Postmarketing Surveillance for Drug Abuse Supports Nonscheduled Status of Tramadol

ST. LOUIS--When tramadol (Ultram) received FDA approval last yearfor use in moderate to moderately severe pain, its abuse potentialwas felt to be low (1.5 cases of abuse per 100,000 patients inthe European experience).

Thus, the Drug Abuse Advisory Committee recommended that tramadolnot be "scheduled," subject to a strict postmarketingsurveillance program to be administered by an independent steeringcommittee, said Theodore Cicero, PhD, of Washington UniversitySchool of Medicine, who heads the steering committee.

"This was viewed jointly by the FDA and the sponsor [Ortho-McNeilPharmaceutical] as an experiment," Dr. Cicero said at a symposiumheld in conjunction with the 8th World Congress on Pain. He addedthat the company is required to state in its advertising thattramadol has "low abuse, not no abuse potential."

Proactive Methods

Although the independent steering committee receives all noticesof adverse event reported to the sponsor and the FDA, it is alsousing more proactive methods of gathering data.

In cooperation with the National Institute on Drug Abuse (NIDA),the committee has established relationships with all NIDA grantholders studying populations at risk. "Should they detectabuse in their particular catchment area, they let us know immediately,"Dr. Cicero said.

Furthermore, the committee has developed a list of 150 "keyinformants," ie, people who direct methadone clinics or drugtreatment programs and "know what's going on in the streetculture," he said.

Other methods of gathering information include surveys of painspecialists and use of the Internet. "There are about 35discussion groups of recreational drug users who, to our amazement,readily talk about the pharmacology and possible abuse potentialof new drugs," Dr. Cicero said.

The committee monitors tramadol sales, distribution, and prescribingpractices down to the 5-digit zip code. "We did not expectto see a nationwide epidemic of abuse, but, rather, if it occurred,it would be in very small areas of the country. Therefore, weneeded this degree of sensitivity," Dr. Cicero commented.

Hot Spots

Indeed, the committee found no abuse among heroin addicts in thenortheast corridor. "They experimented with tramadol andranked it very low; they won't buy it on the street," hesaid. Instead, the committee found, as predicted, regional outbreaks,or hot spots. For example, 13 of a total of 75 cases of abusereported to date have occurred in Atlanta.

In April, in a site visit to Atlanta, the committee talked withtheir key informants and NIDA grantees in the area and also interviewedpatients. They found no evidence of so-called "script doctors"--physicianswho prescribe certain drugs excessively to meet the needs of abusers.

Rather, the problem appeared to be that well-intentioned physicianswere prescribing the agent to "the wrong patients,"Dr. Cicero said. Twelve of the 13 cases involved patients witha known history of opiate abuse who had been given tramadol asa "nonaddictive" alternative for pain relief.

The committee then met with the sales force involved in marketingtramadol in the area to remind them that the message they mustconvey to physicians is that the agent has "low abuse, notno abuse potential," he said, adding that physicians maysimply have not heard the message correctly or may have misinterpretedit.

In the short time since the intervention, there has been a sharpdecrease in reporting of abuse cases from Atlanta, Dr. Cicerosaid, suggesting that the intervention was effective.

He noted that although the surveillance results overall are stillpreliminary, the data at this point (showing about 1.5 cases ofabuse per 100,000) do not justify any change in the control statusof the drug.

Dr. Cicero believes the monitoring program could become a modelsystem that would allow the FDA "to feel comfortable notscheduling a compound with low abuse potential as long as a carefulsurveillance program is in place."