Common Antidepressants Interact with Common Opioid Medication to Lessen Pain Relief, UH Study Finds

Findings could help explain apparent opioid drug-seeking behavior and opioid overuse

UH Clinical Update | June 2019

Common antidepressants interact with the opioid pain medication tramadol to make it less effective for pain relief, according to a new study from University Hospitals. 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 could also help explain why some people exceed the prescribed dose of tramadol, increasing their risk of addiction. The study was published recently in the journal Pharmacotherapy.

Researchers reviewed the medication records of 152 patients at UH Cleveland Medical Center and UH Geauga Medical Center, a campus of UH Regional Hospitals who received scheduled tramadol for at least 24 hours. All participants in the study were admitted as inpatients or observation status. Those patients who were also 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 the secondary analysis, it ended up being four times as much over their entire hospital stay,” says 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 says.

What explains the interaction between tramadol and these antidepressants?

“Tramadol relies on activation of the CYP2D6 enzyme to give you that pain control,” Frost says. “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 says. “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 says, 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 says. “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 says. “And for healthcare providers, if you have a patient approaching you saying this medication isn’t working for me, ask whether there an interaction at play.