Antidepressants Can Interfere With Pain Relief Of Common Opioids

Combining some common antidepressants and opioids can undercut the relief of the painkillers.

Antidepressants may dampen the effects of some common opioids, resulting in less effective pain management according to research findings published Wednesday. The researchers suggest physicians should consider alternative pain management strategies for patients on antidepressants.

Opioids come in two broad varieties: those that act directly and others that have to be chemically processed by the body before they can begin to relieve pain. Direct-acting opioids, like morphine or oxycodone, can get right to work.

The other kind are called “prodrugs” and include hydrocodone, the opioid ingredient in Vicodin. Prodrugs need to be metabolized in the liver before they’re able to bind with pain receptors in the brain.

The problem, according to Tina Hernandez-Boussard, the Stanford computational biologist who co-led the study published Wednesday in the journal PLOS ONE, is that selective serotonin reuptake inhibitors, or SSRIs, like Prozac or Zoloft, inhibit the activity of an enzyme in the liver, called CYP-2D6, that metabolizes prodrug opioids.

If the enzyme can’t do its job, then the opioid can’t either — or at least not as well.

Prodrug opioids and SSRIs are two of the most commonly prescribed medications in the US, meaning this interaction could potentially affect millions, according to Hernandez-Boussard.

“There was theoretical evidence that suggested SSRIs might block prodrug opioids, but we didn’t know if it actually affected patient outcomes,” says Hernandez-Boussard.

To find out, Hernandez-Boussard and her team mined the electronic medical records of 4,300 surgical patients who had previously been diagnosed with depression. About half of those patients were taking an SSRI antidepressant. The researchers used a machine learning approach to tease apart the effects of SSRI use, opioid type, and pre- and postoperative pain, as measured on a 0-10 scale.

The researchers found that patients on an SSRI who were prescribed a prodrug opioid, such as Vicodin, had significantly more pain after surgery than all other groups when they left the hospital. This effect persisted up to two months after surgery. “On average, SSRI and prodrug opioid patients had 1 point worse pain on the 0 to 10 scale,” says Hernandez Boussard.

One specific result of their analysis underlined the dampening effect of SSRIs for Hernandez-Boussard. As a rule, patients with higher pre-operative pain tend to have higher post-operative pain.

The researchers found that patients on SSRI medication with higher pre-operative pain tended to get prescribed non-prodrug opioids, which are often considered stronger. Despite having more pain before surgery, these SSRI/non-prodrug patients fared better than the lower preoperative pain SSRI/prodrug patients.

“This is an important study,” says Jenny Wilkerson, a professor of pharmacodynamics at the University of Florida who wasn’t involved in the study. She says that genetic variations in the CYP-2D6 enzyme can interfere with opioid metabolism in other ways, and that this study advances our understanding of how SSRIs alter the effectiveness of opioids. She adds that she’d like to more studies in different populations to better understand the impact of this interaction on patients.

Hernandez-Boussard says these results could lead to better pain management and reduce opioid prescriptions. “If the opioids aren’t being activated and you’re not getting appropriate pain management, you’re going to take more opioids and you’re going to take them for a longer period of time,” she says. Apart from patients simply being in more pain than they need to be, this interaction “could lead to misuse or abuse down the road.”


“This combination of SSRIs and prodrug opioids is likely pretty common,” says Hernandez-Boussard. Consequently, she says the potential interaction should be recognized and discussed at the point of care.

“Every opioid has a side effect, not one opioid that is better than another,” says Hernandez-Boussard. “Possibly for patients taking SSRI, morphine or oxycodone, direct-acting drugs which don’t need to be broken down by the liver might be a better choice.”

Wilkerson echoes the importance of a discussion between physicians and patients about SSRI use and pain management options, a conversation that can be complicated by mental illness. “Patients shouldn’t feel stigmatized for being depressed or in pain,” she says, “patients have to advocate for their best personal care.”

Patients who are depressed and taking SSRIs are already a vulnerable population, known to experience more pain, and to have more trouble managing it. Hernandez-Boussard hopes that this study will help doctors tailor pain treatment towards the millions of Americans taking antidepressants.

“We need to think about how we can tailor treatment towards more vulnerable groups,” she says. “More work needs to be done, but this is a good first step.”

7 Responses

  1. What I don’t like about this piece is the complete speculation that it could lead to “misuse or abuse down the road”. If this were a court of law it would be “objectionable” as conjecture. Also the statement that opioids might be contraindicated. What about a higher dose? These are attempts to make there observational study relevant to current topics or clinical practice but it is just such stretches that have gotten us into our current predicament. A clinician might see these comments as “results” of the study when they are not.

  2. Ok, kids, take a breather.
    This study and might I add a very early one at that isn’t a ” Ban the evil opioids” study. After reading and rereading I feel that it’s makes some sense. This lady isn’t suggesting that opioids aren’t for those that also are prescribed mental health medications. Based on her findings of a small group (post-op patients) that a certain class of SSRI Meds could interfere with a certain group of pain medication. If that certainly is the case she further suggests taking a different kind of pain medication. Short. Sweet and Simple.
    I’m very interested in this study as I feel this is the tip of the iceberg.
    I take an SNRI, temporarily an aminoketone (another type of antidepressant). When the aminoketone is stopped I’ll resume lithium and asenipine. I presently take short acting oxycodone and Nucynta ER. On the 15th I will switch to two a day long acting oxycodone. As I’ve been on the former regimen 4-5 yrs. How these meds interact and if my mental health meds detract efficacy from my pain management meds is very curious to me.
    As stated earlier, this study is in its infancy and isn’t the definitive on how and what to prescribe. Most Drs pain management and mental health alike are probably unaware of this study. Take it with a grain of salt and take care.

  3. I am wondering now if this could be why there are so many that need the higher doses? I see this quite a bit in the groups that I am in, that they metabolize quicker and need higher amounts. I know quite a few are also on antidepressants and it seems like this could be the reason why they don’t seem to work well for them.

  4. So, what are their suggestions for “alternative pain management therapies”? Hmm? I honestly would like to know as I may need another lumpectomy or even a radical mastectomy… however, if the answer involves meditation and guided image therapy, you know what you can do with those. 😉

  5. Thank you for this.. I’d like to show it to my doctor to see if she would be willing to switch me from hydrocodone to oxycodone. I knew this was an issue for me since I received my results from my drug metabolization test a while ago, I just wasn’t sure what to ask for in substitution of the hydrocodone. Hopefully this won’t be an issue but it seems doctors are more reluctant to prescribe oxycodone over hydrocodone. Is there a reason for this? The way I understood it is that they are equivalent to each other, is that not the case? I’ll do anything to try to help my pain relief. I believe I now have Tarlov Cysts and I am not looking forward to dealing with them. I have already been through one misunderstood condition and came out on the other side for the better but it took years and a lot of money to get to the right doctors. The thought of having to do it all over again is frightening and depressing.

  6. oh for god’s sake; is it actually legal to publish anything any more without concluding that “X” will be helpful in reducing opioid Rxes b/c that is obviously desirable in all cases.”

    And ““Patients shouldn’t feel stigmatized for being depressed or in pain,” she says, “patients have to advocate for their best personal care.” is just freakin’ hilarious. She really needs to look at the real world.

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