Tramadol and Esketamine Nasal Spray: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Tramadol
Esketamine Nasal Spray
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.
What happens
Increased traMADol exposure, an increased risk of CNS depression and an increased risk of seizures, serotonin syndrome and opioid toxicity
Interaction Deep Dive
Concomitant use of traMADol and a CYP3A4 inhibitor that are also CNS depressants may increase traMADol exposure, and may result in greater levels of M1, the active metabolite of traMADol and may also increase the risk of respiratory depression, profound sedation, coma, and death. Evaluate patients closely for seizures, serotonin syndrome and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of traMADol is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the traMADol exposures will decrease, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to traMADol. If use of a CYP3A4 inhibitor is necessary in a patient receiving traMADol, consider reducing the dose of traMADol. When discontinuing a CYP3A4 inhibitor in a patient receiving traMADol therapy, consider an increase in the traMADol dose and monitor patients at frequent intervals for signs of opioid withdrawal. Reserve concomitant use to patients for whom alternatives are inadequate. If concomitant use is necessary, use the lowest dose and shortest duration necessary to achieve treatment goals. Consider using a lower dose of traMADol or the CNS depressant and titrate the dose based on clinical response. Closely monitor the patients for signs and symptoms of sedation and respiratory depression1.
Why it happens (mechanism)
Inhibition of CYP3A4-mediated metabolism of traMADol; additive CNS depression
Literature reports
3 reports — tap to read
a) Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics 1.
b) Between 2004 and 2011, there was an increase in nonmedical use-related emergency department visits involving opioid analgesics and benzodiazepines (from 11 to 34.2 per 100,000 population). During this timeframe, drug over dose deaths from taking the prescribed or greater than prescribed doses of both opioid analgesics and benzodiazepines also increased (from 0.6 to 1.7 per 100,000). The proportion of prescription opioid analgesic overdose deaths that were associated with benzodiazepine use also increased from 18% to 31% 2.
c) The rate of overdose death among patients co-dispensed benzodiazepines and opioid analgesics were 10 times higher than patients dispensed opioid analgesics alone (7 per 10,000 person years vs 0.7 per 10,000 person years). Patients taking opioid analgesics who had a history of benzodiazepine prescriptions had an increased risk of fatal overdose compared with patients taking opioid analgesics with no history of benzodiazepine prescription. A similar risk of fatal overdose was observed in patients with a current benzodiazepine prescription. The risk of drug overdose death increased as the daily benzodiazepine dose also increased 2.
Common questions
Can I take Tramadol and Esketamine Nasal Spray together?
Increased traMADol exposure, an increased risk of CNS depression and an increased risk of seizures, serotonin syndrome and opioid toxicity Always confirm with your pharmacist or prescriber before making any change.
How serious is the Tramadol and Esketamine Nasal Spray 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 strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Tramadol or Esketamine Nasal Spray 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: Tramadol hydrochloride oral tablets, tramadol hydrochloride oral tablets. Strides Pharma, Inc (per DailyMed), East Brunswick, NJ, 2025. DailyMed
- US Food and Drug Administration (FDA): Drug Safety Communications: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. US Food and Drug Administration (FDA). Silver Spring, MD. 2016.
Keep reading about Tramadol
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