Tramadol Interactions That Shouldn’t be Underestimated

Tramadol Interactions That Shouldn’t be Underestimated – Introduction

Tramadol is an opioid analgesic that can relieve moderate and severe pain. It changes the way the brain and nervous system typically respond to pain. Tramadol and its M1 metabolite bind to μ-opioid receptors, while the other mechanism is a weak inhibition of norepinephrine and serotonin reuptake. (1-2)

Although an effective pain reliever, tramadol brings several safety risks, even when taken at recommended doses not exceeding 300mg daily. Tramadol, similar to other opioids, increases the risk of addiction, abuse, and misuse.

Even more, its therapeutic effect and safety profile can be affected by other medications when used together, such as antidepressants, diuretics, and antibiotics. As a result, serious side effects and life-threatening conditions, including respiratory depression and serotonin syndrome, may occur. (1-2)

This article is all about these and other tramadol drug interactions. Keep reading to learn about the medications that are not recommended for use with tramadol.

Tramadol Interactions

Tramadol interacts with a long list of medications differently. For example, when tramadol is used with digoxin, digoxin toxicity can rarely occur. Another tramadol interaction is with warfarin, increasing the prothrombin time (the time needed for clot formation). (1)

In other cases, drug interaction may cause an increased risk of side effects, as is the case with anticholinergic drugs. When used together, tramadol increases the risk of urinary retention and/or severe constipation; the result might be paralytic ileus. (1)

Medications that Induce and Inhibit the CYP3A4 Enzyme

CYP3A4 is the most important enzyme in the human body for drug metabolism. It is present in the liver and intestine and metabolizes 30-50% of the drugs. (3-4)

Medications like rifampin, carbamazepine, or phenytoin induce the CYP3A4 enzyme; this results in a reduced plasma concentration of the substrates (drugs that the CYP3A4 enzyme metabolizes). And the opposite, inhibitors of CYP3A4 (e.g., erythromycin, ketoconazole, ritonavir) inhibit the enzyme’s activity, so the concentration of the substrates in plasma increases. (5)

During concomitant use of tramadol and CYP3A4 inducer, the plasma concentration of tramadol decreases. Less available tramadol amount means lower efficacy or onset of a withdrawal syndrome in patients who have developed a physical dependence on tramadol. After the CYP3A4 inducer discontinuation, the enzyme will continue to work regularly, and the tramadol concentration in plasma will increase. Increased amount leads to the opposite side, increasing tramadol’s therapeutic effect, duration, and risk of seizures, serotonin syndrome, and potentially fatal respiratory depression. (1)

When the CYP3A4 inhibitor is taken together with tramadol, the plasma concentration of tramadol can be increased but also a risk of severe side effects. Stopping treatment with CYP3A4 inhibitor will reduce tramadol concentration, decreasing opioid efficacy and possible signs and symptoms of opioid withdrawal. (1)

Serotonin syndrome is one of the life-threatening side effects due to drug interaction. It happens when the serotonin level in the body is too high. It can cause severe symptoms like high fever, tremors, seizures, irregular heartbeat, and unconsciousness. Such conditions require early diagnosis and medical treatment. (1, 6-8)

Respiratory depression is another life-threatening condition. Harder breath or not having enough oxygen are warning signs of respiratory distress. If the symptoms are not recognized on time, respiratory depression may lead to respiratory arrest and death. (9)

Inhibitors of the CYP2D6 Enzyme

CYP2D6 is an enzyme in the body that belongs to the cytochrome P450 family. CYP2D6 is responsible for the metabolism of up to 20% of drugs, such as antidepressants, antiarrhythmics, beta-blockers, and opioid analgesics. Inhibition of this enzyme leads to decreased metabolism of CYP2D6 substrates and increased concentration of those drugs. Quinidine, fluoxetine, paroxetine, bupropion, etc., are medications that are inhibitors of CYP2D6. (1, 3)

When CYP2D6 inhibitor is used with tramadol, this may result in an increased plasma concentration of tramadol that increases and prolongs the therapeutic effect. Increased tramadol concentration also increases the risk of side effects, including seizures and serotonin syndrome. (1)

The concomitant use of tramadol and CYP2D6 inhibitor decreases the M1 plasma concentration, which may result in signs and symptoms of opioid withdrawal in patients who have developed a physical dependence on tramadol. After CYP2D6 inhibitor discontinuation, M1 plasma concentration increases, which could prolong therapeutic effects. At the same time, side effects related to opioid toxicity may increase and may cause potentially fatal respiratory depression.

This interaction with CYP2D6 inhibitors is critical to understand for an adequate dosage adjustment if this dual treatment is necessary. (1)

Benzodiazepines and Other Central Nervous System (CNS) Depressants

Benzodiazepines are medications that decrease the activities of the nervous system. Based on the effect of the benzodiazepine, the brain releases the neurotransmitter gamma-aminobutyric acid (GABA). GABA makes the nervous system less active, so benzodiazepines have amnestic, anxiolytic, hypnotic, and sedative effects and are used to treat various diseases, including anxiety, panic disorder, insomnia, status epilepticus, and others. (10)

There are other CNS depressants, like anxiolytics, tranquilizers, muscle relaxants, general anesthetics, and antipsychotics, that also slow down brain activity and can treat anxiety, panic, acute stress reactions, and sleep disorders. (11)

Benzodiazepines, other CNS depressants, and alcohol have an additive effect when used with tramadol. This effect increases the risk of hypotension, profound sedation, respiratory depression, coma, and death. (1)

Due to the severe side effects, tramadol can be used with these medication groups only if there is no other alternative, at a minimum dosage and as short as possible, under the guidance of a doctor. (1)

Serotonergic Drugs

Serotonin is naturally produced in the body and helps several body functions, including mood, happiness, sexual desire, and sleep. A lack of serotonin can manifest with depression and anxiety. (8)

Serotonergic drugs are various groups of medications that elevate serotonin levels in the body through different mechanisms of action. For example, escitalopram, a selective serotonin reuptake inhibitor (SSRI), inhibits serotonin reuptake. Or, dextromethorphan and methylenedioxymethamphetamine (MDMA or ecstasy) increase serotonin release, while lithium, sumatriptan, or lysergic acid diethylamide (LSD) stimulate serotonin receptors. Using two or three medications together may cause a high level of serotonin in the body.

Serotonergic drugs are medications that belong to the following groups: (14)

  • SSRIs – Selective serotonin reuptake inhibitors (e.g., citalopram, fluoxetine, paroxetine);
  • SNRIs – Serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine, sibutramine, venlafaxine);
  • TCAs – Tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline);
  • Triptans (e.g., almotriptan, sumatriptan, frovatriptan);
  • 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, palonosetron); (12)
  • Drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol);
  • MAOIs – Monoamine oxidase inhibitors (e.g., isocarboxazid, phenelzine, and selegiline). (13)

If there is a need for concomitant use of tramadol and a serotonergic drug listed above, the combination should be used with caution due to the risk of serotonin syndrome. When prescribing both medications, the doctor will closely monitor the patient during treatment initiation and dose adjustment. In case of serotonin syndrome signs appear, tramadol should be discontinued. (1, 15)

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are medications used to treat depression, panic disorder, social phobia, and other nervous system disorders. They block the enzyme monoamine oxidase responsible for breaking down neurotransmitters. Neurotransmitters (norepinephrine, serotonin, dopamine, and tyramine) are chemicals that carry messages between brain cells. When monoamine oxidase is inhibited, the neurotransmitter level increases, impacting the cells affected by depression. Isocarboxazid, phenelzine, tranylcypromine, selegiline, and linezolid (the only one in this group that is used as antibiotic) are some of the MAOIs. (9, 13)

These oldest antidepressants have existed since the 1950s. Today MAOIs have limited use due to their side effects and the availability of newer and safer antidepressants. Aside from the most common side effects (dry mouth, nausea, diarrhea or constipation, headache, insomnia, and dizziness), serotonin syndrome and opioid toxicity are rare side effects that raise safety concerns. (9, 13)

As explained before, serotonin syndrome is life-threatening, and therefore tramadol is not recommended for use in combination with MAO inhibitors or within 14 days of stopping such treatment. Another reason for not using MAOIs and tramadol simultaneously is opioid toxicity (e.g., respiratory depression, coma) due to their interaction. (1, 15)

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

Butorphanol, nalbuphine, pentazocine, and buprenorphine are some of the mixed agonist/antagonist and partial agonist opioid analgesics. In patients who take full opioid agonist analgesics, the combination treatment of agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms. For this reason, the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics should be avoided. (1)

Muscle Relaxants

Medications that affect muscle function are called muscle relaxants or muscle relaxers. Antispastics (e.g., baclofen) and antispasmodics (e.g., cyclobenzaprine, carisoprodol) are two classes that have different ways of working and side effects. Skeletal muscle relaxants help to relieve muscle pain, while smooth muscle relaxants treat symptoms of abdominal pain, including spasms and cramps. (16-17)

In some drug interactions, tramadol can strengthen the therapeutic effect of other medicines. That is the case with muscle relaxants, where tramadol may enhance the neuromuscular blocking action of skeletal muscle that muscle relaxants do. However, this interaction may result in an increased degree of respiratory depression.

If tramadol is used with muscle relaxants and symptoms of respiratory depression occur, your doctor will decrease the tramadol dosage.


Diuretics are medications that help the kidney to eliminate water and salts. Water elimination means a reduced amount of fluids that flow into the bloodstream and a blood pressure decrease. (18)

Opioids like tramadol induce the release of antidiuretic hormone and, by that, reduce the efficacy of diuretics. Diminished diuresis and reduced blood pressure can be the signs of the interaction between diuretics and tramadol and a need to increase the diuretic dosage. (1)

Final Takeaways for a Safe Therapy

For additional safety usage of tramadol:

  • Always tell your doctor and pharmacist the medications that you take, including over-the-counter products;
  • Use tramadol as prescribed by your doctor. Follow the initial therapy of 100 mg and slowly increase it every five days for the required therapeutic effect achievement. Don’t take more than 300 mg daily;
  • The most common side effects, at a rate at least twice then placebo, are dizziness, headache, somnolence, constipation, flushing, pruritus, nausea, vomiting, insomnia, and dry mouth;
  • Tramadol is mainly contraindicated in children younger than 12 years of age, children below 18 years following tonsillectomy and/or adenoidectomy, and people with hypersensitivity. Find out other contraindications in Medication Guide.
  • Read the Medication Guide to learn about the signs and symptoms of the possible side effects. Then, tell your doctor or report adverse events to the Food and Drug Administration’s (FDA) MedWatch Adverse Event Reporting program online ( or by phone (1-800-332-1088).

Your safety comes first, while for pain management, there are other medical options.

See Also

Gabapentin Interactions

Cyclobenzaprine Interactions

Doxycycline Interactions

Meloxicam Interactions

Lisinopril Contraindications

Acetaminophen Contraindications

Aspirin Contraindications

Ibuprofen Contraindications

Paxlovid Contraindications

Bupropion Side Effects

Shingles Vaccine Side Effects

1. Food and Drug Administration, ULTRAM® ER (tramadol hydrochloride) extended-release tablets for oral use, C IV, Prescribing information, 2017 Aug,

2. MedlinePlus, Tramadol, 2022 Jan,,called%20opiate%20(narcotic)%20analgesics.

3. Rommel G. Tirona, Richard B. Kim, CYP3A4/CYP3A5, Clinical and Translational Science (Second Edition), 2017

4. Bradley L. Urquhart, Thomas D. Nolin, CYP3A4, Chronic Renal Disease (Second Edition), 2020

5. J. R. Horn, P. D. Hansten, Drug Interactions with CYP3A4: An Update, Pharmacy Times, December 2015 Heart Health, Volume 81, Issue 12

6. Mayo Clinic, Serotonin Syndrome, 2022 Jan,,cause%20death%20if%20not%20treated.

7. Mayo Clinic, Monoamine oxidase inhibitors (MAOIs), 2019 Sept,,Tranylcypromine%20(Parnate)

8. Cleveland Clinic, Serotonin, 2022 Mar,,blood%20clotting%20and%20sexual%20desire

9. John Hopkins Medicine, Signs of Respiratory Distress,

10. Cleveland Clinic, Benzodiazepines (Benzos), 2023 Jan,

11. National Institute of Drug Abused, Prescription CNS Depressants Drug Facts, 2018 Mar,

12. National Library of Medicine, Antiemetic Serotonin-5-HT3 Receptor Blockers, 2022 Nov,

13. National Library of Medicine, Monoamine Oxidase Inhibitors (MAOI), 2022 Jul,,and%20depression%20with%20atypical%20features

14. Charles H. Brown, MS Pharm, RPh, CACP, Drug-Induced Serotonin Syndrome, US Pharm. 2010;35(11):HS-16-HS-21.

15. Drugbank online, Tramadol, 2023 Jan,

16. Cleveland Clinic, Muscle Relaxers, 2023 Feb,

17. Mayo Clinic, Use of antispasmodics for the treatment of abdominal pain, 2022 Jan,

18. Mayo Clinic, Diuretics, 2021 Aug,,This%20reduces%20blood%20pressure.


Follow us