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7 Interactions found for:

Cymbalta and tramadol
Interactions Summary
  • 6 Major
  • 1 Moderate
  • 0 Minor
  • Cymbalta
  • tramadol

Drug Interactions

Major
Tramadol + Cymbalta

The following applies to the ingredients: Tramadol and Duloxetine (found in Cymbalta)

GENERALLY AVOID: Due to its serotonergic activity, coadministration of tramadol with serotonin-enhancing drugs such as SSRIs, SNRIs, nefazodone, trazodone, and mirtazapine may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. Patients receiving tramadol with serotonin-enhancing drugs may also have an increased risk of seizures due to additive epileptogenic effects of these agents.

MANAGEMENT: In general, the use of tramadol in combination with highly serotonergic agents should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when initiating or increasing the dosages of these agents. The potential risk for serotonin syndrome should be considered even when administering serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination half-life.

References

  1. Sternbach H "The serotonin syndrome." Am J Psychiatry 148 (1991): 705-13
  2. Ciraulo DA, Shader RI "Fluoxetine drug-drug interactions. II." J Clin Psychopharmacol 10 (1990): 213-7
  3. "Product Information. Effexor (venlafaxine)." Wyeth-Ayerst Laboratories PROD (2001):
  4. "Product Information. Ultram (tramadol)." McNeil Pharmaceutical PROD (2001):
  5. Mason BJ, Blackburn KH "Possible serotonin syndrome associated with tramadol and sertraline coadministration." Ann Pharmacother 31 (1997): 175-7
  6. Mills KC "Serotonin syndrome: A clinical update." Crit Care Clin 13 (1997): 763
  7. Chan BSH, Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG "Serotonin syndrome resulting from drug interactions." Med J Aust 169 (1998): 523-5
  8. Egberts AC, ter Borg J, Brodie-Meijer CC "Serotonin syndrome attributed to tramadol addition to paroxetine therapy." Int Clin Psychopharmacol 12 (1997): 181-2
  9. Duggal HS, Fetchko J "Serotonin syndrome and atypical antipsychotics." Am J Psychiatry 159 (2002): 672-3
  10. Lange-Asschenfeldt C, Weigmann H, Hiemke C, Mann K "Serotonin syndrome as a result of fluoxetine in a patient with tramadol abuse: plasma level-correlated symptomatology." J Clin Psychopharmacol 22 (2002): 440-1
  11. Kesavan S, Sobala GM "Serotonin syndrome with fluoxetine plus tramadol." J R Soc Med 92 (1999): 474-5
  12. Gonzalez-Pinto A, Imaz H, De Heredia JL, Gutierrez M, Mico JA "Mania and tramadol-fluoxetine combination." Am J Psychiatry 158 (2001): 964-5
  13. Martin TG "Serotonin syndrome." Ann Emerg Med 28 (1996): 520-6
  14. Houlihan DJ "Serotonin syndrome resulting from coadministration of tramadol, venlafaxine, and mirtazapine." Ann Pharmacother 38 (2004): 411-3
  15. "Venlafaxine + tramadol: serotonin syndrome." Prescrire Int 13 (2004): 57
  16. Mahlberg R, Kunz D, Sasse J, Kirchheiner J "Serotonin syndrome with tramadol and citalopram." Am J Psychiatry 161 (2004): 1129
  17. Mittino D, Mula M, Monaco F "Serotonin syndrome associated with tramadol-sertraline coadministration." Clin Neuropharmacol 27 (2004): 150-1
  18. "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company (2004):
  19. Freeman WD, Chabolla DR "36-Year-old woman with loss of consciousness, fever, and tachycardia." Mayo Clin Proc 80 (2005): 667-70
  20. Lantz MS, Buchalter EN, Giambanco V "Serotonin syndrome following the administration of tramadol with paroxetine." Int J Geriatr Psychiatry 13 (1998): 343-5
  21. Kitson R, Carr B "Tramadol and severe serotonin syndrome." Anaesthesia 60 (2005): 934-5
  22. "Product Information. Pristiq (desvenlafaxine)." Wyeth Laboratories (2008):
  23. "Product Information. Savella (milnacipran)." Forest Pharmaceuticals (2009):
  24. "Product Information. Nucynta (tapentadol)." PriCara Pharmaceuticals (2009):
  25. "Product Information. Viibryd (vilazodone)." Trovis Pharmaceuticals LLC (2011):
  26. "Product Information. Fetzima (levomilnacipran)." Forest Pharmaceuticals (2013):
  27. Shakoor M, Ayub S, Ahad A, Ayub Z "Transient serotonin syndrome caused by concurrent use of tramadol and selective serotonin reuptake inhibitor." Am J Case Rep 15 (2014): 562-4
  28. US Food and Drug Administration (FDA) "FDA Drug Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM491302.pdf" (2018):

Drug and Food Interactions

Major
Tramadol + Food

The following applies to the ingredients: Tramadol

GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur. In addition, alcohol may affect opioid release from sustained-release formulations.

GENERALLY AVOID: Grapefruit or grapefruit juice may increase the plasma concentrations of opioid analgesics by inhibiting CYP450 3A4-mediated metabolism of these agents, although the interaction has not been studied. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with opioid analgesics. Any history of alcohol or illicit drug use should be considered when prescribing an opioid analgesic, and therapy initiated at a lower dosage if necessary. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with opioid analgesics should preferably avoid the consumption of grapefruit and grapefruit juice.

References

  1. "Product Information. Alfentanil Hydrochloride (alfentanil)." Akorn Inc (2017):
  2. "Product Information. TraMADol Hydrochloride (traMADol)." Advagen Pharma Ltd (2024):
  3. "Product Information. Jamp Tramadol (tramadol)." Jamp Pharma Corporation (2024):
  4. "Product Information. Tramadol (tramadol)." Sigma Pharmaceuticals Plc (2025):
  5. "Product Information. Tramedo (tRAMadol)." Alphapharm Pty Ltd (2024):
  6. "Product Information. Alfentanil (alfentanil)." Hameln Pharma Ltd (2022):
  7. "Product Information. Butorphanol Tartrate (butorphanol)." Apotex Corporation (2024):
  8. "Product Information. Codeine Sulfate (codeine)." Lannett Company Inc (2024):
  9. "Product Information. Meperidine Hydrochloride (meperidine)." Genus Lifesciences Inc. (2024):
  10. "Product Information. Dsuvia (SUFentanil)." AcelRx Pharmaceuticals (2023):
  11. "Product Information. Dzuveo (sufentanil)." Aguettant Ltd (2024):
  12. "Product Information. Pethidine (pethidine)." Martindale Pharmaceuticals Ltd (2025):
  13. "Product Information. Meperidine Hydrochloride (meperidine)." Sandoz Canada Incorporated (2023):
  14. "Product Information. Pethidine (Juno) (pethidine)." Juno Pharmaceuticals Pty Ltd (2024):
  15. Cherrier MM, Shen DD, Shireman L, et al. "Elevated customary alcohol consumption attenuates opioid effects." Pharmacol Biochem Behav 4 (2021): 1-27
  16. Fuhr LM, Marok FZ, Fuhr U, Selzer D, Lehr T "Physiologically based pharmacokinetic modeling of bergamottin and 6,7-dihydroxybergamottin to describe CYP3A4 mediated grapefruit-drug interactions." Clin Pharmacol Ther 114 (2023): 470-82
  17. "Product Information. TraMADol Hydrochloride ER (traMADol)." Trigen Laboratories Inc (2025):
  18. "Product Information. Codeine Contin (codeine)." Purdue Pharma (2025):

Moderate
Cymbalta + Food

The following applies to the ingredients: Duloxetine (found in Cymbalta)

GENERALLY AVOID: Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Duloxetine alone can increase serum transaminase levels. In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations. The median time to detection was about two months. Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed. Duloxetine does not appear to enhance the central nervous system effects of alcohol. When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

MANAGEMENT: Due to the risk of liver injury, patients prescribed duloxetine should be counseled to avoid excessive use of alcohol. Duloxetine should generally not be prescribed to patients with substantial alcohol use.

References

  1. "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company (2004):

Drug and Pregnancy Interactions

The following applies to the ingredients: Tramadol

Use is not recommended

AU TGA pregnancy category: C
US FDA pregnancy category: Not Assigned

Risk Summary: There is insufficient data in humans to inform a drug-associated risk for major birth defects and miscarriage; prolonged use of opioids during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Comments:
-This drug is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.

This drug has been shown to cross the placental barrier, with an umbilical vein to maternal vein serum concentration ratio of 0.83. Animal studies have shown at very high doses, this drug has an effect on organ development, bone growth, and mortality rate. Prolonged maternal use of opioid analgesics during pregnancy may result in respiratory depression and physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. There have been postmarketing reports of neonatal seizures, neonatal withdrawal syndrome, fetal death, and still births. There are no adequate and well-controlled studies in pregnant women.

Chronic use of opioids may cause reduced fertility; it is unknown whether these effects are reversible.

AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

References

  1. "Product Information. Ultram (tramadol)." McNeil Pharmaceutical PROD (2001):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  3. Cerner Multum, Inc. "Australian Product Information." O 0
  4. "Product Information. Ultram ER (tramadol)." PriCara Pharmaceuticals (2015):

The following applies to the ingredients: Duloxetine (found in Cymbalta)

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned.

Risk summary: Observational study data have not produced clear drug-associated risks regarding adverse events or major birth defects.

Comments:
-A pregnancy exposure registry is available.
-Neonates exposed to this drug late in the third trimester may require respiratory support, tube feeding, and/or prolonged hospitalization.
-Exposed neonates should be monitored after delivery for direct toxic effects of this drug, drug discontinuation syndrome, and serotonin syndrome.
-Women who discontinued antidepressant use during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant use.

Animal studies have revealed increased perinatal toxicity and fetotoxicity at doses potentially correlated with maternal toxicity. There are no controlled data in human pregnancy.

Some neonates exposed to SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors) late in the third trimester had clinical findings including respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. This clinical picture is consistent with either direct toxic effect of SSRIs and SNRIs, drug discontinuation syndrome, or serotonin syndrome.

A less than 2-fold increase in postpartum hemorrhage was determined by observational data in patients exposed to the drug within 1 month before birth.

A study of women with a history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

To monitor maternal-fetal outcomes of pregnant women exposed to antidepressant therapy, a National Pregnancy Registry for Antidepressants has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/

Healthcare providers are encouraged to register patients receiving Cymbalta by calling the Cymbalta Pregnancy Registry at 1-866-814-6975 or by visiting www.cymbaltapregnancyregistry.com.

AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

References

  1. "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company (2004):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  3. Cerner Multum, Inc. "Australian Product Information." O 0

Drug and Breastfeeding Interactions

The following applies to the ingredients: Tramadol

Use is not recommended

Excreted into human milk: Yes

Comments:
-The US FDA recommends against the use of tramadol during breastfeeding due to risks of serious adverse reactions in breastfed infants; this drug is not recommended for obstetrical preoperative medication or for post-delivery analgesia in nursing mothers because its safety in infants and newborns has not been studied.
-If infants are exposed through breastmilk, they should be monitored for excess sedation and respiratory depression.

Serious adverse reactions in breastfed infants may include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death. Newborns have limited capacity to metabolize the active 0-desmethyltramadol.

A study in 75 mothers reported an average milk concentration of 748 mcg/L; this translates to an average infant dose of 112 mcg/kg and a maternal weight-adjusted dose of 2.24% and 0.64% for the drug and its metabolite, respectively. Reanalysis of the data using a population pharmacokinetic model showed a maternal weight adjusted dose of 2.2% for extensive metabolizers and 2.6% for poor metabolizers. The amount of drug present in breast milk represents a maximum of 2.6% of the proposed IV newborn dose. This drug can increase prolactin levels; however, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.

References

  1. "Product Information. Ultram (tramadol)." McNeil Pharmaceutical PROD (2001):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  3. Cerner Multum, Inc. "Australian Product Information." O 0
  4. United States National Library of Medicine "Toxnet. Toxicology Data Network. http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT" (2013):
  5. "Product Information. Ultram ER (tramadol)." PriCara Pharmaceuticals (2015):
  6. US Food and Drug Administration (FDA) "FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm" (2017):

The following applies to the ingredients: Duloxetine (found in Cymbalta)

Use is not recommended and a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Excreted into human milk: Yes

Comments:
-Some experts state that a more thoroughly studied alternative agent (e.g., nortriptyline, paroxetine, sertraline) may be preferred while breastfeeding premature or neonates.
-The American Academy of Pediatrics classifies other antidepressants as agents for which the effect on nursing infants is unknown but may be of concern.
-Exposed infants should be monitored for developmental milestones, feeding, sedation, weight gain, especially in younger infants who are exclusively breastfed and/or when breastfed infants are exposed to multiple antipsychotropic agents.

The estimated neonatal dose is approximately 0.1% to 0.3% of the maternal dose.

References

  1. "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company (2004):
  2. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  3. Cerner Multum, Inc. "Australian Product Information." O 0
  4. United States National Library of Medicine "Toxnet. Toxicology Data Network. http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT" (2013):
  5. Briggs GG, Freeman RK. "Drugs in Pregnancy and Lactation." Philadelphia, PA: Wolters Kluwer Health (2015):
  6. National Library of Medicine (US) "Drugs and Lactation Database (LactMed) https://www.ncbi.nlm.nih.gov/books/NBK501922/" (2019):

Therapeutic Duplication Warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

Switch to: Consumer Interactions

Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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