Naltrexone: Mechanism of Action and Clinical Applications
Naltrexone is a pure opioid receptor antagonist that blocks the euphoric effects of opioids by competitively binding to opioid receptors, preventing opioids from activating these receptors. 1
Mechanism of Action
- Acts as a competitive antagonist primarily at mu opioid receptors, but also affects kappa and delta opioid receptors 1
- Blocks the subjective and reinforcing effects of opioids for 24-72 hours depending on dosage 1
- Has no abuse potential and does not cause dependence 1
- For alcohol dependence, the mechanism is not fully understood but likely involves blocking the effects of endogenous opioids that contribute to alcohol's rewarding effects 1
Pharmacokinetics
- Well absorbed orally but undergoes significant first-pass metabolism with bioavailability of 5-40% 1
- Peak plasma levels occur within one hour of dosing 1
- Mean elimination half-life is 4 hours for naltrexone and 13 hours for its active metabolite 6-β-naltrexol 1
- Primarily excreted by the kidneys (53-79% of dose) 1
Clinical Applications
Opioid Use Disorder
- Blocks the euphoric effects of opioids for 24-72 hours depending on dosage 1
- Available in oral form (50 mg daily) or as long-acting injectable/implant formulations providing naltrexone release for at least 1 month 2
- Most effective in highly motivated patients with stable social support 3
- Patients must be completely opioid-free before starting (7-10 days for short-acting opioids) to prevent precipitated withdrawal 3
Alcohol Use Disorder
- Reduces alcohol consumption and craving 1
- Standard dosage is 50 mg once daily 1
- Clinical trials showed higher abstention rates (51% vs 23%) and lower relapse rates (31% vs 60%) compared to placebo 1
- Alternative dosing regimens include 100 mg Monday/Wednesday and 150 mg Friday 3
Formulations
- Oral tablets: 50 mg daily dosing 1
- Extended-release injectable: 380 mg monthly 3
- Implant formulations: Providing release for up to 7 months (many lack regulatory approval) 2
Precautions and Contraindications
- Contraindicated in patients with current opioid use or dependence due to risk of precipitated withdrawal 3
- Contraindicated in acute hepatitis or liver failure 3
- Not recommended for patients requiring opioid pain management 3
- Liver function tests should be monitored at baseline and every 3-6 months 3
Side Effects
- Generally mild and transient 2
- Most common: nausea, constipation, headache, dizziness, insomnia, and dry mouth 4
- Gastrointestinal effects are most commonly reported 5
Effectiveness Considerations
- Limited compliance with oral naltrexone is a known drawback 2
- Most effective when combined with psychosocial support, behavioral therapies, and counseling 3
- Depot formulations significantly improve medication compliance in both opioid and alcohol dependence 2
- Not uniformly helpful to all patients; expected effect is a modest improvement in conventional treatment outcomes 1
Important Clinical Considerations
- For opioid use disorder, naltrexone is most effective when administered under conditions that enforce compliance 1
- For alcohol use disorder, naltrexone reduces craving and is particularly effective in patients with high craving levels 6
- Genetic factors (mu opioid receptor gene variations) may predict treatment response 6
- Must hold oral naltrexone for 2-3 days prior to elective surgical procedures if opioids are expected to be used perioperatively 4
Naltrexone represents a valuable pharmacological option for treating both opioid and alcohol use disorders, particularly when integrated into a comprehensive treatment program that includes behavioral support.