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Opioid Analgesics: Classification, Morphine Pharmacology & Poisoning

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I. Classification of Opioid Analgesics

A. Based on Source / Origin

B. Based on Receptor Activity (Efficacy)

C. Based on Chemical Structure

D. Based on Duration of Action

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II. Morphine - Detailed Pharmacology

Mechanism of Action (MoA)

• Inhibition of adenylyl cyclase → reduced cAMP
• Opening of K⁺ channels → membrane hyperpolarization
• Closure of voltage-gated Ca²⁺ channels → reduced neurotransmitter release
• Net result: decreased neuronal excitability and inhibition of nociceptive signal transmission at spinal and supraspinal levels

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Pharmacokinetics (ADME)

• Absorbed from GI tract, all parenteral routes, and rectal mucosa
• Oral bioavailability is only ~25% due to significant first-pass glucuronidation in the liver
• Crosses the blood-brain barrier at a considerably lower rate than more lipid-soluble opioids (e.g., heroin, fentanyl, methadone)
• Can be administered epidurally or intrathecally for direct spinal analgesia

• ~1/3 of plasma morphine is protein-bound after a therapeutic dose
• Does not persist in tissues; tissue concentrations low 24 h after last dose

• Primarily conjugated with glucuronic acid in the liver:
  • Morphine-6-glucuronide (M6G) - pharmacologically active; approximately twice as potent as morphine; contributes significantly to analgesia
  • Morphine-3-glucuronide (M3G) - major excretory metabolite; minimal analgesic activity
  • Small amounts of morphine-3,6-diglucuronide
• Minor pathway: N-demethylation to normorphine

• 90% excreted in the first 24 h, primarily as M3G via glomerular filtration
• Enterohepatic circulation accounts for small amounts in feces/urine for several days
• Very little morphine is excreted unchanged

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Pharmacological Actions

1. Central Nervous System (CNS)

• Analgesia: Raises pain threshold and alters the subjective reaction to pain; effective for dull, constant, visceral pain more than sharp, intermittent pain
• Euphoria/Dysphoria: At therapeutic doses produces sense of well-being; dysphoria may occur in the absence of pain
• Sedation: Drowsiness, mental clouding, inability to concentrate; does not produce true anaesthesia at standard doses
• Respiratory Depression: Decreases sensitivity of respiratory centre in medulla to CO₂ - this is the primary cause of death in overdose. Effect is dose-dependent
• Suppression of Cough Reflex (Antitussive): Depresses cough centre in medulla
• Nausea and Vomiting: Stimulates the chemoreceptor trigger zone (CTZ) in the area postrema
• Miosis (Pinpoint Pupils): Stimulation of the Edinger-Westphal nucleus of the oculomotor nerve; characteristic even in overdose. Tolerance to miosis does NOT develop
• Truncal Rigidity: High doses can produce "wooden chest" syndrome

2. Cardiovascular System

• Causes peripheral vasodilation (arteriolar and venous), partly due to histamine release → orthostatic hypotension
• At therapeutic doses, minimal effect on heart rate and cardiac output in supine patients
• IV morphine causes bradycardia (vagal stimulation)
• Useful in acute left ventricular failure and pulmonary edema - reduces preload and anxiety

3. Gastrointestinal System

• Decreases GI motility (both circular and longitudinal muscle tone) → constipation; one of the most persistent effects with no tolerance development
• Increases tone of smooth muscle sphincters (pyloric, ileocecal, anal)
• Increases biliary duct pressure and biliary colic (spasm of sphincter of Oddi)
• Antiemetic effect at the vomiting centre (but stimulates CTZ)
• Decreases gastric acid secretion and pancreatic/biliary secretions

4. Genitourinary System

• Increases tone of urinary bladder trigone and sphincter → urinary retention
• Reduces uterine tone → may prolong labor

5. Neuroendocrine

• Inhibits release of GnRH, CRH → decreased LH, FSH, ACTH, cortisol
• Stimulates prolactin and ADH (antidiuretic hormone) release
• Inhibits TSH release

6. Skin

• Histamine release → pruritus (especially on face and trunk), flushing, sweating

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Therapeutic Uses

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Adverse Effects

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Contraindications

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Drug Interactions

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III. Note on Morphine Poisoning and Its Management

Causes

• Clinical overdosage - excessive therapeutic dose
• Accidental overdose - especially in children or in patients with altered pharmacokinetics (renal/hepatic failure)
• Suicidal intent - morphine is considered an "ideal suicidal poison" due to its painless mode of death
• Delayed absorption - injection into poorly perfused (cold/shocked) skin, with sudden absorption when circulation is restored
• Drug abuse / Recreational overdose

Fatal Dose

Clinical Features

Coma + Pinpoint (miotic) pupils + Respiratory depression

• Euphoria, elated mood, talkativeness
• Flushed face, restlessness
• Hallucinations, manic signs, seizures (especially in children and neonates)
• Nausea, vomiting

• Giddiness, drowsiness, headache
• Nausea, vomiting, pruritus (histamine release)
• Pinpoint pupils (pathognomonic), conjunctival congestion
• Cyanosis of lips and face
• Pulse and BP relatively normal at this stage

• Unresponsiveness, deep coma
• Depressed or absent respiration, cyanosis
• Pinpoint pupils persist
• Falling BP, feeble pulse
• Cold, clammy skin
• Flaccid skeletal muscles, relaxed jaw, tongue may occlude airway
• Terminal: gradual hypotension, facial flush
• Death from respiratory failure (nearly always)

Differential Diagnosis

1. Alcoholic intoxication (smell of alcohol, lab support)
2. Barbiturate poisoning (lab support)
3. Carbolic acid/phenol poisoning (characteristic smell, urine analysis)
4. Intracranial hemorrhage
5. Cerebral malaria (Falciparum)
6. Carbon monoxide poisoning (spectroscopic blood examination)
7. Diabetic coma, epilepsy, uremia, hysteria, meningitis, heat stroke

Laboratory Diagnosis

• Marquis test: Suspect sample + Marquis reagent (5 mL of 40% formaldehyde in 100 mL sulfuric acid) → fine purple-red color → violet → blue (positive for morphine/opiates)
• Urine/blood toxicology screen
• Serum morphine levels

Autopsy Findings (Postmortem)

1. Deep cyanosis of nails, lips, palms, and soles
2. Intense congestion of all internal organs
3. Froth at the mouth and nostrils

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Management of Morphine Poisoning

A. Immediate Priorities - ABC

1. Establish patent airway - the very first step
2. Assisted ventilation - bag-mask ventilation or mechanical ventilator if apneic
3. Positioning - lateral decubitus to prevent aspiration

B. Gastric Decontamination

1. Gastric lavage with potassium permanganate solution (KMnO₄) - 250-300 mL should be left in the stomach after lavage to prevent enterohepatic reabsorption (due to enterohepatic circulation of morphine)
2. Activated charcoal - adsorbs remaining drug; repeat doses (twice daily) to interrupt enterohepatic circulation
3. Saline cathartic (to hasten GI transit)

C. Specific Antidote

1. Naloxone (Narcan) - the definitive antidote
   • Pure opioid receptor antagonist (competitive, at μ, κ, δ)
   • Rapidly reverses respiratory depression, coma, and analgesia within 2 minutes of IV administration
   • Dose: 0.4-2 mg IV (adult); 0.1 mg/kg IV (child) - can also be given IM, SC, or intranasal (4 mg nasal spray - Narcan®)
   • Repeat every 2-3 min if no response, especially for potent opioids (fentanyl derivatives may need much higher doses)
   • Caution: Naloxone has a shorter half-life (~1 hour) than many opioids - patient may relapse into coma; monitor closely and repeat or use infusion
   • In dependent patients, naloxone precipitates acute withdrawal syndrome
   • Total dose should not exceed 75 mg in adults
2. Naltrexone - 50 mg orally, repeated as required (longer-acting oral antagonist; mainly used for dependence management)
3. Physostigmine - 0.04 mg/kg IV (limited role; sometimes used adjunctively)

D. Supportive Measures

1. IV fluids for hypotension
2. Vasopressors if hypotension is refractory
3. Forced diuresis - especially in cases complicated by rhabdomyolysis (seen with severe prolonged hypoxia)
4. Anticonvulsants - for seizures (especially in children)
5. Monitoring - continuous pulse oximetry, respiratory rate, BP, pupils
6. Hemodialysis - not useful for morphine itself, but may be needed for metabolic complications

Management of Chronic Opioid Dependence (Brief)

• Methadone maintenance - cross-tolerant opioid substitution, long-acting
• Buprenorphine/naloxone (Suboxone) - sublingual partial agonist + antagonist combination
• Naltrexone (extended-release IM) - opioid antagonist; blocks euphoric effects for 30 days
• Counseling, behavioral therapy, social support

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• Goodman & Gilman's The Pharmacological Basis of Therapeutics, pp. 474-543
• Lippincott Illustrated Reviews: Pharmacology, p. 728-729
• Essentials of Forensic Medicine and Toxicology, 36th Edition, pp. 550-552
• Katzung's Basic and Clinical Pharmacology, 16th Edition