Opioid Intoxication, Withdrawal, and Use Disorder

1. Opioid Intoxication (Overdose)

• Opioid overdose is the most common cause of drug overdose death.
• Pathophysiology
  • Agonism of mu ($\mu$) receptors in CNS $\to$ modulation of synaptic transmission (closing voltage-gated Ca${}^{2+}$ channels presynaptically, opening K${}^{+}$ channels postsynaptically).
• Clinical Features
  • Classic Triad:
    1. Respiratory Depression (RR < 12/min is the best predictor of toxicity).
    2. CNS Depression (lethargy, coma).
    3. Miosis (Pinpoint pupils).
  • Other findings: $\downarrow$ bowel sounds, hypotension, bradycardia, hypothermia, hyporeflexia.
  • Key Exception: Meperidine causes mydriasis (dilated pupils) due to anticholinergic effects and carries a risk of Serotonin Syndrome + Seizures.

Warning

The absence of miosis does not rule out opioid overdose as hypoxia, co-ingested drugs (e.g., cocaine, amphetamines), and/or medications (e.g., atropine) may cause mydriasis, thereby counteracting the miotic effect of opioids.

• Treatment
  • Airway protection (ABCs) is priority #1.
  • Naloxone (Opioid antagonist): IV, IM, or Intranasal.
    • Short half-life; may require redosing to prevent re-sedation.

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2. Opioid Withdrawal

• Pathophysiology
  • Cessation of mu-agonism $\to$ Noradrenergic hyperactivity (Locus ceruleus).
• Clinical Features
  • Timeline: Starts 6–12 hrs after last dose (short-acting) or 24–48 hrs (long-acting).
  • GI: Diarrhea, nausea, vomiting, abdominal cramping.
  • Autonomic/CNS: Dilated pupils (mydriasis), piloerection (“cold turkey”), diaphoresis, tachycardia, hypertension.
  • Specific Signs: Yawning, lacrimation, rhinorrhea.
  • Note: Withdrawal is not life-threatening in adults (unlike alcohol/benzo withdrawal), but is extremely uncomfortable.

Mnemonic

Opioid yawning

• Neonatal Abstinence Syndrome (NAS)
  • Neonate born to opioid-dependent mother.
  • Sx: High-pitched cry, tremors, seizures, sneezing, poor feeding, diarrhea.
  • Tx: Swaddling/calm environment; if severe, Morphine or Methadone.
• Management
  • Symptomatic: Clonidine/Lofexidine (${\alpha }_2$-agonists to blunt sympathetic surge), Loperamide (diarrhea), NSAIDs.
  • Substitution: Buprenorphine or Methadone taper.

Mnemonic

• Methadone? The recovering heroin addict I met had one .
• Buprenorphine boops the morphine

Warning

Naloxone is for opioids overdose. Giving naloxone for acute opioid withdrawal or neonatal abstinence syndrome will result in more severe withdrawal symptoms and is contraindicated.

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3. Opioid Use Disorder (OUD) Management

Long-term Pharmacotherapy (Medication-Assisted Treatment) is standard of care to reduce cravings and relapse risk.

• Methadone
  • Mechanism: Long-acting full mu-agonist.
  • Pros: Good for patients with high tolerance; suppresses cravings well.
  • Cons: Very long half-life (risk of accumulation/OD); QT prolongation; requires daily visits to a registered clinic (stigma/inconvenience).
• Buprenorphine
  • Mechanism: Partial mu-agonist.
  • Pros: Ceiling effect (lower risk of respiratory depression); can be prescribed in office setting.
  • Cons: Can precipitate withdrawal if given too soon (must wait for mild withdrawal symptoms before induction).
  • Note: Often combined with Naloxone (Suboxone) to prevent IV abuse (Naloxone is not active orally/sublingually, but blocks effect if crushed and injected).
• Naltrexone
  • Mechanism: Long-acting opioid antagonist (IM injection Vivitrol).
  • Pros: Blocks euphoric effects if patient relapses; no physical dependence.
  • Cons: Patient must be fully detoxified (7–10 days opioid-free) before starting, or it will cause severe precipitated withdrawal.

High-Yield Pharmacology Buzzwords

• Loperamide: Antidiarrheal; mu-agonist that does not cross the Blood-Brain Barrier (low abuse potential).
• Dextromethorphan: Antitussive; NMDA antagonist at high doses (abuse potential). can cause Serotonin Syndrome.
• Tramadol: Weak mu-agonist + inhibits 5-HT/NE reuptake. Risk of Seizures and Serotonin Syndrome.
• Codeine: Prodrug metabolized to morphine by CYP2D6. Ultra-rapid metabolizers (genetics) risk toxicity.