Is Your Antidepressant Lessening Pain Relief with Opioids by a Factor of 3 or 4?

Is Your Antidepressant Lessening Pain Relief with Opioids by a Factor of 3 or 4?

According to a study published in the journal Pharmacotherapy, common antidepressants interact with the opioid, tramadol, making it less effective for pain relief by a factor of three or four.

These findings from University Hospitals Cleveland Medical Center have important implications for people suffering in pain, as some are suspected of drug-seeking, but may in fact be under-medicated and just are seeking more effective pain relief. These findings also could help explain why some people exceed the prescribed dose of tramadol.

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 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 antidepressants., but this is the first to document the effects of this interaction in a real-world setting with pain 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.

So, what’s going on 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 and substantially reduced pain relief.

“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?”

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What a nice article, really complete. This is a very important issue these days


I don’t understand why Tramodol is so popular as a pain medication it has the highest risk of all pain meds for psychiatric side effects. Low dose ie 10mg slow release straightforward Morphine Sulphate is equivalent to two tramodol tablets, the standard dose, and avoids these risks. It’s also cheap. For breakthrough pain oromorph can be used but whoops no we aren’t allowed to say that an opioid and what’s more one that is not a synthetic overpriced one developed by Big Pharma, might treat pain (Tramodol is synthetic and was developed by big pharma). NSAIDS have a 1 in 1400 chance of death by stomach bleed yet here in the UK anyway they are available over the counter? We are living in a mad mad world.


Wouldn’t the next logical hypothesis be there is a possibility that the increase in the use of antidepressants and correlating increase in chronic pain cases could be related? If one deactivates the enzyme and one activates it. Wouldn’t there be an increase in pain for some people?


These doctors should be concerned that their patients will file a slander lawsuit against them! My primary physician got angry when I asked for a tramadol refill and basically called me a drug seeker, bitched me out and made me sign this opioid form or she would not give me the refill. She is very well aware that I have had a double mastectomy, 6 months of chemo 33 radiation treatments and 5 reconstruction surgeries all breast cancer related in the last 2 years and have been on some of the strongest narcotics and have not become addicted to anything. I am not in denial either and I have proof from my oncologist, plastic surgeon and my employer. The only thing I take now is TRAMADOL for chronic back pain which I have had for many years which she is also aware of so I decided to wean down from four 50 mg tabs to one 50 mg tab of tramadol a day with complete success. If I am addicted to anything its feeling normal and being able to function and hold a job.

I’m just saying if she ever speaks to me in that manner again there will be an issue.

The CYP2D6 enzyme also plays a role in converting dietary tyrosine to endogenous morphine. Over time, it has been found that patients on SSRI drugs develop higher serotonin output but also a stronger diurnal dopamine-morphine variation. A common complaint in major depressive disorder is sleeplessness and exhaustion. These CYP2D6 effects help the patient regulate sleeping and waking. A good research question is whether non-drowsy opioids like Mitragynine (from the Kratom plant) can help with pain control in folks who also have major depression.

This entire field deserves serious research. People in pain are seeking relief. Crooks who want to force us into useless quack treatments should accept that reality and find an honest line of work. When we say we’re in pain, we mean it. Don’t tell me to meditate about accepting death, when medication that actually works, is available.

Charles Poirier

Tramadol is a very mild pain reliever to begin with. Of course Physicians like to start out with the mildest thing for the least amount of time and there is a thing called a stigma associated with pain and of course Physicians and other Physicians judge each other on their prescribing habits and also there is a State Board of Pharmacy and State Board of Medicine that they have to worry about. This whole idea of pain relief using opioids has been totally blown out of proportion. Normally doctors can tell when somebody is addictive prone and so can pharmacists. As a former pharmacist it is my opinion that I have seen may be one out of 200 or 300 people be addiction prone and most drug addicts start out having the thought that if one doesn’t work two or three we probably will and this should be caught by the doctor or pharmacist and dealt with.The current and future laws that are in the works prohibit doctors from properly treating pain and the government thinks that they know the solution by prohibiting doctors from prescribing opioids. The whole problem lies in illegal drugs not prescribing by doctors. Our Congress should realize they are doing the exact opposite of what is needed for a solution the drugs coming over the Border are the main problem and not doctors!!!!


My situation is being initially forced to take the antidepressant Cymbalta in order to taper down from my once effective opioid medications! First of all I didn’t start out being depressed, I don’t have nerve pain. My pain is specifically due to an autoimmune disease, rheumatoid arthritis and widespread body pain due to fibromyalgia.
I WAS living a fairly normal life when treated with the medications specific to RA and the proper amount of opioid medications, which I had been successfully treated with for almost 20 years.
Since being forced onto an anti-depressant and my pain medication reduced, my pain is worse, I’m constantly fatigued, and I don’t feel normal.
I should have the choice to take the medications that were most effective for my diseases and pain, that gave me the best quality of life instead of being forced to take what some bureaucrat in Washington or some fake pain expert, like Andrew Kolodny, thinks is best!
Regardless of what the fake news reports, prescribed opioids for pain ARE very safe when taken as directed, but I sure can’t say the same thing about these antidepressants!


My doctor,not pain dr who perscibes my pain med,but my primary dr and I had a discussion about pain meds being forced tapered and stopped for chronic pain patients. My doctor said that she gets threatening letters from the CDC about perscriptions for opiates. She said that they ARE threatening. She said that each doctor is allowed to write a certain amount of pain medication perscriptions a year. This is why so many pain management doctors are not taking new patients because they are not allowed to treat ppl as needed. Even if a patient has tried other medications nd physical therapy and steroid shots and other procedures and it dont work,the CDC dont care. They threaten the doctors if they write perscriptions. The CDC also wrote that the dr has to cut back on everyones pain meds. I have been getting 60 a months at low dose but my pain dr walked up to the the front desk last month when I was paying for my office visit I just had. ,handed me my perscription for 60,and said ,next month your only getting 45& it’s not my fault it’s the cdc. I was so upset because she came out in front of the nurse,the receptionist, the patients in waiting room and said this to me. She said I have to tapper .She didnt offer any advice or suggestions or anything. I thought that this was violation of my privacy to come out in front of ppl I dont know and talk to me like that .ppl who need the meds will go to the streets and buy them. They will take risks that they are tainted with fentanyl or something else. I cant understand why they are coming down on the pain patients and drs. The heroin addicts that overdose are mixed in the statistics of all the ppl who overdosed on opiates,all ppl that mixed opiates with other drugs and alcohol and died,and heroin addicts, and anyone who took opiates and died. Pain managements patients are to take drug tests to see if they are taking their medications and not selling them.its clearly that the chronic pain patients are not the issue. W

diana balboni

6 months ago I tried to commit suicide because my primary care doctor of 25 years had been told by the group he works under that he would no longer be able to prescribe opiods or any anti anxiety medication for me not any of his other patients with chronic pain diseases because of the “opioid crisis”. I couldn’t see a life in constant pain. Obviously, I was unsuccessful. I spent 8 days in the hospital, 3 in ICU. After that, I was forced into a psychiatric facility. Although I had been given morphine and my pain meds and my valium in the hospital, I was forced into severe withdrawal in the psych ward (my roommate was having seizures for same). I got sicker than ever. After 3 days of hell, the shrink made me take a drug called Subutex, an opioid that is stronger than the opioid I was on, which makes it impossible to take other opioids. The shrink also refused to acknowledge anxiety disorders as an illness and told his patients to “deal with it” and “live with it”. After 3 weeks of there, I was finally able to get out and return to my home. I had nightmares about him and that place for a month before they started to slowly go away. If they had just individualized patients on a case by case study they would have known that I was closely monitored on the meds my doctor had me on and they were low doses comparatively. I am not alone. I just read yet another article about a man from Ohio who this happened to but he was successful in his suicide. His was carefully planned and successful, leaving his family devastated. There are many cases of this happening. When are lawmakers going to advicate for chronic pain sufferers? How many people have to also die, not by heroin overdose but by tragic suicides?


I took antidepressants for 23 years. I stopped all – Effexor, Welbutrin, Abilify, and Lexapro – 4 years ago. (My first point i was on 4 antidepressants, two moid stabilizers, and 2 anti anxiety.)That’s when my chronic pain started. I have been on a mirage of opioids: vicodin, percocet, oxycontin – with no pain reduction. Nothing. My daily pain is between an 8 to 10. I currently take MorphineXR and Dilauded. My pain is still excruciating. I have always wondered if the antidepressants scrambled my brain and that’s why I can’t reduce my pain. Were my nerve endings irrerversabily damaged? So frustrating nothing helpsmy pain…


A friend was told to use NSAIDS for recurring profound migraines.
Physician told them there lab would be monitored for any problems with NSAIDS. Didn’t tell them why but I knew.
NSAIDS can cause nonreversable
kidney and liver damage.
So my question is how much damage is required before the COMPLIANT patient is allowed Tramadol. Once damage is done and one is 40yo all is downhill as to kidney function. Who establishes the blood levels to stop NSAIDS? If infection attacks kidneys, antibiotics can damage kidney function, and now this person is 65yo and less than half of kidney function they should have Has an MI more kidney loss now down to GFR of 30.
So this patient has a history of ulcerated ulcers can’t take NSAIDS.
Compliant patient because they ask about a pain medication once in 10 yrs of seeing this physician is labeled a drug seeker and possible addict. What A Travisty of negligent injustice to this patient and they have to wait till government agencies provide clear consise guidelines for physician’s that benefit irretractable chronic pain patients appropriate care and medication.
Now a study about about antidepressant but government agencies silent. Suicides, Suicides, Suicides, the collateral damage from these guidelines.
Profound depression ignored, medication abruptly stopped, physician loss, no medical support, dignity stripped, classified a drug seeker addict.
How long will government agencies allow the Suicides, negligence by guidelines, and citizens loss of jobs, insurance, and losses that will never be returned to again. Continued SILENCE SILENCE Suicides
Government agencies don’t and won’t listen.


“Suspected of drug seeking” these educated medical personnel always make those words synomonus with any compliant intracable chronic pain patients. These patients are profiled and placed in medical journals with drug addicts. COMPLIANT intracable chronic pain patient dare not ask for a higher dose, or try another pain medication because this is a sign of mental instability and weakness. We are profiled to the point of banishment from any appropriate
medical care because we are trying to figure out what can help us stay compliant yet pain free. The medical community has lost it’s knowledge of “first do no harm” in prescribing Opoids. Opoids drugs and many others are helpful medications when it comes to relief of pain. Compliant Intracable Chronic Pain Patient’s are legitimate honest citizens just trying to have medical care appropriate for there profound pain. We have no say in our medical care as to the pain level we are experiencing. Our plan of care doesn’t include our input since we are falsely accused of being drug seekers and addicts.
Our medical community needs to revamp there labeling of irretractable chronic pain patients and allow us to discuss our pain level, lack of activity, meds we think might help us and together with our physician develop a plan of care to include pain medication
when needed.
Medical care and pain medication are synomonus and can work together for an irretractable chronic pain patient to live a life of enjoyment.
Help us the compliant intracable chronic pain patients to regain our dignity and use Opoids with a positive medical plan of care.


I know for a fact Baclofen a muscle relaxer when taking hydrocodone and oxycodone my pain meds didn’t work to control pain at all.Pain would become elevated and I believe something in Baclofen blocks pain meds from working .I stopped taking Baclofen and amazing results my pain meds were able to work .Also Baclofen was not working at all I had chronic 24/7 neck spasm that never went away even when taking it .then I was given 10 shots into the muscles with Baclofen and still the spasm stayed since a neck fusion .
So I am just saying they do not mix for effective treatment for me maybe others have had the same issue ..


Well, this was enlightening. I want to know more. I take 60mg duloxitine (cymbalta) once a day and 5mg oxycodone (percocet) twice a day. The opiate does not last very long. Is it possible the duloxitine is inhibiting it? I have zero desire to go up in dose on either medication but my pain is not managed well either.

Hayden Hamby Jr.

THANK YOU Dr. Heck. It’s inspiring to hear from an M.D. that actually listened to patients with real pain management issues. and not immediately suspect that all patients are simply seeking drugs for a “high”. WE, the patients HAVE to be honest about our pain levels because we are truly trying to simply manage our pain and get it down to a level that will allow us to function well enough to do the simple, daily necessities in life. I have not had ONE day without a pain level of at least 5 in 25 years. Now with the CDC “guideline” and the DEA officiating as physicians I have to “live” with an average pain ;level of 7 and 20 to 30 percent of the time in a month period of time, it is higher than a 7. Again, THANK YOU for your professional insight!!!!!!

Homesick Clifford

There seems to be some frenzy about pain relief using opioid types. I’ve been on vicodin now called norco for quite a few years and suffer from acute sciatica that periodically cripples me shoot from lower back to above knee. I take 1 19mg tablet 3xdaily. Doctors have wanted to do surgery which some of my associates are worse than before, and they tell them well ” try again” WOW..I believe most doctors are more concerned for their licence than helping a suffering human. Yes I am addicted..sudden withdrawal would prove that. Politics is the game..some self righteous me first candidate is trying to make a name for himself. for his résumé..YES there are drug seekers ONLY! But I’m nearly 75 and to removed me suddenly from this medicine would kill me! It’s not that difficult to weed out the abusers.. but in this insane political ambience.. Only fools are looking for some band.wagon to bring them fame and fortune..because they go after the doctors..that’s the ” head of the snake”…do that and as always the ” little man” is helpless. Then many will abuse legal alcohol or buy cheap street drugs. AND THEY KNOW IT!!

Toni Taylor

The war on opioids is a war on pain patients. I’m currently lobbying for pain patient protection legislation. I’m mailing packets with pain patients stories to our reps and the media. If you’d like your story included please email it to me at We have to start fighting back or eventually it’ll be impossible to get relief from chronic pain.

Thomas Wayne Kidd

Because pain patients are not productive is what I meant. Thank you. Let’s face it government and their departments, including the HHS cannot be trusted. And I so appreciate the comments of Dr. Debbie Nickels Heck. I remember when I was listened to and believed. Now I am treated as a drug addict, criminal and liar. Thank you Doctor. God bless you.

Thomas Wayne Kidd

Tramadol is not an opioid! It was only declared an opioid because people were supposedly abusing it. We keep getting misinformation and half truths and the madness continues. Let’s face the raw truth, the sick and dying are being singled out for elimination because we can in most cases be as productive. But what I am talking about will not be believed until it becomes plain. Then it will be much to late. People like me will be labelled as insane and put away so their evil plan can continue. Millions in our country alone know little to nothing about the times we are now living in, and this is because they have been living according to the traditions of their elders which has been opposed to the truth since it’s beginning. The plain truth is that we are living in the time of the end of all things pertaining to mankind. Those who actually and truly believe and live according to God’s revealed written Word will survive, those who reject it will perish. It’s this simple. But not many people will actually grasp this and saved themselves. This grieves me in my very spirit. Again I say; Tramadol is not and never was an opioid pain medicine, it only acts like one. Check this out for yourselves.


Yea my anxiety was treated with neurontin because its not controlled yet withdrawal and dependence occur twice as bad with neurontin vs benzos and 3x worse than Klonopin. I think Klonopin is the safest anxiety med around but oh im “a drug abuser” and a liability wen in reality gabapentin is a garbage drug that leaves the patient in a state of withdrawal that can actually kill

Gail Honadle

If you take certain medications, you are Automatically labeled a Drug Seeker. Plaquenil is 1, Valium, Flexeril muscle relaxer, OA, OP medication, and any Physche med you are a Drug Seeker they put that in your Medical Records. And HIPPA is NO LONGER a safety document as it is Shared with any one who prescribes or treats you right down to your Pharmacist.

Debbie Nickels Heck, MD

Once again, BELIEVE YOUR PATIENT! You can learn so much by just listening to what they say. They’re NOT LYING! They’re giving you VITAL information you can pass along to pharm reps which gives them the opportunity to research a REAL WORLD problem. Why do Dr’s so readily jump to the conclusion their patients are lying? I never did! I believed them! Silly me. I them told my reps there was something wrong with the use of one or both of the meds and they needed to report this back to their superiors. By having a policy of ABSOLUTE HONESTY with my patients, we could trust each other. We didn’t have a feeling of antagonism with each other. I realize that was unique and it’s the main aspect of being in practice I miss: the uniqueness of honesty I had in my practice with patients most practices didn’t have which I’ve always felt was so pathetic. We learned so much that helped each other.

Lisa M Howard

This made me smile, people are beginning to see that most are not drug seeking.
This is just the beginning!
Thank u Staff!