Pregabalin 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
Pregabalin
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.
These two medicines can add up in a way that slows your breathing. Your pain medicine contains codeine, an opioid that can make you drowsy and slow your breathing. Pregabalin (Lyrica) is a nerve medicine that also calms the brain and can add to that sleepiness. Taken together, they can make you very drowsy and, in serious cases, cause dangerously slow or shallow breathing.
This warning is based on how these drugs work rather than on strong studies with this exact pair, but it is taken seriously. The good news is your care team can manage this by starting low, watching how you respond, and adjusting your doses. Call them right away if you feel very sleepy, confused, or short of breath.
Effect: Additive CNS and respiratory depression when codeine (an opioid; also an active mu-agonist independent of CYP2D6 conversion to morphine) is combined with pregabalin.
- Mechanism: Additive CNS depression (PD interaction), not PK-based. Not a prodrug-related concern.
- Direction/magnitude: Increased sedation and risk of serious, life-threatening, or fatal respiratory depression; magnitude not quantified.
- Onset: Unspecified.
- Evidence: Theoretical, but rated major.
- Management: Monitor for sedation and respiratory depression, particularly with underlying respiratory impairment; consider initiating pregabalin at a low dose. Manage depression with observation, supportive measures, and reducing/withdrawing CNS depressants.
What happens
An increased risk of respiratory depression
Interaction Deep Dive
Serious respiratory depression that may be life-threatening or fatal has occurred when pregabalin is taken together with other CNS depressants. When pregabalin is given alongside another CNS depressant, particularly an opioid, and in patients who already have compromised respiratory function, watch for signs of sedation and respiratory depression, and consider starting pregabalin at a low dose. To manage respiratory depression, use close observation, supportive measures, and reduction or discontinuation of CNS depressants (pregabalin included)5.
Why it happens (mechanism)
Additive CNS depression
How to manage this interaction
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is used when the benefit outweighs the risk, and your team has ways to keep it safe.
- Your team may start pregabalin at a low dose and adjust it, individualized to you.
- They may monitor you more closely for excessive sleepiness or slowed breathing, especially if you have any lung or breathing problems.
- Avoid adding alcohol or other sedating medicines without checking first.
- Get help right away for very slow or shallow breathing, extreme drowsiness, confusion, or trouble waking.
Raise any concerns with your pharmacist or prescriber before changing anything.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) Data from the FDA Adverse Event Reporting System (FAERS) database show that from January 1, 2012 through October 26, 2017, there were 49 cases of respiratory depression linked to gabapentinoids (gabapentin n=15; pregabalin n=34). At least one respiratory risk factor, such as age-related decline in lung function or concurrent use of a CNS depressant, was noted in 92% of these cases. Twelve deaths were recorded (24%), and each of these deaths involved at least one reported respiratory risk factor. Small randomized studies in healthy volunteers have shown that gabapentinoids, both by themselves and combined with opioids, suppress respiratory function. End-tidal CO2 rose in an additive manner when pregabalin was given with remifentanil, and hourly apneic events occurred more often with gabapentin than with placebo. Observational research indicates a higher risk of postoperative respiratory depression among patients receiving preoperative gabapentinoids versus those with no preoperative gabapentinoid exposure 1.
b) When a single 600 mg dose of gabapentin enacarbil (another gabapentinoid) was given 2 hours after a single 60 mg dose of morphine sulfate extended-release in 18 subjects, visual analog scale assessments 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 (another gabapentinoid). In these patients, the mean gabapentin AUC was 44% higher than when gabapentin was administered on its own. The pharmacokinetics of morphine were unchanged 34.
Common questions
Can I take Pregabalin and Acetaminophen And Codeine together?
Codeine and pregabalin both depress the central nervous system, so together they raise the risk of heavy sedation and dangerously slow breathing; take them as prescribed and contact your care team about any extreme drowsiness or breathing trouble. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Pregabalin 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 Pregabalin and Acetaminophen And Codeine interaction managed?
Keep taking both exactly as prescribed unless your care team tells you otherwise. This combination is used when the benefit outweighs the risk, and your team has ways to keep it safe. Your team may start pregabalin at a low dose and adjust it, individualized to you. They may monitor you more closely for excessive sleepiness or slowed breathing, especially if you have any lung or breathing problems… 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 Pregabalin 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: Pregabalin oral capsule, pregabalin oral capsule. Alembic Pharmaceuticals, Inc (per Dailymed), Bedminster, NJ, 2025. DailyMed
Keep reading about Acetaminophen And Codeine
Keep reading about Pregabalin
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