Acetaminophen And Codeine and Elagolix: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jun 30, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Elagolix
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Here's what's going on. Codeine is a "prodrug," meaning your body has to convert it into morphine to actually relieve pain. Elagolix (Orilissa) can speed up one of the liver enzymes that processes codeine, which can leave you with less of the active pain-relieving morphine. So your codeine may not work as well, and if your body is used to the opioid, you could feel early withdrawal signs like restlessness, sweating, a runny nose, or achiness.
The good news: this is a theoretical concern, not something proven to happen in everyone. Your care team can manage it by watching how well your pain is controlled and adjusting your dose if needed. Let them know if your pain medicine stops working or you feel withdrawal.
Mechanism: Elagolix is a CYP3A4 inducer. Codeine is a prodrug requiring CYP2D6 activation to morphine. Increased CYP3A4 activity shunts codeine toward norcodeine, reducing substrate available for CYP2D6-mediated conversion, lowering active morphine exposure.
Direction/effect: Reduced codeine and morphine AUC/Cmax, decreased analgesic efficacy, and possible precipitation of withdrawal in opioid-dependent patients.
- Evidence: theoretical; magnitude not quantified.
- Onset: unspecified.
- Management: Monitor for reduced analgesia and withdrawal signs; codeine dose may be increased and individualized as needed. If elagolix is later discontinued, anticipate rising opioid effect and consider dose reduction, monitoring for sedation/respiratory depression.
What happens
Reduced codeine and morphine exposure, reduced opioid efficacy and precipitation of opioid withdrawal
Interaction Deep Dive
Concomitant use of codeine with CYP3A4 inducers may result in reduced codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If concomitant use is needed, closely monitor patients for decreased efficacy or signs of opioid withdrawal syndrome, and consider increasing the dose of codeine as necessary. If a CYP3A4 inducer is being discontinued, consider codeine dose reduction and closely monitor patients for signs of respiratory depression or sedation12.
Why it happens (mechanism)
Induction of CYP3A4-mediated codeine metabolism
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team.
- Watch for signs your pain relief is weaker than usual, or early opioid withdrawal (restlessness, sweating, runny nose, muscle aches, stomach upset).
- Report these to your pharmacist or prescriber. Your codeine dose may need to be adjusted and individualized by your care team.
- Important: if elagolix (Orilissa) is ever stopped, tell your team, because your codeine effect may increase again and the dose may need lowering.
- Do not change either dose on your own.
Management is individual — confirm any change with your pharmacist or prescriber.
Common questions
Can I take Acetaminophen And Codeine and Elagolix together?
Elagolix may make codeine work less well and could trigger opioid withdrawal, so tell your care team if your pain relief drops or you feel withdrawal, and let them know if elagolix is ever stopped. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Elagolix interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Acetaminophen And Codeine and Elagolix interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team. Watch for signs your pain relief is weaker than usual, or early opioid withdrawal (restlessness, sweating, runny nose, muscle aches, stomach upset). Report these to your pharmacist or prescriber. Your codeine dose may need to be adjusted and indivi… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Elagolix need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (2)
- Product Information: Codeine sulfate oral solution, codeine sulfate oral solution. Hikma Pharmaceuticals USA Inc(per FDA), Berkeley Heights, NJ, 2023. DailyMed
- Product Information: Codeine sulfate oral tablets, codeine sulfate oral tablets. Hikma Pharmaceuticals USA Inc. (per FDA), Berkeley Heights, NJ, 2023. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Elagolix
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist