Generic Name

Naltrexone

Mechanism

Naltrexone primarily acts as a potent, selective antagonist at:
• µ‑opioid (MOR) receptors → blocks analgesic, euphoria, and respiratory‑depressant effects of opioids.
• κ‑ and δ‑opioid receptors → limits aversive and dysphoric consequences.

By occupying these sites, naltrexone blocks endogenous opioid peptides (endorphins, enkephalins) and exogenous opioids, reducing craving and reinforcing effects of drug use.

In alcohol dependence, naltrexone decreases β‑endorphin–mediated dopaminergic release in the nucleus accumbens, thereby lowering alcohol craving and relapse risk.

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Pharmacokinetics

• Absorption: Oral absorption ~ 50 % (first‑pass hepatic metabolism).
• Half‑life: 4 – 7 h (oral); 13–15 h for intramuscular extended‑release (380 mg).
• Metabolism: Extensive hepatic glucuronidation → naltrexone‑glucuronide (inactive).
• Elimination: Renal excretion (~70 %), with the rest excreted in bile.
• Peak plasma: 1–2 h (oral); >1 week to steady state (extended‑release).
• Special populations: No dose adjustment for age, weight, or mild renal impairment. Hepatic impairment increases exposure; monitor for toxicity.

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Indications

• Opioid Use Disorder (OUD)
• Continuation therapy after detoxification.
• Prevention of relapse in patients who have abstained ≥7 days.
• Alcohol Use Disorder (AUD)
• Adjunct to behavioral therapy to reduce cravings, relapse, and heavy drinking.
• Adjunctive Use
• Reduction in opioid dosage for chronic pain when combined with opioid agonists (excluded from these guidelines).

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Contraindications

• Contraindications
• Presence of opioids/agonist drugs or ongoing opioid withdrawal.
• Severe hepatic failure or unexplained elevations of ALT/AST >3×ULN (unless carefully monitored).
• Intoxication with opioid analgesics or recent use of heroin (must be fully detoxified).
• Warnings
• Hepatotoxicity – frequent LFT monitoring during first 3 months.
• Withdrawal precipitating – abrupt introduction during opioid intoxication may cause severe withdrawal.
• Pregnancy: Category C – use only if benefits outweigh risks.
• Myasthenia gravis: can worsen respiratory function; avoid use.

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Dosing

• Oral initiation: Begin with 12.5 mg on Day 1 → 25 mg on Day 2 → 50 mg thereafter (flexible taper based on compliance).
• Extended‑release: Should be given in a healthcare setting; injection site (gluteal, deltoid) rotated.

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Adverse Effects

• Common (≥10 %)
• Nausea, vomiting, diarrhea
• Headache, dizziness, insomnia
• Fatigue, abdominal pain
• Post‑injection site pain, soreness
• Serious (≤1 %)
• Hepatotoxicity (ALT/AST ↑, jaundice) – assess early; discontinue if ALT >5×ULN.
• Acute liver failure – rare; consider liver transplantation if severe.
• Severe opioid withdrawal (if initiated during intoxication).
• Rare allergic reactions (rash, anaphylaxis).

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Monitoring

• Baseline: LFTs (ALT, AST, bilirubin), pregnancy test (women of childbearing potential).
• Frequency:
• Oral therapy – LFTs at 2 weeks, 4 weeks, 8 weeks; then every 3 months.
• Extended‑release – LFTs at 24 h, 1 week, 1 month post‑injection, then every 3 months.
• Clinical:
• Signs of withdrawal (autonomic instability, agitation).
• Adherence (pill counts, injection records).
• LFT trend graph to detect early hepatotoxicity.

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Clinical Pearls

• Detox first: Start only after patients are opioid‑free for ≥7 days to avoid precipitating withdrawal.
• Oral titration improves tolerance and adherence—slow stepwise increases prevent nausea.
• Extended‑release injection reduces diversion risk and improves compliance; ideal for patients with poor adherence to oral regimens.
• Alcohol therapy – max 100 mg/day if tolerated; higher doses yield diminishing returns and increase GI upset.
• Pregnancy challenges: Use when benefits clearly outweigh risks; counsel on birth‑control necessity.
• Hepatic monitoring: A rapid rise in transaminases within 1–2 weeks frequently predicts hepatotoxicity; early discontinuation often reverses injury.

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• *References: UpToDate, American Academy of Addiction Medicine, Goodman & Gilman's Pharmacologic Basis of Therapeutics.*