Tramadol and Sertraline (A brief guide)

In this guide, we will discuss What Tramadol and Sertraline are and some considerations when combining both medications since they can lead to a life-threatening condition called serotonin syndrome. 

Tramadol and Sertraline

Using Tramadol and Sertraline together can increase the risk of developing a very serious condition called serotonin syndrome which includes symptoms such as confusion, hallucinations, seizures, changes in blood pressure, increased heart rate, fever, excessive sweating, shivering/shaking, blurred vision, muscle spasm or stiffness, tremors, incoordination, stomach cramps, nausea, vomiting, and diarrhea ( 

If you experience any of the symptoms, contact your doctor immediately or call emergency services since severe cases can result in coma and death.

In addition, combining tramadol and sertraline can heighten the risk of seizures not related to serotonin syndrome. 

This interaction may be more likely to happen to elderly people, undergoing alcohol or drug withdrawal, have a history of seizures, or have a condition that affects your central nervous system (e.g. brain tumor or head trauma).

In addition, it is recommended to avoid alcohol intake while being treated with tramadol and sertraline.

Do not attempt to stop any medication without contacting your doctor. 

The interaction between tramadol and sertraline happens because they both have the ability to increase serotonin levels in your body, causing serotonin syndrome to develop.

The high levels of serotonin may cause certain changes in your body temperature, blood pressure, muscles, and behavior. 

In addition, symptoms from serotonin syndrome can range from mild to severe and it can become life-threatening. 

But what is Tramadol and what is Sertraline? Tramadol is considered a pain reliever used to treat moderate to severe pain in adults.

In contrast, sertraline is classed as an antidepressant from the group of drugs called Selective Serotonin Reuptake Inhibitors (SSRIs) which is meant to balance the serotonin (neurotransmitter) levels in the brain.  

“Serotonin is a crucial neurotransmitter. It is found in the brain as well as the digestive tract. Serotonin is also found in blood cells called platelets. It plays a crucial role in regulating mood. That is why some of the most successful antidepressants are called SSRIs (selective serotonin reuptake inhibitors). Serotonin also impacts libido and sexual function as well as the memory, digestion, sleep, and blood clotting (”

This is why when there is excessive serotonin circulating in the body it can lead to “serotonin syndrome.”

The pain reliever Tramadol plus sertraline for depression could prove dangerous if not deadly.

A study from 2013 reviewed case reports of Serotonin Syndrome associated with the combination of tramadol and antidepressant drugs in recommended doses, also described the mechanisms of the drug interaction and identified the potential risk factors for Serotonin Syndrome. 

They concluded after reviewing the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use.

The only contraindicated combination would be combining Tramadol with MAOIs but not other antidepressants in common use today.

“These case reports do suggest several factors associated with a greater risk of Serotonin Syndrome, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased.”

Another study from 1997 studied the case of a 42-year-old woman that developed certain atypical symptoms, after taking multiple medications including tramadol and sertraline.

Her tramadol dosage was recently increased resulting in what they believed was a serotoninergic syndrome.

It is important to notice how the susceptibility and reaction to this combination differ from one person to the other, meaning under certain circumstances some people are more likely to develop Serotonin Syndrome. 

What you should do about this interaction?

If you are taking tramadol and sertraline, let your doctor or health care professional that you are taking them together. 

As mentioned by if you experience the following symptoms, such as muscle twitching, tremors, shivering, and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea contact your doctor right away (WebMD). 

Your doctor may already be aware and know what to do and can keep monitoring you.

It is recommended not to start, stop or change the medicine dosage checking with them first. 

What Is Serotonin Syndrome?

According to “Reports continue to appear describing serotonin syndrome following combined use of tramadol (Ultram) with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs). Because serotonin syndrome can be serious and is often difficult to detect, it is important for health professionals to be alert for this reaction. A recent study from Australia found that many patients are exposed to drug interactions that can result in serotonin syndrome.”

But, what is serotonin syndrome?

This is considered to be caused by an excess of the neurotransmitter serotonin in the brain and usually results from the administration of 2 or more serotonergic drugs at the same time.

However, Serotonin syndrome also can occur with excessive doses of a single serotonergic drug.

According to symptoms can include confusion, agitation, and fever, which are relatively nonspecific and can be caused by many disorders other than serotonin syndrome.

Other symptoms are more specific, however, and thus are more useful in the early detection of serotonin syndrome.

These include myoclonus (muscle jerking), muscle rigidity, and tremor.

Serotonin syndrome also can cause sweating, incoordination, seizures, and coma. As discusses, severe cases of serotonin syndrome can be fatal.

But, what about Tramadol?

There are some cases reported taking Selective Serotonin Reuptake Inhibitors or SNRIs who developed serotonin syndrome while taking concurrent tramadol.

Reported cases involved combining tramadol with citalopram, fluoxetine, paroxetine, nefazodone, sertraline, and venlafaxine.

Some evidence suggests that mirtazapine also may interact with tramadol, but more evidence is needed.

Possible risk factors

Existing evidence suggests that higher plasma concentrations of tramadol and/or SSRIs increase the risk of serotonin syndrome.

Some people have actually tolerated this combination of tramadol and sertraline and only developed the syndrome when the dose of one or both drugs is increased. 

Additionally, Tramadol is said to be metabolized by CYP2D6, and some SSRIs are moderate- to-potent inhibitors of CYP2D6 (eg, fluoxetine, paroxetine, duloxetine).

Also, some genetic deficiencies in the CYP450 isozymes that metabolize tramadol or SSRIs may increase the risk of serotonin syndrome by increasing plasma concentrations. 

As mentioned by, “One patient who developed serotonin syndrome following tramadol and citalopram had decreased activity of the isozymes involved in the metabolism of both tramadol (CYP2D6) and citalopram (CYP2C19).”

It seems that Tramadol is not the only opioid analgesic that interacts. Drug Meperidine, which is used to relieve moderate to severe pain, has long been known to have serotonergic effects and has produced severe serotonin syndrome when combined with drugs such as nonselective monoamine oxidase inhibitors (eg, tranylcypromine). 

Cases, where meperidine has been combined with SSRIs,  have also been reported to have cause serotonin syndrome.

Fentanyl also has serotonergic effects and, like meperidine, has been associated with serotonin syndrome when combined with SSRIs.

Morphine does not appear to have serotonergic effects and may be safer when combined with serotonergic drugs.

A reported case of Tramadol + Sertraline

This case was reported in

Person Q. “I have been taking tramadol, amitriptyline, and sertraline for more than three years. I was having a hard time with my depression and told my doc it was getting worse.

She increased the dose of sertraline from 100 mg to 150 mg. Five days later I had a seizure. Nobody could understand why.”

“My electrolytes were abnormal, so I went back to see the doctor a few weeks later and asked if the increased dosage could have been the cause.”

“She dismissed that idea, but since then I have seen two other doctors who both expressed concern about this combination of drugs. One of them said it could be a lethal cocktail, and the combination could well have caused my seizure. I feel as if I’ve been misled by someone I trusted. I’d be grateful for your opinion.”

Why is this blog about tramadol and sertraline important?

It is important is to consider that certain medications can’t be combined because they can evolve into a life-threatening condition.

It is always recommended to consult with your physician about any medications that you are taking before you start taking a new medication he/she just prescribed or if they are aware of the possible drug interaction then they can monitor you closely and educate you on the symptoms and warning signs to be aware. 

In addition, knowing the type of drug each medication belongs to, the risk factors associated with the treatment and what they do can be very useful in helping to prevent future issues.

Also, even though some consider Tramadol and antidepressants a safe combination, monitoring and counseling should be given when you are starting a new serotoninergic drug or if your dose gets increased. 

Please feel free to comment in the comments section below!

Frequently Asked Questions (FAQs) about Tramadol and Sertraline

Can you take tramadol with antidepressants?

It is not recommended to take tramadol with antidepressant medication since it is believed that tramadol can increase the amount of serotonin in your brain putting you at risk for a condition called serotonin syndrome, which can be fatal.

What medications should not be taken with tramadol?

Medications that should not be taken with tramadol include but are not limited to Advil (ibuprofen), Aleve (naproxen), Ambien (zolpidem), aspirin, Aspirin Low Strenght (aspirin), Benadryl (diphenhydramine), Celebrex (celecoxib), Cymbalta (duloxetine).

Can you take tramadol with mirtazapine?

Tramadol and mirtazapine are not recommended to be taken together unless instructed and monitored by your doctor or medical provider.

Using both medications can increase the risk of seizures not related to serotonin syndrome.

Does tramadol increase serotonin?

Tramadol increases the concentration of serotonin in the synapses between the serotoninergic neurons found in the brain stem.

This extra concentration of serotonin can cause some of the positive effects of the medication, such as pain relief. 

Is Tramadol an SSRI drug?

Tramadol is not an SSRI.

It is considered a mu-opioid receptor agonist as an inhibitor of the reuptake of norepinephrine and serotonin in the central nervous system. 

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