Is it safe to take Naltrexone (50mg daily) with Tylenol 3 (acetaminophen and codeine) and morphine?

Naltrexone and Opioid Co-Administration: Critical Safety Concern

Do not take naltrexone 50mg daily with Tylenol 3 (codeine) or morphine—naltrexone will block the analgesic effects of these opioids and may precipitate acute opioid withdrawal if you are opioid-dependent. 1

Mechanism of Contraindication

• Naltrexone is a mu-opioid receptor antagonist that directly blocks the therapeutic effects of opioid agonists like morphine and codeine 1, 2
• The antagonism occurs at the same receptor sites where morphine and codeine produce analgesia, rendering these pain medications ineffective 2, 3
• In opioid-dependent patients, naltrexone can precipitate acute withdrawal symptoms including agitation, muscle aches, sweating, nausea, and potentially severe cardiovascular effects 1, 4

Clinical Guidelines on This Combination

The American Gastroenterological Association explicitly states that naltrexone-containing medications should not be used in patients requiring short-term or long-term opiate therapy because naltrexone could reduce analgesic efficacy or precipitate withdrawal 1

• Naltrexone must be discontinued before any procedures requiring opioid analgesia (such as endoscopies using fentanyl) 1
• The National Comprehensive Cancer Network warns against using mixed agonist-antagonist combinations with pure opioid agonists, as this can precipitate withdrawal in opioid-dependent patients 5

Special Formulation Exception

• There exists a specific extended-release morphine/naltrexone combination product (EMBEDA) designed for chronic pain management where naltrexone is sequestered within the pellet core 2, 4
• When taken intact as directed, this formulation releases minimal naltrexone (therapeutic naltrexone concentrations remain undetectable in most patients), allowing morphine to provide analgesia 2, 4
• The sequestered naltrexone only becomes bioavailable if the capsule is crushed or tampered with, serving as an abuse-deterrent mechanism 2, 4
• This is fundamentally different from taking standard naltrexone 50mg daily tablets alongside separate opioid medications 2

What Happens If Combined

• Complete or near-complete blockade of opioid analgesia—your pain will not be controlled despite taking morphine or codeine 1, 2
• Risk of precipitated withdrawal if you have been taking opioids regularly and have developed physical dependence 1, 4
• Wasted medication costs and continued suffering from uncontrolled pain 1

Alternative Pain Management Strategies

If you require both opioid antagonist therapy (for alcohol use disorder or opioid use disorder maintenance) and pain control:

• Naltrexone must be discontinued at least 7-10 days before initiating opioid therapy to allow receptor availability 1
• Consider non-opioid analgesics: acetaminophen alone (without codeine), NSAIDs, gabapentinoids, or topical agents depending on pain etiology 1
• For severe pain requiring opioids, work with your prescriber to temporarily hold naltrexone therapy 1
• Regional anesthesia or interventional pain procedures may provide analgesia without systemic opioids 1

Critical Timing Considerations

• Naltrexone has a duration of action of 24-72 hours depending on dose 1
• After stopping naltrexone 50mg daily, wait at least 7-10 days before expecting full opioid analgesic response 1
• Do not attempt to "override" naltrexone blockade by taking higher opioid doses—this increases overdose risk without improving analgesia 1