Chapter 13  ·  Module 3

Adverse Effects, Tolerance, and Opioid Overdose

Organ system effects, tolerance patterns, overdose triad, and naloxone reversal

Adverse Effects by System

System Effect Mechanism Clinical Note
Central nervous system Sedation Mu activation in reticular activating system Partial tolerance develops; worst at initiation
Central nervous system Miosis Mu activation at Edinger-Westphal nucleus Tolerance does NOT develop; persists in chronic users
Central nervous system Euphoria Mu activation in nucleus accumbens Tolerance develops rapidly; drives dose escalation in opioid use disorder
Respiratory Respiratory depression Mu activation in pre-Botzinger complex Primary cause of death; blunts carbon dioxide drive
Gastrointestinal Constipation Peripheral mu activation in enteric neurons Tolerance does NOT develop; requires prophylactic bowel regimen
Gastrointestinal Nausea and vomiting Mu activation at area postrema Partial tolerance develops within days to weeks
Urinary Urinary retention Peripheral mu activation; urethral sphincter tone More common with neuraxial opioids; more common in men
Skin Pruritus Central mu activation at spinal cord Central mechanism, not histamine; antihistamines only partially effective

The Opioid Overdose Triad

Sign 1

Coma

  • Unresponsive to stimulation
  • Mu activation in reticular activating system
  • Low Glasgow Coma Scale score

Sign 2

Miosis

  • Pinpoint pupils (1–2 mm)
  • Edinger-Westphal nucleus activation
  • Present even in chronic users (no tolerance)
  • Absent miosis: consider co-ingestion

Sign 3

Respiratory Depression

  • Slow, shallow, or absent breathing
  • Pre-Botzinger complex suppression
  • Primary cause of death
  • Airway and ventilation: first priority

Naloxone: Reversal Agent

Pharmacology

Mechanism and Kinetics

  • Pure competitive mu, kappa, and delta antagonist
  • No intrinsic agonist activity
  • Onset (intravenous): 1–5 minutes
  • Duration: 30–90 minutes
  • Shorter acting than most opioids it reverses
  • Routes: intravenous, intramuscular, intranasal spray

Clinical Risks

Resedation and Withdrawal

  • Resedation: naloxone wears off while opioid still active
  • Highest risk: methadone, extended-release opioids, transdermal fentanyl
  • Repeat doses or infusion may be needed
  • In dependent patients: precipitates acute withdrawal
  • Goal: restore breathing, not full reversal

Tolerance: What Tolerizes and What Does Not

Tolerance develops to: analgesia, euphoria, sedation, respiratory depression, nausea.

Tolerance does NOT develop to: constipation, miosis. These persist throughout the course of chronic opioid therapy regardless of duration or dose.

Opioid-induced hyperalgesia: dose escalation worsens pain rather than improving it. Paradoxical improvement with dose reduction distinguishes it from tolerance.