OPIOID ANALGESIC

OPIOIDS (MORPHINE-LIKE) ANALGESICS

AND ANTAGONISTS

Opioids –
natural or synthetic; produce morphine-like effects.
They act by binding to specific opioid receptors in the CNS »»»
effects mimic the action of endogenous peptide neurotransmitters
(e.g., leu- and met-enkephalins).
They relieve severe pain - essential in treatment of major diseases,
trauma, and surgery.
Danger of the drug abuse.
Although the opioids have a broad range of effects, their primary use
is to relieve intense pain and the anxiety that accompanies it.
Antagonists – they can reverse actions of opioids, important
clinically – treatment of overdose.
 History of Opioids
• Opium is extracted from poppy seeds (Paper
somniforum)
• Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression
 Terminology
• “opium” is a Greek word meaning “juice,” or
the exudate from the poppy
• “opiate” is a drug extracted from the exudate
of the poppy
• “opioid” is a natural or synthetic drug that
binds to opioid receptors producing agonist
effects
 Mechanism of Action

bind to G-protein-coupled neural receptors (mu, delta,kappa) to

reduce adenylyl cyclase activity, to reduce prejunctional calcium
conductance, which causes a decrease in neurotransmitter release,
and to enhance postjunctional potassium conductance, which causes
a decrease in cell responsiveness to excitatory neurotransmitters
Action of endogenous and exogenous opioids at opioid receptors
 Opioid Receptors
μ-receptors are thought to be responsible for most of the analgesic
effects of opioids, and for some major unwanted effects (e.g.
respiratory depression, euphoria, sedation and dependence). Most of
the analgesic opioids are μ-receptor agonists.

δ-receptors are probably more important in the periphery, but may

also contribute to analgesia.

κ-receptors contribute to analgesia at the spinal level, and may elicit

sedation and dysphoria, but produce relatively few unwanted effects,
and do not contribute to dependence. Some analgesics are relatively κ-
selective.
 Mu and Kappa Receptor Activation

Response Mu-1 Mu-2 Kappa

Analgesia

Respiratory
Depression
Euphoria

Dysphoria

Decrease GI
motility
Physical
Dependence
Effects of opioids
Opiods: dose-response relationship
comparison of the maximum efficacy and addiction/abuse liability
of commonly used narcotic analgesics
 Morphine
The prototype opioid, is derived from opium, a crude
material obtained from the seed pod of the opium poppy
plant

Many other derivatives of the opium plant (opiates) and

other drugs with similar effects (opioids) have been
discovered or synthesized

morphine is still one of the most widely used opioids

The opioids are classified in several ways:

(1)strength of analgesic effect (strong and weak

agents);

(2) ratio of agonist to antagonist effects (pure

agonists, mixed agonist-antagonists, and partial
agonists that act both as an opioid agonist and
antagonist, and antagonists)

(3) actions (analgesic, antitussive, and antidiarrheal

drugs)
 Therapeutic uses morphine
The major therapeutic application for morphine and other strong opioids
(e.g., fentanyl, hydromorphone, methadone) is the management of
moderate to severe pain (e.g., pain associated with trauma, burns,
cancer, acute myocardial infarction, and renal or biliary colic).

Weaker opioids such as codeine and pentazocine are used to manage

mild to moderate pain
Management of diarrhea (e.g.,codeine, diphenoxylate, loperamide)

dyspnea associated with pulmonary edema secondary to acute left

ventricular failure

suppression of the cough reflex (codeine, dextromethorphan)

maintenance and withdrawal therapy for opioid dependence

(methadone, buprenorphine)
 Division (in relation to the activity)

1. Strong agonists (e.g. morphine, meperidine=pethidine,

methadone, fentanyl, sufentanil, alfentanil, remifentanil)
2. Moderate agonists (e.g. propoxyphene, codein, oxycodone)
3. Mixed agonist-antagonists (e.g. pentazocine, buprenorphine,
nalbuphine, butorphanol)
4. Other analgesics ( tramadol)
5. Antagonists (naloxone, naltrexone)
OPIOID ANALGESICS AND ANTAGONISTS

STRONG AGONISTS
Alfentanil
Fentanyl
Heroin
Meperidine
Methadone
Morphine
Remifentanil
Sufentanil
MODERATE/LOW AGONISTS
Codeine
Oxycodone
Propoxyphene
MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
Buprenorphine
Butorphanol
Nalbuphine
Pentazocine
ANTAGONISTS
Naloxone
Naltrexone
OTHER ANALGESICS (according to
Lippincott´s
Tramadol Pharmacology, 2006
 Morphine
CNS effects
– Respiratory depression and suppression of
cough: reducing the responsiveness of the
respiratory centers in the brain stem to blood
levels of carbon dioxide and inhibiting directly
the respiratory center.
 Morphine
CNS effects
– Nausea and vomiting: stimulating the
chemoreceptor trigger zone. In most cases,
after therapeutic dose, subsequent doses of
morphine do not produce vomiting.
– Miosis: pinpoint pupils are indicative of toxic
dosage prior to asphyxia. It can be block with
atropine.
 Morphine
Cardiovascular effects:
– Orthostatic hypotention can occur due to
vasomotor medullary depression and
histamine release.
Gastrointestinal effect:
– Reduces gastrointestinal motility, causing
constipation
– Decreases biliary and pancreatic secretions.
– Constriction at the spincter of Oddi causes an
increase in biliary pressure.
 Morphine
Other systemic effects:
– Increases detrusor muscle tone in the urinary
bladder, producing a feeling of urinary. Vesical
sphincter tone is also increased, making
voiding
– Inhibits the cellular immunity and humoral
immunity, which is significant in withdrawal
syndrome and tolerant in chronic
administration.
Farmakokinetik Opioid
 Adverse effects
Respiratory depression is the most important effect.

Nausea and sometimes dysphoria can occur.

Increase biliary tract pressure.

Allergic reactions.

Bronchoconstrictive action.

Tolerance and Dependence

Contraindications and cautions

Use in patients with head injures

Use during pregnancy

Use in patients with impaired

pulmonary function

Use in patients with impaired hepatic or

renal function
 Interaksi Obat
• Obat yang bekerja secara sentral seperti
barbiturat, fenotiazin, penghambat MAO,
antidepresan trisiklik→↑efek sedatif dan
depresi pernafasan
• Fenotiazin→↑efek menurunkan tek.darah
• Amphetamine→↑analgesia dari morphin dan
mengurangi efek sedasi dan depresi
pernafasan
 Keracunan Akut Morfin
• Gejala : coma, miosis, ↓eksterm dari pernafasan
(hingga 2-4 tarikan nafas permenit), sianosis,
suhu tubuh rendah, kehilangan tonus otot
rangka.
• Tindakan :
→Pembebasan jalan nafas dan pemberian O2
→memberikan suatu antagonis morfin untuk
menghilangkan kelumpuhan pernafasan
(naloxone sbg antagonis kompetitif)
→Shock ditangani, mungkin perlu pemberian Ab
untuk pencegahan pneumonia
 Methadone
Mechanism of action: The actions of methadone are mediated by
the µ receptors

Therapeutic uses: Methadone is used as an analgesic as well as in

the controlled withdrawal of dependent abusers from heroin and
morphine. Orally administered, methadone is substituted for the
injected opioid. The patient is then slowly weaned from methadone

Methadone causes a withdrawal syndrome that is milder but more

protracted (days to weeks) than that of other opioids.
 Fentanyl
Has a shorter duration of action than morphine.

Available for parenteral use only. Used as a preanesthetic

medication and for pre- and postoperative pain
Fentanyl (or morphine) is used to supplement the analgesia and
sedative-hypnotic effects of nitrous oxide and halothane equals
“balanced anesthesia.”
Rapid IV administration of high doses may cause severe truncal
muscle rigidity that can be reversed by naloxone

Available as a transdermal patch and lozenge.

 Meperidine
Mechanism of action: Meperidine binds
to opioid receptors, particularly µ
receptors. However, it also binds well to
º receptors

Therapeutic uses: Meperidine provides

analgesia for any type of severe pain.

It has significantly less effects on uterine

smooth muscle than morphine and is
the opioid commonly employed in
obstetrics
Pharmacokinetics:
• Meperidine is well absorbed from the
gastrointestinal tract, and is useful when an
orally administered
• However, meperidine is most often
administered parenterally
• The drug has a duration of action of 2 to 4
hours, which is shorter than that of morphine
Adverse effects:
• Large or repetitive doses of meperidine can
cause anxiety, tremors, muscle twitches, and
rarely, convulsions due to the accumulation of
a toxic metabolite, normeperidine.
Time to peak effect and duration of action of several
opioids administered intravenously
 Codeine
Although the pharmacologic effects of
codeine are similar to those of
morphine, it has about one-twelfth the
analgesic potency of morphine.

Be used mainly for cough suppressant

and milder pain.

It produces less sedation, respiratory

depression, fewer gastrointestinal
effects, and less addiction and
withdrawal.
 Pethidine

It is very similar to morphine (one-seventh to one-tenth potent) in

pharmacologic effects by μ-receptor agonists.

Therapeutic uses: analgesic, cardiac asthma, sedation (decrease the

dosage of anesthetic )and artificial hibernation.

It has no gastrointestinal or antitussive action because of shorter-acting.

Adverse effect: also causes respiratory depression and possesses

addiction liability, although withdrawal effects are less severe than with
morphine.
 Tramadol
• a centrally acting analgesic that binds to the µ-
opioid receptor
• it weakly inhibits reuptake of norepinephrine
and serotonin
• It is used to manage moderate to moderately
severe pain
• Its respiratory-depressant activity is less than
that of morphine
Adverse effects commonly observed in individuals
treated with opioids
Opiate Withdrawal syndrome
Opioid Antagonists
Pure antagonists include naloxone
(short-acting) and naltrexone
(long-acting). They block μ-, κ-
and -δ receptors more-or-less
equally

Naloxone does not affect pain

threshold normally, but blocks
stress-induced analgesia, and can
exacerbate clinical pain
Opioid Antagonists
Naloxone rapidly reverses opioid-induced
analgesia and respiratory depression, and is
used mainly to treat opioid overdose or to
improve breathing in newborn babies
affected by opioids given to the mother.

Naloxone precipitates withdrawal

symptoms in morphine-dependent patients
or animals.
Clinical Use of Analgesic Drugs

A progressive approach is often

The choice and route of
administration of analgesic
drugs depends on the nature
and duration of the pain
used, starting with nonsteroidal
anti-inflammatory drugs,
supplemented first by weak
opioid analgesics, and then by
strong opioids
Clinical Use of Analgesic Drugs
In general, severe acute pain (e.g. trauma, burns,
post-operative pain) is treated with strong opioid
drugs (e.g. morphine, fentanyl) given by injection.

Mild inflammatory pain (e.g. arthritis) is treated with

non-steroidal anti-inflammatory drugs (e.g. aspirin)
supplemented by weak opioid drugs (codeine,
pentazocine) given orally if required.

Severe pain (e.g. cancer pain, severe arthritis or back

pain) is treated with strong opioids given orally,
intrathecally, epidurally or by subcutaneous injection.
Clinical Use of Analgesic Drugs

Chronic neuropathic pain is

often unresponsive to opioids,
and treated with tricyclic
antidepressants (e.g.
amitriptyline), or other drugs,
such as carbamazepine
ALHAMDULILLAH….