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Tramadol Abuse and Dependence Among Physicians
To the Editor: Historically, new opioid pain medications have been introduced as having low abuse liability and then later found to have significant risk. Tramadol achieves its analgesic activity from an M1 metabolite with potent opioid properties and through inhibition of reuptake of monoamines.1 Following release of this product, reports of tramadol abuse began to occur and package insert warnings regarding abuse have been heightened 3 times. The US Food and Drug Administration’s (FDA’s) MEDWATCH system has received hundreds of spontaneous reports of tramadol-associated abuse, dependence, and withdrawal.2 Among individual opioids listed in the 2001 and 2002 annual reports of the American Association of Poison Control Centers Toxic Exposure Surveillance System, tramadol ranked second to oxycodone in number of exposure cases.3 Other reports, sponsored by the manufacturer, have suggested low abuse liability; however, their conclusions are problematic due to methodologic issues. For example, in 1 report4 the total number of physicians admitting abuse of tramadol was divided by the total number of physicians being monitored, without measuring the percent of these physicians actually taking the drug. In April 1998 the FDA cited the lack of comparative data as a major reason for the committee’s decision to not recommend scheduling tramadol.5 The present study reports relative frequency of tramadol abuse compared with other drugs.
Methods. Records of all physicians monitored in the Alabama Physician Health Program and the Michigan Health Professionals Recovery Program 1994-2002 were analyzed for all drugs mentioned. Physicians were referred to these programs because of concerns regarding substance abuse and all underwent evaluation and treatment and participated in monitoring. In reviewing their records, 3 distinct categories of tramadol abuse were noted: (1) primary tramadol dependence included cases in which tramadol was the sole drug or the initial drug of choice; (2) tramadol relapse included cases in which an individual was in remission from previous addiction but relapsed to addictive drug use involving tramadol; and (3) tramadol substitution categorized individuals who used tramadol when their primary drug of abuse was not available or as an attempted self-detoxification. The study received a waiver from the ethics committee of the Medical Association of the State of Alabama.
Results. Five hundred ninety-five records were reviewed and 872 drug mentions were found. Opioids were mentioned second only to alcohol (Table). Among opioids tramadol was the third most frequently mentioned. Tramadol accounted for 10% of all opioid mentions, exceeding those of fentanyl, codeine, propoxyphene, oxycodone, morphine, and butorphanol.
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Table. Drugs Abused by Physicians in Alabama and Michigan, by Category
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Of the 33 physicians who mentioned tramadol, 32 had a diagnosis of substance dependence, and 1 had a diagnosis of substance abuse. The frequency of the 3 patterns of tramadol abuse were: primary tramadol abuse (24%), relapse associated with tramadol use (42%), substitution of tramadol for the drug of choice (30%), and unknown (3%).
Comment. Tramadol was mentioned relatively frequently as a drug abused by physicians, although it was rarely the primary drug of choice. The finding that tramadol was mentioned more frequently than fentanyl, oxycodone, dilaudid, and other known highly addictive opioids could be explained by an intrinsic abuse liability that was higher than previously thought. Alternatively, its availability and lack of being scheduled under the Controlled Substances Act could make it more attractive as a drug of abuse. Concerns regarding toxicity relate not only to abuse potential but also to seizures related to excessive dosage and to respiratory depression and risk of fatal overdose, a risk common to other opiates. More recently tramadol has been released in combination with acetaminophen, raising concern about liver toxicity with overdose. An important limitation of this study is that it did not attempt to examine the proportion of physicians actually exposed to each opioid who develop abuse or dependence. However, given the frequency of its mentioned abuse, physicians should be aware of this risk.
Access to Data: Dr Skipper had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analyses.
Gregory E. Skipper, MD
gregskipper{at}usa.net
Alabama Physician Health Program
Montgomery
Carol Fletcher, PhD, RN
Veterans Health Administration
Michigan Health Professional Recovery Program
Ann Arbor, Mich
Rosei Rocha-Judd
Alabama Physician Health Program
David Brase, PhD
Rockville, Md
1. Gillen C, Haurand M, Kobelt DJ, Wnendt S. Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol. 2000;362:116-121.
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2. Brinker A, Bonnel RA, Beitz J. Abuse, dependence, or withdrawal associated with tramadol. Am J Psychiatry. 2002;159:881.
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3. Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2003;21:353-421.
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4. Knisely JS, Campbell ED, Dawson KS, Schnoll SH. Tramadol post-marketing surveillance in health care professionals. Drug Alcohol Depend. 2002;68:15-22.
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5. Food and Drug Administration Center for Drug Evaluation and Research Drug Abuse Advisory Committee. The Scientific Evidence for Initiating a Scheduling Action for Ultram (tramedol hydrochloride). April 28, 1998. Available at: www.fda.gov/ohrms/dockets/ac/98/transcpt/3411t2.rtf. Accessed August 18, 2004.
Letters Section Editor: Robert M. Golub, MD, Senior Editor.
JAMA. 2004;292:1818-1819.
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