Do Not Use! The Pain Drug Tramadol (ULTRAM/ULTRACET) and Serotonin Syndrome

Australian drug regulatory authorities have received 171 reports of suspected adverse reactions with the pain drugs tramadol (ULTRAM) or tramadol in combination with acetaminophen (ULTRACET) since Ultram began being marketed in Australia in late 1998. In six of these reports, a very serious adverse reaction known as the serotonin syndrome was listed as the adverse reaction. Tramadol is a drug that increases serotonin levels by blocking the storage of the chemical in nerve cells. A summary of these reports was published in the December 2001 issue of the Australian Adverse Drug Reactions Bulletin.

The box below lists the features of the serotonin syndrome. To establish the existence of this condition in a patient at least 3 of the 10 clinical features listed. These must occur following either the addition of a new drug that increases serotonin levels or an increase in the dose of a drug that raises serotonin levels.

Four of the six reports of serotonin syndrome to the Australian authorities described the use of tramadol in patients who were also taking antidepressants known to increase the concentration of serotonin in the brain. These included the selective serotonin reuptake inhibitors (SSRIs) sertraline (ZOLOFT) and citalopram (CELEXA), the selective monoamine oxidase inhibitor (MAOI) moclobemide (a drug not available in the U.S. that releases serotonin from nerve cells), and a combination of the tricyclic antidepressants amitriptyline (ELAVIL) and clomipramine (ANAFRANIL), both of which block the storage of serotonin in cells.

Lists of currently marketed SSRIs and MAOIs appear in the box below.

Another of the six reports involved a person who was taking the dietary supplement St. John’s Wort, also believed to increase serotonin levels. The final report described the use of a relatively high daily dose of tramadol, 400 milligrams, in an elderly man. Four of the six patients recovered after treatment while one patient required admission to the intensive care unit and had not recovered at the time the Australian Adverse Drug Reactions Bulletin summary was published. The outcome was unknown in another patient.

Tramadol was approved for use in this country by the Food and Drug Administration (FDA) in March 1995. We listed the drug as Do Not Use in the 1999 edition of Worst Pills, Best Pills because it appears to be no more and sometimes less effective than the combination of codeine with acetaminophen. In addition, shortly after the drug was approved safety warnings had to be added to its professional product labeling, or “package insert,” about the risk of seizure or convulsion with its use and its ability to cause dependence. The newly marketed combination of tramadol with acetaminophen (ULTRACET) was listed as Do Not Use in the October 2001 issue of Worst Pills, Best Pills News for the same reasons tramadol was listed as Do Not Use.

Both ULTRAM and ULTRACET carry the same warning about using either product with MAO inhibitors or SSRI antidepressants and serotonin syndrome.

Use with MAO Inhibitors and Serotonin Re-uptake Inhibitors
Use ULTRAM with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of ULTRAM with MAO inhibitors or SSRIs increases the risk of adverse events, including seizure and serotonin syndrome.

What You Can Do

You should not be using tramadol either in the form of ULTRAM or ULTRACET if you are taking an MAO inhibitor or SSRI antidepressant.

If you develop the symptoms of serotonin syndrome while taking tramadol, immediately discontinue the tramadol and contact your doctor.