Common antidepressants interact with the opioid pain medication tramadol to make it less effective for pain relief

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Common antidepressants interact with the opioid pain medication tramadol to make it less effective for pain relief, according to a study from University Hospitals (UH).

These findings have important implications for the opioid epidemic, suggesting that some patients suspected of drug-seeking may in fact be under-medicated and just are seeking more effective pain relief.

They also could help explain why some people exceed the prescribed dose of tramadol, increasing their risk of addiction.

The study was published in the journal Pharmacotherapy.

Researchers reviewed the medication records of 152 patients at UH Cleveland Medical Center and UH Geauga Medical Center who received scheduled tramadol for at least 24 hours.

All participants in the study were admitted as inpatients or observation status. Those patients who also were taking the antidepressants Prozac (fluoxetine), Paxil (paroxetine) or Wellbutrin (bupropion) required three times more pain medication per day to control “breakthrough” pain throughout the day, when compared with patients not taking those antidepressants.

“As we looked at in secondary analysis, it ended up being four times as much over their entire hospital stay,” said Derek Frost, a pharmacist at UH and lead author of the study.

Previous studies with healthy volunteers have shown effects on blood levels when combining tramadol with these particular antidepressants.

However, this is the first study to document the effects of this interaction in a real-world setting with patients.

“We knew that there was a theoretical problem, but we didn’t know what it meant as far as what’s happening to pain control for patients,” Frost said.

What explains the interaction between tramadol and these antidepressants?

“Tramadol relies on activation of the CYP2D6 enzyme to give you that pain control,” Frost said.

“This enzyme can be inhibited by medications that are strong CYP2D6 inhibitors, such as fluoxetine, paroxetine and bupropion.”

According to Frost, it’s likely that millions of Americans may be suffering the ill effects of this drug-to-drug interaction.

“These drugs are super-common,” he said. “

They’re all in the top 200 prescription drugs. In addition, chronic pain and depression and anxiety go hand in hand.

Many chronic pain patients are taking antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), which many of these CYP2D6 inhibitors fit into.

There are a lot of patients who experience both, unfortunately.

The likelihood that somebody on one of these offending agents and tramadol is relatively high.”

Fortunately, Frost said, this problem has a relatively easy fix.

“We have a lot of other antidepressants available that are in the same class of medication that don’t inhibit this particular enzyme, such as Zoloft (sertraline), (Celexa) citalopram and Lexapro (escitalopram),” he said.

“You also have other options for pain control – non-opioid medications such as NSAIDs.

If we need to use opioids, a scheduled morphine or a scheduled oxycodone would avoid this interaction.”

“For patients who have the combination of chronic pain and depression or anxiety, keep in mind that this interaction does exist,” Frost said.

“And for health care providers, if you have a patient approaching you saying this medication isn’t working for me, is there an interaction at play?”


Patients taking the most common form of antidepressant who are given the most widely prescribed opioid experience less pain relief, Stanford University School of Medicine investigators have discovered.

The finding could help combat the opioid epidemic, as poorly managed pain may lead to opioid abuse. 

As many as 1 in 6 Americans takes antidepressants, mostly selective serotonin reuptake inhibitors. Stanford researchers found that SSRIs reduce the effectiveness of hydrocodone and codeine, which are often prescribed to patients who have recently undergone surgery. 

“This research is part of our effort to find ways to combat the opioid epidemic,” said Tina Hernandez-Boussard, PhD, MPH, associate professor of medicine, of biomedical data science and of surgery at Stanford.

“We’re very interested in identifying how we can reduce opioid exposure while still managing patients’ pain.”

A paper describing the research was published Feb. 6 in PLOS ONE.

Hernandez-Boussard and Ian Carroll, MD, assistant professor of anesthesiology, perioperative and pain medicine at Stanford, share senior authorship. The lead author is graduate student Arjun Parthipan.

Antidepressant inhibits enzyme

The researchers focused on the interaction between opioids and SSRIs because they knew that certain opioids, called prodrug opioids, need a liver enzyme to convert them into an active form that eases pain.

SSRIs inhibit this enzyme, so the researchers hypothesized that patients taking SSRIs in combination with prodrug opioids would receive less pain relief.

Prodrug opioids include codeine and hydrocodone, which is sold under brand names such as Vicodin, Lorcet and Lortab. SSRIs include Prozac, Paxil, Zoloft and Celexa.

For the study, the research team analyzed de-identified data for 4,306 surgical patients with a diagnosis or symptoms of depression in the electronic health records at Stanford Health Care.

The researchers found that the patients on SSRIs who were prescribed prodrug opioids experienced more pain when they left the hospital, as well as three weeks later and eight weeks later.

The patients on both SSRIs and prodrug opioids registered nearly one point more pain on a scale of 1 to 10 than the patients not on SSRIs who were prescribed prodrug opioids. 

Algorithm predicts opioid response

The researchers built a machine-learning algorithm that predicts how a patient will respond to different types of opioids.

The algorithm is available online

The study focused on surgery patients because they nearly always receive opioid prescriptions, yet the findings apply to anyone taking short-term opioids. 

Carroll noted that hydrocodone is the most frequently prescribed drug in the nation. With SSRIs the most frequently prescribed class of drugs, he said, the chance that any patient will be on both drugs is high. 

There’s no proof that better pain management reduces the number of opioid overdoses, cautioned Carroll. But poor pain control has been shown to be a risk factor for chronic pain, and it may lead to more prolonged opioid use, along with misuse. 

“Presumably, every day you take opioids, the risk you’ll abuse it increases,” Carroll said. 

The authors concluded that to manage pain for patients on SSRIs, prescribers should choose nonopioids or direct-acting opioids. Direct-acting opioids, which include morphine, fentanyl and oxycodone, do not need the liver enzyme to convert the drug into a form that eases pain. 

Prescribers typically choose hydrocodone or codeine because of a perception that they are milder than hydromorphone, whose trade names include Dilaudid and Exalgo, or morphine, Carroll said. 

“The prescribing of hydrocodone has more to do with history and perception,” he said. “The liver converts hydrocodone into hydromorphone and converts codeine into morphine,so the result is the same.”

Carroll added that depressed patients’ complaints about pain after receiving opioids are often dismissed because of their mental state, when the problem lies in an unfortunate drug interaction. 

“Depressed patients are at greater risk for pain, and we’re failing them because we’re not educated enough about the drugs we’re giving them,” he said.

Hernandez-Boussard is a member of Stanford Bio-X, and she and Carroll are members of the Stanford Cancer Institute

Other Stanford co-authors of the study are research scientist Imon Banerjee, PhD; Keith Humphreys, PhD, professor of psychiatry and behavioral sciences and the Esther Ting Memorial Professor; Steven Asch, MD, MPH, professor of medicine; and Catherine Curtin, MD, associate professor of surgery. 

The work was funded by the Agency for Health Care Research and Quality

Stanford’s departments of Medicine, of Biomedical Data Science, of Surgery and of Anesthesiology, Perioperative and Pain Medicine also supported the work.


More information: Derek A. Frost et al. Efficacy of Tramadol for Pain Management in Patients Receiving Strong Cytochrome P450 2D6 Inhibitors, Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy (2019). DOI: 10.1002/phar.2269

Provided by University Hospitals Cleveland Medical Center

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