How long must a patient be opioid‑free before starting low‑dose naltrexone (LDN)?

Opioid-Free Period Required Before Starting Low-Dose Naltrexone

Patients must be completely opioid-free for a minimum of 7–10 days for short-acting opioids before starting any dose of naltrexone, including low-dose naltrexone (LDN), to avoid precipitating severe and potentially life-threatening opioid withdrawal. 1, 2, 3

Required Opioid-Free Duration by Opioid Type

The mandatory abstinence period depends on the specific opioid used:

• Short-acting opioids (e.g., oxycodone, hydrocodone, heroin): Minimum 7–10 days opioid-free 1, 2, 3
• Buprenorphine: Up to 14 days may be required, as patients transitioning from buprenorphine are vulnerable to precipitated withdrawal for as long as two weeks 2
• Methadone: Patients may be vulnerable to precipitated withdrawal for as long as two weeks after discontinuation 2
• Long-acting opioids: 36–48 hours minimum before buprenorphine induction (which itself requires completion before naltrexone) 4

Why This Timeline Is Critical

Naltrexone is a competitive opioid receptor antagonist that will immediately displace any remaining opioids from receptors, precipitating acute withdrawal severe enough to require hospitalization. 1, 2 This occurs because:

• Naltrexone has a plasma half-life of 4 hours, but its active metabolite (6-β-naltrexol) has a 13-hour half-life 1, 5
• The antagonist effects persist for 2–3 days after a single dose 1, 5
• Even trace amounts of opioids remaining in the system will be forcibly displaced from receptors 1

Verification of Adequate Opioid-Free Period

Before initiating naltrexone (including LDN), clinicians must verify complete opioid abstinence using:

• Urine drug screening to confirm absence of opioids 3
• Naloxone challenge test: Administer naloxone and observe for 30 minutes; if no withdrawal symptoms occur, naltrexone can be safely started 4, 3
• Clinical assessment using a validated opioid withdrawal scale to ensure the patient is experiencing at least mild spontaneous withdrawal symptoms (not precipitated withdrawal) 4

Special Considerations for Low-Dose Naltrexone

The same 7–10 day opioid-free requirement applies to low-dose naltrexone (1–5 mg daily) as to standard-dose naltrexone (50 mg daily). 6, 7 This is because:

• Even low doses of naltrexone (25 mg) can precipitate withdrawal if opioids are present 2, 7
• The mechanism of competitive receptor antagonism operates regardless of naltrexone dose 1
• Studies using LDN for non-suicidal self-injury employed doses of 25–50 mg/day, still requiring complete opioid abstinence 7

Induction Protocol After Adequate Opioid-Free Period

Once the 7–10 day (or longer) opioid-free period is confirmed:

1. Start with half-dose on Day 1: Administer 25 mg naltrexone on the first day to assess tolerance 3
2. Advance to full dose on Day 2: If 25 mg is tolerated, increase to 50 mg daily (or prescribed LDN dose) 3
3. Monitor closely: Patients should be observed for withdrawal symptoms, depression, and hepatotoxicity 1, 6, 2

Common Pitfalls to Avoid

• Do not shorten the opioid-free period based on patient self-report alone; always verify with objective testing 2, 3
• Do not assume buprenorphine users can start naltrexone after 7 days; they may require up to 14 days opioid-free 2
• Do not prescribe naltrexone to patients who "might" still be using opioids; precipitated withdrawal is a medical emergency 1, 2
• Do not use the same timeline for switching from methadone to buprenorphine (which requires 36–48 hours) as for starting naltrexone (which requires 7–10 days minimum) 4

Alternative Rapid Induction Approaches

Recent research has explored abbreviated detoxification protocols combining clonidine and naltrexone to shorten the drug-free phase 3, and outpatient protocols using low-dose oral naltrexone with brief buprenorphine tapers 8. However, these specialized protocols still require medical supervision and do not eliminate the fundamental requirement for opioid abstinence before full-dose naltrexone administration 8.

The 7–10 day minimum opioid-free period is not negotiable for safe naltrexone initiation, regardless of whether standard or low-dose naltrexone is prescribed. 1, 2, 3