Tramadol — also known by the brand names Ultram, ConZip, or Rybix — is a synthetically produced opioid medication primarily used for pain management. Using it with other medications, like antidepressants, may exacerbate its side effects.

Tramadol Specifics

If tramadol is used according to its prescribed conditions, it is generally safe.

Tramadol is considered to have a far less addiction potential than other opioids that are commonly associated with abuse, such as Vicodin (acetaminophen and hydrocodone) or OxyContin (oxycodone).

It works similarly to other opioid drugs, but because of its relatively safer abuse potential profile, it is classified in the Schedule IV category by the U.S. Drug Enforcement Administration. Many of the widely known prescription opioids are classified as Schedule II, a much higher level.


Many substances may reduce feelings of depression, but antidepressant medications are specifically designed for the treatment of depression.

There are several types of antidepressants.

  • The oldest group of drugs, monoamine oxidase inhibitors (MAOIs), work by interrupting the breakdown of a group of neurotransmitters that may be involved in the regulation of mood. This group includes Parnate (tranylcypromine) and Nardil (phenelzine).
  • Second-generation antidepressant medications are tricyclic antidepressants (TCAs). They are primarily designed to increase levels of norepinephrine, dopamine, and serotonin while reducing the effectiveness of acetylcholine. This group includes Anafranil (clomipramine) and Elavil (amitriptyline).
  • Selective serotonin reuptake inhibitors (SSRIs) are probably the best-known antidepressants. These drugs selectively block the reabsorption of serotonin. Prozac (fluoxetine) is an example.
  • Newer antidepressants include norepinephrine and dopamine reuptake inhibitors like Wellbutrin (bupropion) and serotonin and norepinephrine reuptake inhibitors like Cymbalta (duloxetine).
  • Ketamine, a dissociative hallucinogen or anesthetic that was recently approved for the treatment of depression, primarily works on the excitatory neurotransmitter (NDMA).

Combining Tramadol and Antidepressants

There is research showing the potential for the combination of tramadol and antidepressants to trigger potentially fatal serotonin syndrome.

For this reason, it is generally accepted that tramadol and antidepressant medications should not be used together.

What is Serotonin Syndrome?

Serotonin syndrome (SS) is a very serious and potentially fatal condition that occurs when there is an overload of the neurotransmitter serotonin in the brain.

The syndrome most often occurs as a result of combining two medications that increase serotonin levels in the brain, particularly mixing antidepressant medications or one antidepressant medication with another substance that increases serotonin levels.

The effects of serotonin syndrome include significant confusion and changes in mental status, a hypertensive crisis, muscle rigidity, and the breakdown of muscle tissue in the system (rhabdomyolysis).

The syndrome can be fatal, particularly if suddenly increased hypertension causes seizures, a heart attack, or a stroke.

Do Tramadol and Antidepressants Increase the Risk of SS?

The findings of a recent research review published in the Journal of Pharmacy Practice indicated that when the medications are taken in therapeutic doses, there is no increased risk of SS.

The use of tramadol with an MAOI, even when both are used for medical reasons and within the confines of their prescribed doses, could lead to increased risk of contracting serotonin syndrome.

Otherwise, research findings indicate that tramadol could safely be used with antidepressant medications as long as the medications were used within the confines of recognized medical practice.

There were also several cases of serotonin syndrome in the research studies used by the review. The individuals who developed SS in the studies were examined to develop a list of risk factors that could be associated with an increased probability of developing SS when combining antidepressants and tramadol.

Risk Factors for SS

A risk factor is a condition that increases the probability that one may develop a condition, disorder, or disease. Risk factors are not direct causes. They only increase the probability that something may happen. Having more than one risk factor increases the probability even more.

Your Risk of Developing Serotonin Syndrome as a Result of Concurrent Use of Tramadol and an Antidepressant Increases if You:

  • Abuse tramadol while taking an antidepressant.
  • Are over the age of 65. Elderly individuals tend to metabolize drugs more slowly and have different reactions to drugs than younger people.
  • Have certain genetic factors.
  • Take more than one antidepressant medication or take another medication that increases serotonin in your system.

Using tramadol in very high amounts while taking antidepressants may significantly increase your risk of developing SS.

How does Tramadol Interact with Antidepressants?

Some of the side effects that may be increased when tramadol and antidepressants are combined include:

  • Significant anxiety
  • Nausea, constipation, and other gastrointestinal issues
  • Dizziness, headache, and lightheadedness
  • Increased heart rate, shallow breathing, or overactive reflexes
  • Allergic reactions
  • Psychosis or seizures, in rare cases

If you take alcohol, illicit drugs, or even prescription medications along with an antidepressant and tramadol, you further risk experiencing side effects that can be severe and, in some cases, even life-threatening.

Always consult a doctor before taking tramadol and antidepressant medications together.

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