Can naltrexone (Naltrexone) and morphine (Morphine) be used concomitantly?

Naltrexone and Morphine: Contraindicated for Concomitant Use

Naltrexone should NOT be used concomitantly with morphine or any other opioid medications. This is an absolute contraindication based on both mechanism of action and clinical safety concerns 1, 2.

Mechanism-Based Contraindication

• Naltrexone is a pure opioid antagonist that competitively blocks mu, kappa, and delta opioid receptors, thereby completely blocking or markedly attenuating the effects of morphine and other opioids 2
• When administered together, naltrexone renders morphine therapeutically ineffective for pain control, as it prevents morphine from binding to opioid receptors 2
• The blockade is competitive and potentially surmountable, but attempting to overcome naltrexone blockade with high-dose opioids can result in serious injury, coma, or death 2

Risk of Precipitated Withdrawal

• Administration of naltrexone to patients currently using opioids like morphine will precipitate acute and severe opioid withdrawal syndrome 3, 2
• Withdrawal symptoms include bone and muscle pain (15.9% incidence), nausea, vomiting, sweating, tachycardia, hypertension, tremulousness, seizures, pulmonary edema, cardiac arrhythmias, and in severe cases, cardiac arrest 3
• This precipitated withdrawal is more severe than spontaneous withdrawal from opioid discontinuation and may require hospitalization 2

Required Opioid-Free Period

• Patients must be completely opioid-free for a minimum of 7 to 10 days before starting oral naltrexone to avoid precipitation of withdrawal 2
• Patients transitioning from long-acting opioids like methadone or buprenorphine may require up to 2 weeks opioid-free before naltrexone initiation 2
• Patients should have no symptoms of opioid withdrawal before taking the first naltrexone dose 2

Clinical Guideline Recommendations

• The American Gastroenterological Association explicitly states that naltrexone-bupropion ER (which contains naltrexone) should not be used concomitantly with opiate medications 1
• This contraindication applies to all opioid-containing medications including analgesics (like morphine), antidiarrheal preparations, and antitussive medications 2
• Current opioid use is an absolute contraindication for naltrexone therapy 3

Emergency Opioid Administration

• In emergency situations requiring opioid analgesia in a patient taking naltrexone, the amount of opioid required may be substantially greater than usual 2
• The resulting respiratory depression may be deeper and more prolonged than expected 2
• For perioperative planning, oral naltrexone should be held for 3-4 days prior to elective procedures where opioids will be needed 1, 3
• Extended-release intramuscular naltrexone requires 24-30 days after the last injection before opioids can be safely administered 1, 3

Special Formulation Exception

• The only scenario where naltrexone and morphine are intentionally combined is in the specific FDA-approved formulation of morphine sulfate with sequestered naltrexone core (MS-sNT) 4, 5
• In this formulation, naltrexone remains sequestered within the pellet core and is not systemically absorbed when taken as directed 5, 6
• The naltrexone is only released if the formulation is tampered with (crushed or chewed), serving as an abuse-deterrent mechanism 4, 5
• This is NOT the same as prescribing separate naltrexone and morphine products together, which remains contraindicated 2

Clinical Pitfalls to Avoid

• Do not assume low-dose naltrexone (LDN) is safe with opioids—the opioid antagonism occurs at all naltrexone doses 7
• Always obtain a complete opioid use history before prescribing naltrexone, including over-the-counter products containing codeine 2
• Warn patients explicitly that they will not experience pain relief from opioid medications while taking naltrexone 2
• Ensure patients carry medical identification indicating naltrexone use in case of emergency requiring opioid analgesia 2