L5 Pharma

OPIOID ANALGESICS & ANTAGONISTS

❖ Analgesics are drugs that relieve pain due to multiple causes.

Opioid (Narcotic) Agonists:

➢ Opioids are drugs with morphine-like effects.
Sources:
1. Plant: morphine - codeine (termed opiates or opium alkaloids; natural alkaloids;
products of opium poppy).
2. Synthetic: fentanyl - methadone - heroin - pethidine…. (opioids)
3. Endogenous: endorphins - enkephalins - dynorphins (opiopeptides) released in the
body, acting on opioid receptors, producing morphine-like effects.
Mechanism of Action:
1. Opioid receptors, μ (mu) (mediate most effects of opioids), κ (kappa) & δ (delta), and σ
(Sigma) are Gi protein-coupled receptors present in the CNS and periphery (e.g. GIT). ‫لها جدول‬
2. Activation of receptors → neuronal inhibition through:
a) Inhibition of Ca2+ entry→ ↓ release of excitatory neurotransmitters including substance P.
b) Stimulation of K+ outflux→ hyperpolarization of neuronal membrane.
3. Opioids (directly or through release of opiopeptides) activate receptors in:
• Afferent pain-conducting fibers→ peripheral analgesia.
• Spinal cord → spinal analgesia.
• Brain stem, thalamus & cerebral cortex→ supraspinal analgesia.

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• Limbic system → euphoria & ↓emotional response to pain (patient may still feel the
pain but the feeling is not unpleasant).

(mu) (kappa) (delta)

Analgesia Analgesia Analgesia
Respiratory depression Respiratory depression Respiratory depression
Reduced GI. motility Reduced GI. motility Reduced GI. motility
Sedation Sedation Affective behavior
Miosis Miosis Reinforcing actions
Euphoria Dysphoria, Proconvulsant
Muscular rigidity psychotomimetic
Physical dependence Physical dependence

Actions, Uses, Adverse Effects & Contraindications (CI) of Morphine:

Uses Actions Adverse Effects & CI
1. Analgesic in: I. Main Effects • Masks pain

• Acute trauma. A. Analgesia CI: acute undiagnosed

abdomen
• Chronic visceral pain ↓Pain perception & emotional
response to pain • Sedation - Narcosis
• Postoperative pain
B. Sedation • Drug dependence
• Cancer pain
C. Euphoria (sometimes dysphoria)
• Myocardial infarction

2. In Anesthesia

• Preanaesthesia

• CV surgery

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II. Inhibitory Effects

3. Acute pulmonary edema in A. ↓VMC → venular & arterial VD -Hypotension
LVF:
B. ↓Respiratory Center→
• ↓preload & after load
↑CO2 → Cerebral VD & -Respiratory depression &
• ↓Respiratory distress asphyxia neonatorum
↑ Intracranial tension
• ↓ anxiety -↑ Intracranial tension
CI: head injury (+ respiratory
depression + Vomiting, miosis
C. ↓Cough Center and altered mentation interfere
4. Antitussive Replaced by with assessment of case)
Codeine &
D. ↓H.R.C -Hypothermia
Dextromethorphan (less
addictive) E. ↓Uterine muscle tone -Delayed labor

III. Stimulatory Effects

A. ↑Oculomotor (E.W.) nucleus → -Miosis (PPP;pin point pupil)
miosis
B. ↑CTZ → vomiting
-Nausea – vomiting

C. Vagal centre → Bradycardia

-Bradycardia
D. Urinary & GI Tracts
-Urine Retention
↑tone of wall & sphincters
5. Antidiarrheal (CI: enlarged prostate)
(spasmogenic) but ↓peristalsis
Loperamide &
→stools stagnate & harden due -Biliary colic (CI: B. colic
Diphenoxylate (less
to fluid absorption. alone)
addictive, more widely
used) E. Histamine release -Constipation
-Hypotension – itching -
bronchospasm(CI: asthma)
Other CI: extremes of age - hypothyroidism - liver dysfunction (↓opioid metabolism)
• Tolerance develops to all effects except constipation and miosis.

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Classification of Opioids Agonists:

➢ Opioid Antitussives (Less addictive than morphine)
• Codeine • Dextromethorphan (See Respiration)
➢ Opioid Antidiarrheals (Less addictive than morphine)
• Loperamide • Diphenoxylate (See GIT)
➢ Opioid Analgesics:
I. Pure Agonists:
1. Strong :Morphine - Fentanyl - Methadone - Pethidine - Heroin
2. Moderate : Codeine - Tramadol
3. Weak Propoxyphene (Oral): Analgesic + paracetamol or aspirin in mild to moderate
pain.
II. Mixed Agon.-Antag: Buprenorphine - Butorphanol – Pentazocin

I. Pure Agonists
1. Morphine (see table).
➢ Given IV - IM - SC - Epidurally- Orally (extensive 1st pass metabolism)
2. Pethidine [IM - Oral]
➢ Analgesic used in acute moderate & severe pain e.g. trauma, postoperative pain, biliary
colic (used alone) or labor pain.
Pethidine differs from morphine in:
1. Shorter acting & less potent: Less (biliary colic- constipation- urinary retention-
vomiting and addiction).
2. Less respiratory depressant in neonates & does not delay labor → preferred during
labor (↓ risk of asphyxia neonatorum).
3. Atropine-like action: dry mouth, blurred vision, …..
4. ↑Risk of convulsions (with high dose, MAOIs or in renal failure due to accumulation of
the pethidine metabolite, norpethidine).
3. Methadone [Oral, efficacy equal to morphine).]
Uses:
1. Treatment of opioid Addicts (detoxification & maintenance):
Orally-active & long acting, thus, it is used to replace morphine or heroin in addicts. Gradual
withdrawal of methadone is associated with less severe & smoother withdrawal symptoms.
2. Analgesic in severe chronic pain

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4. Fentanyl: (IV- epidural or spinal - transdermal patch - infusion)

- More potent than morphine with rapid onset & shorter action (preferred in anesthesia).
- High anesthetic doses→ chest wall rigidity → ↓ thoracic compliance →↓ ventillation.
Uses:
1. Analgesic in severe pain e.g. perioperative, labor & cancer pain.
2. In anesthesia (for its analgesic & sedative effects):
• Preanesthetic medication.
• IV anesthetic in cardiovascular surgery (safer).
• Conscious sedation - neuroleptanalgesia – neuroleptanesthesia.

5. Tramadol
Mechanism:
1. Inhibiting uptake of 5- HT and NA.
2. Weak Mu agonist (only partially antagonized by naloxone).
• Less (constipation, R.C depression & addiction) than morphine.
• ↑ Risk of convulsions.

Uses: (oral, IM, IV, rectal)

• Analgesic in postoperative & chronic moderate pain - neuropathic pain.

Conscious Sedation & Neuroleptanalgesia:

(Amnesia, sedation & analgesia without complete loss of consciousness)
Uses: minor procedures or for diagnostic purposes (e.g. endoscopy).
Conscious Sedation
• IV benzodiazepine (e.g. midazolam) + opioid analgesic (e.g. fentanyl).
• Easily reversed by flumazenil & naloxone (advantage).

Neuroleptanalgesia
• Neuroleptic (e.g. droperidol) + opioid analgesic (e.g. Fentanyl).
• Converted to neuroleptanesthesia by adding 65% nitrous oxide in O2

6. Codeine (Oral)
• Analgesic + paracetamol or aspirin in moderate pain.
• Antitussive

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N.B. Heroin
• Semisynthetic derivative: Diacetylmorphine converted to morphine in CNS.
• Rapid onset (greater lipid solubility→ crosses BBB more than morphine) & short duration
→ ↑ risk of abuse (not used clinically in most countries).

II. Mixed agonist-Antagonist

μ κ
Buprenorphine Partial Agonist Antagonist
Pentazocin
Butorphanol Antagonist Agonist

Actions:
1. In absence of morphine → act as Agonists → strong analgesic
2. In presence of morphine (addict) → act as Antagonists → withdrawal.
Advantages as Analgesics over Pure Agonists
1. Less addiction (less euphoria → less craving).
2. Weak withdrawal symptoms
3. Respiratory depression is NOT ↑ by ↑ dose (ceiling effect)

Uses (parenteral, sublingual, oral)

1. Analgesic in severe pain.
2. Treatment of opioid Addicts as an alternative to methadone

Drug Interactions of Opioids

1. Opioids + other CNS depressants (sedatives, alcohol, antidepressants &
antipsychotics) → additive CNS depression.

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2. Pethidine + MAOIs→ hyperpyrexia- respiratory depression - convulsions.

[Pethidine Hydrolysis (major) Meperidinic acid Coniugated with
glucuronic acid
Demethylation Normepridine (excitation)

- Nonselective MAOIs inhibit hydrolysis not demethylation]

Acute Morphine Toxicity

➢ Coma - Respiratory depression - Pin pointed pupil (diagnostic).
Treatment: Support respiration- Naloxone (IV).

Pure Opioid Antagonists

Naloxone Naltrexone & Nalmefene

IV & short-acting Oral & long-acting

Management of Acute toxicity Maintenance therapy in Addicts

1. Acute opioid toxicity: Repeated as 1. Opioid abuse (after full detoxification)Blocks

necessary to avoid relapse into coma. euphoria of opioids → loss of desire to take drug
(prevents relapse).
2. Asphyxia neonatorum
In opioid- induced respiratory 2. Alcohol abuse

depression in newborns. ↓ Craving in chronic alcoholics.

A/E: uncommon: may ↑in BP & A/E: Nausea – Headache

pulmonary edema + Naltrexone → Hepatotoxicity

+ Naltrexone → Hepatotoxicity

َ َ َ ُ َ َ ُ َ َ َ َّ َ َ َ
‫درك يف غ ِد‬ ‫ما ال ينال اليوم ي‬ ‫جاح ِل َع ر َث ٍة‬
ِ ‫الن‬ ‫ال تقنطن ِمن‬

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