Opioids and Analgesics

Opioid Analgesics and Antagonists

• Opioid analgesics are "opium-like analgesics" derived from the opium poppy plant (Papaver somniferum)
• Opioid receptors include μ (Mu), κ (Kappa), and δ (Delta) receptors

Opioid Receptors

• μ (Mu) receptor: analgesia (supraspinal level), euphoria, sedation, physical dependence, miosis
• μ2 receptor: analgesia (spinal level), respiratory depression, inhibition of GI motility
• κ (Kappa) receptor: analgesia (spinal level), dysphoria, psychotomimetic effect, sedation, inhibition of GI motility
• δ (Delta) receptor: analgesia (spinal and affective component of supraspinal), respiratory depression, reinforcing action, inhibition of GI motility, proconvulsant action

Classification of Opioids

• Agonists at μ receptors: Morphine, codeine, pethidine, oxycodone, dextropropoxyphene
• Agonists at κ receptors: Fentanyl
• Agonists at δ receptors: Methadone, tramadol
• Mixed Agonist-Antagonists and Partial Agonists: Pentazocine (antagonist at μ receptor, agonist at κ and δ receptors), Buprenorphine (partial agonist at μ receptor, antagonist at κ and δ receptors)

Opioid Antagonists

• Pure antagonists at μ, κ, and δ receptors: Naloxone, Naltrexone, Nalmefene

Mechanism of Action of Opioids

• Opioid agonists bind to opioid receptors (G-protein coupled receptors) and produce the following actions:
  • Inhibit adenylate cyclase → decrease in cell excitability (through μ & δ receptors)
  • Activate potassium channels → hyperpolarization of neurons → decrease in neuronal excitability (through μ & δ receptors)
  • Suppress N-type voltage-gated calcium channels → reduced intracellular Ca2+ → decreased release of neurotransmitters from presynaptic neurons (through κ receptors)

Pharmacological Actions of Morphine

• Central Effects:
  • Stimulant Effects: Analgesia, euphoria, dysphoria, sedation, respiratory depression, vasomotor center depression, cough suppression, miosis, nausea and vomiting, convulsions
  • Depressant Effects: Cardiovascular system, gastrointestinal tract, biliary tract, urinary bladder, and bronchi
• Peripheral Effects:
  • Cardiovascular System: Postural hypotension, bradycardia, and depression of the vasomotor center in the medulla
  • Gastrointestinal Tract: Increased sphincter tone, decreased GI motility, and constipation
  • Biliary Tract: Contraction of biliary tract smooth muscle, biliary spasm, and increased intrabiliary pressure
  • Urinary Bladder: Constriction of the urinary sphincter, difficulty in urination, and contraction of the detrusor muscle
  • Bronchi: Bronchospasm due to the release of histamine from mast cells

Tolerance and Dependence

• Tolerance: Reduction in effect with repeated dosing (or higher dose is required to produce the same effect)
• Dependence:
  • Psychological Dependence: Emotional cravings for the drug due to euphoria and pain relief
  • Physical Dependence: Continued presence of the drug is needed to maintain physiological equilibrium

Management of Opioid Dependence

• Methadone: Long-acting agonist at μ receptors, used to substitute for opioids to spare withdrawal symptoms
• Management involves withdrawal of opioids and substitution with methadone, followed by tapering of methadone doses over weeks