelsoccurlaterinelderlypatientsthaninyoungadult
patients)andremainconstantforupto72h.
-Ahighincidenceofnauseaandvariablebloodlevels
-Experimentalstudieshaveexploredthepossibilityofaninhalationdeliveryof
liposome-encapsulatedfentanyl.

(Morgan,2006
 - The distribution half-lives of all of the opioids are
fairly rapid
(520 min).
- The low fat solubility of morphine :
> slows passage across the bloodbrain barrier
> its onset of action is slow
> its duration of action is prolonged.
- The high lipid solubility of fentanyl and sufentanil:
> rapid onset and short duration of action.
- The high nonionized fraction of alfentanil at
physiological pH
and its small Vd :
> increase the amount of drug available for binding
in the brain
> more rapid onset of action and shorter duration
than fentanyl following iv. even though it is
less lipid soluble than
Physical Characteristics of Opioids That Determine
Distribution
Opioid Analgesic
Pharmacokinetics
Biotransformation

- Biotransformation on the liver

- Their clearance depends on liver blood flow.
- The small Vd of alfentanil is responsible for a short
elimination half-life (1.5 h).
- Morphine undergoes conjugation with glucuronic
acid to form morphine 3-glucuronide and morphine 6-
glucuronide.
- Meperidine is N-demethylated to normeperidine, an
active metabolite associated with seizure activity.
- The end products of fentanyl, sufentanil, and
alfentanil are inactive.
- Remifentanil biotransformation is so rapid and so
complete by ester hydrolysis nonspecific
esterases in blood (red cells) and tissue.
biotransformation :
- eliminated by the kidneys
- less than 10% undergoing biliary excretion
- 510% of morphine is excreted unchanged in
the urine
(renal failure prolongs its duration of
action)
-The accumulation Normeperidine has an excitatory
effect on
the central nervous system, leading to
myoclonic activity and
seizures that are not reversed by
naloxone.
- Fentanyl plasma levels occurs up to 4 h after the
last intravenous dose (enterohepatic
recirculation or mobilization of
sequestered drug)
- Metabolites of sufentanil are excreted in urine
and bile
 PHARMACODYNAMICS OF
OPIOIDS
Opioids bind to specific receptors located
throughout
the central nervous system and other tissues.
The pharmacodynamic properties of specific opioids
depend
on which receptor is bound, the binding affinity, and
whether the receptor is activated
Four major types of opioid receptor : mu () , with
subtypes
-1, -2, kappa ( ), delta ( ), and sigma ( ).
 PHARMACODYNAMICS OF
OPIOIDS
Activation of opioid receptors inhibits the
presynaptic release of excitatory
neurotransmitters from terminals of nerve
carrying nociceptive activity
Opioid do not alter responsiveness of afferent
nerve
endings to noxious stimulation, nor do they
impair
conduction of nerve impulses along
peripheral nerves
 Classification of Opioid Receptors
Receptor Effect Agonist Antagonist
Supraspinal analgesia Endorphins

Euphoria Morphine

Miosis Meperidine

Nausea & Vomiting Fentanyl Naloxone

Mu-1
Urinary retention Sufentanil

Pruritus Alfentanil

Remifentanil

Spinal analgesia

Sedation

Hypoventilation Same as for Mu-1 Naloxone

Mu-2
Bradycardia

Ileus

Delta Modulation of Mu receptor activity Enkephalins Naloxone

Analgesia (high intensity pain may not

be relieved)

Sedation
Dynorphins Naloxone
Kappa Miosis

Dysphoria

Diuresis
Dysphoria Pentazocine

Sigma Hallucinations Pentazocine

Respiratory stimulation Ketamine?

 Uses and Doses of Common
Opioids
Common Opioid
Analgesics
Opioid Drug
Interactions
Major Adverse Effetcs of the
Opioid Analgesics
Intraspinal
Opioid
 Effects on Organ Systems
Opioids do not seriously impair cardiovascular function.
Meperidine tends to increase heart rate
High doses of morphine, fentanyl, sufentanil, remifentanil,
and alfentanil are associated with a vagus-mediated
bradycardia
Opioids do not depress cardiac contractility
Meperidine and morphine evoke histamine release , it s can be

minimized in susceptible patients by slow opioid infusion,

adequate intravascular volume, or pretreatment with H 1 and
H2 histamine antagonists.
Opioids depress ventilation, particularly respiratory rate.
Response to a CO2 challenge is blunted and hypoxic drive is
decreased
 Effects on Organ Systems
Reduce cerebral oxygen consumption
Increases in cerebral artery blood flow
velocity
and intracranial pressure following opioid
boluses
in patients with brain tumors or head trauma
Stimulation of the medullary chemoreceptor
trigger zone is responsible for a high
incidence of
nausea and vomiting.
 Effects on Organ Systems
Opioids slow gastric emptying time by reducing
peristalsis.
Opioid-induced contraction of the sphincter of
Oddi.
Fentanyl, sufentanil, and alfentanil can induce
chest wall rigidity severe enough to prevent
adequate ventilation.
Intravenous meperidine (25 mg) has been found
to be the most effective opioid for decreasing
shivering.
 Dr. Isngadi,M.Kes., SpAn
SIP : 446.DS/346.1/35.73.306/2008
STR : 3511501208017261
Praktek : RSU.DR Saiful Anwar
Jl Jaksa Agung Suprapto no 2 Malang
Telp: 08123385910 - 03418669333
Malang, 04 Maret
2009

R/ ni. Pethidin 100 mg amp. I

(satu)
Simm.

Pro : Tn Soeharto
Umur : 48 th
 Dr. Isngadi,M.Kes., SpAn
SIP : 446.DS/346.1/35.73.306/2008
STR : 3511501208017261
Praktek : RSU.DR Saiful Anwar
Jl Jaksa Agung Suprapto no 2 Malang
Telp: 08123385910 - 03418669333
Malang, 04 Maret
2009
R/ni. Tab.Codein mg 15
no VI

(Enam)
S.t.d.d
tab. I
 References
1. Morgan GE, Maged S Jr. Mikhail, Murray Mj. Clinical
Anesthesiology, 4th
Edition, McGraw-Hill Companies. 2006
2. GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS - 11th Ed. The McGraw-Hill Companies. 2006
3. Stoelting KR. Pharmacology & Physiology in Anesthetic Practice,
4th Ed. Lippincott-Raven, 2006
4. Katzung, BG. Basic & Clinical Pharmacology, Ed. Prentice Hall
International. 2006