Drug Profile

Do Not Use: These drugs are no more effective than similar drugs, are addictive and cause seizures.

Tramadol (ULTRAM) was first sold in the United States in 1995. It is heavily promoted to doctors as being equivalent to acetaminophen and codeine (TYLENOL WITH CODEINE) and having a low potential to cause addiction. In fact, tramadol appears to be no more (and sometimes less) effective than combinations of codeine with aspirin or acetaminophen.[1] One observational study published in 2021 also found that, compared to treatment with codeine, initiation of treatment with tramadol was associated with a higher risk of adverse cardiovascular events, fractures and death from any cause.[2]

In 2014, the Drug Enforcement Administration (DEA) classified tramadol as a controlled substance in the weakly restricted schedule IV.[3] (See acetaminophen for an alternative drug.)

Adverse effects

Within the first year of tramadol being on the market in the United States, serious adverse effects were reported to the Food and Drug Administration (FDA), in some cases after just the first dose. These adverse effects included seizures and severe allergic reactions.

Potential for addiction and overdose

Tramadol's effects are similar to those of the narcotic pain relievers morphine and codeine, including the potential to cause addiction. Ortho-McNeil Pharmaceutical, the producer of the drug, advertised heavily to doctors that tramadol had a low potential for abuse. However, among the adverse events reported to the FDA within the drug's first year on the market were 115 reports of drug abuse, dependence, withdrawal or intentional overdose.[4] Countless consumers who were not told that tramadol was addicting may have unknowingly become dependent on this drug. Patients who are rapid metabolizers of the drug are more susceptible to addiction and unintentional overdose.[5],[6]

In 2019, BMJ published an article warning that tramadol was associated with an increased risk of drug dependence when used to treat short-term pain.[7]

Seizures and convulsions

Within the first year of the drug being available in the United States, the FDA received 83 reports of seizures or convulsions among people using tramadol.[4] During the drug's second year on the market, the FDA received more than 200 reports of seizures. (The FDA conservatively estimates that for every report of an adverse drug reaction, 10 go unreported.) Many of the reports noted that the seizures occurred within one day of starting tramadol. Most of these people were healthy and between the ages of 20 and 39 years, and most had no previous history of seizures.

Seizures or convulsions can occur at recommended dosages, although an overdose may increase the risk of tramadol-related seizures. Taking tramadol with antidepressant drugs, including the newer selective serotonin reuptake inhibitors (SSRIs) and older tricyclic antidepressants, increases the risk of seizures.[8]

Serotonin syndrome

Serotonin syndrome may occur when tramadol is used with SSRI or selective serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants or when used with triptans (migraine drugs).[9]

Serotonin syndrome develops when the body is exposed to too much of the naturally occurring chemical serotonin. Serotonin is found in the brain, blood and gastrointestinal tract. The combination of triptans with SSRIs or SNRIs can increase serotonin to extremely high levels that could result in serotonin syndrome.

The symptoms of serotonin syndrome include:

• restlessness
• hallucinations
• loss of coordination
• rapid heartbeat
• rapid changes in blood pressure
• increased body temperature
• overactive reflexes
• nausea
• vomiting
• diarrhea

Other serious adverse effects

The FDA-approved product labeling for tramadol also warns that the drug may cause severe hypotension (low blood pressure) and fainting. Use of the drug also has been linked to cases of severe hypoglycemia (low blood sugar) leading to hospitalization and hyponatremia (low blood sodium levels). [10]

Foreign reports of adverse effects

Problems with tramadol have been reported in other countries. For example, in 2002 tramadol was the third most frequently involved drug in withdrawal reactions reported to British drug regulatory authorities.[11]

The Swedish adverse reaction database, SWEDIS, contains 71 reports from 1996 to 2005 of abstinence/withdrawal symptoms with tramadol. Of those, 25 also were classed as dependence, habituation or increased tolerance.

New Zealand's Centre for Adverse Reactions Monitoring has received multiple reports of suspected adverse reactions to tramadol. Evidence of an interaction between oral tramadol and the anticoagulant (blood thinner) warfarin (COUMADIN) has been provided by both international and local case reports, although the mechanism has yet to be determined. This interaction results in an elevated international normalized ratio (an abnormally long time for blood to clot), and in some cases it has resulted in hemorrhaging or bruising.[12]

In November 2011, Prescrire International published an article on four case reports of tramadol withdrawal symptoms in infants whose mothers took tramadol during pregnancy. The article stated that pregnant women experiencing pain should not take tramadol due to its effects on infants exposed in utero and that newborns should be monitored for symptoms of withdrawal.[13] Another article in Prescrire International in March 2011 reviewed the occurrence of hypoglycemia associated with tramadol and codeine use. According to the article, cases of hypoglycemia occurred in patients who were 70 years of age on average. The article also stated that other risk factors for hypoglycemia were noted in more than one-third of the patients studied.[14]

In 2019, JAMA published a study showing that tramadol was associated with an increased risk of death from any cause in patients 50 years and older who have osteoarthritis.[15]

In 2022, Arthritis Research and Therapy published a study demonstrating that tramadol, when compared with nonsteroidal anti-inflammatory drugs (NSAIDs), was associated with a higher risk of death, blood clots in the veins and hip fractures in patients with osteoarthritis.[16]

In 2022, the European Journal of Pain published a study showing that tramadol, when compared with NSAIDs, was associated with an increased risk of pneumonia in patients aged 50 years and older.[17]

In 2022, the European Journal of Clinical Pharmacology published a study showing an increased risk of bleeding when tramadol was used with some blood thinner drugs, including warfarin .[18]

In 2023, Drugs in R&D published an article showing that taking ULTRACET, a combination pill consisting of tramadol and acetaminophen, was associated with a higher risk of low blood sodium levels than was taking acetaminophen alone.[19]

Regulatory actions surrounding tramadol

2010: The FDA updated the warning section of the drug label for tramadol products with information concerning the risk of overdose and suicide and the risk of tramadol-related deaths in patients who are addiction-prone or are taking tranquilizers or antidepressants.[20]

2011: The FDA issued an advisory concerning the strength of acetaminophen in prescription drug products. The FDA requested that drug manufacturers limit the strength of acetaminophen in prescription drug products to 325 milligrams per tablet. The agency also required that a boxed warning that highlights the potential for severe liver injury be added to the drug label of all acetaminophen-containing prescription products. The agency stated that another warning highlighting the potential for allergic reactions (swelling of the face, mouth and throat; difficulty breathing; itching; or rash) also would be added to the drug label.[21]

2012: Public Citizen petitioned the FDA to require changes in the drug labeling for opioid pain medications in an effort to prevent overprescribing. At that time, the labels of opioid analgesics simply stated that they were approved for moderate-to-severe pain. The requested changes related only to opioids used for noncancer pain.

2013: The FDA granted the petition in part and denied it in part. Specifically, the agency denied the request to recommend both a maximum duration of use and a maximum daily dosage for treatment of noncancer pain in the labels of all opioid mediations. As a result, drug companies can continue to promote these pain medications as safe and effective for long-term use by noncancer patients in whom the risks are likely to outweigh the benefits.[22]

2016: The FDA issued a safety warning for the entire opioid class of drugs concerning potential harmful interactions with other medications, problems with the adrenal glands and decreased sex hormone levels.[23]

The FDA required the addition of a boxed warning, the agency's strongest warning, to the labels of opioid and benzodiazepine drugs stating that profound sedation, depressed breathing, coma and death can occur when these medications are used together.

2017: The FDA announced that it was restricting the use of tramadol in children and requiring changes in the product labeling accordingly.[24] Tramadol should not be used to treat pain in children younger than 12 years. Tramadol should not be used in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids. A new warning was added to tramadol's label stating that it is not recommended in adolescents between 12 and 18 years of age who are obese or have conditions such as obstructive sleep apnea or severe lung disease. A strengthened warning was added that tramadol is not recommended in mothers who are breastfeeding because of the risk of serious adverse reactions in breastfed infants.

2019: On Nov. 6, Public Citizen petitioned the DEA and FDA to reschedule tramadol from the weakly restricted schedule IV to the more tightly restricted schedule II because it is overprescribed, often misused, highly addictive and potentially deadly.[25] Action on the petition is pending.