Study Finds Antidepressants Make Tramadol Less Effective for Pain Relief

By Pat Anson, PNN Editor

Common antidepressants interact with the opioid medication tramadol to make it less effective for pain relief, according to a small new study from University Hospitals (UH) in Cleveland. The findings suggest that some patients who exceed their prescribed dose of tramadol may be under-medicated and are seeking more effective pain relief.

Prescriptions for tramadol – which is sold under the brand names Ultram and ConZip – have increased in recent years because it is widely perceived as a “safer” opioid with less rick of addiction. Many patients, however, say tramadol is not as effective as hydrocodone, oxycodone and other opioids.  

UH researchers reviewed the prescription records of 152 patients who received tramadol for at least 24 hours.

Those patients who were also taking the antidepressants Prozac (fluoxetine), Paxil (paroxetine) or Wellbutrin (bupropion) required three times more tramadol per day to control their breakthrough pain, compared to patients not taking the antidepressants.

Previous studies on healthy volunteers have shown effects on blood levels when combining tramadol with those particular antidepressants. However, this was the first study 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," said Derek Frost, PharmD, a UH pharmacist and lead author of the study, which was published in the journal Pharmacotherapy.

Frost says millions of Americans may be suffering the ill effects of this drug-to-drug interaction.

"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.

“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."

Frost says the 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."

Tramadol is a synthetic opioid that was rescheduled by the Drug Enforcement Administration in 2014 as a Schedule IV controlled substance, a category that means it has a low potential for abuse. That same year, hydrocodone was rescheduled as a Schedule II drug, meaning it has a high potential for abuse. Many patients who were taking hydrocodone were switched to tramadol as a result of the rescheduling.

Is Tramadol Just as Addictive as Other Opioids?

By Pat Anson, PNN Editor

Patients recovering from surgery who take the opioid tramadol have a slightly higher risk of prolonged use than those receiving oxycodone or other short acting opioids, according to a large Mayo Clinic study.

Prescriptions for tramadol – which is sold under the brand names Ultram and ConZip – have been increasing because it is widely perceived as a “safer” opioid with less rick of addiction. The new study, published in The BMJ, appears to debunk that claim, at least for surgery patients.

Mayo Clinic researchers looked at health data for over 350,000 patients who were prescribed opioids after undergoing 20 common surgeries in the U.S. between 2009 and 2018. A little over 7% of the patients were still refilling opioid prescriptions 90-180 days later. When the researchers dug a little deeper into the data, they found that patients taking tramadol had a 6 percent higher risk of prolonged use compared to other opioids.  

"This data will force us to reevaluate our postsurgical prescribing guidelines," says lead author Cornelius Thiels, DO, a general surgery resident in Mayo Clinic School of Graduate Medical Education. "While tramadol may still be an acceptable option for some patients, our data suggests we should be as cautious with tramadol as we are with other short-acting opioids."

Tramadol is a synthetic opioid that was classified as a Schedule IV controlled substance by the Drug Enforcement Administration in 2014, a category that means it has a low potential for abuse. That same year, hydrocodone was rescheduled as a Schedule II drug, meaning it has a high potential for abuse.

Many patients who were taking hydrocodone were switched to tramadol as a result of the rescheduling.


Over half (53%) of the patients in the Mayo Clinic study were prescribed hydrocodone, about a third (37.5%) received oxycodone (also a Schedule II drug) , and only 4% received tramadol.

"We found that people who got tramadol were just as likely as people who got hydrocodone or oxycodone to continue using opioids past the point where their surgery pain would have been expected to be resolved," said senior author Molly Jeffery, PhD, the scientific director of research for the Mayo Clinic Division of Emergency Medicine. "This doesn't tie to the idea that tramadol is less habit forming than other opioids."

Jeffery and his colleagues say the DEA and FDA should consider reclassifying tramadol to a level that better reflects the risk of prolonged use.

"Given that tramadol is not as tightly regulated as other short-acting opioids, these findings warrant attention," said Thiels.

In 2017, the FDA banned the use of tramadol in children under the age of 12, citing a handful of cases where children died or had serious breathing problems after using the drug.

Tramadol was classified as a Schedule 3 drug in the United Kingdom in 2014. It is an unscheduled drug in Canada, but Health Canada is currently reviewing its status.

FDA Bans Use of Codeine and Tramadol in Children

By Pat Anson, Editor

The U.S. Food and Drug Administration is tightening restrictions on the use of codeine and tramadol in young children.

The agency says the opioid medications carry "serious risks" for children under the age of 12, including slowed or difficult breathing and possibly even death. The FDA is also recommending against the use of codeine and tramadol by breastfeeding mothers due to possible harm to their infants.

Codeine is approved to treat mild pain and cough, while tramadol is used to treat moderate pain. Codeine is usually combined with other medicines, such as acetaminophen, in prescription pain medication, as well as in some over-the-counter (OTC) cough and cold remedies. The FDA action only applies to prescription codeine.

"We know that some children who received codeine or tramadol have experienced life-threatening respiratory depression and death because they metabolize these medicines much faster than usual, casing dangerously high levels of active drug in their bodies," said Doug Throckmorton, MD, deputy director for regulatory programs, at the FDA Center for Drug Evaluation and Research.

"This is especially concerning in children under 12 years of age and adolescents who are obese or have conditions that may increase the risk of breathing problems, like obstructive sleep apnea or lung disease. Respiratory depression can also occur in nursing babies, when mothers who are ultra-rapid metabolizers take these types of medicines and pass it along to their children through their breast milk."

In a review of adverse event reports from 1969 to 2015, the FDA said it identified 64 cases of serious breathing problems, including 24 deaths, with codeine-containing medicines in children younger than 18. The agency also identified nine cases of serious breathing problems, including three deaths, with the use of tramadol by children.

The majority of serious side effects with both codeine and tramadol occurred in children younger than 12, and some cases occurred after a single dose.

The FDA is requiring drug makers to add a tougher warning to the labels of codeine and tramadol products, alerting healthcare providers and parents that codeine should not be used to treat pain or cough and tramadol should not be used to treat pain in children younger than 12.

The new labeling also cautions against their use in adolescents between 12 and 18 who are obese or have conditions such as obstructive sleep apnea or severe lung disease. Breastfeeding mothers will also be warned not to use the medications.

The FDA said it is considering additional regulatory action for the OTC codeine products that are available in some states. It is also considering an FDA Advisory Committee meeting to discuss the role of prescription opioid cough-and-cold medicines, including codeine, to treat cough in children.

The agency did not recommend or suggest any alternatives to codeine and tramadol to treat childrens' cough or pain. OTC medicines such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) also have risks and side effects.

"We understand that there are limited options when it comes to treating pain or cough in children, and that these changes may raise some questions for health care providers and parents. However, please know that our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe," said Throckmorton.

In 2015, the FDA approved the use of OxyContin in children ages 11 to 16  who are in severe pain, a move widely panned by addiction treatment activists who claimed kids would get easily hooked on the painkiller. 

Tramadol ER Visits Soar as Prescriptions Rise

By Pat Anson, Editor

Emergency room visits in the U.S. involving tramadol have nearly tripled in the last decade, coinciding with a sharp increase in the number of prescriptions for the opioid pain reliever.

According to a report by the Substance Abuse and Mental Health Services Administration (SAMHSA), emergency room visits involving adverse reactions to tramadol rose from 10,901 visits in 2005 to 27,421 visits in 2011. A second SAMHSA report  found a similar increase in the number of ER visits related to the abuse or misuse of tramadol. The vast majority of patients were treated and released.

Ironically, tramadol is considered less risky than other opioid painkillers and doctors have been increasingly prescribing it. The IMS Institute recently reported the number of tramadol prescriptions in the U.S. nearly doubled from 28 million in 2010 to over 44.2 million in 2014.

Tramadol is the active ingredient in brand name pain relievers such as Ultram, Ultracet, Ryzolt and Rybix.

“Tramadol is not abused as much as most pain medication, but it is often overtaken in an effort to obtain additional pain relief.  Like with all pain medication, excessive amounts can cause serious harm,” said Lynn Webster, MD, past president of the American Academy of Pain Medicine and vice president of scientific affairs at PRA Health Sciences.


Webster predicted that tramadol would be prescribed even more often when hydrocodone was reclassified in 2014 by the Drug Enforcement Administration from a Schedule III drug to a more restrictive Schedule II medication. Tramadol is a Schedule IV drug, meaning it has less potential for abuse than other narcotic pain relievers.

“In the past several years there has been tremendous pressure to reduce prescribing strong opioids. Tramadol has been used in place of other opioids. But it is not without risks as well,” said Webster in an email to Pain News Network.

“The rise in problems associated with tramadol underscores the larger problem of an unmet need to effectively treat pain. Most people, including policymakers, don't realize how many people are desperate to have their pain treated.”

About two-thirds of the ER visits related to misuse or abuse involved tramadol that was taken with other opioid pain relievers or anti-anxiety drugs (benzodiazepines). When tramadol is combined with other drugs that depress the central nervous system its sedative effects can be enhanced, causing seizures and a potentially fatal drug reaction known as serotonin syndrome.

Women were far more likely to have a tramadol-related trip to the ER than men, according to SAMHSA.

The greatest increase in tramadol-related misuse or abuse occurred in patients aged 55 and older. A SAMHSA spokesman said the higher number of older adults was not surprising because seniors are more likely to combine tramadol with other medication.

"Tramadol and other pain relievers can help to alleviate pain, but they must be used carefully and in close consultation with a physician," said SAMHSA Chief Medical Officer Elinore McCance-Katz, MD. "Like all medications tramadol can cause adverse reactions, which can be even more severe if the drug is misused. We must all work to lower the risks of taking prescription drugs.”