Using data from observational postmarketing studies, investigators have extrapolated a tramadol abuse rate for the general tramadolexposed population.5,6 Ortho-McNeil, Ultram’s manufacturer, funded a surveillance program that compiled tramadol abuse and withdrawal case reports from 2 sources: (1) periodic surveys for tramadol abuse case reports from a group of 255 substance abuse experts studying and caring for addiction communities, and (2) voluntary ADE case reports from health care professionals and consumers received by Ortho-McNeil. Over 3 years of surveillance, the program received 454 case reports classified as tramadol abuse. Over 5 years of surveillance, 422 cases of substance withdrawal, with primarily opioid withdrawal symptoms, were reported. There are significant threats to the validity and generalizability of the investigators’ estimated abuse rate of 1 to 3 cases per 100,000 tramadol-exposed patients. The abuse cases were collected in nonrepresentative samples of the tramadol-exposed population. Tramadol exposure is likely suppressed in addiction communities with access to preferred, more potent or euphoriant opioids than tramadol. Voluntary case reports of tramadol abuse significantly underestimate the actual number of abuse cases in the tramadol-exposed population. In addition, the low survey return rate (49%) further decreases the accuracy of any estimation of tramadol abuse rates.
Prospective studies among patients with known abuse, or at high risk of abuse, reported a tramadol abuse rate, as well as subjective experiences of tramadol withdrawal. A 3-year post-marketing cohort study measured tramadol’s nonmedical misuse rates using urine drug testing for tramadol among 1601 participants in 4 US state monitoring programs for impaired healthcare professionals.7 Tramadol exposure occurred in 140 (8.7%) participants. Thirty-nine (28%) were classified as extensive experimentation or abuse of tramadol. Overall, the rate of extensive experimentation or abuse was 18 cases per thousand personyears. The Hawthorne effect, where awareness of being monitored alters a subject’s behavior, may threaten these measured frequency rates’ generalizability. Another prospective study assessed the subjective tramadol withdrawal experience in 219 patients with a diagnosis of “Tramadol misuse” who were attending 6 drug detoxification centers in China.8 Validated drug dependence symptom scales found that while the degree of physical dependence reported was uniformly mild, the majority of patients reported the psychic dependence symptom of tramadol craving.
The FDA’s Drug Abuse Advisory Committee performed a formal review of the tramadol abuse evidence in 1998, including the data from OrthoMcNeil’s surveillance studies and federal case reporting/surveillance programs. The FDA did not recommend changing tramadol’s unscheduled status.9 The FDA’s considered decision to not schedule tramadol as a controlled substance implies its abuse risk to the general population is low. in comparison to its novel analgesic benefit.
Recommendations from others
Ortho-McNeil’s revised 2001 product package insert for Ultram states, “Tramadol may induce psychic and physical dependence of the morphine type (mu-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.” (italics in original, emphasizing 2001 addition). The risk for patients with a history of substance abuse has been observed to be higher.10
CLINICAL COMMENTARY
Though it may not have high abuse potential, prescribe tramadol cautiously
David M. Schneider, MD
Sutter Medical Center Family Practice Residency Program, Santa Rosa, Calif
Although tramadol appears to have a low potential for abuse, the literature does reveal evidence of abuse, addiction, and withdrawal, even in patients without a history of such problems. We do not know if tramadol is less addictive than other narcotics in high-risk patients. For patients at risk for dependence, tramadol is a reasonable alternative to other opioids, but abuse appears more likely in these patients. Tramadol may be most appropriate for treatment of acute painful conditions, but it can be administered chronically under a watchful eye. Providers should prescribe it cautiously, particularly in patients with a history of abuse or addiction, at least until more definitive evidence surfaces.