Tramadol (Ultram, generic and with acetaminophen in Ultracet) carries a risk of substance abuse (strength of recommendation [SOR]: B, based on case report surveillance programs). While it appears that tramadol's risk of substance abuse is low (SOR: B, based on case report surveillance programs), tramadol is associated with a withdrawal syndrome usually typical of opioid withdrawal (SOR: B, based on case report surveillance programs, and a prospective descriptive study)

Mackler, Leslie

McDiarmid, Todd

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C L I N I C A L  I N Q U I R I E S72 JANUARY 2005 / VOL 54, NO 1 · The Journal of Family PracticeWhat is the addiction riskassociated with tramadol?■ EVIDENCE-BASED ANSWERTramadol (Ultram, generic and with acetamino-phen in Ultracet) carries a risk of substance abuse(strength of recommendation [SOR]: B, based oncase report surveillance programs). While itappears that tramadol’s risk of substance abuse islow (SOR: B, based on case report surveillanceprograms), tramadol is associated with a with-drawal syndrome usually typical of opioid with-drawal (SOR: B, based on case report surveillanceprograms, and a prospective descriptive study). ■ EVIDENCE SUMMARYTramadol is a novel, central-acting synthetic opioidwith weak mu-opioid activity, and is approved fortreatment of moderate to moderately severe pain inadults. Anecdotally, some clinicians have assumedthis popular analgesic’s nonscheduled status underthe Controlled Substance Act (CSA) means tramadolhas no substance abuse potential. (The term “abuse”herein denotes substance abuse or dependence.) Evidence of tramadol abuse in the US comes pri-marily from federally operated programs collectingadverse drug event (ADE) data. The MedWatch pro-gram of the Food and Drug Administration (FDA)provides a central depository for receiving and com-piling postmarketing voluntary case reports. Whilepassive reporting systems can significantly under-estimate serious ADE numbers, these reports areoften the first evidence of an ADE after a new drug’srelease into the market.1 MedWatch has received766 case reports of abuse associated with tramadol,as well as 482 cases of withdrawal associated withtramadol from the drug’s initial US marketing in1995 through September 2004.2,3The Drug Abuse Warning Network (DAWN) isa federally operated, national surveillance systemthat monitors trends in drug-related emergencydepartment visits. Over the period from 1995 to2002, DAWN reported drug-related emergencydepartment visits mentioning tramadol in morethan 12,000 cases. Tramadol case numbers sig-nificantly increased 165% during this time. Forperspective, during the same period, DAWN foundnalbuphine (Nubain, also not CSA scheduled) in118 cases, propoxyphene drug combinations (CSAClass IV) in more than 45,000 cases, codeine drugcombinations (CSA Classes III & V) in about50,000 cases, and hydrocodone drug combina-tions (CSA Class III) in around 128,000 cases.4Using data from observational postmarketingstudies, investigators have extrapolated a tra-madol abuse rate for the general tramadol-exposed population.5,6 Ortho-McNeil, Ultram’smanufacturer, funded a surveillance program thatcompiled tramadol abuse and withdrawal casereports from 2 sources: (1) periodic surveys fortramadol abuse case reports from a group of 255substance abuse experts studying and caring foraddiction communities, and (2) voluntary ADEcase reports from health care professionals andconsumers received by Ortho-McNeil. Over 3years of surveillance, the program received 454case reports classified as tramadol abuse. Over 5years of surveillance, 422 cases of substancewithdrawal, with primarily opioid withdrawalsymptoms, were reported. There are significantthreats to the validity and generalizability of theinvestigators’ estimated abuse rate of 1 to 3 casesper 100,000 tramadol-exposed patients. Theabuse cases were collected in nonrepresentativesamples of the tramadol-exposed population.Tramadol exposure is likely suppressed in addic-tion communities with access to preferred, morepotent or euphoriant opioids than tramadol.Voluntary case reports of tramadol abuse signifi-cantly underestimate the actual number of abusecases in the tramadol-exposed population. Inaddition, the low survey return rate (49%) furtherdecreases the accuracy of any estimation of tra-madol abuse rates.Prospective studies among patients withknown abuse, or at high risk of abuse, reported atramadol abuse rate, as well as subjective experi-ences of tramadol withdrawal. A 3-year post-mar-C L I N I C A L  I N Q U I R I E SJANUARY 2005 / VOL 54, NO 1 · The Journal of Family Practice 73C O N T I N U E Dketing cohort study measured tramadol’s nonmed-ical misuse rates using urine drug testing for tra-madol among 1601 participants in 4 US state mon-itoring programs for impaired healthcare profes-sionals.7 Tramadol exposure occurred in 140(8.7%) participants. Thirty-nine (28%) were clas-sified as extensive experimentation or abuse of tra-madol. Overall, the rate of extensive experimenta-tion or abuse was 18 cases per thousand person-years. The Hawthorne effect, where awareness ofbeing monitored alters a subject’s behavior, maythreaten these measured frequency rates’ general-izability. Another prospective study assessed thesubjective tramadol withdrawal experience in 219patients with a diagnosis of “Tramadol misuse”who were attending 6 drug detoxification centersin China.8 Validated drug dependence symptomscales found that while the degree of physicaldependence reported was uniformly mild, themajority of patients reported the psychic depend-ence symptom of tramadol craving.The FDA’s Drug Abuse Advisory Committeeperformed a formal review of the tramadol abuseevidence in 1998, including the data from Ortho-McNeil’s surveillance studies and federal casereporting/surveillance programs. The FDA did notrecommend changing tramadol’s unscheduled sta-tus.9 The FDA’s considered decision to not sched-ule tramadol as a controlled substance implies itsabuse risk to the general population is low in com-parison to its novel analgesic benefit. ■ RECOMMENDATIONS FROMOTHERSOrtho-McNeil’s revised 2001 product packageinsert for Ultram states, “Tramadol may inducepsychic and physical dependence of the morphinetype (mu-opioid). Dependence and abuse, includingdrug-seeking behavior and taking illicit actions toobtain the drug are not limited to those patients withprior history of opioid dependence” (italics in origi-nal, emphasizing 2001 addition). The risk forpatients with a history of substance abuse hasbeen observed to be higher.10Todd McDiarmid, MD, Leslie Mackler, MSLS,Moses Cone Health System, Greensboro, NC■ CLINICAL COMMENTARYThough it may not have high abusepotential, prescribe tramadol cautiouslyAlthough tramadol appears to have a low poten-tial for abuse, the literature does reveal evi-dence of abuse, addiction, and withdrawal, evenin patients without a history of such problems.We do not know if tramadol is less addictivethan other narcotics in high-risk patients.  Forpatients at risk for dependence, tramadol is areasonable alternative to other opioids, butabuse appears more likely in these patients.Tramadol may be most appropriate for treat-ment of acute painful conditions, but it can beadministered chronically under a watchful eye.Providers should prescribe it cautiously, partic-ularly in patients with a history of abuse oraddiction, at least until more definitive evidencesurfaces.David M. Schneider, MD, Sutter Medical Center FamilyPractice Residency Program, Santa Rosa, CalifREFERENCES1. Brewer T, Colditz GA. Postmarketing surveillance andadverse drug reactions: current perspectives and futureneeds. JAMA 1999; 281:824–829.2. Brinker A, Bonnel RA, Beitz J. Abuse, dependence, or with-drawal associated with tramadol. Am J Psychiatry 2002;159:881–882.3. Adverse Event Reporting System. Freedom of InformationReport. Rockville, Md: Office of Drug Safety, Food and DrugAdministration: search November 1997 to September 2004.4. Drug Abuse Warning Network. Emergency DepartmentTrends From DAWN: Final Estimates 1995 to 2002. Availableat: dawninfo.samhsa.gov. Accessed on August 25, 2004.5. Cicero TJ, Adams EH, Geller A, et al. A postmarketing sur-veillance program to monitor Ultram (tramadol hydrochloride)abuse in the United States. Drug Alcohol Depend 1999;57:7–22.6. Senay EC, Adams EH, Geller A, et al. Physical dependence onUltram (tramadol hydrochloride): both opioid-like and atypicalwithdrawal symptoms occur. Drug Alcohol Depend 2003;69:233–241.7. Knisely JS, Campbell ED, Dawson KS, Schnoll SH. Tramadolpost-marketing surveillance in health care professionals. DrugAlcohol Depend 2002; 68:15–22.8. Liu ZM, Zhou WH, Lian Z, et al. Drug dependence and abusepotential of tramadol. Zhongguo Yao Li Xue Bao 1999;20:52–54.9. FDA Drug Abuse Advisory Committee. The ScientificEvidence for Initiating a Scheduling Action for Ultram (tra-C L I N I C A L  I N Q U I R I E S74 JANUARY 2005 / VOL 54, NO 1 · The Journal of Family Practicemadol hydrochloride). 1998. Available at: www.fda.gov.10. Murray L, ed. Physicians’ Desk Reference. 58th ed.Montvale, NJ: Thomson PDR; 2004:2496.What are the indications for evaluating a patient with cough for pertussis?■ EVIDENCE-BASED ANSWERPertussis should be considered in infants withapnea or severe coughing illnesses of any dura-tion, and in older children or adults with pro-longed cough (eg, longer than 2 weeks), especial-ly if accompanied by inspiratory whoop or house-hold exposure to a prolonged cough illness(strength of recommendation [SOR]: B, based onconsecutive cohort studies with poor referencestandards). Coughing paroxysms, posttussivevomiting, and absence of fever, while typical ofpertussis, are of little help in distinguishing itfrom other causes of prolonged coughing illnesses(SOR: B, based on consecutive cohort studieswith poor reference standards). ■ EVIDENCE SUMMARYPertussis is an important cause of cough in allage groups. Ten prevalence studies of adoles-cents and adults seeking medical attention for aprolonged cough (defined variously as >1–4weeks) found acute pertussis in 12% to 32%.1While cough longer than 2 weeks, inspiratorywhoop, posttussive vomiting, coughing parox-ysms, and absence of fever are commonly associ-ated with pertussis, relatively few studies haveassessed the sensitivities and specificities ofthese symptoms. The Table summarizes resultsfrom 5 cohort series of children and adults withlaboratory-confirmed pertussis. Comparisongroups were variously defined by negative per-tussis cultures, negative pertussis serology, orserologic confirmation of other respiratory infec-tions. Likelihood ratios (LR) were calculatedfrom the data presented in each paper.The magnitude and variability of these likeli-hood ratios suggest that individual symptoms maybe of limited help in distinguishing pertussis fromother causes of prolonged cough. Combinations ofsymptoms may be slightly more helpful. In a studycomparing 10 patients with culture-confirmed per-tussis with 10 patients with serologically con-firmed mycoplasma pneumonia, the combination ofcough >14 days and whoop had a sensitivity of80%, a positive LR (LR+) of 8 and a negative LR(LR–) of 0.22.2 A cohort series of children aged <5years with suspected pertussis compared 33 withpositive cultures to 55 with negative cultures. Theconstellation of spasmodic cough and lymphocyto-sis (>10,000) had a sensitivity of 83%, a LR+ of2.5, and a LR– of 0.25. Cough >14 days withwhoop and vomiting had a sensitivity of 67%, aLR+ of 3.2, and LR– of 0.42.3Infants aged <6 months with pertussis are at par-ticular risk for atypical presentations and seriouscomplications. In a US series of 18,500 infants withpertussis, apnea was seen in 64% of infants under 1month and in 44% between 6 and 11 months. Fortypercent of the 6- to 11-month-olds had received atleast 3 doses of pertussis vaccine.4 A British study of126 infants aged <5 months admitted to the pedi-atric intensive care unit with apnea, bradycardia, orrespiratory failure found that 20% had pertussis.Apnea as a predictor of pertussis had a sensitivity of68% and a specificity of 60%.5Pertussis should be considered early in theevaluation of young infants with cough. In a case-control study comparing 15 fatal cases of pertus-sis with 32 who survived (infants aged <6months), the mean number of days from symptomonset to hospital admission were 5.3 (fatal) and8.6 (survivors). Rates of apnea on admission were40% and 52%.6 A case series of 9 infants aged <7weeks requiring admission to an intensive careunit for pertussis found that 8 had been sick forless than 4 days at the time of admission. All 9presented with poor feeding and cough, and 5 hadexperienced apnea.7■ RECOMMENDATIONS FROM

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