Gabapentin Enacarbil and Acetaminophen And Codeine: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Gabapentin Enacarbil
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.
Both of your medicines can slow down your brain and body. Codeine is an opioid pain reliever, and gabapentin enacarbil (Horizant) calms nerve activity. When taken together, they can add up and make you very sleepy or slow your breathing. In rare cases, breathing can become dangerously slow.
The warning signs to watch for are heavy drowsiness, confusion, or slow, shallow, or pauses in breathing. This does not mean you cannot use both, but your care team may start the gabapentin low and keep a closer eye on you. Please talk with your pharmacist or doctor so they can tailor your doses and check in on how you feel.
Effect: Additive CNS depression increasing the risk of sedation and respiratory depression when codeine (opioid) is combined with gabapentin enacarbil.
- Mechanism: Pharmacodynamic (additive CNS/respiratory depression); no CYP-based PK interaction. Codeine is a CYP2D6 prodrug, but that does not alter this PD interaction.
- Direction/magnitude: Enhanced CNS depression; serious, life-threatening, or fatal respiratory depression reported with gabapentinoid plus opioid.
- Onset: Unspecified. Evidence: Theoretical/labeled warning.
- Management: Monitor for sedation and respiratory depression, especially with underlying respiratory impairment; consider initiating gabapentin at a low dose. Treat with supportive measures and reduction/withdrawal of CNS depressants.
What happens
An increased risk of respiratory depression
Interaction Deep Dive
Concomitant use of gabapentin and other CNS depressants has resulted in serious, life-threatening, or fatal respiratory depression. If gabapentin is coadministered with another CNS depressant, especially with an opioid and in patients with underlying respiratory impairment, monitor for symptoms of respiratory depression and sedation, and consider initiating gabapentin at a low dose. Manage respiratory depression with close observation, supportive measures, and reduction or withdrawal of CNS depressants (including gabapentin)5.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. Because these two add together in the brain, your care team can manage this safely.
- Your team may start gabapentin enacarbil at a lower dose and adjust it individually.
- They may monitor you more closely for heavy sedation or slowed breathing, especially if you have any lung or breathing problems.
- Watch for excessive drowsiness, confusion, or slow or shallow breathing, and get help right away if these occur.
- Tell your pharmacist about any other sedating medicines, alcohol, or sleep aids you use.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) The FDA Adverse Event Reporting System (FAERS) database recorded 49 cases of respiratory depression associated with gabapentinoids between January 1, 2012 and October 26, 2017 (gabapentin n=15; pregabalin n=34). In 92% of these cases, a respiratory risk factor was reported, such as age-related decline in lung function or concurrent use of a CNS depressant. There were twelve deaths (24%), and each of these fatalities involved at least 1 respiratory risk factor. Small randomized trials in healthy volunteers have shown that gabapentinoids, both alone and combined with opioids, impair respiratory function. End-tidal CO(2) rose in an additive manner following exposure to pregabalin plus remifentanil, and apneic episodes per hour were more common during gabapentin exposure than with placebo. Observational data indicate a higher risk of postoperative respiratory depression when preoperative gabapentinoids are used versus no preoperative gabapentinoid exposure 1.
b) When 18 subjects received a single 600 mg dose of gabapentin enacarbil 2 hours after a single 60 mg dose of extended-release morphine sulfate, visual analog scale measurements showed greater somnolence or sedation, dizziness, and nausea compared with either drug given alone. There were no changes in the Cmax or AUC of gabapentin, morphine, or morphine's active metabolite 2.
c) In a study involving 12 volunteers, a single oral 60 mg dose of controlled-release morphine was given 2 hours before a single oral 600 mg dose of immediate-release gabapentin. In these participants, the mean gabapentin AUC was 44% higher than when gabapentin was administered alone. The pharmacokinetics of morphine remained unchanged 34.
Common questions
Can I take Gabapentin Enacarbil and Acetaminophen And Codeine together?
Taking codeine with gabapentin enacarbil can add up to cause heavy sedation and, rarely, dangerously slow breathing. Keep taking both as prescribed and ask your care team to monitor you and adjust doses if needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Gabapentin Enacarbil and Acetaminophen And Codeine 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 Gabapentin Enacarbil and Acetaminophen And Codeine interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. Because these two add together in the brain, your care team can manage this safely. Your team may start gabapentin enacarbil at a lower dose and adjust it individually. They may monitor you more closely for heavy sedation or slowed breathing, especially if you have any lung or breathing problems. Watch for excessi… 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 Gabapentin Enacarbil or Acetaminophen And Codeine 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 (5)
- US Food and Drug Administration (FDA): Drug Safety Communications: FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR) when used with CNS depressants or in patients with lung problems. US Food and Drug Administration (FDA). Silver Spring, MD. 2019.
- Product Information: HORIZANT(R) oral extended-release tablets, gabapentin enacarbil oral extended-release tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2013. DailyMed
- Product Information: Neurontin(R) oral capsules, tablets, solution, gabapentin oral capsules, tablets, solution. Parke-Davis, New York, NY, 2010. DailyMed
- Product Information: GRALISE(R) oral tablets, gabapentin oral tablets. Abbott Laboratories, North Chicago, IL, 2011. DailyMed
- Product Information: HORIZANT(R) oral extended-release tablets, gabapentin enacarbil oral extended-release tablets. Azurity Pharmaceuticals, Inc. (per FDA), Woburn, MA, 2025. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Gabapentin Enacarbil
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