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OPIOID ANALGESICS AND ANTAGONISTS

Opioid analgesics are drugs that mimic the effect of Morphine.
Sources of Opioid analgesics:
1) Plant: - Morphine, Codeine (natural products of Opium poppy)
2) Synthetic: - Fentanyl, Methadone, Pethidine, Heroin.
3) Endogenous: - Endorphins, Encephalins and Dynorphins (Opiopeptides)
released in the body, acting on Opioid receptors and producing Morphine-like
effects.

Mechanism of action of Opioids:

1- Opioid receptors (mu, kappa and delta) are G-protein coupled receptors present
in CNS and periphery (e.g. GIT).
2- Opioids decreases pain perception and emotional response to pain by stimulating
receptors in:
• Afferent pain conducting fibers.
• Spinal cord (spinal analgesia).
• Thalamus, brain stem and cerebral cortex (supra-spinal analgesia).
• Limbic system: - decreases emotional response to pain and inducing euphoria
(patient may still feel pain but the feeling is not unpleasant).
3- Opioids activate the receptors directly or through the release of endogenous
opiopeptides. This results in neuronal inhibition through:
a) Inhibition of calcium entry decreasing release of excitatory neurotransmitters e.g.
Substance-P.
b) Stimulation of potassium outflux resulting in hyperpolarization of neuronal
membrane.

Mu receptors mediate most of the effects of opioids: - Analgesia, Sedation, Euphoria,

Dependence, Respiratory depression, inhibition of GIT motility.
Kappa receptors mediate spinal analgesia, sedation, and dysphoria.

Pharmacological actions of Opioids:

I- Main effects:
A- Analgesia: - Decreases pain perception and emotional response to pain.
B- Sedation.
C- Euphoria (sometimes dysphoria).

II- Inhibitory effects:

1- Vasomotor centre: causing venular and arterial dilatation.
2- Respiratory depression.
3- Inhibition of the cough centre.
4- Inhibition of uterine muscle.
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III- Stimulatory effects:

1- Stimulation of the oculomotor nucleus producing miosis.
2- Stimulation of CTZ producing nausea and vomiting.
3- Increases smooth muscle tone but inhibit peristalsis leading to constipation.
4- Stimulation of the release of ADH.
5- Histamine release producing Hypotension, itching and bronchospasm.
v Tolerance develops to all effects except constipation and miosis.

Therapeutic uses of Opioids:

1) Analgesics in:
• Acute pain (trauma).
• Chronic dull pain (visceral).
• Post-operative pain and Cancer pain.
2) Anaesthesia (Morphine or Fentanyl).
3) Myocardial infarction and Acute Pulmonary Edema (Morphine): Decreases
pain and anxiety, arteriolar and venodilator (decreases venous congestion and
pulmonary edema).
4) Antitussive (Codeine and Dextromethorphan).
5) Anti-diarrheal: Use Loperamide or Diphenoxylate because they are less
addictive than Morphine.

Adverse effects of Opioids:

1) Sedation and narcosis.
2) Drug dependence.
3) Respiratory depression.
4) Nausea and vomiting.
5) Miosis.
6) Constipation and urine retention.
7) Hypotension, itching and bronchospasm (due to Histamine release).
8) Delay labor and Asphyxia neonatorum (Respiratory depression in the newborn).
9) Mask the diagnosis of acute abdomen (mask pain).
10) Biliary spasm.

Contraindications of Opioids:
1) Acute undiagnosed abdomen (mask pain).
2) Head injury (Opioids cause respiratory depression leading to increased CO2
resulting in cerebral vasodilatation with increased intracranial tension).
3) Bronchial asthma (Opioids cause Histamine release).
4) Biliary colic (Opioids increase intra-biliary pressure and aggravate the colic).
5) Patients with enlarged prostate (Opioids decrease motility of the bladder wall and
cause urine retention).
6) Extremes of age, Hypothyroidism and liver dysfunction (decreased Opioid
metabolism).
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Drug interactions of Opioids:

A- Addictive CNS depression with other CNS depressants e.g. Sedative-hypnotics,
Alcohol, Antidepressants, Antipsychotics.
B- Pethidine + MAOIs results in Hyper-pyrexic coma, Respiratory depression and
Convulsions.

Classification of Opioid analgesics

I- Strong Opioid analgesics:
A- Pure Agonists:
1. Morphine.
2. Fentanyl.
3. Methadone.
4. Pethidine.
5. Heroin.
B- Partial Agonists:
e.g. Buprenorphine: - less addictive & less respiratory depression.

II- Moderate Opioid analgesics:

- Codeine: - Analgesic
- Antitussive

II- Weak Opioid analgesics:

- Propoxyphene: Oral.
• Analgesic combined with Paracetamol in mild to moderate pain.

Pure Agonists

1) Morphine: - IV, IM, SC, Oral (Extensive first-pass metabolism)

Uses:
a) Analgesia in severe pain e.g. chronic dull visceral pain, acute pain of trauma,
post-operative pain, cancer pain.
b) Anaesthesia (safer in cardiovascular surgery).
c) Myocardial infarction and acute pulmonary edema: decreases pain and
anxiety, arteriodilator and venodilator producing decreased venous congestion
and pulmonary edema.

Acute Morphine toxicity: - Coma, respiratory depression, pin-point pupil.

Treatment:
- Support respiration.
- Opioid antagonist: Naloxone I.V, repeated when necessary.
- Gastric lavage.
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2) Fentanyl: - I.V
• More potent than Morphine with rapid onset and short duration.
Uses:
a) Analgesic in severe pain.
b) Anaesthesia (safe in cardiovascular surgery).
c) Combined with Droperidol (neuroleptic) to induce neurolept-analgesia or
neurolept-anaesthesia.

3) Methadone: - Oral.
Uses:
a) Treatment of Opioid addicts (Detoxification and maintenance): Orally active
with long duration of action. Gradual withdrawal of Methadone is associated with
less severe and smoother withdrawal symptoms.
b) Analgesic (efficacy equal to Morphine) in severe chronic pain.

4) Pethidine: - I.M and Oral.

• Most widely used opioid analgesic in moderate and severe pain e.g. chronic dull
visceral pain, acute pain of trauma, post-operative pain, cancer pain.
• It differs from Morphine in the following:
a) Less potent.
b) Less spasmogenic: Less biliary spasm, less constipation, less urine retention (due
to short duration of action).
c) Less respiratory depression in neonates (short duration of action).
d) It does not delay labour therefore preferred during labour with less risk of
Asphyxia neonatorum.
e) Atropine-like action: - Dry mouth, Blurring of vision, tachycardia.

5) Heroin:
• Diacetylmorphine converted to Morphine in CNS.
• Rapid onset (crosses Blood-Brain-Barrier better than Morphine) and short
duration increases risk of drug abuse (not used clinically in most countries).

Partial Opioid agonists (e.g. Busprenorphine)

Advantages over pure agonists:
1) Less addiction.
2) Respiratory depression is not increased by increasing the dose (ceiling effect) due
to their antagonist effect.
Buprenorphine:
• Partial opioid agonist.
• Long acting and more potent than Morphine.
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Uses:
1- Analgesic in severe pain.
2- Treatment of addicts as an alternative to Methadone.

Pure Opioid Antagonists

I- Naloxone: - I.V and short acting therefore used in emergencies: (0.1 – 0.4mg I.V).
Uses:
1) Acute opioid toxicity: Repeated as necessary to avoid relapse into coma since
duration of action is shorter than that of opioids.
2) Asphyxia neonatorum (due to Morphine administration during labour): Reverses
respiratory depression in the newborn.

II- Naltrexone:
Oral and long acting, therefore used in maintenance therapy in treatment programs for
addicts:
• Block the euphoric effects of opioids resulting in loss of the desire to take the
drug.
• Given after complete detoxification, otherwise it would precipitate a withdrawal
syndrome.