SSRIs May Impair Effectiveness of Some Opioids

SSRIs May Impair Effectiveness of Prodrug Opioids For Post-op Pain – Pain Medicine NewsJun, 2019

A multidisciplinary team of researchers from Stanford University and the VA Palo Alto Healthcare System recently published findings that indicate patients taking selective serotonin reuptake inhibitors (ssRIs) and treated with prodrug opioids to manage postsurgical pain may have worse pain outcomes than those prescribed active opioids (PLoS One 2019;14[2]:e0210575).

“An anesthesiologist came to us with information about this relationship that’s showing up in bench labs,” Dr. Hernandez-Boussard told Pain Medicine News, explaining how one of her co-authors was intrigued by an increasing body of research pointing to potentially antagonistic interactions between prodrug opioids and ssRIs affecting the cytochrome enzyme CYP2D6 in the liver (Acad Emerg Med 2014;21[8]:879-885).  

The prodrug opioid uses it for metabolism throughout the body and the ssRI inhibits its activation. “[He] asked if we could put it through our algorithms to find out if that relationship shows up on a clinical level.”

Her team pulled the electronic health records of 41,713 patients at Stanford University Hospital who underwent orthopedic, vascular and/or general surgeries from 2006 to 2014 based on International Classification of Diseases, 9th and 10th revisions and Current Procedural Terminology codes.

They recorded data on demographics, diagnosis, treatment plan, procedures, diagnostic results and any other medications within 30 days of the date of surgery, as well as all clinical notes and medication history up to six months before admission for surgery.

The analysis left 4,306 patients in the sample:

  • 606 patients taking an ssRI and a prodrug,
  • 1,285 patients taking an ssRI only,
  • 802 patients taking a prodrug only, and
  • 1,613 patients receiving neither drug.

The best performing of three predictive models tested found that patients on ssRIs and treated with prodrug opioids for pain management experienced a mean difference in pain score of 0.559 higher at discharge (0.720 on a 0-10 scale) than those who received active opioids (0.161)—a trend that continued through follow-up at both three weeks and eight weeks.

“Though the overall effect seems small, it is clinically significant,” Dr. Hernandez-Boussard said. “And it’s an average; there are quite a number of patients with much more severe pain effects.”

For the investigators, the implications are clear.

“We provide the first direct clinical evidence that the known ability of ssRIs to inhibit prodrug opioid effectiveness is associated with worse pain control among depressed patients,” they wrote. 

In addition, considering the known causal and correlative relationships between pain and depression, and how frequently health care providers write prodrug opioid prescriptions for patients already on ssRIs, they conclude that “the study results imply that prescribers might instead choose direct-acting opioids (e.g., oxycodone or morphine) in depressed patients on ssRIs.”

And here’s some of the actual study:

Predicting inadequate postoperative pain management in depressed patients: A machine learning approach – Plos One – February 6, 2019

Widely-prescribed prodrug opioids (e.g., hydrocodone) require conversion by liver enzyme CYP-2D6 to exert their analgesic effects. 

The most commonly prescribed antidepressant, selective serotonin reuptake inhibitors (SSRIs), inhibits CYP-2D6 activity and therefore may reduce the effectiveness of prodrug opioids

We provide the first direct clinical evidence that the known ability of SSRIs to inhibit prodrug opioid effectiveness is associated with worse pain control among depressed patients.

Current prescribing patterns indicate that prescribers may not account for this interaction when choosing an opioid. The study results imply that prescribers might instead choose direct acting opioids (e.g. oxycodone or morphine) in depressed patients on SSRIs.


Opioids are currently a first-line treatment of postoperative pain and surgery may be a gateway to opioid misuse

Depression is a common comorbidity and effects postoperative pain management.

Longitudinal epidemiologic studies evaluating depression indicate that patients with depression are between two to five times more likely to have a new chronic pain problem at follow-up from one to eight years later

Antidepressants are the most commonly prescribed class of medications in the US and selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed type of antidepressant.

New evidence suggests that SSRI’s could inhibit the metabolic conversion of certain opioids known as prodrug opioids, e.g. hydrocodone and codeine decreasing their efficacy for pain management.

Opioids are thought to exert their analgesic effects by binding to the Mu opioid receptor in the brain and spinal cord.

Some opioids directly bind to the mu-opioid receptor in their native form including oxycodone, morphine, hydromorphone, fentanyl, and methadone.

Other opioids require chemical conversion to an active form by a de-methylation reaction mediated in the human liver by CYP-2D6, a member of the cytochrome p450 enzyme system

Such drugs are known as prodrug opioids, requiring metabolism and chemical modification to exert their pharmacological effect.

Examples include hydrocodone– the most commonly prescribed drug in the nation which is the opioid ingredient in Vicodin, Lortab, and Norco. A recent study suggested that the interaction of a CYP-2D6 inhibitor might be important in reducing the effectiveness of hydrocodone.

Understanding the effects on pain control of the common antidepressant SSRI, a CYP-2D6 inhibitor, is essential to manage pain control is this vulnerable population with mental illness.


The findings from this study demonstrate that depressed patients receiving SSRIs and prodrug opioids had inferior postoperative pain control and this drug-drug combination can accurately predict the increase or decrease in pain scores at discharge, 3 week and 8 week follow-up visits.

 We also present evidence that this drug-drug interaction is not taken into account when prescribing analgesics; the prescribing of prodrug opioids did not differ by SSRI medications. Our findings indicate that depressed patients taking SSRIs should receive a direct-acting rather than prodrug opioid for postoperative pain control.

In conclusion, our results suggest that prodrug opioids for postoperative pain control after discharge are less effective than active form opioids in patients on SSRIs. T

he inhibition of metabolic conversion of the prodrug opioids by the SSRI had been theorized to impair pain control, however ours is the first study to demonstrate this interaction in a clinical population of depressed patients using SSRI’s therapeutically.

Our predictive model may help future researchers better personalize pain management regimes. If confirmed, prescribers should consider alternatives to prodrug opiates in pain management for patients taking SSRIs.

2 thoughts on “SSRIs May Impair Effectiveness of Some Opioids

  1. Kathy C

    This did not get any mass media attention. The fact is that anti depressants were highly marketed for pain and or depression. Anti Depressants were the first line treatment, for any patient reporting pain. Physicians were more than eager to prescribe anti depressants, it was more cost effective than diagnosing the underlying pain, and because these drugs were not opiates, the marketing told them that these drugs were “not addictive.”

    Prescribing anti depressants had a two fold purpose, it acted as a place holder for patients without a diagnosis, and unlikely to get one, while it made it appear that the patient was treated. Once a patient was given an anti depressant, it meant that their symptoms could be ignored, even if the symptoms were due to the anti depressant. For many patients, those with less highly reimbursing insurance, women, and minorities, it meant that the cause of the pain could be ignored, and go untreated.

    This should be a serious scandal, but once again these factual studies will be buried. No mass media will cover this story, because it would shed light on the corruption and profiteering in the healthcare industry.

    Anti depressants are ubiquitous, something like one fifth of the population is taking an anti depressant. Nearly every patient who reports pain, is prescribed an anti depressant, or a noxious combination of gabapentin, muscle relaxers, and some are even prescribed anti psychotics, when they report inability to sleep. The most obvious symptoms, due to untreated pain, distress, lack of sleep and inability to function, are treated instead of the pain. The combination of these drugs, lead to more depression, frustration and distress, which they interpret as a mental health issue, instead of untreated pain.

    One way to interpret this information is that the rampant over prescribing of anti depressants, may have led to more post operative pain and opioid addiction. Of course women, and minorities would have been more likely to be prescribed anti depressants, and would have waited longer for for these surgeries. Lower income people often postpone medical appointments, and wait longer for medical care. When these groups did report post surgical pain, they would have been ignored, and the pain attributed to psychological factors or even “Catastrophizing.”

    Once again a serious phenomenon did not get studied, because the medical and pharmaceutical industries, did not see anything profitable there. This kind of research could cut into profits, for the pharmaceutical industry. We won’t be seeing a discussion of this on the Standford Pain Twitter feed, or their newsletter, it could effect their industry funded research.

    The patients who did experience this drug reaction would have been blamed for reporting increased pain, or the increased pain would have been attributed to depression. Countless researchers have been studying Mindset and attitude, in relation to post operative pain. Not all people taking anti depressants are actually depressed, these drugs have been widely prescribed for numerous conditions, like pain, or the distress over being sick.

    Once again, this proves that they are Gas Lighting us all. There was no industry funding for researching these drugs, it was easier to attribute these interactions, to the patients mindset hysteria or catastrophizing. Of course there was a lot more research funding finding fault with patients instead of looking at the healthcare system or pharmaceutical industry. They do not make any distinction between “depression” due to long term pain and distress, and actual clinic depression. They have not studied the devastating effects from Gas Lighting patients. Due to no clear reporting requirements, there is not much data about this topic.

    There are plenty of medical and health related websites promoting anti depressants for pain, and post op pain. It looks like post op depression is a really common occurrence. Surgery is a trauma on the body, and almost no research has been done on reducing, or identifying this trauma. Patients who undergo adverse events before or after surgery, are often Gas Lighted, by hospital personnel. A post surgical patient or a patient with chronic pain before the surgery, that reports increased pain, would be accused of opioid addiction, or a mental health issue, if they were taking opioids or an anti depressant. The media has often reported that people taking opioids before surgery, people who have a lot pain prior to surgery, are more likely to become “addicted.” There is still no clear distinction between dependence and addiction, for journalists and content marketers.



Other thoughts?

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.