September 2008 DEA/OD/ODE

Tramadol was approved for marketing as a noncontrolled analgesic in 1995 under the trade name of Ultram®. Although the company initially claimed that this substance produced only very weak narcotic effects, recent data demonstrate that opioid activity is the overriding contributor to the drug’s pharmacological activity. Because of inadequate product labeling and lack of established abuse potential, many physicians felt this drug was safe to prescribe to recovering narcotic addicts and to known narcotic abusers. As a consequence, numerous reports of abuse and dependence have been received.

Tramadol is approved for the treatment of moderate to moderately severe pain in adults. Although the Department of Health and Human Services has not recommended the scheduling of this substance in the Controlled Substances Act (CSA), a requirement necessary for DEA to place a substance under control, the Food and Drug Administration (FDA) has required the manufacturer of Ultram® to inform physicians about recent abuse data. The approved labeling has been modified on three separate occasions to include new information under the "Drug Abuse and Dependence" section. The labeling currently contains the following language:

"ULTRAM may induce psychic and physical dependence of the morphine-type (µ-opioid). Dependence and abuse, including drug-seeking behavior and taking illicit actions to obtain the drug are not limited to those patients with prior history of opioid dependence. The risk in patients with substance abuse has been observed to be higher. ULTRAM is associated with craving and tolerance development. Withdrawal symptoms may occur if ULTRAM is discontinued abruptly."

Tramadol is a novel analgesic having both opiate agonist activity and monoamine reuptake inhibition that contribute to its analgesic efficacy. Opioid activity is due to both the parent compound and the more active O-desmethylated metabolite. Tramadol acts on the monoamine reuptake systems by inhibiting the reuptake into nerve terminals of both norepinephrine and serotonin. Apart from analgesia, tramadol may produce a number of symptoms including dizziness, somnolence, nausea, and constipation similar to other opioids. High doses of tramadol, often in combination monoamine oxidase (MAO) inhibitors or serotonin-selective reuptake inhibitors (SSRIs), have been associated with a serotonin syndrome consisting of convulsions, hyperthermia, muscle rigidity and pain.

Tramadol is well absorbed orally. It can be administered in 50 to 100 mg tablets as needed for pain relief every 4 to 6 hours, not to exceed 400 mg/day. Seizures have occurred in patients taking recommended doses but are more likely at high doses associated with abuse of this medication. Tolerance, dependence and addiction to tramadol have been demonstrated. Abrupt cessation from tramadol has been associated with two types of withdrawal syndromes. One is typical of opioid drugs with flu-like symptoms, restlessness and drug craving. This type of withdrawal syndrome is encountered in about 90 percent of cases of withdrawal from tramadol. Another withdrawal syndrome (encountered in about 10 percent of cases of tramadol withdrawal) is atypical of opioids and is associated with hallucinations, paranoia, extreme anxiety, panic attacks, confusion, and numbness and tingling in the extremities.

According to the System to Retrieve Drug Evidence (STRIDE), a federal database for the seized drugs analyzed by DEA forensic laboratories, there were 13 drug items of tramadol from 11 different cases in 2007. These items included 3,639 tablets, 157 capsules and 20.5 grams of powder. According to the National Forensic Laboratory System (NFLIS), state and local forensic laboratories analyzed 776 exhibits of tramadol in 2007.

MedWatch is a FDA database of adverse events of case reports voluntarily submitted to the FDA. From initial marketing in 1995 through September 2004, the FDA received 766 case reports of tramadol abuse and 482 cases of withdrawal associated with tramadol. It is most commonly abused by narcotic addicts, chronic pain patients, and health professionals.

Tramadol is currently not controlled under the CSA.