DEPARTMENT OFHEALTH AND HUMAN SERVICES Office of the Secretary

The Honorable Michele Leonhart Acting Administrator Drug Enforcement Administration Lincoln Place- West 700 ArmyNavy Drive, Room 12060 Arlington, VA 22202

Dear Ms. Leonhart: 

## SEP 16 2010 Assistant Secretary for Health Office of Public Health and Science Washington 0.C. 20201

Pursuant to the Controlled Substances Act [CSA, 21 U.S.C. 811 (b). (c), and (t)], the Department ofHealth and Human Services is recommending that the substance tramadol be added to Schedule IV ofthe CSA. Tramadol is an opioid analgesic that produces its primaryopioid-like action through an active metabolite reterred to as the M 1metabolite (0-desmethyltramadol). Tramadol (50 mg/tablet), under the trade name ofULTRAM',
was first approved for marketing in the United States in March 1995 as an immediatcrelease product for the treatment ofmoderate to moderately-severe pain. ULTRACET',
an immediate-release, combination product, was approved in August 200

### I. The first generic versions were approved in June 2002 and 2008. In September2005, December 2008, and May 2010, FDA approved the extended release tramadol products: ULTRAM" ER, RYZOLTTM, and tramadol hydrochloride extended-release capsules, respectively. Accordingto drug abuse databases, tramadol abuse occurs in the United States. In addition, abuse and adverse events oftramadol are similarto those ofotheropioids currently controlled under the CSA. The data demonstratethat public health and safoty risks oftramadol result from its abuse as an opioid.

FDA and the National Institute on Drug abuse have also considered the abuse potential and dependence producing characteristics oftramadol. After reviewing the available information, the agencies concludethat tramadol should be controlled in Schedule IV. Enclosed is a document prepared by FDA's Controlled Substance Staffthat is the basis for the recommendation.

Should you have any questions regarding this recommendation, please contact Corinne P. Moody, Science Policy Analyst, Controlled Substance Staff, Center for Drug Evaluation and Research, at (301) 796-5402.

Enclosure Sincerely yours,

' I , _..-;:- f 

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## ,l._··;'---../: c_L,**~,>** 

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### ?' \ ,«.U,.**~** <...;; ·, "'.. Howard K. Koh, M.D., M.P.H. Assistant Secretary for Health

U.S. Public Health Service

### Basis for the Recommendation to Schedule Tramadol In Schedule IV ofthe Controlled Substances Act

I. SUMMARY

The Food and Drug Administration (FDA), pursuant to 21 U.S.C. 811 (c), recommends that tramadol be listed in Schedule IV ofthe Controlled Substances Act (CSA).

Tramadol is an opioid analgesicthat produces its primaryopioid-like action through an active metabolite, referred to below as the Ml metabolite (0-desmethyltramadol). Tramadol (50 mg/tablet), under thetradename ofULTRAM, was first approved for marketing in the United States in March 1995 as an immediate-release product for the treatment ofmoderateto moderately severe pain. An immediate-release combination product, ULTRACET (containing 37.5 mg tramadol hydrochloride and 325 mg acetaminophen) was approved in August 2001. The first generic versions were approved in June 2002 (ULTRAM) and 2008 (ULTRACET). In September2005, December 2008, and May2010, FDA approved the extended-release tramadol products, ULTRAM ER, Ryzolt, and tramadol hydrochloride extended-release capsules, respectively. These products arc formulated to contain I00, 200, and 300 mg oftramadol hydrochloride and are intended for once-dailytreatment for management ofmoderateto moderately severe chronicpain requiring around-the-clocktreatment for an extended periodof time.
This evaluation discusses the scientific and medical information relative to each ofthe eight factors determinative ofcontrol under the CSA, presents findings in the three required areas to recommend schedulinga substance intheCSA, and contains areconunendation regarding scheduling. In determining therelative abuse potentialoftramadol, FDA has evaluated all available abuse potential data from scientific and medical literature, animal and human laboratory and clinicaltrial data, as well as actual use data. According to drug abuse databases, tramadol abuse occurs in the United States. In addition, abuse and adverse eventsoftramadol arc similarto those ofotheropioids currently controlled under the CSA. Thedata demonstratethat public health and safetyrisks oftramadolresult from its abuse as an opioid. Thebasis for therecommendation to schedule tramadol in Schedule IV of the CSA is described below.

II. BACKGROUND

Pursuant to 21 U.S.C. 811 (c) ofthe CSA, the Secretaryofthe Department ofHealth and Human Services (HHS) is required to consider, in a scientific and medical evaluation, eight factors determinative ofcontrol under the CSA. Following consideration ofthe eight factors, the Secretary must make three findings to recommend scheduling a substance in the CSA. These findings relateto the substance's abuse potential, legitimate medical use, and safetyor dependencepotential.

### The eight factors are:
1. Thedrug's actual orrelative potential for abuse 2. Scientific evidence ofthe drug's pharmacological effects, ifknown 3. The stateofcurrent scientificknowledgeregarding the drug or substance 4. Its history and current pattern ofabuse 5. The scope, duration, and significance ofabuse 6. What, ifany, risk there is to thepublic health 7. Itspsychic orphysiological dependence liability 8. Whether the substance is an immediate precursorofa substance already controlled.
The FDA performs the administrative responsibilities for evaluating a substance for control under the CSA, with concurrence ofthe National Institute on DrugAbuse (NIDA), as described in the MemorandumofUnderstanding (MOU) ofMarch 8, 1985 (50 FR 9518-20).

In October and November 2005, FDA accepted for filing five citizen petitions requesting that the CommissionerofFood and Drugs recommend scheduling tramadol and/or its extended-release formulation(s) under the CSA. Two petitioners requested that the CommissionerofFood and Drugs recommend designation ofextended-release formulations oftramadol in Schedule Ill of the CSA. These petitioners also requested that FDA reevaluatethe product labeling for extended-release formulations oftramadolbased upon currently available safety information related to serotonin syndrome, and considerthe potential for an increased risk ofdose-dependent seizures ordose-dependent serotonin syndrome as an additional reason to require scheduling. Two otherpetitioners opined that available data would support scheduling oftramadol at the level ofSchedule !II. 

### A comment submitted to the public dockets for these citizen petitions on behalfofOrtho-McNeil, Inc., an affiliate ofthe new drug application holder for ULTRAM, took
an oppositeview and recommended that tramadol not be scheduled under the CSA.

In October and November 2005, the Drug Enforcement Administration (DEA) received four citizen petitions to initiate proceedings to place tramadol under control in the CSA. Three of these petitions (frompetitioners who also submitted citizen petitions to FDA) specifically requested theplacement oftramadol in Schedule III, while the remaining petition did not specify
a particular level ofcontrol. On July 3, 2006, the DEA formally accepted these petitions. Jn a letterdated April 25, 2007, and sent to the Assistant Secretaryfor Health, HHS, the DEA provided its own review document on tramadol and requested from HHS, pursuant to 21 U.S.C. 811(b), a scientific and medical evaluation and schedulingrecommendation for tramadoI.



### In evaluating the relative abuse potential oftramadol, FDA reviewed and evaluated all ofthe available data onthe abuse potential on tramadol from the following:

• Articles from scientific and medical literature
• Reports from the Substance Abuse and Mental Health Services Administration (SAMHSA) [Drug Abuse Warning Network (DAWN) and National Survey on Drug Use and Health (NSDUH)]
• Reports from the Drug Enforcement Administration (DEA).



### 2Regulatory History


### Tramadol was first marketed by Grunenthal in Germany in 1977 as a treatment for pain. As of 2000, tramadol was registered and marketed in more than 70 countries.

In 1995, ULTRAM, an oral tablet dosage form containing 50 mg oftramadol, was approved and marketed in the United States as an analgesic. A combinationproduct under the trade name ULTRACET (containing 37.5 mg tramadol hydrochloride and 325 mg acetaminophen) was approved for marketing in the United States onAugust 15, 2001. Since 2002, numerous generic tramadol-containing drug products have been approved. New dosage forms oftramadol, orally disintegrating tramadol tablets (50 mg) and extended-release tramadol tablets (100 mg, 200 mg, 300 mg), were approved in 2005. An additional extended-release tablet was approved in December 2008, and an extended-release capsule was approved in May2010.
At the time ofapproval ofULTRAM in 1995, little information on abuse potential oftramadol
was known. Priorto this date, tramadol was marketed in the United Kingdom and Germany and other countries, but there was a lack ofdata available on its abuse. The following was known about the drug's abuse-related chemistry and pharmacology at the time:
• Tramadol is a racemate with (+) and (-) enantiomeric forms.
• Tramadol racematehas weak mu (μ)-opioid binding activity. In addition, the(+)- tramadol enantiomer inhibits serotonin (5-HT) reuptakc.
• (-)-Tramadol mainly inhibits norepinephrine (NE) reuptake, stimulating a2-adrenergic receptors but has even less affinity for μ-opioid receptors than the ( +)-enantiomer. The ( +)-enantiomerwas found to have 10-fold higher analgesic activity than the (-)- enantiomer.
This profile ofactivity is not typical ofdrugs ofabuse orcontrolled substances.
However, tramadol metabolizes to several metabolites ofwhich the Ml metabolite, 0- 

### desmethyltramadol, has strong μ-opioid activity. In the view ofthe SponsorofULTRAM, the activity oftramadolwas due to the 5-HT and NE activity and weakμ- opioid activity ofthe parent substance. The contribution ofthe Ml metabolite to the overall activity was not weighted very high. Human abuse potential studies in recreational opioid studies showed that compared to morphine oroxycodone, drug abuse signals (euphoria and drug liking) were generated, but only at very high doses (750 mg) and peaked at a later time than the comparatordrugs. The
occurrenceofconvulsions in one study was considered an adverse effect that could deter abuse. In addition, somepreclinical studies assessing respiratorydepression produced questionable results that were not consistently comparable to other opioids (morphine and oxycodone). The self-administration study in Rhesus monkeys showed limited self-administration and did not include an opioid as a positive control.
The data werejudgedto be insufiicient for scheduling tramado1under the CSA at the time of approval. However, the FDA and the sponsor, Ortho-McNeil, agreed to an extensive postmarketing surveillanceplan to monitor abuse ofthe drug post approval. The sponsor set up a

3

### scientific advisorypanel to provide advice onthe postmarketing program and to review data collected nationwide.
Abuse in the United States was recognized soon after FDA approval, resulting in revisions to the product labeling and the addition ofnew warnings. A "Dear Healthcare Provider" letter issued by Ortho-McNeil on March 20, 1996, warned ofdrug abuse as well as seizures and anaphylactoid reactions. This letter stated "115 spontaneous domesticreports ofadverse events described as drug abuse, dependence, withdrawal, orintentional overdose have been received. This does not include cases ofaccidental overdose. Patients with a past orpresent history of addiction ordependence on opioids account for the majority ofthese reports. ULTRAM should not be used in such patients."

In 1998, FDA convened the Drug Abuse Advisory Committee (DAAC) to review 3 years of post-marketing abuse data for ULTRAM. The FDA asked the DAAC for recommendations on what datathe agency should require in making adecision on scheduling and whetherthe Committee was ofthe opinion that reports ofabuse and pharmacological features ofULTRAM
are "similarto other opioids which are scheduled." Ortho-McNeil maintained that although the drug producesopioid-like effects, a delayed onset makes abuse ofULTRAM unlikely.
Boththe parent substance (tramadol) and the Ml metabolite contribute to the drug's efficacy as an analgesic. Efficacy relates to the plasma concentration ofeach, and their relativeμ- opioid receptor affinities and efficacies. The metabolism oftramadol (a relatively weakμ- opioid) to Ml (a strongμ- opioid) is an important contributorto theμ- opioid activityoftramadol.

The DAAC responded with the following proposals: 1. More monitoring ofabuse ofULTRAM is needed to determine whether it should be categorized as an opioid. 2. Scheduling should remain an option. 3. Future analyses should depend not onlyon reports from the Sponsor, but also onchanges in abuse trends. 4. Comparison ofdata with otheropioid drugs is needed. 5. Abusereports ofthreeorfour otherdrugs that are in the same pharmacological class orused for the same indication should be compared.
Since approval oftramadol in the United States, and since the 1998 advisory committee meeting, additional new data from a variety ofsources have been obtained. Reports ofabuse, dependence, and safety issues (serotonin syndrome and seizures) have appeared in the scientific and medical literature. Drug discrimination studies, used to assess abuse potential, have also
now been documented in the scientific literature. Thesereports and studies, as well as other studies, have improved our understanding oftramadol's mechanism ofaction, particularly as applied to the consequences oftramadoluse including opioid abuse and dependence. In addition, several years ofdatarelated to drug abuse/misuse, diversion and safetyhave been obtained from the DrugAbuse WarningNetwork, National Survey ofDrug Use and Health (NSDUH), National Forensic Laboratory Information System (NFLIS), the American



### 4Association ofPoison Control Centers' National Poison Data System, and the Florida Department ofLaw Enforcement Medical Examiner's Office. According to Griinenthal USA in 2007, tramadol is regulated by numerous countries in a manner that is comparable to control under the CSA in the United States, in that limits onprescribing and dispensing and criminal sanctions are applied. A partial listing ofthe countriesthat have such restrictions for tramadol is provided in Table I.

5Table 

### 1. International Special Prescribing Requirements (Source: Grunenthal USA, Inc. April 27, 2007)

Country Requirement

Austria Psychotropic, CategoryIV Bahrain a Restricted Prescription a

, Special Prescription Fonn Belarus 0 Under special governmental control according to the "List ofStrong Acting Substances", not listed as narcotic b Bulgaria Narcotic Estonia Listed as psychotropic, not listed as narcotic: not more than 3 g tramadol perprescription Finland Listed as psychotropic, not listed as narcotic: separate, original prescription, prescription is kept bythe pharmacy afterthehand-over ofthe first packageofthe prescription Greece Category C (productsbelonging in this category are prescribed by special prescription for narcotics (with two lines), legalized by Prefecture, kept for 3 years (forcontinual treatment with Prefectural Decision) Jordan c Listed as psychotropic, not listed as narcotic c Kuwait a Controlled prescription a
, normal prescription form Lithuania Narcotic Qatar Restricted prescription, listed as psychotropic/ Schedule II, like buprenorohine and pentazocine, not listed as narcotic R . o Under special governmental control according to the "List ofStrong Acting

ussra Sb "I'd .b u stances , not 1ste as narco!Ic Ukraine 0 Under special governmental control according to the "List ofStrong Acting Substances", not listed as narcotic b United Restricted prescription, listed as Category IV: "drugs with therapeutic Arab advantage and some misuse potential" like for example diazepam or Emirates flurazepam, not listed as narcotic Venezuela Restricted prescription (pharmacy must keep receipt), not listed as narcotic
a 'Restricted' or "controlled' isnot treated as equivalent to 'narcotic' or 'psychotropic', but tncans limited dosage per period for the patient. The patient can get the products only fro1n hospital pham1acies. lbedoctorhas to handle prescription paperwork and the prescriber should be a specialist. Thenutnber ofpossible prescriptions per period is limited. Thepharmacist should identify thepatient orrelative when dispensing and takethe si!,'llalure. Quarterly follow-ups shouldbe conducted by the physician. b In Russia and the former Commonwealth ofIndependent States (CIS)-countries, the trarnadol dosage tOrms (except Tramal suppositoriesand Tramal Retard) are classified in the "List ofStrong Acting Substances and Poisons". Pharmacists may be subject to severe penalties ifthey dispense these products without a valid prescription. c Jordan has established a scheduling system with 4 different schedules. Schedule I comprises drugs like morphine and cocaine. Schedule 2 comprises drugs like codeine and dihydrocodeine. Schedule 3 contains exempt preparations, e.g. when compounded with one or more other int,,Tfedients and containingnot more than 100 mg of drug per dosage unit and with a concentration ofnot more than 2.5o/o in undivided preparations. Codeine and dihydrocodeine are also included in Schedule 3. Schedule 4 comprises cannabis. Tramadol belongs to Schedule 2, with the exemption oftramadol presentations containing less than 100 mg per dosage**unit~** these preparations belong lo Schedule 3. Scheduling oftramadol is therefore comparable to that ofcodeine in Jordan.

6

### Five Citizen Petitions were filed with the FDA in October and November 2005. Petitioners requested that the CommissionerofFood and Drugs recommend scheduling tramadol and/orthe extended-release formulation(s) oftramadol under the CSA. Two petitioners requested that the CommissionerofFood and Drugs recommend designation ofextended-release formulations of tramadol in Schedule III ofthe CSA. These petitioners also requested that FDA reevaluate the product labeling for extended-release formulations oftramadolbased upon currently available safety information related to serotonin syndrome, and considerthe potential for an increased risk ofdose-dependent seizures ordose-dependent serotonin syndrome as an additional reason to require scheduling. Two other petitioners opined that available data would support scheduling of tramadol at the level ofSchedule III. A comment submitted to the public dockets for these citizen petitions on behalfofOrtho-McNeil, Inc., an affiliate ofthe NOA holder for ULTRAM, took an oppositeview and recommended that tramadol not be scheduled.
The current labeling states that tramadol is a centrally-acting synthetic opioid analgesic. The ULTRAM labeling approved September 9, 2009, describes the drug's activity further, as follows:

"

...its mode of action is notcompletely understood,from animal tests, at least two complementarymechanisms appearapplicable: bindingo/parentandMI metabolite to μ-opioid receptors and weak inhibition o/reuptakeo/norepinephrineandserotonin. Opioidactivity is due to both lowaffinitybindingo/theparentcompoundandhigher affinity binding(}/the 0-demethylatedmetaboliteMI to μ-opioid receptors. Jn animal models, M 1 is up to 6 times morepotent than tramadol inproducinganalgesia and200 times morepotentin μ-opioid binding. Tramadol-induced analgesia is onlypartialZv antagonizedby the opiate antagonLl·t naloxone in severalanimaltests. The relative contribution of both tramadol andM 1 to human analgesia is dependent upon theplasma concentrations oleach compound(see CLINICAL PHARMACOLOGY, Pharmacokinetics.)

Tramadol has been shown to inhibit reuptake olnorepinephrine andserotonin in vitro, as have some otheropioidanalgesics. These mechanisms may contribute independentlv to the overallanalgesicprofile ofULTRAM. Analgesia in humans begins approximately within one hourafieradministration andreaches apeakin approximatelyf\1.o to three hours. Apart.from analgesia, ULTRAMadministration mayproduce a constellation <Jf .1ymptoms (including dizziness, somnolence, nausea, constipation, sweatingandpruritus) similarto that of otheropioids. Jn contrast to morphine, tramadol has notbeen shown to
cause histamine release. Attherapeutic doses, ULTRAMhas no e[/ect on heart rate, lefiventricularfunction orcardiac index. Orthostatic hypotension has been observed."



### As the public health risks oftramadolthat result from its abuse and its opioid pharmacology are recognized and understood more fully, FDA is now recommending that tramadol be scheduled under the CSA.

7HI. EVALUATING TRAMADOL UNDERTHE EIGHT FACTORS

Factor 1: Tramadol's Actual or Relative Potentialfor Abuse "Abuse" is not defined in the CSA. However, the legislative history ofthe CSA 1describes the potential for abuse ofa particulardrug orsubstancebythe following indicators:
a) Individuals are taking the substance in amounts sufficient to create a hazard to their health orto the safety ofother individuals orto the community; b) There is significant diversion ofthe drug orsubstance from legitimate drug channels;
c) Individuals are taking the substanceon their own initiative ratherthan on the basis of medical advice from apractitioner licensed bylaw to administer such substance, and;
d) The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the samepotential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contraryto or without medical advice, orthat it has a substantial capabilityofcreating hazards to the health ofthe user orto the safetyof the community.

When assessing the abuse potential ofa substance, the Secretaryconsiders multiple factors. data sources, and analyses. No single test, by itself; provides a complete characterization ofa substance's abusepotential. The prevalence, frequency, and manner ofuse by the general public and specific subpopulations, the amount ofmaterial that is available for abuse, as well as the evidence ofparticularrisks are all considered.
Animal, human, and epidemiological data are useful in assessing a substance's abuse potential. A comprehensive scientific evaluation ofthe relative abusepotential ofa substance includes consideration ofthe receptorbinding affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus effects, dependenceproducing potential, pharmacokinetics/metabolism and routes ofadministration, toxicities, assessment ofthe clinical efficacy-safetydatabase relative to actual abuse, human abuse potential studies, and thepublic health risks after marketing. Epidemiologicaldata, as well as evidence ofclandestine production and illicit trafficking, are also important indicators ofabuse potential. The above four indicators ofabuse potential are discussed in more detail as theyrelateto tramadol below.

I. Individuals are taking the substance in amounts sufficient to create a hazardto their health orto thesafety of other individuals orto the community.

1 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91 si Congress Sess. (1970) reprinted in U.S.C.CAN. 4566. 4603.
8

### The medical literature contains reports illustrating that individuals are taking tramadoIin amounts sufficient to create ahazard to theirhealth and to the safety ofother individuals orto the community (Aknine et al., 2000; Bozic et al., 1999; Ehrenreich and Poser, 1993; Goeringer et al., 1997; Jovanovic-Cupic et al., 2006; Lange-Asschenfeldt et al., 2002; Leo et al., 2000; Reeves and Liberto, 2001; Ritvo et al., 2007; Soyka et al., 2004; Stoehret al., 2009; Tjaderbom et al., 2009; and Yates et al., 200l). These publications, many ofwhich are recent, demonstratethat abuse oflargedoses oftramadol occurs on adaily basis and contributes to the development of dependence, seizures, the serotonin syndrome, and other medical problems.

The Drug Abuse Warning Network (DAWN) also provides evidence ofthe use oftramadol in amounts sufficient to cause harm. DAWN dataontramadol are discussed in detail under Factor 4. In 2007 and 2008, the estimated national, annual number ofemergency department (ED) visits related to the nonmcdical use2 

### oftramadolwas 8,039 and 11,850, respectively. For 2007 and 2008, withrespect to nomnedical ED visits involving tramadol products alone (in the absence ofotherdrugs present), 1,819 and 788, respectively, resulted from "overmedication"2 

### while 1,476 and 2,016, respectively, ofvisits were placed under the category of"other." By design, the "other"2 

### category captures most ofthe documented drug abuse cases.
The American Association ofPoison Control Centers' National Poison Data System, discussed in detail under Factor4, shows that for 2007 and 2008 there were 1,847 and 2,476, respectively,
case mentions involving intentional exposure to tramadol alone. Reasons for the exposures included suicide, intentional misuse, orintentional abuse. Although the numbers ofcases under each category for reason ofexposure are not specified, it is probable that some ofthe cases involved the use ofelevated doses oftramadol resulting in adverse effects. This is supported by the behavioral effects oftramadol at large doses, as described in Factor2, below.

2. There is significantdiversion o/the drug orsubstance.from legitimate drug channels.


### The DEA National Forensic LaboratoryInfonnation System (NFLIS) provides data on tramadol containing exhibits encountered in the course ofstate and local law enforcement investigations. Drug exhibits are analyzed in state and local forensic laboratories. Under Factor4, there is a detailed examination oftramadoldata in the NFLIS database. The data show that for each ofthe years from 2000 through 2008, tramadol was present in drug exhibits seized in the courseoflaw



### ,**~** Nonn1edical use ofpharmaceuticals includes prescription and OTC pharmaceuticals in ED visits that are ofthe following case types:

•

• Ovennedication-This category was designed to capture nonmcdical use, overuse, and 1nisuse of prescription and O"fC medications that are not documented as drug abuse in the medical chart. Afaliciouspuisoning--TI1is category was designed to capture cases ofdrug use in which the patient was administered a drug byanother person for amaliciouspurpose. Drug-facilitated sexual assault is one type ofmalicious poisoning, but other types ofmalicious poisonings, such as product tampering, would be classified in this category as well.
Other-This category includes all drug-related ED visits that could not be assi&'lled to anyofthe other
seven types. Bydesign, most cases ofdocumented drug abuse will fall into this category.

9

### enforcement activity. In 2008, forensic laboratories analyzed 1,093 such exhibits. This number is greaterthan the number ofexhibits shown to contain pentazocine [C-IV) orbutorphanol [CIV], but less than the number ofexhibits found to contain hydrocodone [C-111), codeine [C-11, III, VJ, and buprcnorphine [C-111). The number oftramadolexhibits is close to the number of exhibits for propoxyphene [C-IV). These exhibits were seized 

### in the course ofcriminal investigations involving drugs and provide evidence ofthe diversion oftramadol in the United States.

Further evidence for the diversion oftramadol is the following: 1) DAWN ED visits involving nonmedical use oftramadol; 2) National Survey ofDrug Use and Health (NSDUH) data indicating nonmedical use oftramadol; and 3) American Association ofPoison Control Centers (AAPCC) National Poison Data System data showing intentional exposure cases resulting from misuse and abuse oftramadol. One aspect of"nonmedical use" and "intentional misuse" or "intentional abuse" would be use oftramadolby individuals who do not have a valid prescription for the drug, thereby suggesting the possibility ofdiversion from legitimate sources. These databases are discussed in detail under Factor4.
The possibilityofdivcrsion oftramadol is mentioned in the ULTRAM label that was last approved on September 9, 2009. Under the heading of"Physical Dependence and Abuse" is the following statement: Dependence andabuse. includingdrug-seeking behaviorandtaking illicit actions to obtain the drug, are notlimitedto thosepatients v.ithpriorhistory of'opioiddependence. 

### Knisely et al. (2002) observed in a postmarketing surveillance studyoftramadol use among health care professionals that among 140 participants, who had a least onepositive tramadol urine specimen, 87 did not report having legitimate prescriptions for obtaining the drug. Inciardi et al. (2006) examined the diversion oftramadol and other opioids overthe period ofJanuary 2002 through March 2004, as reported bydrug diversion investigators from police agencies in all 50 states. During the first quarter, 42 cases involved tramadol diversion. During each ofthe remaining eight quarters, approximately 30 cases oftramadol diversion were noted. The number oftramadoldiversion cases was less than the number ofdiversion cases for other controlled substances such as hydrocodoneproducts (C-III) and oxycodonc (C-ll).


### 3. Individuals are taking the substance on their own initiative rather than on the basis of'

medicaladvice from apractitionerlicensedby law to administersuch substances.



### Evidence exists indicatingthat individuals taketramadol on their own initiative rather than on the basis ofmedical advice from a practitioner licensed by law to prescribe tramadol. This evidence includes case reports ofabuse and dependence to tramadol in the medical literature. Epidemiological data (DAWN, NSDUH and AAPCC) also suggest tramadol use in the absence ofmedical supervision. These databases arc discussed in detail under Factor4.
Cases oftramadol use by individuals on their own initiative ratherthan on thebasis ofmedical advice are documented in the published literature (Aknine et al., 2000; Bozic et al., 1999;

10

### Ehrenreich and Poser, 1993; Goeringer ct al., 1997; Jovanovic-Cupic et al., 2006; LangeAsschenfeldt et al., 2002; Leo et al., 2000; Reeves and Liberto, 2001; Ritvo et al., 2007; Soyka ct 

### al., 2004; Stoehr ct al., 2009; Yates et al., 2001).

An examination ofthe DAWN data shows that overthe period of2004through 2008, the national annual estimates ofED visits related to nonmedical use, including abuse, oftramadol and its combinations increased from approximately4,800 to over 11,800. Upon normalization of the number ofnonmedical ED visits relative to I00,000 prescriptions dispensed, the rate ofED visits for tramadol/combinations was found similarto the rates for codeine/combinations [C-11, III, 

### VJ primarily) and proproxpyhene products (C-IV], but lowerthan the rates ofhydrocodone/ combinations [C-lll], buprenorphine/combinations [C-Ill], and ofanumber ofSchedule II 

### opioids. Accordingto the 2007 NSDUH, an estimated 1,559,000 individuals have used tramadol nonmedically at least once in their lifetime. In addition, 57,000 individuals reporting initiation ofany pain relieveruse during thepast year, also reported nonmedical use oftramadol. Both lifetime nonmedical use, as well as nonmedical use overthepast year among new initiates of pain reliever use, is lower for tramadol products when compared to oxycodone products [C-II],
or

### to hydrocodone products (C-III].

The AAPCC's National Poison Data System shows that for 2006, 2007, and 2008 there were 1,482, 1,847, and 2,476, respectively, case mentions involving intentional exposure to tramadol alone. Reasons for the exposures include intentional misuse, intentional abuse, and suicide.
The studies ofKnisely et al. (2002) and lnciardi et al. (2006), mentioned above and showing diversion oftramadol, also support the fact that tramadol is used in the absence ofappropriate medical supervision.

4. The substance is so relatedin its action to a substance alreadv listedas havinga

potentialfiJ1· abuse to make it hkelvthat itwill have the samepotential.forabuse as such substance, thus making it reasonable lo assume that there may be significant diversions.fi'om legitimate channels, significant use contrwy to or withoutmedical advice, orthat ithas asubstantial capability of creatinghazards to the health of the
userorto the safety of the community.



### As discussed in detail under Factor 2, tramadol is an opioid. Tramadol shares pharmacological activities with opioids that are scheduled under the CSA. As such, the abuse potential of tramadol would be expected to be related to its opioid properties, and to be diverted from legitimate sources, to be used in 

### the absence ofmedical supervision and to represent a safety
concernto the community.
The opioid activity oftramadol is primarily due to its metabolite, 0-desmethyltramadol, commonlyknown as "Ml". Effects include, but are not limited to, analgesia, respiratory depression, miosis, cough suppression, and inhibition ofbowel motility. These effects may have
a longer onset ofaction compared to otheropioids, and are most likely due to accumulation of the active metabolite. Preclinical studies show that tramadol, as other opioids in Schedules 1

11

### through IV, exhibits complete generalization to morphine [C-11]. A limited number of preclinical studies indicatethat tramadol produces some, but limited, reinforcing effects. Animal studies, discussed under Factor 7, show that repeated administration oftramadol results in dependencedevelopment, characterized by a withdrawal syndrome similar in intensity to pentazocine [C-IV] orpropoxyphene [C-IV].

In clinical studies, the subjective reinforcing effects oftramadol were compared with morphine [C-11] and oxycodonc [C-11], but not to opioids in Schedules Ill, IV orV. These studies indicate that tramadol produces some reinforcing subjective effocts at high (supratherapeutic) doses. A similardose dependency, in which supratherapeutic doses but not therapeutic doses, produce reinforcing subjective effects is also observed with the opioid propoxyphcne [C-IV], thereby making propoxyphene an appropriate comparatordrug for tramadol with respect to producing reinforcing effects. Tramadol and propoxyphene, as well as otheropioids, have a greater probabilityofeliciting adverse effects at higherdoses. These studies and separate studies examining propoxyphene abuse potential indicatethat the subjectivereinforcing effect of tramadol is less thanthat ofSchedule II opioids and more comparable to that ofpropoxyphene [C-IV]. Clinical studies evaluatingthe abuse potential oftramadol are discussed in detail under Factor2. SummaryofRelevant Findings and Conclusions from Factor 1.


### An evaluation ofthe accumulated information demonstratesthat the indicators ofa drug's potential for abuse, as described in the legislativehistory ofthe CSA, are present for tramadol. Individuals taketramadol in the absence ofmedical supervision and in amounts sufficient to create a hazard to their health. Tramadol is diverted from legitimate sources. Tramadol produces effects similarto opioids known to have an abuse potential and that are controlled under the CSA.

The available information shows that the abuse potential oftramadol is less than that ofSchedule III drugs and similarto that ofdrugs in Schedule IV. Preclinical self-administration studies show that tramadol produces limited reinforcing effects, consistent with a lower schedule. Clinical studies indicatethat tramadol produces subjective reinforcing effects similarto that ofmorphine (C-ll] and approaching that ofoxycodone [C-Il] at high (supratherapeutic doses) but not at therapeutic doses. A similardose dependency occurs with propoxyphene [C-IV]. These observations indicate that the subjective reinforcing effects, a reflection ofabuse potential, of tramadol is less than that ofmorphine [C-11] oroxycodone (C-11], but similarto that of propoxyphene [C-IV]. Dependence is one ofthe driving forces in the abuse ofdrugs. As such, thedevelopment of dependenceto adrug can contribute to its abuse potential. Animal studies indicate that tramadol
causes a mild to moderate level ofdependence as evidenced by awithdrawal syndrome similar to that produced bypentazocine [C-IV] and propoxyphene [C-IV]. A small number ofclinical studies indicatethe occurrence ofdependence in painpatientstaking therapeutic doses of tramadol; however, a variety ofcase report studies document dependence to tramadol resulting from supratherapeutic doses oftramadol. Clinical studies showthat tramadol can cause suppression ofopioid withdrawal that is quantitatively less than that produced by morphine [C12II] orbuprenorphine [C-III]. The information available regarding dependence is supportive ofan abuse potential for tramadol less than that ofSchedule III drugs and similar to that ofSchedule IV. Epidemiological data also support an abuse potential for tramado

### 1 that is consistent with drugs in Schedule IV. NSDUH shows that the number ofindividuals reporting lifetime misuse of tramadol is less than that ofthe numberreporting lifetime misuse ofeitheroxycodone products [C-II] orhydrocodone combination products [C-lll]. NSDUH supportsthe scheduling of tramadol in the CSA and the placement oftramadolin a less restrictive schedule than Schedule Ill. DAWN data show that the number ofED visits per 100,000 prescriptions is lower than that ofopioids in Schedules II and Ill, but similarto that ofpropoxyphene [C-lV]. NFLIS data for 2008 show that the number oflaw enforcement encounters with tramadol was closeto the number for propoxyphene [C-IV]. These data support the placement oftramadol in Schedule IV.



### Factor2: Scientific Evidence ofTramadol's Pharmacological Effects General Pharmacology ofTramadol

An examination ofthe general pharmacology, including behavioral pharmacology, oftramadol reveals that tramadol produces manypharmacological effects similarto those ofopioids, and as such can be considered an opioid. Opioids are drugs ofabuse that are controlled in various schedules underthe Controlled Substances Act. Atthe same time, however, in contrastto many opioids that act directly without requiring metabolismto produceopioid like effects, the opioid pharmacologyoftramadolprimarily resides with its metabolite, 0-desmcthyltramadol [not scheduled], designated "Ml", and to a much lesser extent with tramadol, the parent drug. In addition, tramadol resembles someopioids, but not most opioids, in having the additional pharmacological effects ofblockingthe reuptake ofnorepinephrine and serotonin.

This sectionpresents the fu1dings on the pharmacology for tramadol and its Ml metabolite. Collectively, these findings show that although the pharmacological profile oftramadoldoes differ is some ways (i.e., primaryopioid activity associated with metabolite and inhibition of norepinephrine and serotonin reuptake) from that ofopioids, the overall general pharmacology, including behavioral pharmacology, oftramadol is consistent with that ofopioids and thereby supporting the scheduling oftramadol. Receptor Binding
The opioid receptorbinding activity oftramadol and 0-desmethyltramadol {Ml) [not scheduled] has been examined in a number ofstudies (Bamigbade et al., 1997, 1998; Dayer et al., 1997; Frink et al., 1996; Gillen et al., 2000; Hennies et al., 1988; Lai et al., 1996; Raffa ct al., 1992; Scott and Perry, 2000). By way ofcomparison, Table 2, adapted from Frink et al. (1996), shows μ-opioid receptorbindingofmorphine [C-11] and codeine (C-11]; the opioid antagonist naloxonc [not scheduled]; and tramadol and its Ml metabolite. The affinity ofmorphine [C-11] to theμopioid receptor is approximately 10-100 times greaterthan Ml and 300 times greaterthan tramadol. Althoughthe affinity ofcodeine [C-II] to the μ-opioid receptor is less than that of racemic M1and (+)-Ml, it is noted that codeine activity is largely attributed to its biotransformation to its active metabolite, morphine (Frink et al., 1996).

13Table 2. Inhibition ofSpecific Opioid Receptor Ligand Binding to Rat Brain. (Adapted from Frink et al., 1996.)
Ki values (moles/liter; tnean of3 or n1ore determinations) Drug orMetabolite Opioid Receptor Binding Assays [3H]DAMGO [3H]Naloxone (μ-Agonist) (μ-Antagonist) Naloxone* 1.8 x IO

-9 I.I x IO

-9 Morphine* 5.8 x IO

-9 2.2 x IO

-9 (T)-Ml 2.2 x IO -8 1.7 x IO

-8 Racemic Ml 4.0xlo-8 2.8 x 10 -8 C'odeine* 0.8 x IO

-6 1.3 x IO

-6 (-)-Ml 1.9 x IO

-6 1.8 x IO

-6 (')-Tramadol 4.lxI0-6 4.4 x IO

-6 Racemic Tratnadol 6.7 x 10

-6 8.3x 10-6 (-)-Tramadol 2.0 x IO

-4 1.3 x IO

-4 

### *Morphme IS scheduled under C-Jl

Codeine is scheduled under C-IL C-111, or C-Vdependent on dose and combination with other analgesics Naloxone is not scheduled.
In two studies (Hennies et al., 1988; Raffa et al., 1992), tramadol and other analgesics were evaluated for displacement ofeither [3H]naloxone or [3H]DAMGO from μ-opioid receptors in rat brain preparations. These studies also showed that tramadol has a relatively weak affinity for the μ-opioid receptor. Forblocking μ-opioid binding, tramadol was approximately IO-fold less potentthan codeine [C-11], 60-fold weakerthan d-proproxyphene [C-IVJ, I000-fold weakerthan methadone [C-ll], and 6000-fold weaker than morphine [C-11].

Gillen et al. (2000) demonstrated very low affinity ofracemictramadol, but high affinity of(+)- MI, to the human opioid receptorin CHO-Kl cells. Competitivebinding analysis using tritiated naloxone revealed that tramadol (Ki of2.4

### ±I.I μM) was approximately 700 fold less than that of(+)-Ml (Ki of3.4

### ±0.2 nM). The affinities ofracemictramadol and(+) Ml were approximately 3,800 and 5.5-fold less than that ofmorphine, respectively. Opioid receptors transduce their signals via G-proteins (Chakrabarti et al., 1995; Fedynyshin and Lee, 1989; Selley and Bidlack, 1992). Receptor-medicated G-protein activation is measured by the ability ofagonists to stimulate [35S]GTPyS binding in isolated membranes (Hilfet al., 1989). Gillen et al. (2000) used this assay to determinethe potency and relative efficacy, that is, the ability compared to other substances to cause transduction ofthereceptor, ofmorphine, fontanyl, tramadol, and tramadol metabolites Ml, M2, M3, M4 and M5. Forthis study, cloned human opioid receptors were inserted into the membranes ofChinese hamster ovarycells. Racemic (±)- tramadol was found to have little intrinsic efficacy at the opioid receptor, a finding consistent with a very low affinity for binding to thereceptor. In addition, the M2, M3 and M4 metabolites had no atlinity for thehuman opioid receptor while the M5 metabolite showed only low affinity and low intrinsic activity for the opioid receptor. By contrast, the Ml metabolite showed a high intrinsic efficacy at thehuman opioid receptorthat was between the relative intrinsic efficacies ofmorphine [C-11] and fentanyl [C-11]. Based onthe high binding affinity and intrinsic efficacy
14ofthe Ml metabolite forthe human opioid receptor, the authors concluded that the Ml metabolite accounts for the μ-opioid component ofthe analgesic effects oftramadol (Gillen et al., 2000). More recently, Nakamura et al. (2008) using the 

## [35S]GTPyS binding and morphine binding assays, showed that Ml, but not tramadol, had functional activity at opioid receptors in
mouse brain.

Inhibition ofSerotonin and Norepinephrine Reuptake

Studies have shownthat tramadol can inhibit in vitro neuronal uptake ofnorepinephrine and serotonin (Raffa et al., 1992; Driessen and Reimann, 1992; Raffa et al., 1993; Driessen ct al., 1993; Reimann and Hennies, 1994; Frink et al., 1996). These effects show specificity with regard to the enantiomeric form oftramadol. The (-)-enantiomer is effective in blocking the reuptakc ofnorepinephrine, while the (+)-enantiomer is primarily involved in blocking the neuronal reuptake ofserotonin (Raffa et al., 1992; Driessen and Reimann, 1992; Raffa et al., 1993; Driessen et al., 1993; Frink et al., 1996). 0-Desmethyltramadol (Ml) is effective in both blocking reuptake and blocking release ofnorepinephrine and serotonin (Driessen and Reimann. 1992; Driessen et al., 1993; Frink et al., 1996). Among opioids, tramadol is not unique with respect to inhibition ofserotonin and norepinephrine reuptake. Methadone [C-II], meperidine [C-11], and levorphanol [C-11] inhibit serotonin and norepinephrine reuptake (Codd et al, 1995; Larson and Hyttcl, 1985; Latta et al., 2002; Mennini et al., 1978; Moffat and Jhamandas, 1976). Analgesia

Tramadol was studied in a wide variety ofpreclinical animal models ofpain (Dhasmana ct al., 1989; Girard et al., 2001; Hennies et al., 1988; Kayser et al., 1991, 1992; Munro, 2009; Nickel, 1987). These tests demonstrated a dose-related antinociceptive effect oftramadol following oral, intravenous, subcutaneous, and intrapcritoneal administration. The animal models included tailpressure, paw-pressure, and electrically induced vocalizationtests in rats; tail-flick, hotplate, and abdominal constriction tests in mice and rats; and the electrical tooth-pulp stimulation test in rabbits. Using the rat hot-plate assay, Hennies et al. (1988) showed that the intravenous administration ofeither tramadol or Ml produceddose-dependent analgesia. When the authors compared this analgesic activityto otheropioids, the following descending orderofanalgesic activity was found: hydromorphone [C-11] >hydrocodone [C-JI] >morphine [C-JI] > Ml > codeine [C-11] = tramadol. Animal studies showed that naloxone onlypartially antagonizes antinociceptive effects oftramadol, indicating the involvement ofadditional mechanisms (i.e. inhibition ofnorepinephrine and serotonin reuptake) in the analgesic effectsoftramadol (see above) (Kayser et al., 1991; Raffa et al. 1992). Studies indicate arole for both opioid receptor stimulation and inhibition ofnorepinephrine and serotonin reuptake in the overall analgesic effects oftramadol (Codd et al., 1995; Desmeules et al., 1994; Desmeules et al., 1996; Fox et al., 2009; Ide et al., 2006; Raffa et al., 1992; and Raffa et al., 1993).

A large numberofclinical studies demonstratethe analgesic effects oftramadol in various pain states in humans (forreview see Grond and Sablotzki, 2004, Prommer, 2005; Reeves and Burke, 2008; Rhoda Lee et al., 1993; Sunshine, 1994). This analgesic effect involvesbothopioid mechanisms, via the Ml metabolite, and the mechanism ofnorepinephrine and serotonin reuptakeblockade. In clinical studies withtramadol, the production ofanalgesia is consistent

15

### with M 1formation, commencing within one hourofadministration and peaking 2to 3hours later. Laugesen et al. (2005) showed that tramadol coadministration with paroxetine, an inhibitor ofCYP206, to inhibit Ml formation, resulted in a reduced analgesic response to tramadol. In addition, pharmacogcnetic studies demonstrated the geneticallypolymorphic nature ofthe enzyme, CYP206, which is involved in, among otherthings, the conversion oftramadolto the Ml metabolite (for review: Rollason et al., 2008). As a result ofthis polymorphism, individuals
can be divided into groups which metabolize tramadol to the Ml metabolite either slowly (poorly), extensively or ultrarapidly (Enggaard et al., 2006; Kirchheiner et al., 2008; Poulsen et al., 1996; Rollason ct al., 2008; Stamer et al., 2007). These studies further demonstratethat the analgesic effect oftramadol attributed to an opioid mechanism is greater in extensive metabolizers and ultra-rapid metabolizers as opposed to poor metabolizers. The opioid related analgesic effects positively correlateto thepresence ofthe Ml metabolite.
The analgesic effects oftramadol were compared to analgesics in Schedules Ill and IV. In a double-blind, randomized control trial involving 1I8 patients with chronic pain, comparable analgesic responses to oral daily dosing with eitherhydrocodone/acetaminophen (C-Ill] or tramadol were found (Rodriquez et al., 2008). In a randomized, prospective, double-blind clinical trial, Turturro et al. (1998) compared tramadol to hydrocodone/acetaminophen (C-Ill] for treatment ofacute musculoskeletal pain caused by minor trauma. Thirty-three patients received tramadol (I

### 00 mg orally) and an equal number received hydrocodone 5mg/acetaminophen 500 mg. Tramadol was significantly less effective than treatment with hydrocodone/acetaminopben [C-lll].


### Richter et al. (1981) compared the analgesic effects oforally administered tramadol (50 mg) to pcntazocine (50 mg) [C-IV] and placebo in a multicenter, double-blind trial with patients in acutepain. Tramadoldisplayed an analgesic effect similarto that ofpentazocine with each drug being superior to placebo. Sunshine et al. (1991) compared the analgesic etfoctiveness of tramadol (75 or 100 mg p.o.) to that ofplacebo and the combination of650 mg acetaminophen plus 100 mg proproxyphene napsylate [C-!V] in 161 patients with severe postoperative pain after
cesarean section. Tramadol at both dose levels was an effective analgesic with the 150 mg tramadol dose being statistically superiorto the acetaminophen-proproxyphene combination [CIV]. Moore and McQuay (1997), in a single-patient data meta-analysis of3453 postoperative pain patients, reported that single oral doses oftramadol (75

- 150 mg) had analgesic efficacy equivalent to combinations ofacetaminophen 650 mg plus proproxyphene I

### 00 mg [C-IV] and aspirin 650 mg plus codeine 60 mg [C-III].
Miotic Effoct Morphine and most μ-opioid agonists cause constriction ofthe pupils (Reisine and Pasternak, I996). In clinical studies, tramadol was also shown to causepupillaryrestriction, the onset of which is delayed several hours following tramadol administration (Fliegert et al., 2005; Krueger and Muller-Limmroth, 1978; Knaggs et al., 2004; Slanaret al., 2007). This delayed miotic effect results from the delayed formation ofthe tramadol MI metabolite. Additional support for the importance ofthe metabolite is the observation that tramadol produces a more pronounced miosis in extensive metabolizers as opposed to poor mctabolizers oftramadol (Fliegert et al., 2005; Slanar et al., 2007). Ultra-rapid metabolizers resulting from CYP206 (enzyme that

16

### metabolizes tramadol to the Ml metabolite) gene duplication allele show an even greater miotic effect to tramadol than do extensive metabolizers (no gene duplication) (Kirchhciner et al, 2008). Urinary Effects Morphine [C-II] causes urinary retention such that in some cases ofmorphine therapy catherization maybe required (Reisine and Pasternak, 1996). Evidence exists indicating that tramadol can also cause urinary retention. Pandita et al. (2003) demonstrated in rats that tramadol and morphine [C-II] caused urinary retention and that pretreatment with naloxone blocked this effect. The authors concluded that tramadol produced urinary retention in conscious rats by stimulating >t-opioid receptors. Cases describing describing urinary retention in humans taking tramadol are in the medical literature (Anonymous, 2001; Meyboom et al., 1999). Respiratory Effect Opioids tend to depress respiration (Reisine and Pasternak, 1996). As documented in the labeling for ULTRAM, tramadol can also depress respiration, particularly in cases ofoverdose or when combined with other central nervous system depressants. Teppema et al. (2003) showed that tramadol causes adose-dependent respiratory depression in cats in the dosage range ofI to 4 mg/kg. Naloxone treatment prevented more than 50% ofthe respiratory depression suggesting arole ofthe opioid receptor in causing respiratory depression. Considering that naloxone did not completelyblock the respiratory depression caused by tramado

### I, it was suggested that a monoaminergic mechanism also contributed to the respiratory effects oftramadol. Barnung et al. (1997) documented respiratorydepression following administration oftramadol, 100 mg four times daily, in apatient with impaired renal function. The respiratorydepression
was reversed with administration ofnaloxone. Stamer et al. (2008) recentlydocumented the
occurrenceofrespiratorydepression in an individual with renal impairment receiving tramadol via patient-controlled analgesia. The respiratory depression was reversed by naloxone. Subsequent examination revealed that the individual had a CYP2D6 gene duplication: this resulted in the ultra-rapid metabolism oftramadolto the active Ml metabolite, which was considered the cause ofrespiratorydepression.
Antitussive Effect Morphine [C-11] and otheropioids suppress the coughreflex (Reisine and Pasternak, 1996). This effect was demonstrated for tramadol. Friderichs et al. (1978) demonstrated that tramadol had antitussive effects in guinea pigs (cough induced by ammonia vapors) and in anesthetized cats (mechanical stimulationofthe cough reflex). Tramadol suppressed cough in cats (Nosalova et al., 1991). Hennies et al (1988) showed that bothtramadol and 0-desmethyltramadol (Ml) suppressed cough in rats exposed to aqueous ammonia solution. Antitussive efficacy decreased in the following order: hydromorphone [C-ll] >hydrocodone [C-11] >tramadol =morphine [C11] = 0-desmethyltramadol >codeine [C-II].

17Nauseant and Emetic Effects

Nausea and vomiting are typicallyunpleasant side effects associated with the use ofopioids (Reisine and Pasternak, 1996). Nausea and vomiting are common side effects seen with tramadol treatment (forreview, see Radbruch et al., 1996). In the label approved September 9, 2009, for ULTRAM, nausea and vomiting are listed as significant adverse effects associated with
use ofthe product in clinical trials.

Intestinal Effects

Bowel dysfunction leading to constipation is a common effect produced byopioids (Pappagallo, 2001; Bell et al., 2008). Opioids tend to reduce the propulsive contractions (peristalsis) ofthe small and large intestines (Reisine and Pasternak, 1996). This action, along with increases in anal sphinctertone, contributes to opioid-induced constipation (Reisine and Pasternak, 1996).
Tramadol inhibits gastrointestinal motility in the mouse (Raffa et al., 1993; Dursteler et al., 2006), rat (Planas et al., 2003) and guineapig (Herbert et al., 2007). In the mouse, tramadol had
a weak inhibitory effect oncolonicpropulsive motility, withthe (

### +)-enantiomerbeing more potentthanthe racemic or(-)-enantiomer (Raffa et al., 1993). In the rat, tramadol was approximately 38 times less potentthan morphine [C-II] in inhibiting gastrointestinal transit time (Planas et al., 2003). In the guinea pig, Ml (0-desmethyltramadol), as well as tramadol, inhibited intestinalperistalsis, with the former having greater potency (Herbert et al., 2007). Naloxone blocked the inhibitory effects oftramadol and 0-desmethyltramadol thereby indicating
an opioid mechanism ofaction.

The effect oftramadolon gastrointestinal motility in humans is suggested bythe fact that constipation is a problem with the use oftramadol. As evidenced bythe labeling for ULTRAM, constipation is one ofthe most frequently occurring adverse events reported in clinical trials. In contrast to morphine [C-Il], tramadol appears to have a minimal effect on gastric emptying in humans when given intravenously (Crighton et al 1998; Wilder-Smith and Bettiga, 1997). At analgesic doses, tramadol delays colonictransit, which may account for its constipating effects (Maurer et al., 1996; Wilder-Smith and Bettiga, 1997 and Freye and Latasch, 2000).
PreclinicalAbuse Potential Studies. Drug discrimination and intravenous self-administration studies are important animal studies that help in the assessment ofthe abuse potential ofa drug. Drug discrimination studies are ofvalue in discerning the class orclasses ofdrugs to which atest drug belongs, based on similar stimulus clues. Intravenous self-administration studies evaluatethe reinforcing effects ofa drug. Tramadol was evaluated in a limited number ofdrug discrimination studies using rats and selfadministration studies using the Rhesus monkey. Those studies are described below.

18Drug Discrimination Studies
Several drug discrimination studies using rats indicatethat tramadol displays symmetrical generalization to morphine (C-ll]. This effect is antagonized by naloxone, thereby demonstrating that the shared stimulus cues are opioid in nature. Studies ofstimulus generalization oftramadol relative to otheropioids, including those in Schedules III and IV, arc not reported. However, studies demonstratethe lack ofgeneralization oftramadolto methamphetamine [C-ll central nervous system stimulant) and selected antidepressant drugs (norepinephrinereuptakeblockers). Tramadol also does not generalize to the alpha-adrenergic agonist, flupirtine and the 5-HTIb agonist, anpirtoline. These studies indicatethat the discriminative stimulus cues oftramadol are typical ofclassical opioids like morphine. However, these studies do not provide information as to which schedule tramadol should he placed.

Ren and Zheng (2000), using a drug discrimination paradigm in rats, examined the generalization oftramadolto morphine [C-Il). Rats were trained to discriminate morphine (4 mg/kg s.c.) from saline using a fixed ratio (FRI0) schedule offood reinforcement. Once training
was completed, test doses ofeither morphine (0.56- 10 mg/kg s.c.) ortramadol (3.2-56mg/kg s.c.) were evaluated for generalization to morphine. Full generalization was achieved with morphine at doses of2.37mg/kg and higher and with tramadol at doses of32 mg/kg and higher. ED50 values for substitution were 2.04 (1.00

- 4.21) mg/kg and 20.94 (11.00

- 39.08) mg/kg for morphine and tramadol, respectively. Generalization by morphine and tramadol wasblocked by the concomitant administration ofnaltrexone (0.01

- 0.05 mg/kg). In this same study, tramadol
was also observed not to generalize to methamphetamine (C-ll) in rats trained to discriminate from saline 0.5 mg/kg s.c. methamphetamine. This studydemonstrated that tramadol shares interoceptive cues withthe opioid, morphine [C-Il], but not with the central nervous system stimulant, methamphetamine [C-Il]. Blockade ofthe cues demonstrates the opioid nature ofthe interoceptive cues evoked bytramadol and morphine and are further demonstrated by the blockade ofthese cues by naltrexonc.

In a studyby Filip et al. (2004), tramadol was evaluated for generalization to morphine [C-ll], naloxone [not scheduled] and a number ofantidepressants [not scheduled]. Rats were trained to distinguishtramadol (20 mg/kg s.c.) from saline using a two-choice water-reinforcement paradigm. Test drugs were administered intraperitoneally (i.p.). Thenon-controlled drugs, fluoxetine, milnacipram, reboxetine, roxindol and venlafaxine were given at 60 minutes, naloxone at 45 minutes, and morphine [C-11], nomifonsine [not controlled] and tramadol at 30 minutes priorto testing. Ofthe drugs tested, only morphine (1 - 3 mg/kg) showed generalization to tramadol. Concomitant naloxone (0.1

- 1mg/kg) administration attenuated the stimulus effects oftramadol (20 mg/kg) as well as the substitution evoked by morphine (2 mg/kg). The effects ofmorphine and naloxone were obtained without altering the animals' response rates. Of the antidepressants studied, onlymilnacipram (I0 mg/kg) and reboxetine (I0 mg/kg) enhanced the stimulus effects oftramadol. The authors concluded that the stimulus cue for tramadol involved a μ-opioid mechanism and that this cue could be modulated bynoradrencrgic uptake inhibitors. In addition, this study confirmed the results obtained by Ren and Zheng (2000), namely that tramadol shares specific interceptive cues with morphine [C-ll]. This selectivity is

19further demonstratedbythe lack ofstimulus generalization between tramadol and a number of antidepressant drugs.

Two other studies examined the discriminative cue oftramadol. Swedberg et al. (1988), using a two-choice FRS shocktermination schedule, demonstrated that tramadol (8, 16 and 32 mg/kg i.p.), as well as codeine [C-Il] (3, 10 and 30 mg/kg i.p.) and pentazocine [C-IV] (3.0, 10.0 and 17.6 mg/kg i.p.) did not generalizeto flupirtine, a non-scheduled analgesic which acts via an alpha-adrenergic mechanism, and not an opioid mechanism. In a separate studyby Swedberg et al. (1992), tramadol (8, 16 and 32 mg/kg i.p.) as well as codeine [C-11] (1.0, 3.0, 10.0, and 30.0 mg/kg i.p.) and pentazocine [C-lVJ (1.0, 3.0, 10.0 and 17.5 mg/kg i.p.) showed no generalization to anpirtoline in rats trained to discriminate anpirtoline [not controlled] (2.0 mg/kg i.p.) from saline. Based on stimulus testing with otherdrugs in this study, the authors concluded that the discriminative stimulus effocts ofanpirtoline primarily involved agonistic actions at serotonin I B (5-HTlb) receptors. The study also demonstrated that tramadol, as well as the opioids codeine [C-11] and pentazocine [C-IV], do not share interceptive clues with alpha-adrenergic agonists.

Besides displaying stimulus generalization to tramadol, morphine also generalizes to a variety of otheropioids. In various drug discrimination studies using rats, morphine displays high specificity ofthe stimulus cue and completely generalizes, and therefore displays similar interoceptive cues, to the following opioids: fentanyl [C-ll], methadone [C-ll], sulfentanil [C-11], meperidine [C-ll], codeine [C-11], etorphine [C-11], oxymorphone [C-ll], hydrocodone [C-11], buprenorphine [C-111], proproxyphene [C-IV], pentazocine [C-IV] and butorphanol [C-IV] (Kuhn et al., 1976; Shannon and Holtzman, 1976; Shannon and Holtzman, 1977; Niksic et al., 1978; Shannon and Su, 1982; Shook et al., 1984; Paronis and Holtzman, 1994; Holtzman, 1997; Morgan and Picker, 1996; Tomkins et al., 1997). The selective nature ofthe drug discrimination datagenerated for bothmorphine and for tramadol provide supportthat tramadolproduces opioid-like effects. Drug Self-Administration Studies Yanagita (1978) provides the sole report documenting the intravenous self-administration of tramadol in animals. To evaluatethe reinforcing effects oftramadol, Yanagita (1978) conducted three intravenous self-administration studies using Rhesus monkeys. In the first study, tramadol supported self-administration behaviornonstatistically, when first initiated using the central
nervous system stimulant, lefetamine. In the second study, monkeys initiated and maintained significant but low levels oftramadol**selt~administration;** thereby leaving no doubt that tramadol produces reinforcing effects. Thethird study was a progressive ratio studydemonstrating again that tramadol produces limited reinforcing effects. A positive opioid control was not used in these studies. Collectively, these studies suggest that tramadol produces limited reinforcing effects.

In the first study, four monkeys were initiallytrained to self-administer 0.1 mg/kg/injection of lefetamine [C-1!] at arateofgreaterthan 100 injections within a 4-hourperiod onconsecutive days. This was followed by saline substitution for lefetamine and continued until the daily number ofinjections fell below 20. The lefetamine-saline procedure was repeated so that monkeys came to discriminate the effects and extinguish orrestart self-administration,

20immediately (or within 24 hours at the most) ofstarting saline or lefotamine, respectively. Once training was completed, test drug was administered 4 hours per day for three consecutive days. The orderoftreatment was lefetamine (always at 0.1 mg/kg/inj), saline, l.O mg/kg/inj of tramadol, lefetamine, saline, 0.25 mg/kg/inj oftramadol, lcfetamine, saline, and 0.06 mg/kg/inj oftramadol. The number ofinjections taken during each test period was detennined and data
was expressed in terms ofthepercentageoflefetamineresponding. All four monkeys increased the injection rate oftramadol at a unit dose of0.25 mg/kg/inj compared to saline selfadministration; however, the mean values ofbothgroups were not statistically significantly different. At a unit dose of0.06mg/kg/inj, one monkey displayed a clear increase ofselfadministration oftramadol compared to saline. However, when the mean values in each group were considered, no statistical significancewas observed. The author concluded that this study demonstrated a non-significant trend oftramadoltowardproducing reinforcement ofdrug seeking behavior, particularlyat the 0.25 mg/kg dose. However, this effect was less than that previously shown in separate studies bythe authorfor either pentazocine [C-IV) or codeine [C11) (Yanagita et al., 1975).

In a second study, Yanagita (1978) evaluated tramadol for initiation ofself:administration in two drug naive monkeys and in two monkeys with previous drug selt:administration experience. Initiation ofself-administration did not occurwhen monkeys received access for 4 to 6 weeks to tramadol at aunit dose ofO.l mg/kg/injection. However, increasing the unit doseten-fold to 1.0 mg/kg/inj. resulted in initiation oftramadol self:administration in all four monkeys as compared to saline self-administration. At the end ofthe first two weeks, the average number ofdaily injections for the four monkeys was 97.0, 48.1, 39.9 and 188.9. By the end of6 weeks, one monkey died and the number ofaverage daily injections for the remaining three monkeys was 193.7, 129.9 and 51.4. During the active injection periods, the monkeys experienced convulsions, diminution ofspontaneous motility, mydriasis, anorexia, nausea, and vomiting. At weeks 2 and 4 ofthe study, naloxone (1.0 mg/kg s.c.) was administered to test for precipitated withdrawal. Mild to moderate, but not severe, withdrawal signs were observed in all four monkeys.

The third Yanagita (1978) studyexamined thereinforcing effects oftramadol. Forthis study, a progressive ratio test oflow rate was performed on two ofthe Rhesus monkeys that had initiated tramadol self:administration in the previous study. Thenumber ofleverpresses for each dose (1.0 mg/kg/inj) was doubled every four doses until the ratio reached 128: I. The highest ratio, which monkeys reached before extinguishing drug-seeking behavior, was determined. One of the monkeys progressed to aratio of64: I on the second day after initiation ofthe test, but thereafter,the animal began to extinguish self-administration. The second monkey reached a ratio of32: I onthe fourth day, and then self-administration was extinguished.

Based on this study, the author concluded that tramadol is reinforcing. The reinforcing effect of tramadol is yet another similaritythat tramadol has to opioids in Schedules ll

- V, and supports the scheduling ofthe drug. Yanagita (1978) did not use apositive opioid control; however, the results ofthis study indicate a limited reinforcing effect as compared to opioids in ll and Ill, thereby indicating placement oftramadol in a lower schedule.

21Human Abuse Potential Studies

- Subjective Reinforcing Effects ofTramadol

Evaluation ofthe subjective positivereinforcing effects ofdrugs in human subjects provides important informationregarding the drug's abuse potential. Four clinical studies evaluating the subjective reinforcing effects oftramadol are described below. Two ofthe studies submitted to the FDA under NOA 20-281 demonstratethat at high, greaterthan therapeutic doses, tramadol produces subjective positive reinforcing effects when given orallyorintravenouslyto nondependent, opioid experienced subjects. A similarpatternofdose dependent reinforcing effects is observed with the opioid, propoxyphene [C-IV] (Fraser and Isabel, 1960; Jasinski et al., 1977; and Jasinski and Preston, 1986).

Two Studies Submitted to FDA under NOA 20-281
The abuse potential ofintravenous tramadol was compared to that ofintravenous morphine in a study submitted after approval ofULTRAM. Subjects were non-dependent, opioid experienced male volunteers enrolled into a single inpatient site. Thereweretwo segments to the study. In each segment, selfand observer-rated subjective, behavioral, and physiological effects were measured. Instruments werethe Subject Drug Rating Questionnaire (SDRQ), Subject Drug Identification Questionnaire (SDIQ), Addiction Research Center Inventory (ARC!) Subscale A, Subject-Specific Drug Effect Questionnaire (SSDEQ), Observer Drug Rating Questionnaire {ODRQ), and the Observer-Specific Drug Effect Questionnaire (OSDEQ).

In the initial single-blind segment, six subjects received either intravenous morphine (20 mg) [Cl!] orplacebo, in random order, followed by each ofthe tramadol doses (I00, 200, 300, and 400 mg) administered in ascending order. At least 48 hours separated treatments. Various measurements were taken at 15 minutes priorto dosing and at various intervals following dosing up to 24 hours. Quantitation consisted ofdetermining the 24-hour area-under-the-curve (AUC) and maximum effect observed. Two ofthe SDRQ questions included "Likethe Effect?" and "How High AreYou?" Forboth questions, the 24-hourAUC for 20 mg morphine was larger than that for 400 mgtramadol, though thepeak effect score was higher for 400 mg tramadol compared to morphine. The larger 24-hourAUC values ofmorphine resulted from the more rapid drop in scores for 400 mg tramadol. Using SDIQ, subjects were asked "How much is the effect you feel like that ofan opiate?" The larger 24-hourAUC for morphine compared to all doses oftramadol indicated that subjects were less likely to identifytramadol, as compared to morphine, as an opiate. However, the mean peak scores for 400 mg tramadol and 300 mg tramadol indicated that at least initially, subjects recognized tramadol as an opiate. Tramadol produced more dysphoria than morphine. As the dose oftramadol increased, dysphoria scores decreased. Tramadol produced sedation in a dose-dependent manner with the 400 mg dose surpassingthe 20 mg morphine dose. Overall, this initial single-blind study showed that at the higher intravenous dose of400 mg, tramadol produced opiate-like effects, including "liking" and
a euphoric "high" (as evidenced by the SDRQ), that transiently surpassed that produced by 20 mg morphine. Lower doses oftramadolwere less effective in producing these effects. In light ofthe high doses oftramadolrelative to morphine, required to producereinforcing effects, tramadoIhas an abuse potential but it is less than that ofmorphine.

22

### The second segment ofthe study utilized a five-treatment, double-blind, single-dose, LatinSquare crossoverdesign in which I0 non-dependent, opioid experienced subjects received tramadol ( l00 and 200 mg), morphine (l

### 0mg and 20 mg) [C-Jl], and placebo, intravenously. The original intent to evaluatethe 400 mg dose oftramadolwas terminated as seizures developed in one ofthe subjects receiving this dose. Measurements ofsubjective, behavioral, and physiological effects were similar to those described above in the initial single-blind segment. Forthe various abuse parameters, the Sponsor plotted effects as a function oftime and generated 12-hourAUC values. Data analysis included generation ofdata ofmaximum response, time ofmaximum response, and time to return to baseline. Forthe SDRQ questions of "Feel theEffect?", "Likethe Effect", and "How High Are You", the 12-hour AUC results of morphine 20 mg dose clearly were higher than for othertreatments. The morphine 10 mg and tramadol 200 mg 12-hourAUC scores for these questions were similar, primarily due to the longer duration ofaction oftramadol. Tramadol at adose of100 mg consistently scored only slightly greaterthan that ofplacebo. Across the three questions, the morphine 20 mg and often
even the morphine l0 mg doses consistentlypeaked to a larger extent than did tramadol200 mg. With regard to identification as an opiate (using the SDIQ), morphine 20 mg had the highest "opiate" identification score, followed by the morphine 10 mg, then the tramadol 200 mg dose. On the ARC! MBG subscale, which is a measure ofeuphoria, both morphine doses scored higher than did tramadol (100 or200 mg). Also, based on the LSD subscale ofthe ARC!, tramadol produced more dysphoria than did morphine. The overall results ofthis second segment indicate that tramadol at intravenous doses of100 mg and 200 mg has a low abuse potential, certainly lowerthan that ofintravenous morphine [C-ll] at doses of 10 mg and 20 mg.
A second study submitted after approval ofULTRAM compared the abuse potential oforal tramadol to that oforal oxycodone [C-ll] using non-dependent, opioid experienced volunteers. Sec published abstract byJasinski et al. (1993). The studyconsisted oftwo segments. The first segment was a single-blind escalating dose detcnnination ofthe highest safo single-doseof tramadol in six former addicts. All were required to be able to distinguish oral oxycodonc from placebo. Subjects were first given oxycodone 40 mg orplacebo. This was followed by successive treatment days with tramadol at doses of300 mg, 450 mg, 600 mg, and 750 mg in ascending order. Subjects received treatments on alternative days. A Drug Rating Questionnaire-Subject (DRQS) was used to evaluatethe subjective effects ofeach treatment. The test was given 15 minutes priorto treatment and at various intervals up to 24 hours posttreatment. Effects were analyzed as a function to time. Questions ofprimary importance on the DRQS were "How much do you feel the drug?", "How much do you like the effects ofthe drug?", "How much do you dislike the drug?", and "How high are you now9" Ageneral examination ofthe time response curves for these questions show that 40 mg oxycodone and tramadol, in adose-dependent manner, produced "liking" and a "high" significantly above that of placebo. At adose of 600 mg and 750 mg, tramadol produced peak rating scores for "focling an effect" and "drug liking" that were close to, but less than that produced by 40 mg oxycodone. With regard to producing a "High", 40 mg oxycodone was superiorto the doses oftramadol, particularly in the earlytime periods (out to 5-8 hours). At the 300 mg dose oftramadol, these
scores were considerably less than that seen for oxycodone. For all doses, the effects oftramadol
were slower in onset and oflongerduration compared to effects produced by oxycodone. Peak effects ofoxycodoneoccurred within a couple ofhours, while peak effects oftramadol occurred at 5+ hours.

23

### The second part ofthe study was a completely randomized double-blind crossovertest of tramadol (175 mg, 375 mg and 750 mg), oxycodone (20 mg and 40 mg) and placebo. The methodologyused was similarto that found in the first segment (dose ranging study) ofthe study except that twelve subjects (non-dependent, opioid experienced) were used instead ofsix. Similar results as found in the first segment ofthe study were produced. Oxycodone (20 mg and 40 mg) and tramadol (350 mg and 700 mg) produced "feel the drug effect" and "liking" scores that were substantiallygreaterthan placebo. Tramadol 175 mg produced placebo-like effects. For "feel the drug effect", tramadol 750 mg produced a larger response than did oxycodone20 mg but slightly less response compared to oxycodone 40 mg. This effect oftramadolwas slower in onset and longer in duration. Tramadol 750 mg also produced "liking" which was slower in onset and of!ongerduration than that produced by oxycodone.
Both segments ofthe study provided support that tramadol, particularly at the higher doses, produces subjective reinforcing effects, thereby indicating an abuse potential for the drug. The study results also indicated that these effects were somewhat less than those produced by 40 mg oxycodone [C-II], suggesting that tramadol has a lowerrelative abuse potential. Subjective Reinforcing Effects ofPropoxyphene

- Dose Dependency Similar to Tramadol
Tramadol at higher than therapeutic doses produces subjective reinforcing effects similar to or approaching those ofmorphine [C-II] and oxycodone [C-11]. Examination ofthe medical literature shows a similar dose dependency for propoxyphene [C-IV] with regard to producing opioid-like subjective reinforcing effects. Proproxyphene [C-IV], at clinically relevant oral doses (65 mg for the hydrochloride salt and l00 mg for the napsylate salt) failed to evoke subjective effects in drug abusers (Fraser and Isabell, 1960; Jasinski et al., 1977). However, an increased dose of 160 mg proproxyphene HCl [C-IV] given to fonner opiate addicts produced subjective reinforcing effects that were significantly less than those produced by morphine sulfate [C-II], but similarto the reinforcing effects produced by pentazocine [C-IV] (Fraser and Rosenberg, 1963). At still higher doses, specifically420 mg and 620 mg proproxyphene HCI [C-lV] and 620 mg and 700 mg proproxyphenenapsylate [ClVJ), significant subjective reinforcing effects ofpropoxyphenewere comparable to morphine [C-1!] ormethadone [C-II] in heroin addicts (Fraser and Isabel, 1960; Jasinski et al., 1977; and Jasinski and Preston, 1986). Significant adverse effects were observed at these higher doses. The reinforcing effects (pharmacodynamic response) are dose related for drugs like propoxyphene (C-IV) and tramadol. These effects were observed in clinical laboratory studies at doses that were greaterthan the recommended therapeutic doses. At supratherapeutic doses, they each canproduce reinforcing effects similarto other controlled substances.
Conclusions: Subjective Reinforcing Effects as Related to Abuse Potential ofTramadol
Studies show that tramadol, at single doses above the therapeuticallyprescribed single doses, produces subjective reinforcing effects that are significantly greaterthan those ofplacebo and arc similarto or approach those produced by morphine [C-Il] and oxycodone [C-II] [at therapeutically prescribed single doses], respectively. At elevated doses, there is an increased

24

### likelihood ofexperiencing seizures. Bycontrast, at single therapeutic doses oftramadol, subjective reinforcing effects are not generally observed. Theseresults support the placement of tramadol in a CSA schedule less restrictive than that ofSchedule II. No clinical abuse liability studies have been identified that evaluated tramadol's subjective reinforcing effects relative to a Schedule lII orIV positive control. However, the dose dependencyoftramadol for producing subjective reinforcing effects is similarto that observed in other studies looking at the effects of propoxyphene [C-IV] to produce subjective reinforcing effects. At therapeutic doses, propoxyphene docs not cause subjective reinforcing effects. However, at elevated doses sufficient to cause significant adverse effocts, propoxyphene [C-IV] produces subjective reinforcing effects similar to those produced by morphine ormethadone. This similaritybetween tramadol and propoxyphene suggests tramadol is appropriate for Schedule JV placement. SummaryofRelevant Findings and Conclusions for Factor 2
Tramadol is an opioid. Receptorbinding and efficacy studies indicate that tramadol primarily acts via its Ml metabolite to interact with the μ-opioid receptorto producequalitatively a variety ofpharmacological effects commonly produced by opioids that are listed in Schedules II-IV. There tends to be a time delay in the appearance ofthese effocts, indicating the importance ofthe Ml metabolite in evokingthe effects. Generalizationto the morphine stimulus cue provides additional support indicating that tramadol produces effects similarto opioids [C-Jl-IV] Tramadol can block the reuptake ofnorepinephrine and serotonin, effects also produced by such opioids as meperidine [C-II], methadone [C-II] and levorphanol [C-11]. Opioids that are active at the μ-receptor possess morphine-like properties and are scheduled drugs. The fact that tramadol is an opioid provides support for scheduling this drug, but does not delineate the specific schedule in whichto place tramadol.

In three intravenous selt:administration studies in Rhesus monkeys, tramadol produced some reinforcing effocts, thereby showing qualitatively another similarityto that ofopioids. The reinforcing effect oftramadol was limited. No animal self-administration studies utilizing an opioid positive control in schedules II, III, IV or Vhave evaluated the reinforcing effects of tramadol. The limited reinforcing effects oftramadol observed in the selt:administration studies suggest placement oftramadol in a schedule less restrictive than morphine.
Clinical studies showthat tramadol, at singledoses greaterthan therapeutically prescribed, produces subjective reinforcing effectsthat are significantlygreaterthan those ofplacebo and arc similarto or approach those produced by morphine [C-11] and oxycodone [C-Il], respectively. The higher doses may contribute to the seizure risk. Lowerdoses, within the therapeutic range, do not appear to result in subjective reinforcing effects. A similar dose dependency in producing subjective reinforcing effects occurs with propoxyphene [C-IV] in that at elevated doses, but not therapeutic doses, propoxyphene produces subjective reinforcing effocts similarto those of morphine [C-11] and methadone [C-11] at therapeutic doses. This similaritybetween tramadol and propoxyphene provides support for a similar abuse potential and placement oftramadol into Schedule IV.



### 25Factor3. The State ofCurrent Scientific Knowledge RegardingTramadol
Chemistry

The chemical name oftramadolhydrochloride is(±) cis-2-[(dimethylamino) methyl)-1-(3- methoxyphenyl)-cyclohexanolhydrochloride. The drug is also known chemically as(±) cis-2- [(dimethylamino)methyl)-1-(m-methoxyphenyl)-cyclohexanol hydrochloride and as (IRS; 2RS)- 2-(dimcthylamino-methyl)-l-(m-methoxyphenyl)-cyclohcxanolhydrochloride. Tramadol is a 4- phenyl-piperidine analogue ofcodeine resulting in chemical similarities to codeine. Tramadol has two chiral centers, and the drug is marketed as the (±)-cisracemate. Registry numbers for tramadol are CAS-36282-47-0 (hydrochloride salt) and CAS-27203-92-5 (base). Tramadol hydrochloride has a molecular fonnula ofC1 6H25N02 HCl, and a molecular weight of299.84. Tramadol hydrochloride is a white, bitter, crystalline, odorless powderthat is readily soluble in water and ethanol and has a pKaof9.41. The water/n-octanol partition coefficient is 1.35 at pH 7.

Pharmacokinctics

The pharmacokinetics oftramadolwas extensively studied in animals and humans (for review
see Grand and Sablotzki, 2004; Rhonda Lee et al., 1994). Information on the pharmacokinetics oftramadol in humans is in the approved labeling for ULTRAM tramadol products. Information
onthe human pharmacokinetics oftramadoltaken from the approved labeling (September 9, 2009) for ULTRAM is provided below.

The analgesic activityof'ULTRAM® is due to bothparentdrug andthe MI metabolite (5ee CUN/CAL PHARMACOLOGY, Pharmacodvnamics). Tramadol is administeredas a racemate andboth the [-J and[+jf(Jrms of'hoth tramadol andMl are detected in the circulation. Linearpharmacokinetics have been observed.followingmultiple doses of'50 and 100 mg to steady-state. Absorption Racemic tramadol is rapidly andalmost completely absorbedafieroraladministration. The mean absolute bioavailahilityofa JOO mgoraldose is approximately 75%. The
meanpeakplasma concentration of'racemic tramadolandMI occurs at two andthree hours, respectively, afieradministration in healthyadults. Jn general, both enantiomers oltramadofandM 1 followaparallel time course in the hodyfollowingsingle and multiple doses although smalldifferences (- 10%) exist in the absolute amountof each enantiomerpresent. Steady-stateplasma concentrations ofhoth tramadol andMI are achieved within two days withfour timesperday dosing. There is no evidence ofself induction. Distribution The volume of'di.1trihution of tramadolwas 2.6 and2.9 liters/kg in male andfemale subjects, respectively,fiJ/lov.,ing a 100 mg intravenous dose. The bindingof tramadol to humanplasmaproteins is approximately20% andbindingalso appears to he

26independent of concentration up to 1()μglmL. Saturation of plasmaproteinfanding
occurs only at concentrations outside the**clinical~v** relevant range. Metabolism Tramadol is extensively metabolizedafieroraladministration. Approximately30% of"the dose is excreted in the urine as unchangeddrug, whereas 60% of the dose is excretedas metabolites. The remainder is excretedeitheras unidentifiedoras unextractable metabolites. The majormetabolicpathways appear to he N- and 0-demethylation and glucuronidation orsulfation in the liver. One metabolite (0-desmethyltramadol, denoted M1) ispharmacologicallyactive in animalmodels. Formation of M1is dependent on CYP2D6 andas such is subject to inhibition, which may (lffect the therapeutic response (5ee PRECA UTJONS, DrugInteraction). Approximately 7% of thepopulation has reducedactivity of the CYP2D6 isoenzyme of cytochrome P-45(). These individuals are "poor metaholizers" of dehrisoquine, dextromethorphan, tricyclic antidepressants, amongotherdrugs. Basedon apopulation PKanalysis of"Phase Istudies in healthysubjects, concentrations of"tramadol were approximately20% higher in "poor metabolizers"versus "extensive 1netaholizers", H'hile M1concentrations were 4()% lower. Concomitant therapy with inhibitors ofCYP2D6 such as.fluoxetine,paroxetine andquinidine couldresult in significantdrug interactions. In vitro drug interaction studies in human livermicrosomes indicate that inhibitors of CYP2D6such asfluoxetine andits metabolite norfluoxetine. amitriptvline andquinidine inhibit the metabolism (Jftramadol to various degrees. suggesting that concomitant administration olthese compounds couldresult in increases in tramadol concentrations anddecreasedconcentrations ofMI. Thefi11!pharmacological impact of these alterations in terms of eitherefficacy orsafety is unknown. Concomitant use of SEROTONINre-uptake INHIBITORSandMAO JNHIBJTORS may enhance the risk of adverse events, includingseizure (.vee WARNINGS) andserotonin syndrome. Elimination Tramadol is eliminatedprimarilv through metabolism by the liverandthe metabolites
are eliminatedprimarilyby the kidneys. The mean terminalplasma elimination halflives ofracemic tramadol and racemic MI are 6.3 ± I.4and 

### 7.4 ± 1.4hours, respectively. The plasma elimination halflifeofracemic tramadol increasedfrom approximately six hours to seven hours upon multiple dosing.

Other routes for administeringtramadolto humans include intravenous injection, intraperitoneal injection, intramuscular injection and rectal suppositories (Grond and Sablotzki et al., 2004; Quetglas et al. 2007; Rhoda Lee et al., 1993). Tramadol is rapidly absorbed with high bioavailability following rectal administration and intramuscular injection.

Pharmacokinctics ofintranasal tramadol administration has not been examined in humans, but
was recently documented using rats (Zhao et al., 2008). In this study, thephannacokinetics of nasal administration oftramadol hydrochloride was compared to that following oral and intravenous injection. Nasal application to conscious rats resulted in peak plasma levels that
were about 2.5 times higherthan that achieved following oral administration, but less than following intravenous administration. The time to reach peak plasma levels following intranasal

27administration was less than that following oral administration. Elimination was also fast fo !lowing intranasal application.
SummaryofRelevant Findings and Conclusions for Factor 3.

The chemical structures oftramadol and the Ml metabolite share similarities with the chemical structureoftheopioid, codeine [C-ll, C-IIJ and C-V for products]. This similarity is consistent with the findings ofpharmacology studies that demonstratethe opioid activity oftramadol.

Tramadol hydrochloride is available as a racemate in a crystalline form that is soluble in water and ethanol. It is readily absorbed from the gastrointestinal tract, withboth enantiomers as well
as the M

### 1metabolite found in the blood following administration. Tramadol is also readily absorbed via subcutaneous, intramuscular and rectal routes ofadministration. One study, conducted in rats, suggeststhat nasal application may be a very effective means ofadministering tramadol resulting in rapid plasma levels oftramadol.

Tramadol undergoes extensive metabolism to a number ofmetabolites including the Ml metabolitewhich is primarily responsible for the opioid activity oftramadol. This extensive metabolism, in part, provides for possible interactions between tramadol and a varietyofother drugs that undergo metabolismbythe CPY2D6 enzyme.
Factor 4. Tramadol's History and Current Pattern ofAbuse FDA approved ULTRAM, tramadol immediate-release oral tablets, in 1995 for the treatment of moderateto moderately severe pain. Sincethat time, a variety ofothertramadol products including immediate release products, combination products and extended releaseproducts have been approved for marketing in the United States. A detailed regulatoryhistory oftramadol is provided under the "Background" section ofthe Introduction.

Since 1995, new data has been collected regarding the pharmacology, safety, diversion and misuse and abuse oftramadol. These data are discussed undervarious Factors including Factors I, 2, 4, 5, 6 and 7. Abuse data from epidemiological databases is specifically discussed below (Factor4). History and Current Patterns ofTramadolAbuse. Epidemiological Databases

In orderto assess the significance ofabuse oftramadol, data from the DrugAbuse Warning Network (DAWN), the National Survey ofDrug Use and Health (NSDUH), and Annual Reports ofthe American Association ofPoison Control Centers'National Poison Data System are compiled along with law enforcement data from theNational Forensic LaboratoryInformation System (NFLIS). Detailed information on these databases, as well as on annual prescription data (SDI), areprovided below. Collectively, these data support placement oftramadol into Schedule IV.



### 28Prescription Data RegardingTramadol

In the United States, tramadol is an active ingredient in both immediate-release and extendedrelcase pharmaceutical products. Table 3 provides a comparison between tramadol and other analgesics in terms ofannual prescriptions dispensed overtheperiod of2003 to 2008. In 2007 and 2008, more prescriptions were written for tramadol than for any otheropioid otherthan hydrocodone [C-IIIJ and oxycodone [C-IJJ. The annual number ofprescriptions for tramadol surpassed the annual numberofprescriptions ofproproxyphene [C-IVJ and codeine (C-11, Ill, VJ in 2007 and 2008.

Table 3. AnnualNumberofRetail Prescriptions for Opioid Analgesics for 2003 to 2008. (Source: SDI)
Drug" Number ofPrescriptions 2003 2004 2005 2006 2007 2008 Tra1nadol 15.332,231 17,096,302 19.153.871 21.296,233 23,702,369 25,875,743 Hydrocodonc 92,365,758 97,878,121 105,745,912 113,174,017 120,470,945 124,980,045 Oxycodone 29, 157,793 3],339,794 34,317,681 37,628,711 42,209,222 46,711,833 Propoxyphcnc 25,943,076 24,956.256 24,021,977 23,098,536 22,327,677 21,294,469 Codeine 25, 146,991 22,930,145 22,392,432 20,713,445 20,099,522 20,490,308 Fcntanvl 3,980,412 4,444,616 4,658,670 5,099,351 5,545,675 5,684,793 Morphine 3,325,658 3,987,364 4.417,425 4,957,690 5,525,154 6,284,672 Methadone' 2, 171,997 2,779,825 3,420.581 3,913,210 4,181,906 4,440,146 Diphcnoxylatc 3,151,446 2,992,401 2,886,629 3,029,256 3,047,224 2,915,822 Buprcnorphine- 117,479 316,877 590,248 1,070,874 2,105,222 3,764,297 Hvdromorphonc 842,382 993,375 1,228,948 1,408.517 1,638,108 1,889,(!18 Mcperidine 1,717,289 1,615,330 1,568,265 1,526,066 1,416,059 1,252,460 Butorphanol 662,016 593,528 546,161 501,860 470,664 450,564 Pcntazocinc 433,049 376,455 352,357 326,637 314,033 246,785 Oxvmomhonc 15 37 14 28.414 256,442 508,685

Numbers 1nd1cate methadone for use tn treatment ofpa1n and do not include use ofmethadone for treatinent of opioid addiction in drug abuse treatment clinics. 2 Buprenorphine isprimarilyprescribed and dispensed for treatment ofopioid addiction. 3 OxyCodone, fcntanyL morphine, methadone, hydron1orphone, meperidine and oxymorphone are in Schedule II. Hydrocodone combination products and buprenorphine are in Schedule III.**(~odeine** products arc in Schedules II, III and V. Proproxyphcne. butorphanol and pentazocine are in Schedule IV. Diphcnoxylate is in Schedules II and V.

In contrast to the consistent incremental rise in annual prescriptions seen for tramado1overthe period of2003 to 2008, there was a consistent reduction in annual prescriptions for proproxyphene [C-IV], butorphanol [C-IVJ and pentazocine [C-IVJ overthe same period. Whereas there was a slight rise in the numberofprescriptions in 2008, therehasbeen a consistent reduction in annual prescriptions for codeine (C-11, III, VJ overtheperiod from 2003 to 2007. Over each ofthe five years, therehas been a consistent multi-fold greater numberof prescriptions written for tramadol compared to such analgesics as morphine (C-II], fentanyl [CIIJ, methadone [C-II], hydromorphone [C-ll], buprenorphine [C-111], meperidine [C-ll], butorphanol [C-IV], pentazocine [C-IVJ, and oxymorphone (C-ll].

29

### Drug Abuse WarningNetwork (DAWN)

The Drug Abuse Warning Network (DAWN) is a public health surveillance systemthat monitors drug-related visits to hospital emergencydepartments (ED) and drug-related deaths reported to DAWN byparticipating medical examiners and coroners to track the impact ofdrug use, misuse, and abuse in the United States. The Substance Abuse and Mental Health Services Administration (SAMHSA) manages the DAWN system. Major changes to DAWN were made at thebeginning of2003. These changes werethe result of
a redesign that, among other changes, altered most ofDAWN's core features, including the design ofthe hospital sample and the cases eligible for DAWN. These changes resulted in a permanent disruption in trends for the time period priorto 2003. As aresult, comparisons cannot be made between previous DAWN (2002 and prior years) and the current DAWN systems. In addition, changes in the methodology do not allow for national estimates to be computed for 2003, which was the transition yearbetweenthe two DAWN systems. Below arc data on tramadol and otheropioids from both the old and new DAWN systems.
DAWN 1995-2002
Abuse-related ED visits involving tramadol increased from 1995 to 2002 peaking in 2001 (Table 4). Abuse-related deaths increased from45 (1997) to 88 (2002). ED mentions for tramadol were either used alone and in combination with the following substances: alcohol, acetaminophen. amitriptyline, cyclobenzaprine, carisoprodol, hydrocodone, oxycodonc, cannabis, cocaine, sertraline, clonazepam, alprazolam, and zolpidem.
Table 4. DAWN (Drug Abuse Warning Network) Estimate ofTramadol Mentions in Drug Abuse-Related ED Visits in the Coterminous US: 1995-2002. (Source: SAMSHA: Ofiice of Applied Studies.)

Drug 1995' 1996 Tramadol 645' 1290 Hydrocodonc 9686 11419 Buprenorphine 2 I Butorphanol



### ... 239 Pentazocine 153 196 Diclofcnac 210 456
Tn1madol approved for marketing March 1995 RctCrs to an eight 1nonth period 

### 1997 1418 11570 3

...

... 

### 202 725 1998 1999 2000 2001 2002 1972 1113 1810 2329 1714 13611 15252 20098 21567 25197 0



### ... I 1 10 6 19

... 

### ... ... .

### .. 329 262

... 

### 247 17 30 310

... 

### 28

...

'Three dots(

...) indicate that an Wl\.vcightcd count less thlin 30, an cstin1ate less than 30, oran csti1nate v.·ith an RSE greater than 50o/r) has hcen suppressed.


### DAWN (2003

- 2008)

DAWN is currentlydesigned to obtain information on all drug-related ED visits, regardless of the motive for using the drug. All drugs are captured including illicit drugs, prescription and over-the-counterphannaceuticals, dietary supplements, nonpharmaceutical inhalants, alcohol when it is combined with another drug and, for patients under age 21, ED visits where alcohol is

30the only substance. Measures provided by DAWN ofnonmedical use ofaparticular drug resulting in a drug-related ED visit involve at least one ofthe following: 1) Taking more than the prescribed dose ofa prescription pharmaceutical 2) Taking morethan therecommended dose ofan OTC pharmaceutical supplement 3) Taking a pharmaceutical prescribed for another individual 4) Deliberate poisoning with a pharmaceutical by anotherperson: or 5) Documented misuse orabuse ofa prescription orOTC pharmaceutical ordietary supplement. Nonmedical use ofpharmaceuticals may involve pharmaceuticals alone orpharmaceuticals in combination with illicit drugs or alcohol.

National estimated annual ED visits for the period of2004through 2008 resulting from the nonmedical use oftramadol and otheropioids, including their combination products, are provided in Table 5. Overthis period, the number ofestimated ED visits from nonmedical use oftramadol/combinations showed a continuous increase from approximately4,800 ED visits to over 11,800ED visits. As with the other opioids, there was a substantial increase in ED visits in 2008 (11,850) compared to 2007 (8,039). For each ofthe years from 2004 through 2008, the annual nonmedical ED visits for tramadol/combinations was well below that for fentanyl/combinations [C-II], hydrocodone/combinations (65,734) [C-lll], methadone (C-II], morphine/combinations [C-ll], and oxycodone/combination [C-11].

Data from Table 5 shows that overthe period of2004through 2008, the national estimated annual ED visits oftramadol/combinations were more closely in the range ofthose found for hydromorphone [C-11], buprenorphine/combinations [C-lll], codeine/combinations [C-11, lll, V] and propoxyphene/combinations [C-IV]. For all four drugs, there was a substantial increase in the number ofED visits in 2008 compared to in 2007. In 2008, the annual ED visits for tramadol/combinations (11,850) was somewhat higher than that ofcodeine/combination [C-IL III, V] visits (8,235) and a little less than that ofbuprcnorphine/combination [C-lll] visits (12,544) and propoxyphene/combination [C-IV] visits (13,364).
Table 5. DAWN Estimated Annual ED Visits for Nonmedical Use ofSelected Opioids for 2004 Through 2008. (Source: SAMHSA, Office ofApplied Studies) Drug DAWN Estimated Annual ED Visits 2004 2005 2006 2007 2008 Hydrocodone/Combinations' 39,844 47,192 57,550 65,734 89.051 Oxycodone/Combinations' 41,701 52,943 64,888 76,587 105,214 Methadone' 36,806 42,684 45,130 53,950 63,629 Hydromomhone' 3,385 4,714 6,780 9,497 12, 142 Morphine' 13,966 15,762 20,416 29,591 28,818 Fentanyl/Combinations' 9,823 11,211 16,012 15,947 20, 179 Mepcridine/Combinations' 782 383 1,440 997 l,435 Buprenorphine/Combinations-'

-- -- 4,440 7,136 12,544 Tramadol/Combinations' 4,849 5,918 6,048 8,039 11,850 Codeine/Combinationsj 7, 171 6, 180 6,928 5,648 8,235

### ~proxyphene/Combinations" 6,744 7,648 6,220 7,401 13,364 ' 

## ' .l Schedule II; Schedule Ill; Schedule II, Ill. V; 4Schedulc IV; 5Not Scheduled

31

### The rates ofestimated nonmedical ED visits docwnented in DAWN per 100,000prescriptions dispensed for tramadol/combinations as well as other selected opioids are shown in Table 6. Over the period of2004through 2007, the annual rates oftramadol/combination ED visits ranged between 28.4 and 33.9. In 2008, there was a substantial increase in rate ofED visits of tramadol/combinations to 45.8 ED visits per 100,000 prescriptions. Overthe five year period (2004-2008), annual rates oftramadol ED visits were substantially below that ofrates for oxycodone/combinations [C-11], methadone [C-11], hydromorphone [C-11], morphine [C-11], fentanyl/combinations [C-11], meperidine/combinations [C-II], hydrocodone combinations [Clll] and buprenorphine/combinations [C-lll] (2006-2008 only).

Over the period of2004through 2008, therates ofestimated nonmedical ED visits for tramadol/combinations, were more closely in the range for the rates ofcodeine/combinations [C11, Ill, 

### VJ and proproxyphene/combinations [C-IV] compared to the other opioids for which data
was provided and showed substantially higher rates. For all three drugs, there was an increase in rates ofED visits in 2008 compared to 2007. In 2008, the rate ofnonmedical ED visits per I

### 00,000 prescriptions oftramadol/combinations was 45.8 which was between that for proproxyphene/combinations (62.7 ED visits per 100,000 prescriptions) and that for codeine/combinations (40.2 ED visits per 100,000prescriptions).
Table 6. Rates ofDAWN Estimated Annual Nonmedical ED Visits for Selected Opioids for 2004 Through 2008. Rates Calculated as Estimated Annual Number ofED Visits Per 100,000 Prescriptions. (Source: DAWN data is from SAMSHA, Office ofApplied Studies. Prescription data comes from SDI and is found in Table 3 in Factor4) Drug DAWN Estimated Annual Nonmedical ED Visits Per 100,000 Prescriptions 2004 2005 2006 2007 2008 Hydrocodone/CombinationsL 40.7 44.6 50.8 54.6 71.3 Oxycodone/Combinations' 133.1 154.3 172.4 181.4 225.3 Methadone' 1324.0 1247.9 1153.3 1290.1 1446.1 Hydromorphone' 340.8 383.6 481.4 579.8 639.1 Morphine' 350.3 356.8 411.8 535.6 457.4 Fentanyl/Combinations' 221.0 240.6 314.0 287.6 357.0 Meperidinc/Combinations' 48.3 24.4 94.1 70.2 1I

### 0.1 Buprenorphine/Combinations·



### -- -- 414.6 339.0 330.1 Tramadol/Combinations 28.4 30.9 28.4 33.9 45.8 Codeine/Combinations3 

### 31.3 27.6 33.4 28.1 40.2 Proooxyphene/Combinations' 27.0 31.8 26.9 33.1 62.7

- 'Schedule II; 'Schedule Ill; 1Schedulc II, III, V; 4Schcdule IV



### 32For 2007 and 2008, with respect to nonmedical ED visits involving tramadol/combinations alone (in the absence ofotherdrugs present), 1,819 and 788, respectively, resulted from "overmedication"while 1,476 and 2,016, respectively, ofvisits wereplaced underthe category of"other." Bydesign, it is the "others" categorythat captures most ofthe documented drug abuse cases. Approximately 54 % ofthe visits for tramadol involved women. Nonmedical ED visits for tramadol involved individuals across a wide range ofage groups. Ofthetotal ED visits (11,850), 21.4 %, 21.7 %, 26.4 % , and 16.3 % ofthe visits involved individuals in the age ranges of18 to 20, 21 to 29, 30to 44, and 45 to 64, respectively.

In summary, examination ofthe DAWN data indicates that abuse related and nonmedical use of tramado1products result in ED visits. The DAWN datapriorto 2003 documents abuse related ED mentions for each year going back to 1995, the year in which tramadol received approval for marketing in the United States. The new DAWN datadocuments ED visits resulting from the nonmedical use oftramadolthat include, but are not limited to, ED visits resulting from abuse of tramadol. Boththe national estimates ofnonmedicalrelated ED visits and the rates of nonmedical ED visits calculated based on 100,000prescriptions are lower for tramadol/combinations compared to anumber ofthe Schedule II opioids. This is also truewhen tramadol/combinations is compared to the Schedule III drug. buprenorphine, and to hydrocodone combinations. With respect to both national estimatesofnonmcdicallyrelated ED visits and to rates ofthese visits per 100,000 prescriptions, tramadol/combinations more closely compares to the Schedule IV opioid proproxyphene/combinations [C-lV] and to codeine/combinations [C-ll, Ill, V]. Overall, the DAWN data suggest that the potential for abuse oftramadol is less than that ofSchedule II and Ill substances and products most similar to that ofpropoxyphene (Schedule IV).
National Survey on Drug Use and Health (NSDUH)

The National Surveyon Drug Use and Health (NSDUH), operated by SAMHSA, provides information on the nonmedical use ofdrugs in the general United States population age 12 and older. Yearly national and state level estimates ofalcohol, tobacco, illicit drug, as well as forthe nonmedical use ofprescriptiondrugs, are obtained.
The NSDUH provides annual estimates onthe lifetime nonmedical use ofpain relievers. FDA has received from SAMHSA for each ofthe years from 2002 through 2007 specific estimates of lifetime nonmedical use ofhydrocodoneproducts [C-lll], oxycodoneproducts [C-IIJ, and tramadol products. As used in the NSDUH, lifetime nonmedical use ofany pain relieverby an individual means any use ever, even once, ofapain reliever that was not prescribed to an individual orthat the individual tookonly for the experience or feeling that the pain reliever caused.

As seen from Table 7, the number ofindividuals who used tramadol products nonmedically at least once in their lifetime increased from approximately 994,000 in 2002 to 1,559,000in 2007. For each year surveyed, the absolute number ofindividuals reporting lifetime nonmedical use of tramadol was lowerthan that ofindividuals reporting lifetime nonmedical use ofhydrocodone

33products [C-III] oroxycodone products [C-Il]. For example, in 2007 the estimated number of individuals reporting lifetime nonmedical use ofhydrocodoneproducts [C-lll] and oxycodone products [C-Il] were 21,335,000 and 13,055,000, respectively, compared to 1,559,000 estimated individuals havingreported lifetime nonmedical use oftrarnadolproducts.

Table 7. Estimated Lifetime Nonmedical Use ofSelected Pain Relievers, Age 12 and Older. (Source: SAMSHA, OfficeofApplied Studies, 2002-2007 National Survey on Drug Use and Health.)

Drug 2002 2003 2004 2005 2006 Number oflndividuals (in Thousands) Hydrocodone Products' 13,952 16,808 17,734 18,875 OxycodoneProducts' I0,151 11,538 11,925 12,029 Tramadol Products' 994 1,221 1,280 1, 135 Includes V1codm®. Lortab®, or Lorcet®, and hydrocodone combo 1s Schedule Ill 2Includes Percocet®, Percodan® or Tylox®, and OxyContin® in Schedule II 'Includes Iramadol and ULTRAM® 20,755 12,858 1,352 2007
21,335 13,055 1,559

The NSDUH also provided data onthe number ofindividuals who reported 1) initiation ofthe
use ofany pain reliever within the past year and 2) nonrnedical use ofeitherhydrocodone products [C-111], oxycodone products [C-Il], ortramadolproducts within the same period (one year). The data is presented in Table 8below. For each ofthe years overthe period of2002 to 2007, the estimated number ofindividuals who initiated use ofpain relievers and reported nonmcdical use oftramadolwas less than 100,000 (with the highest at 95,000 in 2003 and the lowest at 22,000 in 2006). By contrast, for each ofthe years 2002 to 2007, the number ofpast year initiates for use ofany pain reliever who also used hydrocodoncproducts(> 1,200,000) and oxycodone products(>450,000) nonmedically was greaterthan for thenonmcdical use of tramadol
Table 8. Past YearNonmedical Use ofSelected Pain Relievers According to Past Year Initiates ofAny Pain Reliever, Age 12 and Older. (Source: SAMSHA, Office ofApplied Studies, 2002- 2007 National Surveyon Drug Use and Health.)

Drug 2002 2003 2004 2005 2006 Number oflndividuals (in Thousands) Hydrocodonc Products' 1,349 1,403 1,352 Oxycodone Products- 474 503 608 1·ramadol Products' 56 95 51
'" Includes V1t:od1n(f3.), Lortab®, or Lorcet®, and hydrocodone. 2illcludes Percocet®, Percodan® or Tylox®, and OxyContin® 'Includes tramadol and ULTRAM® 1,314 1,315 455 546 46 22 2007
1,285 592 57

In summary, the NSDUH data indicatethat there is nonmedical use oftramadol and that such use is on the rise. Both lifetime nonmedical use as well as nonmedical useoverthepast year, that is the last 12 months since the datethat individuals completed the survey among new initiates of pain reliever use is lower for tramadol products when compared to oxycodone products [C-11], or to hydrocodone products [C-III]. Collectively, the information from NSDUH shows that

34tramadol is used nonmedically in individuals age 12 and older, and supports placement of tramadol in a schedule less restrictive than Schedule III.

National Forensic Laboratory Information System (NFLIS)

- Law Enforcement Encounters With Tramadol

The National Forensic LaboratoryInformation System (NFLIS) is a program ofthe Drug Enforcement Administration (DEA), Office ofDiversion Control that began in 1997, and systematically collects into a computer database drug identification results and associated information from drug exhibits analyzed by state and local forensic laboratories. Each exhibit is
a quantityofdrug (controlled ornoncontrolled) seized in the course oflaw enforcement activity and subsequently sent to and analyzed by a stateorlocal forensic laboratory. For each exhibit, a variety ofrelated information is provided, including time and date ofdrug seizure, location of drug seizure and identification ofindividual(s) who possessed the exhibit when it was seized. Analyzed exhibits maybe evidence in drug court cases. Information collected within NFLIS is consolidated in quarterly and annual reports available to the public at the DEA Office of Diversion Controlwebsite.
The NFLIS expands each year with recruitment ofadditional state and local laboratories. According to the 2007 NFLIS Annual Report, as ofApril 2008 NFLIS includes 45 state laboratory systems, 95 local ormunicipal laboratories and one territorial laboratory, representing 276 individual laboratories and handling over 88% ofthe nation's annual state and local drug analysis cases. According to the 2001 NFLIS Annual Report, there were only32 state laboratory systems and 45 local laboratories, representing 174 individual laboratories participating in NFLIS. As a result ofthis growth, data provided in NFLIS cannot betrended overthe years. However, NFLIS maybe useful in demonstrating that a substancehas been encountered by law enforcement laboratories and the number ofsuch encounters can be compared within a given year with encounters with other substances. Product-specific data is not available and the data should not necessarily imply criminal activity.

35Table 9. NumberofExhibits in NFLIS ofTramadol and OtherOpioids Analyzed by State and Local Laboratories Annually from 2000-2007. (Source: NFLIS Annual Reports found at ww_w,deagiversion.usdoj.govIntlis/index.html)

2000 2001 2002 2003 2004 2005 2006 2007 2008 Hydrocodone' 3,014 5,890 9,563 JO, 195 13, 113 19,893 26,017 30,504 36,625 Oxycodone.1 2,116 5, 181 8,660 8,576 11,342 15,463 19,923 25,029 32,194 Methadone·'



### -- -- 2,327 2,781 3,904 5,425 7,023 7,496 8,334 Morphine·' 459 872 1,499 1,488 1,902 2,957 3,887 4,202 5,366 Codeinel 926 1,537 1,911 1,824 2,454 2,458 2,597 2,674 3, 148 Buprenorphine
.. 8 11 11 9 148 446 I, 113 2,094 4,291 llydron1orphone" 204 376 622 471 616 1,011 1,303 1,559 1,773 Proproxyphcne" 570 1,022 J,526 1,321 1,348 1,497 1,488 1,306 1,256 Dihydrocodeinc"



### -- 450 721 807 1,315 1, 151 1,290 957 1, 149 ·rra1nadol 1 73 129 238 245 303 490 598 751 1,093 Fcntanyf 23 33 86 152 198 285 1,270 732 525 Mcperidine· 160 267 281 240 231 253 334 316 300 Pentazocine:i 25 60 68 47 63 74 80 88 71 Oxymorphone· 6

-- I 2 3 14 14 34 116 Butorphanor' 5 5 8 8 5 4 9 JO 11 Nalbuphine' 91 132 261 10 6 11 18 7 9

, '',.**~** 

### .. ' , , Noncontrollc<l substances, Schedules IL Ill and V., Schedule II, Schedule III, Schedule IV
Table 9 provides the NFLIS data for tramadol and otherselected opioids. Tramadol is the only drug listed that is not controlled in the CSA. In 2008, thetramadol-containing exhibits were close in numberto that ofexhibits for proproxyphene [C-IV]. For each year, the number of tramadol exhibits was less than the number ofexhibits ofthe Schedule II substances, oxycodone, methadone, morphine and hydromorphone, and hydrocodone [C-III] and codeine [C-II, Ill, VJ. Forthe years 2006

- 2008, thenumber oftramadol exhibits was less than the number ofexhibits ofbuprenorphinc [C-III] seized.

Further examination ofTable 9 shows that for most years, the number oftramadol exhibits exceeded that ofexhibits for the Schedule II drugs, meperidine, oxymorphone and fentanyl and for the Schedule IV drugs pentazocine and butorphanol. The higher numbers oftramadol exhibits mayreflect the more limited availability ofthese Schedule II and IV drugs compared to tramadol. Considering that tramadol is not a controlled substance either at the federal or state level, it is probablethat the numbers oftramadol exhibits analyzed bythe state and local laboratories and documented in NFLIS is considerably lower than the actual number ofexhibits involving tramadol submitted to state and local laboratories. As noted bythe DEA, while tramadol is seized during law enforcement action, tablets may not be analyzed ifidentified as being an uncontrolled pharmaceutical product. It should also benotedthat the NFLIS system may underreport the diversion ofsuchdrugs as the schedule IV drugs butorphanol, pentazocine, proproxyphene, and codeine products [C-11-V]. Being in lower schedules, these drugs may receive lower prioritywith respect to law enforcement investigations, as well as with respect to

36

### submission and analysis in the forensic laboratory ofexhibits suspected ofcontaining these drugs.

American Association ofPoison Control Centers' National Poison Data System (NPDS)
Poison Control Centerdata demonstratethat from 2004 through 2008,the number ofhuman poison exposures to tramadol increased annually. This data indicates tramadol represents a growing risk to the public.

Data on cases ofhuman poison exposure to tramadol and otheropioid analgesics were collected from the Annual Reports ofthe AAPCCs' National Poison Data System for the period of2004 through 2007 (Bronstein et al., 2007; Bronstein et al. 2008; Bronstein et al., 2009; Lai et al., 2006; and Watson et al., 2005). For 2005 through 2008, case data were compiled from calls received by61 Poison Control Centers, covering all 50 states. For 2004, 62 Poison Control Centers received calls covering the 50 states. Each case represents incidences in which the caller
was concerned about ahuman exposureto a substance. All cases were closed, meaning that the Poison Control Centerreporting the case determined that no further information is available or no further follow-up recommendations will be made. Calls onlyrequesting information, including drug identification, were not included.
The annual number ofpoison exposure cases oftramadol and other opioids for the period 2004 to 2008 is provided in Table 10. Overthe period of2004 to 2008, the annual number ofcase mentions for tramadol continuously increased from 3,769 to 9,623, though remaining less than the case mentions ofhydrocodone combination products [C-III] oroxycodone products [C-ll]. In 2007 tramadol ranked third behind hydrocodone combination products and oxycodonc products, in terms ofnumber ofopioid case mentions. When looked at in terms ofrates, the number ofcase mentions per I00,000 prescriptions for tramadol increased from 22 in 2004 to 37 in 2008. Overthe period of2004 through 2007, the poison control centerrates oftramadol case mentions werehigherthan for hydrocodone combination products [C-III] but lower than for oxycodone [C-II], morphine [C-11] and methadone [C-11] products. In 2008, the rate oftramadol
case mentions equaled that ofoxycodone [C-II] case mentions but was less than the rate ofcase mentions for methadone [C-II] and morphine [C-11]. Forthe years 2004, 2005, and 2006, the rates oftramadol case mentions were similar to the rates ofpropoxyphenc [C-lV] case mentions. In 2007 and 2008, tramadol surpassed codeine and propoxyphene in the number ofcase mentions and rates ofcase mentions.

37Table 10. Number ofCase Mentions (Exposures) to Selected Opioids Reported in the Annual Reports ofthe American Association ofPoison Control Centers (AAPCC) Toxic Exposure Surveillance System (NPDS) for 2004

- 2008. (These reports are available at www.aapcc.org/DNN/.) Drug Total No. ofCase Mentions' (No. ofCase Mentons/100,000 Prescriptions)2 2004 2005 2006 2007 2008

Tramadol 3,769 (22) 4,740 (24) 5,965 (28) 7,500 (32) 9,623 (37) Hydrocodone' 22.594 (23) 22,l65 (21) 22,244 (20) 24,472 (20) 26,166 (21) Oxycodone4 12,603 (40) 13,191 (38) 13,473 (36) 15,079 (36) 17,256 (37) Methadone' 3,965 (142) 4,311 (126) 4,558 (117) 5,025 (120) 4,770 (107) Morphine" 3,097 (77) 3,351 (76) 2,603 (52) 3,321 (60) 3,762 (60) Codeine' 7,020 (31) 7,747 (35) 5,986 (29) 5,976 (30) 5,733 (28) Propoxyphene" 6,545 (25) 6,234 (26) 5,670 (25) 5,537 (25) 5.486 (26)

'>. Cases involve by non1ntent1onal and 1ntent1onal exposures. Doesnot include callsJUSt for 1nformat1on. 2Ratcs were determined using annual retail prescription data provided by SDI and tabulated in Table 3.**·~('onsists** ofhydrocodonc combination products in Schedule III. 4Schedule II 5Schedules II. III. Y. In 2005, 71 °/o ofcases involved codeine in combination with acetaminophen or aspirin, suggesting Schedule III or V control. In 2004, 2006and 2007, there were 82o/o, 81°;{i and 84?;;) ofcases detennincd to involve codeine in combination with either acetan1inophen or aspirin, thereby suggesting Schedule III or V control. "Schedule IV Of5,965, 7,500 and 9,623 total case mentions in 2006, 2007, and 2008, respectively, 1,482, 1,847, 2,476 involved "intentional" exposureto tramadol alone. These cases included suicides, intentional misuse, intentional abuse and unknown. The specific breakdownofthenumber of
cases under each ofthese four categories was not provided. Intentional misuse is defined as exposure resulting from the intentional improperorincorrect useofa substance for reasons other than thepursuit ofa psychotropic or euphoric effect. Intentional abuse was drug exposure resulting from the intentional improperorincorrect use ofa substance where the victim was likely attempting to achieve a euphoric orpsychotroplic effect. Although specific case numbers
are not provided this data suggest that at least some ofthe case mentions documented bythe AAPCC database involved poison episodes due to the intentional abuse ormisuse oftramadol alone. SummaryofRelevant Findings and Conclusions ofFactor4

Retail prescription data show that for each ofthe years from 2002 to 2007, there has been 

### a progressive increase in the availability oftramadolcontaining products. In 2007, morethan 23.7 million prescriptions were issued for tramado

### 1products.

Data from DAWN indicates that the nonmedical use, including abuse, oftramadol is associated with visits to the emergencydepartment. DAWN ED visits for nonmedical use oftramadol increased from 2004 to 2007, with 4,849 in 2004 to 8,039 in 2007. Over this time period, the

38

### number ofestimated annual nonmedical ED visits per I00,000 prescriptions resulting from nonmedical use, including abuse, oftramadol is in the same range as that for proproxyphene products [C-IV]; greaterthan that for meperidineproducts [C-11]; and lowerthan that for buprenorphine products [C-III] (2006 and 2007 only), hydrocodone combination products [CIII], and a number ofSchedule II opioid products.
Overall, the annual data from the NSDUH for the period of2002 through 2007 indicates that a smaller number ofindividuals reported using tramadol products nonmedically compared to the number ofindividuals reporting nonmcdical use ofC-III orC-11 opioid products. This includes data for estimated lifetime nonmedical use orfor past-year nonmedical use by past year initiates ofany pain reliever.
Poison Control Centerdata show that from 2004 to 2008, tramadol exposure cases reported have increased substantially. The reporting rate for tramadol (number ofcase mentions per 100,000 prescriptions) increased to agreater extent than otheropioids, from 22 in 2004to 37 in 2008. From 2004 through 2007,the rates (per 100,000 prescriptions) oftramadol case mentions was higherthan for hydrocodone combination products [C-Ill] but lower than for oxycodone [C-11], morphine [C-II] and methadone [C-ll) products. Forthe years 2004 through 2006, the rates of tramadol case mentions were similarto the rates ofpropoxyphene case mentions. In 2007, the rate oftramadol case mentions was similar to codeine [C-ll, Ill, VJ and a little greaterthan propoxyphene [C-IV). Jn 2008, the rate oftramadol case mentions was equal to that ofthe rate ofcase mentions for oxycodone and surpassed that ofthe rates ofcase mentions for either codeine orpropoxyphene case mentions.

Data obtained from DAWN, NSDUH, NFLIS and the AAPCC database collectivelydemonstrate the misuse, abuse, and diversion oftramadol. The data are comparable to other substances (opioids) controlled in the CSA. With respect to boththe rates ofnonmedical ED visits found in DAWN and the number oflaw enforcement encounters found in NFLIS, and the increasing rates ofpoison control center reporting, particularlyoverthe period of2004to 2007, tramadol data most closely resembles that ofpropoxyphene [C-IV). Data from the NSDUH also support a schedule less than that ofSchedule III.

Factor5. The Scope, Duration, and Significance ofAbuse ofTramadol


### An assessment ofthe scope, duration, and significance oftramadol abuse is made by examination ofdatabases that document abuse, as described in Factor 4, review ofstudies of abuse potential that are documented in Factor 2, and consideration ofthe case reports described below (Factor 5). Preclinical studies that demonstrate positive reinforcing and discriminative stimulus effects oftramadol similarto other CSA-scheduled opioids are consistent with the human abuse potential data. 

### Because tramadol has been marketed in the United States since 1995, there is almost 15 years ofpost-marketing epidemiologic abuse-related data in the published scientific literature and from the adverse events reporting system (AERS). The
case reports describe behavior that illustrates an addiction to tramadol: drug craving, increasing the tramadol dose, performing self-injury in order to be prescribed more tramadol, taking high doses despite adverse effects that result, and visiting multiple doctors in order to obtain more prescriptions for tramadol.

39

### Reports in the scientific literature document that tramadol can cause dependency and there
are cases where withdrawal symptoms have been reported (Factor 7). Drug abuse and dependency are determined by evaluation ofapatient's drug-seeking behavior, as evidenced by its nonmedical use and reports ofwithdrawal symptoms when the drug is suddenly withdrawn. Withdrawal symptoms oftramadol are typical ofopioids. Approximately I5 years ofpost-marketing history now indicate that tramadol can and is being abused both in the United States and other countries. The growing evidence includes epidemiologic abuse-related data in the published scientific literature, as well as data from national and state data systems that track drug abuse.
Current data indicate that tramadol, as a noncontrolled opioid, can be abused as a substitute for abuse ofother opioids, which are scheduled, and can produce euphoric effects similar to other controlled opioids, while not being detected by law enforcement and not being subject to the provisions ofthe CSA.

Case Reports from The Medical Literature

Casereports in the medical literature provide information on patterns ofabuse oftramadol when prescribed for treatment ofpain. The case reports describe abuse oftramadol for its euphorigenic and sedating etfocts. Development ofiatrogenic addiction to tramadol is also described.

Ehrcnreich and Poser (1993) reported the case ofa 39-year-old female nurse who was urged by her superiors at work to enterthe psychiatric clinic for treatment oftramadoldependence. At the time ofintiatingtreatment, she was using tramadol for more than 6 years. Urinalyses suggested that she did not use otherdrugs. Thepatient initiallyreceived treatment with tramadol for a toothache. She learned to appreciatethe feeling ofwell-being and "subeuphoria" following tramadol intake. She continued to use the drug despite such use causing social problems (with husband and employers) and physical problems including generalized seizures from high doses. She spent considerable time acquiring tramadol, obtaining some supplies from the traumaward where she worked. She spent substantial time continuing to obtain tramadol. With continued
use oftramadol, the patient developed marked tolerance to the drug resulting in escalation of dose. Attempts to stoptramadol use were not successful. Withdrawal symptoms evoked upon discontinuation oftramadol included drug craving, anxiety, restlessness, irritability, palpitations, hypertension, abdominal cramps, and freezing.

Krummen et al. (1999) reported the abuse oftramadol in Cincinnati, Ohio. The Cincinnati Drug & Poison Information Center (DPIC) documented 362, I07, 515, and 326 tramadol abuse calls in 1995, 1996, 1997 and 1998, respectively. The Cincinnati policedocumented diversion of7,258 doses oftramadol from September 1997 to December 1997 and 11,385 doses in 1998. Tramadol
was listed in boththe Cincinnati Police top I0diverted prescription drugs and the DPIC top 20 prescription drugs abused lists for 1997. Reasons for abuse included: prevention ofwithdrawal



### 40

### from otheropioids when unable to get the narcotic ofchoice, easier availability due to lack of control status, and exclusion from urinalysis screening for drugs ofabuse.

Bozic et al. (1999) reported seizures associated with tramadol abuse occurring in 17 nonepileptic adolescents. General tonic-clonic seizures were associated withhigh doses ofsingle (at least 250 mg) orrepeated tramadol intake. The authors noted that tramadol was apopular substance ofabuse among adolescents and was associated with significant neurologic and hepatictoxicity in overdoses. About 20-30% ofsubjects use tramadol alone and 70% use it in combination with beer, cannabis, orglue.

Leo et al. (2000) described the case ofa46-year old woman who became addicted to tramadol afterbeing prescribed the drug for severe pain from an orthopedic problem. She started increasing tramadol doses above that prescribed. In orderto maintain her supply oftramadol, the
woman made visits to the local hospital emergency room and various doctors' offices. Her use oftramadolcontinued after the orthopedic problem was corrected. Priorto presentation at a detoxification unit, she admitted to taking 30 (50 mg) tramadol tablets per day. Initially, tramadol abuse was associated with feelings ofmild euphoria and sedation. Tolerance to the drug's effects developed, requiring subsequent larger doses. She continued use despite adverse effects and interference with her daily activities.
Aknine et al. (2000) report the case ofa 35-yearold male with ahistory ofintravenous heroin abuse and bromazepam and alcohol abuse. After being initially prescribed tramadol at adose of 300 mg perday, he soon escalated the dose to about 600 mg daily to experience feelings ofwell being and decreased heroin craving. At the time ofdetoxification, he was taking tramadol at daily doses ranging from 100 to 1,000 mg perday.

Yates et al. (2001) describe the case ofa 29-year-old woman who became addicted to tramadol while receiving the drug for amedical condition. Initially, she tookthe prescribed dose ofone 50 mg tablet every4 to 6hours. Gradually, she increased the dose such that after 3years she
was taking about 30 50-mgtablets each day. To maintain her supply oftramadol, she went to several physicians and to different hospitals for medical attention to treat self-induced trauma (e.g., abruised face).

Reeves and Liberto (2001) describe the case ofa28-year old woman who was abusing tramadol in combinationwith carisoprodol. The womanhad ahistory ofalcohol and benzodiazepine abuse. She was prescribed carisoprodol for treatment ofparavertebral muscle spasms. She said that two friends with histories ofnarcotic abuse introduced her to the combination of carisoprodol and tramadol. She subsequentlybegan on her own initiative to take larger doses of carisoprodol and eventually requested tramadol from her doctorto treat headaches. When she
was confronted with her misuse ofcarisoprodol, she admitted that she was seeing different physicians to obtain carisoprodol and tramadol. She took the medications together (one ortwo tramadol tablets with two to four carisoprodol tablets) for about one year to produce an effect she described as profoundly relaxing and euphoric. Eventually she increased the administration of the combination from once daily to four times daily.

41

### Soyka et al. (2003) report that between January 1999 and July 2001, 20 chronic, noncancer pain patients (10 males, 9 females and 1male-to-female transsexual) with physical dependence to tramadol were admitted to the addiction ward ofthe psychiatric hospital ofthe University of Munich. Two ofthe pain patients had a history ofalcohol abuse and two other patients had drug abusehistories. Mean daily tramadol dosage was 745 mg withthe maximum being 2.5 grams. The average length oftramadolconsumption was 4.9 years ranging from 3 months to 15 years. Seventeen ofthe 20 patients had initially received tramadol for chronic nonmalignant pain. Nine ofthe patients had experienced seizures priorto admission. The authors noted that it was difficult to treat these patients. Twelve ofthe 20 patients (60%) left thehospital before completion ofdetoxification against medical advice despite gradualtapering ofmedication and concomitant psychopharmacological and psychotherapeutic treatment. The authors concluded that abuse ordependence to opioid analgesics such as tramadol may be more frequent than previouslythought in chronic nonmalignant pain and not exclusively limited to patients with alcohol orpolysubstance abuse.
Ritvo et al. (2007) present two case reports dealing with tramadol abuse. One case involved a 34-year old female who four years previously was prescribed tramadol for pain. She started using the drug also for the improved mood and increased energy she experienced. In obtaining her drug, she used three different physicians and multiple pharmacies to avoid suspicions of abuse. When her consumption exceeded her local supply network, she turned to Internet pharmacies from which sheobtained enough tramadol to takeup to 1200 mg perday. Use of tramadoIcontinued despite such use interfering with her work and despite unsuccessful attempts to discontinue tramadol use. The second case involved a 44-year old female who started abusing tramadol after her physicians became suspicious that she was abusing hydrocodone [C-lll] and oxycodone [C-1!]. She substituted tramadol obtained from Internet pharmacies, and escalated the dose to 1500mg/day. She continued abuse oftramadoldespite the fact that such abuse interfered with her roles as a mother and wife and despite repeated attempts to stop tramadol use. She finally entered treatment for her addiction afterherhusband discovered $7,000.00 in Internet pharmacy charges for tramadol on his credit card statement.
Stoehr ct al. (2009) described two cases ofabuse and dependence to tramadol. The first case involved a 38-year-old male physician who entered addiction treatment for dependence to tramadol. Fouryears earlier, he first started using tramadol daily for headaches. He used hydrocodone and oxycodone preparations intermittentlybut preferred tramadol because ofthe euphoria and increased energy level he experienced aftertaking the drug. The physician obtained tramadol via drug samples and Internet purchases. He attempted to stoptramadol use several times but ran into difficulty when he experienced rebound headaches and mood changes. His medical history revealed two seizures and depression. Following the second seizure, he sought addiction treatment. At the peak ofhis addiction, the physician was taking 27 tablets (50 mg pertablet) oftramadoldaily. He completed 6 weeks ofinpatient detoxification in a residential treatment program after which he received follow-up care by an addiction medicine physician.
The second case decribed by Stoehr et al. (2009) involved a 57-year-old female who presented to an addiction medicine physician. At the time ofpresentation, she admitted to using tramadol 300 mg five to six times daily for the past 3months. She purchased tramadol from Mexico. She

42expressed a desire to stop taking tramadol but could not do so without assistance. When attempting to stoptramado1use she experienced rhinorrhea, sweats, myoclonictwitching, and anxiety. The woman had a 30-yearhistory ofintermittent substance abuse including abuse ofi.v. pcntazocine, i.v. meperidine, oral hydrocodone and oxycodone. Over the previous 30 years, she had completed multiple substance abuse treatment prohrrams. She had a history that was positive for emotional, physical, and sexual abuse and came from a family with alcohol and drug abuse problems. The addiction medicine physician placed the woman on trazodone and sublingual buprenorphine plus naloxone. She was referred to a counselorfor assistance onher abuse; she
was encouraged to participate in 12-step meetings (i.e., Pills Anonymous). Summary ofCase Reports ofAbuse and Dependence.
The above described published case reports provide information on characteristics and patterns oftramadol abuse withthe development ofdependence. Abuse is primarily bythe oral route. Escalation oftramadoldosing is observed resulting in the use ofvery high doses oftramadol, well outside ofappropriate and recommended clinical dosing regimens and in the absence of medical supervision. Seeking the effects ofeuphoria, well-being and increased energy, as well
as preventingthe experience ofwithdrawal symptoms are reasons given for taking tramadol. In orderto obtain sufficient supplies oftramadol, individuals may doctor-shop (approach multiple doctors for prescriptions), make multiple visits to the emergencyroom, purchase tramadol over the Internet, orpurchasetramadol in Mexico.
The above cases provide documentation ofthe actual abuse oftramadol. In these cases, abuse is via the oral route ofadministration. Currently, marketed tramado1products in the United States
are formulated as tablets intended for oral administration. Such availability allows for the potential oral abuse oftramadol. This is significant considering that reports indicate that oral administration is an important means ofabusing prescription opioids (Havens et al., 2007; Recs Davis and Johnson, 2008; Butler et al., 2008). Studyoflmpaired Health Professionals Impaired health care professionals (N = 1,601) who wereparticipants in treatment programs in four states were recruited for a studyto detennine the incidence oftramadol abuse (Knisely ct al., 2002). Impaired healthprofessionals in treatment programs were selected because they comprise a high risk and accessible population for drug abuse. In addition, they were considered to behighlyknowledgeable about a drug's pharmacology and the relative ease ofavailability of noncontrolled versus controlled substances. Individuals not selected included those with an abuse historyor preference for tramadol. Most ofthe individuals who turned out to be abusers of tramadol had previous histories ofopioid abuse. Each participant's persistent nonmedical use of tramadol was followed. Urine samples were tested for drugs. Results were as follows:
I. One hundred forty (8.74 percent) ofthe impaired health careprofessionals in the study had at least one urine sample that was positive for tramadol. 2. Eighty-seven ofthe 140 trarnadol-exposed population (62.1 percent) did not have a legitimate prescription and experimented with the drug.

433. Twenty-four subjects (1.5 percent oftotal sample; 14.9 percent oftramadol-exposcd population) met study criteria defined as "extensive experimentation." 4. Ofthe 24 "extensive experimenters," 15 met criteria for abuse/dependence, that is, they found tramadol to be superiorto otherdrugs theyhad abused, orthey felt that it was a drugthat could easily avoid detection because it was not scheduled in the CSA. 5. Whentramadol was abused, it was typicallytaken without other drugs ofabuse. 6. By way ofcomparison, hydrocodone-containing products (C-III) (calculated N = 196)
was the most abused opiatebythis population.

Potential Routes ofAdministration for Purposes ofAbuse

As discussed under Factor 3, tramadol is available as the hydrochloride salt which exists as a crystalline powder, readily soluble in water. As such, based upon its physicochemical properties, tramadol hydrochloridehas the potential for abuseby a number ofroutes ofadministration, including oral, intranasal and rectal, as well as by intravenous, intramuscularor subcutaneous injection. Additional evidence for this potential for abuse comes from pharmacokinetic information (also discussed under Factor 3) indicating that tramadol displays high bioavailability when administered bythese various routes ofadministration. Studies show that prescription opioids are abused by a number ofroutes ofadministration including, but not limited to, ingestion, intranasal (snorting) and injection (Havens et al., 2007; Rees Davis and Johnson, 2008; Butler et al., 2008). Drug Abuse Warning Network (DAWN) According to DAWN, in 2008, an estimated 11,850 ED visits nationally were for nonmedical use oftramadol. This reflects an increasing annual trend ofnonmedical ED visits from 2004 (4,849 visits) through 2008. With normalization ofthe visits per 100,000prescriptions dispensed, the rateofnonmedical ED visits for tramadol is similarto that ofcodeine/combinations (Schedule Il, lll, IV) and proproxyphene/combinations (Schedule IV). Therate ofnonmedical ED visits for tramadol was lowerthanthe rates ofED visits for hydrocodone/combinations (Schedule III), buprenorphine (Schedule III) and a number ofSchedule II opioids either alone orin combination products. For 2007 and 2008, 1,819 and 788, respectively, ofnonmedical ED visits involving tramadoVcombinations alone (in the absence ofotherdrugs present) were categorized as "overmedication",2 while 1,476 and 2,016, respectively, oftramadolcombination visits were categorized as "other." By design ofDAWN, the "others"2 category captures most ofthe documented drug abuse cases. Approximately54 % ofthe visits for tramadol involved women. Ofthe total nonmedical ED visits (11,850) in 2008, 21.4 %, 21.7 %, 26.4 % and 16.3 % ofthe visits involved individuals in the age ranges ofl8- 20, 21-29, 30-44 and 45-64, respectively. Overall, DAWN data for the period from 2003 to 2008 show that the nonmedical use oftramadol adversely affects the public health. See Factor4 for a more detailed description ofDAWN data.

National SurveyofDrug Use and Health (NSDUH)

The NSDUH, discussed in detail in Factor4, also provides evidence ofthe nonmcdical use of tramadol products. In 2007, an estimated 1,559,000 individuals used tramadol products nonmedicallyduring their lifetime. Such use is defined in the survey as any use ever, even once,

44oftramadolproducts that were not prescribed to the individual orthat the individual tookonly for the experienceorfeeling that the tramadol product(s) caused. As canbe seen from Table 7 in Factor4, the absolute estimated number oflifetimenonmedical users oftramadol for 2007 was less than that ofoxycodone products(> 13 million) (Schedule II) and hydrocodone products (>21 million) (Schedule III). Nevertheless, the NSDUH data show a sizable number of individuals used tramadol nonmedically at least once in their lifetime.
SummaryofRelevant Findings and Conclusions ofFactor 5

Case reports from the medical literature provide information on patterns oftramadol abuse. The physicochemical properties oftramadol, as well as the available pharmacokinetic dataon tramadol suggest thattramadol has the potential for abuse by a variety ofroutes of administration.

With respect to DAWN national estimates of ED visits related to nonmedical use and to rates of these visits per 100,000 prescriptions, tramadol most closely compares to proproxyphene [C-IV] and to codeine [C-II, III, VJ. ForNSDUH data for each year from 2002-2007, the numberof individuals reporting either lifetime nonmedical useorpast-year nonmedical use oftramadolwas lower than the numberofindividuals reporting lifetime orpast-yearnonmedical use of hydrocodonc products (C-III) oroxycodone products (C-II), thereby suggesting an abuse potential less than that ofSchedule III

. Overall, the dataprovided in Factor5 supportsthe scheduling oftramadol and is consistent with Schedule IV control.

Factor 6. What, IfAny, Risk to the Public Health

The information collected from a variety ofsources shows that there is a risk to public health associated with use and abuse oftramadol. Tramadol produces adverse effects similar to those ofotheropioids. In addition, it is associated with seizure formation, serotonin syndrome, and drug interactions. Nonmedical use oftramado1is associated with emergency room visits. Over the last four years, therehas been a substantial increase in the number ofexposure cases reported by Poison Control Centers in the United States. Data from several sources show thattramadol is associated with deaths.

In orderto assess therisk to the public health associated with tramadol, a number ofinformation
sources were examined. They include: 1) the September 9, 2009, approved labeling for ULTRAM; 2) reports in the medical literature; 3) DAWN emergency room visits and medical examinerreports; 4) data from theAmerican Association ofPoison Control Centers; and 5) data from drug-related deathreports from the Florida Medical Examiner's Office.

Adverse Effects

- Information Documented in Labeling for ULTRAM

Adverse effects associated with the use oftramadol are documented in the label approved September 9, 2009 for ULTRAM. Adverse effects occurring with tramadol are consistent with adverse effects associated with otheropioids.

45

### Table 11. Cumulative Incidence ofAdverse Reactions for UTRAM in Chronic Trials of Nonmalignant Pain (N=427). (Source: Label approved September 9, 2009, for ULTRAM) Up to 7 Days Up to 30 Days Up to 90 Days Dizziness/Vertigo 26% 31% 33% Nausea 24% 34% 40% Constipation 24% 38% 46% Headache 18% 26% 32% Somnolence 16% 23% 25% Vomiting 9% 13% 17% Pruritus 8% 10% 11% "CNS Stimulation" 7% 11% 14% Asthenia 6% 11% 12% Sweating 6% 7% 9% Dyspepsia 5% 9% 13% Dry Mouth 5% 9% 10% Diarrhea 5% 6% 10%

Table 11 provides the cumulative incidencerate ofthe most frequent adverse reactions (5% or moreby 7days) reported following 7, 30, and 90 days oftreatment with ULTRAM. This data
was generated during double-blind oropen-label extension periods in U.S. studies looking at the
use ofULTRAM for treating chronic nonmalignant pain in atotal of550 patients. Some ofthe most frequently reported adverse effects included dizziness, nausea, constipation, headache, and vomiting, all ofwhich are also seen with use ofotheropioids. Evident in Table 11 is the increased incidence ofreported adverse effocts as time oftherapy increases. The overall incidence rates ofadverse effects in the trials were similar for ULTRAM and the active control groups, Tylenol with Codeine #3 (acetaminophen 300 mg with codeine phosphate 30 mg) [CIII], and aspirin 325 mg with codeine phosphate 30 mg [C-III].
SeizuresAssociatedwith Tramadol 

### According to the ULTRAM labeling, approved September 9, 2009:
Seizures have been reported inpatients receiving ULTRAM tt·ithin the recommended dosage range. Spontaneouspostmarketing reports indicate thatseizure risk is increased with doses ofULTRAMabove the recommended range. Concomitant use ofULTRAM increases the seizure risk inpatients taking: selectiveserotonin reuptake inhibitors (SSR! antidepressants or anorectic1), tricyclic antidepressants (TCAs), andothertricyclic compound1· (e.g. cyclobenzaprine, promethazine, etc.), orotheropioid., Administration ofULTRAMmayenhance the seizure risk inpatients taking: MA0 inhibitors, neuroleptics, orotherdrugs that may reduce the seiwre threshold.. Risk of convulsions may also increase inpatients with epilepsy. those ttith a hist01y ofseizures, orinpatients with a recognized riskfor seizure (.rnch



### 46as headtrauma, metabolic disorders, alcohol anddrug withdrawal and CNS infections}. In ULTRAMoverdose, naloxone administration may increase risk of seizure.

Serotonin Syndrome Accordingto label approved September 9, 2009, for ULTRAM:

The development ofapotentially life-threatening serotonin syndrome may occur with the
use oftramadolproducts, including ULTRAM, particularly ·with concomitant use of serotonergic drugs such as SSRls, SNRls, TCAs, MAO/s, andtriptans, with drugs ·which impairmetabolism !!{serotonin (including MAOls}, andwith drugs which impair metabolism of tramadol (CYP2D6 and CPY3A4 inhibitors). This mayoccur 11ithin the recommendeddose (.1·ee CLINICAL PHARMACOLOGY, Pharmacokinetics).

Serotonin .1yndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile bloodpressure, hyperthermia), neuromuscularaberrations (e.g., hyperreflexia, incoordination) and/orgastrointestinal symptoms (e.g., nausea, vomiting. diarrhea).

Tramadol has been associated with numerous casereports in the scientific and medical literature involving the generation ofthe serotonin syndrome. The vast majority ofthese cases involved tramadol administered concomitantlywith otherdrugs that interact with the serotonergic system. (Adverse Drug Reactions AdvisoryCommittee, 2001, 2003, 2004; Choong and Chiculescu, 2008; Egberts et al., 1997; Garrett, 2004; Gnanadesigan et al., 2005; Gonzalez-Pinto et al., 2001; Houlihan, 2004; John and Koloth, 2007; Kesavan and Sobala, 1999; Kitson and Carr, 2005; Lange-Asschenfeldt et al., 2002; Lantz et al., 1998; Llinarcs-Tello et al., 2007; Mahlberg et al., 2004; Markowitz and Patrick, 1998; Mason and Blackburn, 1997; Mittino et al., 2004; Nayyar, 2009; Pilgrim et al., 201 O; Reus and Rawitscher, 2000; Sauget et al., 2002; Sansone and Sansone, 2009; Takeshita and Litzinger, 2009; and Vizcaychipi et al., 2007). Respiratory Depression According to the September 9, 2009, approved label for ULTRAM:
Administer ULTRAMcautiously inpatients atrisk.fin· respiratory depression. In thesepatients alternative non-opioidanalgesics shouldhe considered. When large doses ofULTRAMare administeredwith anesthetic medications or alcohol, respiratory depression may result. Respiratory depression shouldhe treatedas an overdose.
Overdose

The ULTRAM label approved September 9, 2009, notes the following with regard to overdose with tramado1:

47Acute overdosage >eith tramadol can be manifestedhy respiratory depression, somnolenceprogressing to stupororcoma, skeletalmuscle.flaccidity, coldand clamm_v skin. constrictedpupils, seizures, hradvcardia, hypotension, cardiac arrest, anddeath.
Toxicity from tramadol overdose is related in part to its μ-opioid activity, as well as its monoamine oxidase inhibitor (MAO!) activity (Spiller et al., l997). In aprospective studyof tramadol toxicity from seven U.S. poison centers, 126 cases ofoverdose involving tramadol single entitywere reported between October 1995 and August 1996. individuals' ages ranged from 1to 86 years, with a mean and median of26.8 and 25 years, respectively. There were 10 overdose cases in children 6 years ofage oryounger. Reported clinical presentations included lethargy (26), nausea (12), tachycardia (11), agitation (9), seizures (7), coma ( 4), hypertension (4), and respiratory depression (2). Naloxone reversed sedation and apnea in 4 of8 patients. Jn this study, tramadol 500 mg was the lowest dose associated with seizure, and 800 mg was the lowest dose associated with respiratory depression. The authors concluded that muchtoxicity of tramadol appears to be attributable to the MAO uptake inhibition. Agitation, tachycardia, confusion, and hypertension suggested a possiblemild serotonin syndrome. This study found significant neurologic toxicity, without serious cardiovasculartoxicity (Spiller et al., 1997)

DAWN Data

DAWN data arc discussed in depth under Factor4. The DAWN data show that the nonmedical
use oftramadol, as well as otheropioids, leads to emergency department (ED) visits. Rates of ED visits, expressed per 100,000 prescriptions, for tramadol havebeen similarto that of propoxyphcne [C-IV] but lower than that ofSchedule II and III opioids. The DAWN data demonstrate arisk to thepublic health associated withthe nonmedical use oftramadolthat is similarto that ofpropoxyphene [C-IV]. See Factor4 for a more detailed description ofDAWN data.

American Association ofPoison Control Centers'National Poison Data System (NPDS)

Data from the American Association ofPoison Control Center's National Poison Data System (NPDS) shows that overthe period of2004to 2008, there was an increasing public health risk associated with tramadol. The data are discussed in detail under Factor4. Overthe period from 2004to 2008, annual poison case mentions ofactual exposure for tramadol increased from 3,769 to 9,623. In 2007 and 2008, tramadol ranked third behind hydrocodone combination products [C-III] and oxycodone products [C-11] in tenns ofthe number ofpoison case mentions of opioids. Overthis period, therates ofcase mentions per 100,000 prescriptions for tramadol increased from 22 to 37. Overthe period of2004through 2007, the poison control centerrates oftramadol case mentions was higher than for hydrocodone combination products [C-III] but lowerthan for oxycodone [C-11], morphine [C-11] and methadone [C-11] products. In 2008, the rate oftramadolcase mentions equaled that ofoxycodone [C-11] case mentionsbut was less than the rate ofcase mentions for methadone [C-11] and morphine [C-11]. For the years 2004, 2005, and 2006, the rates oftramadol case mentions were similar to therates ofpropoxyphene [C-IV]
case mentions. In 2007 and 2008, tramadol surpassed codeine and propoxyphene in the number

48ofcase mentions and rates ofcase mentions. SeeFactor4 for a more detailed description of AAPCC data.

Information on Tramadol Related Deaths Obtained Fromthe Labeling for ULTRAM

The following statement is taken verbatim from the section entitled "Risk ofOverdosage" in the labeling approved on September 9, 2009 for ULTRAM:

Patients taking tramadolshouldhe warnednot to exceedthe dose recommendedhy theirphysician. Tramadolproducts in excessive doses eitheralone orin comhination v.'ith other CNSdepressants. including alcohol, are a cause oldntg-relateddeaths.
Tramadol Related Deaths Mentioned in the Medical Literature

A numberofreports in the medical literature have documented deaths associated withtramadol (Bynum et al., 2005; Clarkson et al., 2004; Claro! et al., 2003a; Claro! et al., 2003b; De Decker et al., 2008; Goeringeret al., 1997; Levine et al., 1997; Loughery et al., 2003; Lusthofand Zwcipfenning, 1998; Michaud et al., 1999; Mooreet al., 1999; Musshoffand Madea, 2001; Ripple et al., 2000; Tajaderborn et al., 2007). Some ofthese reports describe tramadol alone being the cause ofdeath (Lusthofand Zweipfenning, 1998; Moore ct al., 1999; Musshoffand Madea, 2001; Loughreyet al., 2003; De Decker et al., 2004). Otherreports document tramadol
as a contributing factor to deaths in combination with other drugs such as, but not limited to, benzodiazepines, scrotonergic drugs and other antidepressants (Goeringer ct al., 1997; Michaud et al., 1999; Ripple et al., 2000; Claro! et al., 2003; Claro! ct al., 2003; Bynum et al., 2005; Tajaderborn et al., 2007). Drug-Related Deaths Reported in DAWN

DAWN mortality data are submitted by participating medical examiners (ME) in major metropolitan areas across the United States. Thedrug abuse deaths do not represent the U.S. as a whole, nordo they necessarily represent the total number ofdeaths in which drug abuse was a causal orcontributing factor. Rather, DAWN cases reflect the number ofdrug abuse deaths reviewed, identified, and reported bythe participating medical examiners and coroners in selected areas. A total of395 tramadol abuse-related deaths were reported to DAWN from 1997 to 2002. Thenumberoftramadol-related deaths reported annually in DAWN ME reports increased from 1997 to 2004 (Tables 12 and 13). Most ME mentions for tramadol involved combinations with the following substances: alcohol, acetaminophen, amitriptylinc, cocaine, morphine, oxycodone, and propoxyphene.

49Table 12. DrugAbuse WarningNetwork (DAWN)': DrugAbuse-Related Deaths Involving Tramadol from a Consistently Reporting PaneI1 ofMedical Examiners: 1997-2002

Drug 1997 1998 1999 2000 2001 2002 Tramadol 45 46 58 72 86 88

1 Deathsreported by a consistent panel ofmedical examiners in 28 metropolitan areas. Consistent panels include onlythosejurisdictionsthatreported at least I0 months ofdata each year from 1997-2002. The panel does not include New York City (which didnot submit data for 2001) or Los Angeles (which didnot submit data for 2002). 'source: SuhstanceAhuse andMental Health ServicesAdministration, Office (?f AppliedStudies, DrugAhuse rvarning NetttYJrk.
Table 13. Drug Abuse WarningNetwork (DAWN)': Drug Abuse-Related Deaths Involving TramadoIfrom Two Panels: a Consistently Reporting PaneI1 ofMedical Examiners and a 5-State Panel (2003

- 2004)

DRUG 2003 2004 NAME Numberof Numberof Number of Number of Deaths Single-Drug Deaths Single-Drug Deaths Deaths Drug Drug- Drug Drug- Drug Drug- Drug DrugMisuse related Misuse related Misuse related Misuse related Suicide Suicide Suicide Suicide CONSISTENT PANEL DATA Tramadol 83 25 5 3 114 27 6 5

-- Hydrocodone' 464 100 19 6 625 128 31 8 Pentazocine' 3 0 0 0 4 I 0 0 5-STATE PANEL DATA Tramadol 31 6 2 0 34 4 2 I Hydrocodone 106 16 4 I 86 20 5 1 Pentazocine 2 0 0 0 0 1 0 0

- Schedule lII Schdule IV Drug-Related Deaths Reported bythe Florida Department ofLaw Enforcement

The Florida Department ofLaw Enforcement (FDLE) collects informationon drug-related deaths as reported by medical examiner offices acrossthe stateofFlorida. This information is disseminated in interim and annual Florida Medical Examiner Commission Reportsthat are available for viewing at the FDLE website. Additional information for this document was obtained from staffofthe FDLE, Medical Examiner's Commission.

Total annual deaths involving selected opioids as determined by medical examiners in Florida for each year over the period of2003 to 2008 are shown in Table 14. The number ofdeaths involving tramadol increased from I06 in 2003 to 235 in 2008. Based on communications with stafffrom the FDLE Medical Examiners' Commission, the vast majorityofdeaths involving tramadol also involved otherdrugs. In the small numberofcases in which tramadol only was

50found, the deaths tended to be suicides. Tramadol-related deaths were higher than heroin [C-1] related deaths in 2005, 2006, 2007, and 2008. Foreach ofthe years, the number ofdeaths involving tramadol was less than the number ofdeaths involving hydrocodone combination products [C-lll], fentanyl [C-ll], morphine [C-11], oxycodonc [C-ll], methadone [C-11], and propoxyphene [C-IV], hut higher than the number ofdeaths involving mcperidine [C-II] and hydromorphone [C-11] (except for 2007).

Table l4. Total Annual Drug-Related Deaths Involving Selected Opioids As Identified by Florida Medical Examiners and Collected bythe Florida Department ofLaw Enforcement (FDLE).

Drug 2003 2004 2005 2006 2007 2008 Heroin' 261 180 122 96 110 132 Fcntanyi-' 197 182 178 187 197 235 Hydrocodone• 572 632 648 731 807 870 Hydromorphone' 78 98 108 138 178 199 Meperidine-' 66 42 58 46 33 29 Methadone' 608 849 934 974 1,095 936 Morphinej 511 597 658 601 630 660 Oxycodone·' 632 674 716 

### 923 1,253 1,574 Propoxyphene5 356 347 368 328 341 322 Tramadol" 106 120 147 140 157 235 Other Opioids 1 120 194 230 318 368 307
l Codeine, oxymorphone and, rarely, other op101ds. Majortty arc codeine. 2Schcdu!e I: 'Schedule II; 4Schedule III Combination Products ofHydrocodone; 5Schedule IV; 6Not Scheduled
Table 15 provides abreakdown ofselected opioid related deaths overthe period of2005 to 2008 based onwhether the opioid actually contributed to causing the death orsimplywas identified in the deceased. The determination ofwhetherthe opioid contributed to the death was made by medical examiners. Theopioid could eitherbe the cause ofdeath on its own orbe a contributing factorto the death caused by a combination ofdrugs. Overthe four-year period the percentage ofannual deaths in whichtramadol was detennincd to be a cause ofdeath, compared to thetotal number ofdeaths in which tramadol was present, ranged from 18% to 26%. This was a little higherthan the range found for meperidinc (I0% to 23%). A similarpercentage range was found regarding proproxyphene [C-IV] (22%to 27%) and hydromorphone [C-II] (20%to 22%)
as a cause ofdeath. For each ofthe years, tramadol was determined to be a cause ofdeath in a lower percentageoftotal related deaths than was heroin [C-1], fentanyl [C-11], hydrocodone [CIll], methadone [C-11], morphine [C-11], and oxycodone [C-11].

51Table 15. Opioid-Related Deaths Identified by Florida Medical Examiners and Collected bythe Florida Department ofLaw Enforcement (FDLE). Identification ofDeath Cases In Which Opioids Contributed to the Death Vs. Death Cases in Which Opioid Was Present. Drug 2005 2006 2007 2008 Cause Present Cause Present Cause Present Cause Present lleroin 1 109 13 78 18 65 6 119 13 Fentanyl..: 98 80 112 75 117 80 104 131 Hydrocodone·' 221 427 236 495 264 543 270 600 HydromorphoncL 24 84 31 107 36 142 41 158 Mepcridine.: 8 50 9 37 ' 30 4 25 .)

- Methadone.: 620 314 716 258 785 310 693 243 Morphine..: 247 411 229 372 255 375 300 360 Oxycodone'" 340 376 496 427 705 548 941 633 Proproxypheneq 100 268 71 257 85 256 80 242 Tramadol 31 116 34 106 35 122 56 179 ' 

### ·'

. 

### ' Schedule I, Schedule 11, Schedule lll, Schedule IV SummaryofRelevant Findings and Conclusions ofFactor 6
The available data from a number ofsources indicates that tramadol presents risks to the public health and, as such, supportsthe scheduling oftramadol. Reports in the medical literature and information available in the latest approved label for ULTRAM provide evidence that tramadol produces a variety ofadverse effects, manyofwhich
arc similar to those produced byopioids in Schedules II -V

. Tramadol may exacerbate central
nervous system (CNS) depression, including respiratory depression, when combined with other CNS depressants. Tramadol use may result in seizures either alone orin combination with other drugs. Tramadol may evoke a serotonin syndrome particularly when combined with other drugs that affoct the serotonergic system. Evoking a serotonin syndrome either alone or in combination with other serotonergic acting drugs is not common with opioids. Besides tramadol, meperidine [C-II] and methadone [C-11] are the opioids most documented as evoking serotonin syndrome (see Factor 2).

DAWN datademonstrate a public health risk associated with the nonmedical use oftramadol. Examination ofrate data (number ofED visits per 100,000 prescriptions) suggeststhat this risk is similarto that from propoxyphenc [C-IV] and less than that ofSchedule II and III opioids.

Data from the American Association ofPoison Control Centers demonstratethat unintentional and intentional exposure to tramado1are risks to thepublic health. From 2004 to 2008, there was a continuous increase in the annual number ofcase mentions (poison exposures) for tramadol. This increase was suchthat with respect to opioid analgesics in 2007 tramadol ranked third behind hydrocodone combination products and oxycodone in terms ofthe number ofcase mentions to poison control centers The number (rate) ofcase mentions per 100,000 prescriptions oftramadol increased from 22 in 2004to 37 in 2008. In 2006, the rateofcase mentions for tramadol was similarto that for codeine [C-II, III and VJ and propoxyphene [C-IV].
52In 2007, the rate ofcase mentions for tramadol was closeto that ofcodeinebut higher than that for propoxyphene.

As with all opioids, tramadol overdose can result in death. According to the latest approved label for ULTRAM, deaths are associated with both the intentional and unintentional use of tramadol. Deaths associated with tramadol are also reported in the medical literature. DAWN medical examinerdata documents deaths involvingtramadol overthe period of1997 to 2004, which is the latest date for which data is available. In addition, case reports in the medical literature indicate that tramadol alone can cause death. However, more often death results from the combination oftramadolwith other selected drugs. Death can also occurin the courseof tramadoIabuse.

Data from Florida Medical Examiners Offices and collected by the FDLE indicatethat tramadol is ruled as contributing to deaths in approximately 18% to 26% ofthe total death cases in which tramadol is found to be present. This percentagewas considerably lower compared to heroin [CI], fentanyl [C-Il], hydrocodone [C-lll], methadone [C-II], morphine [C-Il], and oxycodone [Cl!], but similar to thepercentages found for proproxyphene [C-!V], meperidine [C-Il], and hydromorphone [C-1!]. The data indicate that tramadol is less likely to be a contributorto the
cause ofdeaththan are heroin [C-I], fentanyl [C-II], hydrocodonc combinations [C-lll], methadone [C-11, morphine [C-II], oroxycodone [C-II] when these drugs are detected in deceased indivduals. This may suggest alower lethality associated with tramadol compared to these drugs.

The DAWN data and AAPCC data, particularly for 2004-2007, support Schedule IV control of tramadol. The lower lethality associated with tramadol compared to otheropioids, as seen from the Florida Medical Examiner's Office, also suggest a lower schedule for tramadoI, that is, less restrictive than Schedule Ill.

Factor 7: Tramadol's Psychic or Physiological Dependence Liability

Factor 7 information is provided in three major sections. The first section concerns preclinical (animal) studies demonstrating that repeated dosing with tramado1results in dependence development as evidenced by mild to amoderate withdrawal syndrome following either abrupt tennination oftreatment or administration ofan opioid antagonist (precipitated withdrawal). Precipitationwithdrawal studies suggest adegree ofdependence to tramadol similarto that produced by propoxyphene [C-IV] and pentazocine [C-IV]. The second section notes that in the most recently approved ULTRAM label, withdrawal symptoms mayoccur following tcnnination oftramadoltreatment. Thethird section discusses approximately 30 literature articles documenting numerous cases ofphysiological and physical dependence to tramadol.
PreclinicalStudies ofDependence
The dependence liability oftramadol was evaluated in studies using Rhesus monkeys, rats, and mice. These studies show that repeated exposure to tramadol results in mild to moderate levels ofphysical dependence as evidenced by spontaneous orprecipitated withdrawal. These studies

53suggest that thedegreeofdependencedevelopment oftramadol is less than that ofSchedule Ill, but similarto that ofSchedule IV drugs such as propoxyphene and pentazocine.

Preclinical Studies ofSpontaneous Withdrawal

Yanagita (1978) examined for spontaneous withdrawal in Rhesus monkeys given repeated s.c. injections oftramadol. Eight drug naive monkeys were divided into two b>roups. Onegroup, designated the low dosegroup, was given injections oftramadol four times daily underthe schedule of8 mg/kg per unit dose for the first four weeks and 12 mg/kg as the unit dose for an additional four weeks. The second group, considered the high dose group, was administered tramadol at unit doses of8 mg/kg for the first two weeks, 16 mg/kg for the third and four weeks and 24 mg/kg for a final four weeks. At the end of8 weeks, tramadol administration was terminated and monkeys wereobserved for signs ofwithdrawal for 5 days. The severityof withdrawal signs were graded according to criteria established by Seevers (1936) for opiate withdrawal in morphine dependent monkeys. Body weight did not changeduring spontaneous withdrawal in eithergroup. However, three monkeys each in the low and high dosetramadol groups displayed "mild" withdrawal signs, while in thehigh dose groupone additional monkey displayed "intermediate" withdrawal signs. Mild signs ofwithdrawal included apprehension. continual yawning, rhinorrhea, lacrimation, hiccup, shivering, perspiration on face, chattering, and quarreling and fighting. Intermediate signs ofwithdrawal included tremor, anorexia, pilomotor activity, muscletwitching, rigidity, and holding the abdomen. This study demonstrated that tramadol has the potential to produce some physical dependence.

Nickel and Aledter (1987) examined physical dependence development resulting from the repeated oral administration to rats (6 rats pertreatment) oftramadol (50 mg/kg), codeine [C-11] (100.0 mg/kg), buprenorphine (C-III] (4 mg/kg), flupirtine [not scheduled] (50.0 mg/kg), and saline. Rats received treatments on six days ofthe week for 40 days. On the seventhdayofeach week, dosing was omitted. For purposes ofevaluating physical dependence, body weight was measured twice daily. In addition, animals wereobserved for othertypical withdrawal signs such as diarrhea, Straub tail, convulsions, changes in respiratoryrate, pupil diameter, and body temperature. Overthe40-daytreatment period, there was a slowerrise in body weight observed in rats treated with either tramadol, codeine [C-11], orbuprenorphine [C-111] as compared to body weight gain in rats treated with saline or flupirtine (not scheduled]. This reduction in body weight signaled withdrawal. On specificdays in whichdrug was withdrawn, the fluctuation in bodyweight was less for tramadol compared to eithercodeine orbuprenorpbine, thereby indicating a milder withdrawal withtermination oftramadol versus termination ofeither codeine (C-11] orbuprenorphine [C-lll]. In addition, compared to buprenorphine withdrawal, tramadol withdrawal was generallyassociated with a lower level ofother withdrawal effects, such as diarrhea, Straub tail, convulsions, changes in respiratoryrate, pupil diameter, and changes in bodytemperature.
Preclinical Studies ofPrecipitated Withdrawal Yanagita (1978) examined Rhesus monkeys given repeated subcutaneous injections oftramadol for precipitated withdrawal. Eight drug naive monkeys weredivided into two groups. One group, designated the low dosegroup, was given injections oftramadol four times dailyunder

54the schedule of8 mg/kg per unit dose for the first four weeks and 12 mg/kg as the unit dose for
an additional four weeks. The second group, considered the high dose group, received tramado1 at unit doses of8 mg/kg for the first two weeks, 16 mg/kg for thethird and fourth weeks, and 24 mg/kg for a final four weeks. At the end of2, 4, 6, and 8 weeks ofadministration, aprecipitation test was conducted by s.c. injection of 1.0 mg/kg naloxone. As one measure ofwithdrawal, body weight reductions were measured following naloxone challenge. Slight weight loss occurred in
some monkeys in bothgroups suggestive ofa withdrawal syndrome. Monkeys were also observed for otherwithdrawal signs. These other signs were observed in the precipitated withdrawal test at 42 and 56 weeks oftreatment only in three monkeys from thehigh dose group. The withdrawal in all three monkeys was mild based on a classification ofwithdrawal signs in morphine dependent monkeys established by Seevers (1936). Underthis classification, mild signs ofwithdrawal included apprehension, continual yawning, rhinorrhea, lacrimation. hiccup, shivering, perspirationon face, chattering, and quarreling and fighting. 

### Yanagita (1978) concluded that tramadol has some physical dependence potential as evidenced by naloxoneprecipitated withdrawal.

Friderichs et al. (1978) evaluated tramadoI in the withdrawaljumpingtest with mice, with comparison to otheropioids including propoxyphene [C-IV], codeine [C-11], pentazocine [C-!V], morphine [C-11], and methadone [C-11]. Mice received multiple subcutaneous doses, ranging from 8 mg/kgto 75 mg/kg overtwo consecutivedays. Following this treatment, mice received
an intraperitoneal injection of30 mg/kg naloxone and wereobserved forjumpingbehavior. Micereceiving repeatedtreatments oftramadoldisplayed only limited withdrawaljumping in response to naloxone injection. Thenumber of jumps in tramadol-treated animals was comparable with that obtained afterthe administration ofpropoxyphene [C-lV] and lower than after codeine, methadone [C-ll], and morphine [C-ll]. The naloxone precipitatedjumping assay indicated that tramadolproduced a degree ofphysical dependence similar to that of proproyphene [C-IV].
Wakasa et al. (! 994) evaluated precipitated withdrawal in rats receiving short-term frequent intravenous infosions ofvarious opioids. Rats fitted withjugularcatheters received by infusion a fixed dose ofa drug hourly for 72 hours. The following drugs were infosed: tramadol ( 4 and 8 mg/kg), morphine [C-11] (2, 4 or 8 mg/kg), methadone [C-11] (0.5 or 1.0 mg/kg), propoxyphene [C-IV] (4 or 8mg/kg), loperamide (1or2 mg/kg), pentazocinc [C-IV] (4 mg/kg), ethylketocyclazocine (0.25 or0.5 mg\kg), buprenorphine (4 or 8 mg/kg), and thcbaine (I or2 mg/kg). Rats given saline (0.25 ml/kg) served as controls. Thirtyminutes following the final infosion, naloxone ( 4 mg/kg, s.c.) was administered and rats wereobserved for one hour for signs ofprecipitated withdrawal. The severityofwithdrawal signs was scored based on a behavioral (unusual posture, hyperirritability, teeth chattering) sign score, autonomic (lacrimation, diarrhea, salivation) sign score, and bodyweight loss score.
The morphine [C-ll] treatment group displayed the highest total withdrawal score. Other groups showing total withdrawal scores significantlygreaterthan that ofsaline included those treated with methadone [C-11], propoxyphene [C-IV], tramadol, and pentazocine [C-IV], but not those involving treatment with buprenorphine [C-III] orthebaine [C-11]. When looking at individual withdrawal sign category scores, thebehavioral sign scores tended to behigher than the other two scores in the drugs showing relatively low but significant total scores such as with tramadoI,

55pentazocine [C-IV], and ethylketocyclazocine [not scheduled]. In contrast, the scores of autonomic signs and ofbodyweight loss tended to be higher for drugs (morphine, methadone, propoxyphene) showing higher total withdrawal scores. When compared to the saline control group, the tramadol group, treated with either4 or 8 mg/kg tramadol displayed a significant reduction in bodyweight following naloxone administration. Other withdrawal signs observed in the tramadol treated group included salivation, diarrhea, hyperirritability, and unusual posture.
Miranda and Pinardi (1998) compared physical dependence development resulting from repeated subcutaneous administration ofeither morphine [C-11] (I00 and 1.05 mg/kg) ortramadol (100 or 39.1 mg/kg) to mice three times daily for five consecutivedays. The doses of39.1 mg/kg tramadol and 1.05 mg/kg morphine represented the equieffective analgesic doses as determined in the writhing test. Physical dependence was evaluated by the occurrenceofdifforent signs (seizures, wet-dog shakes, urination, diarrhea, pilocrcction,jumps, and tachypnea) induced by the intraperitoneal administration ofnaloxone (I mg/kg). Mice were observed for signs of withdrawal during a 20 minute time period following naloxonc injection. Mice pretreated with 100 mg/kg oftramadol and challenged with naloxone showed onlydiarrhea, urination and piloerection in oneout ofsix animals. In mice pretreated with 39.1 mg/kg tramadol, naloxone administration evoked wet-dog shakes and piloercction in onlyoneout ofsix animals. By contrast, when challenged with naloxone, all (six outofsix) mice pretreated with I00 mg/kg morphine displayedjumps, wet-dog shakes, tachypnea and piloerection while five ofthe six mice also displayed seizures, diarrhea and urination. Mice pretreated with l.05 mg/kg morphine and subsequently injected with naloxone, showed a lower intensity ofwithdrawal as evidenced bythree out ofsix animals showing wet-dog shakes, piloerection and tachypnea. This study demonstrated that under thetreatment conditions examined, tramado1produced only a lesser degree ofphysicaldependencethan morphine. In contrast, morphine pretreatment produced a more robust level ofphysical dependence.
Dependence to Tramadol in Humans
Underthis section are several studies looking at dependencedevelopment in pain patients treated with tramadol and a number ofstudies looking at cross dependence development between tramadol and otheropioids. ln studies ofcross dependence, tramadol produces a modest suppression ofwithdrawal in subjects dependent on other opioids. This suppression appears less than that produced by morphine [C-Il] orbuprenorphine [C-111]. The available studies show that tramadoIshows some cross dependenceto heroin, methadone, morphine and buprenorphine.

Clinical Studies and Case Reports Demonstrating Cross Dependence Between Tramadol and Other Opioids

A number ofstudies examined the ability oftramadolto substitute for otheropioids in individuals who are opioid dependent. These studies are discussed below.

Tamaskar et al. (2003) conducted aretrospective cohort control study in orderto comparethe effectiveness oftramadol versus buprenorphine in the treatment ofopiate withdrawal. Sixty-four heroin abusers were included in the study with 20 placed in the buprenorphinc treatment group and 44 in a tramadol treatment group. All subjects displayed mild to moderate heroin addiction



### 56as defined bytheir use oflessthan ten bags ofheroin daily. The tramadol detoxification group received treatment with tramadol I00 mg orally every4 hours for 24 hours, then I00 mg every six hours for 24 hours, and then 50 mg four times aday and 50 mg three times a day for 24 hours each. Thebuprenorphine detoxification group received treatment with buprcnorphine 0.4 mg, 0.3 mg, 0.2 mg and 0.1 mg subcutaneously six times aday in the first, second, third, and fourth days, respectively. Both groups received clonidine 0.05 to 1.0 mg orally everytwo to four hours,
as needed for breakthroughwithdrawal symptoms. Clonidine is a non-scheduled drug that is approved for treatment ofhypertensionbut is reportedly also used to reduce anxiety, produce sedation, and to treat drug withdrawal (Cregoretti et al., 2009). Otherdrugs given as needed
were hydroxyzine [not scheduled] for anxiety and dicyclomine [not scheduled] for abdominal cramps ornausea. Endpoints ofthe study included improvements ofwithdrawal symptoms, as measured by the Clinical InstituteNarcotic Assessment (CINA), length ofstay in program and requirement for clonidine medication. Tramadol and buprenorphine [C-III] effectively managed acute opioid withdrawal. Subjects displayed essentially identical peak CINA scores on either tramadol orbuprenorphine. Some tramadol patients, however, required larger amounts of clonidine to control breakthrough withdrawal symptoms. In addition, four participants in the tramadol group required several doses ofbuprenorphine [C-III] to control withdrawal symptoms. On the other hand, more patients in the buprenorphine group as opposedto the tramadol group left the programpriorto completing detoxification. Based upon this study, the authors suggested that tramadol might be effective in controlling opioid withdrawal displayed by patients with mild to moderate addiction to heroin [C-1]. Using a retrospective chart review, Sobey et al. (2003) compared the use oftramadolto that of clonidine for management ofacuteheroin [C-I] withdrawal. Fifty-ninepatients were detoxified using tramadol and 85 using clonidine [not scheduled]. Tramadol protocol involved tramadol I00 mg orally every four hours for one day, every six hours ofoneday and everyeight hours for
oneday. This dosage was followed with 50 mg tramadol orally every six hours for one day, every eight hours for oneday and every 12 hours for one day. Clonidine protocol involved 0.1 mg orally every four hours for 2 days, then every six hour for one day, everyeight hours for one day and everytwelve hours for one day. For each day in detoxification, the magnitude of withdrawal symptoms was estimated on a scale ofO to 3, with 0being no detectable withdrawal and 3 being severe withdrawal symptoms. Patients remaining in the detoxification programwere also monitored. Patients detoxified withtramadol had a 23% risk oflcavingthe program against medical advice relative to patients detoxified with clonidine (I00%) and scored an average of 0.24 points lower than clonidine onthe withdrawal symptom scale. This studyprovides evidence that tramadol does display some cross-dependencedevelopment to opioids, in this case, heroin. The authors concluded that tramadol is more effective in managing withdrawal than clonidine [not scheduled], and may be useful in outpatient detoxification.
LofWall et al. (2007) examined tramadol for opioid withdrawal suppression using 10 residential, opioid-dependent adults. Subjects received treatment with morphine (15 mg subcutaneously) four times daily for approximately 6 weeks. This treatment regimen resulted in a mild to moderatedegree ofopioid physical dependence. Spontaneous opioid withdrawal oceun-ed following substitution ofplacebo for scheduled morphine doses 17.5 hours before experimental sessions that occun-ed twice weekly. Acute effects ofplacebo, tramadol (50, 100, 200, and 400 mg orally), naloxone (0.1 and 0.2 mg intramuscularly) and morphine [C-11] (7.5 mg and 15 mg

57intramuscularly) weretested under double-blind, double-dummy, randomized conditions. Participants completed visual analog scales (VAS) and a drug class, identificationquestionnaire. Drug treatments were assessed for agonist and antagonist effects using bothparticipant and observer measures. Tramadol at doses of50 and I00 mg were without any effect and the 7.5 mg morphine dosedid not produceconsistent effects compared to placebo. On the observer-rated antagonist adjective scale, both morphine and tramadol produced evidence ofwithdrawal suppression that continued throughthe last time point; however, morphine immediately reduced antagonist adjective scale scores while tramadol 200 and 400 reduced scores beginning at 120 and 90 minutes, respectively. The authors speculated that the delay was dueto the oral administration oftramadol and to the metabolism oftramadolto theMl metabolite. On the participant rated antagonist scale, tramado

### I at 400mg, but not at 200 mg, caused significant reductions compared to placebo. Using a different scale for measuring withdrawal, namely a modified Himmelsbach scale (Kolb and Himmelsbach, 1938), 200 and 400 mg tramadol, as well
as 15 mg morphine, significantly reduced the severityofwithdrawal symptoms. Again, the withdrawal suppression bytramadol was significantlydelayed compared to that produced by morphine. Based upon the results from the study, the authors concluded that tramadol produced
a modest suppressionofopioid withdrawal in subjects with a mild to moderatedegree ofopioid physical dependence. This suggests cross dependence development between tramado1and other opioids, such as morphine.

In addition to clinical studies, there are several case reports in the published literaturethat provide evidence ofcross dependence development between tramadol and opioids, as seen by suppression ofwithdrawal symptoms upon termination ofextended tramadol treatment. These
case reports include Leo et al. (2000) and Ritvo et al. (2007).

A case report by Leo et al. (2000) indicates cross-dependence development oftramadol to methadone [C-ll]. The case report concerned a 45-yearold female who had a history oftaking up to 30 (50 mg) tablets oftramadol in divided doses daily. Upon attempting to stop tramadol use, she presented to the emergencyroom with symptoms ofanxiety, dysphoria, restlessness, irritability, abdominal cramping, and lowerextremitycramping. Upon subsequent admission to
a detoxification facility, she received 

### IO mg methadone [C-Il]. When this did not relieve her withdrawal symptoms, she was given a second I0 mg dose that did mitigatethe symptoms. The methadone [C-ll] dosing was reduced over eight successive days by 2.5 mg daily. Significant reductions occurred in subjective symptoms ofopiate withdrawal.

Ritvo et al (2007) provided two case reports documenting the use ofbuprenorphinc/naloxone [Clll] to alleviate withdrawal symptoms caused by prolonged use ofhigh doses oftramadol. One
case involved a 34-year old female who was abusing 1200 mg/day oftramadolobtained by doctor shopping and purchases oftramadol overthe Internet. Upon attemptingto stoptramadol use, she presented for treatment oftramadol withdrawal, including symptoms ofrestless pain, muscle stiffuess,joint soreness, anxiety and lethargy. She was subsequentlytitrated to a dose of 32 mg/8 mg buprenorphine/naloxone [C-lll], after which time withdrawal symptoms disappeared. The second case involved a44-year old fomale who admitted to using 1500 mg/day oftramadolpurchased overthe Internet. Upon attempting to ceasetramadol use, shedeveloped symptoms ofwithdrawal successfullytreated with buprenorphine/naloxone [C-lll] (32mg/8mg).

58Both ofthese case studies provide support for cross dependence development between tramadol and buprenorphine.

The clinical substitution studies (Leo et al., 2000; Lotwall et al., 2007; Ritvo et al., 2007; Sobely et al., 2003; and Tamaskar ct al., 2003) demonstratetramadol cross-dependenceto heroin [C-1], morphine [C-11], methadone [C-11] and buprenorphine. Onlythe studies ofLotwall et al. (2007) and Tamaskar et al. (2003) provide information on the relative degree ofcross dependence development compared to other scheduled opioids. LofWall et al. (2007) notes the "modest" suppression ofopioid withdrawal in comparison to morphine [C-11]. The increased number of breakthrough opioid withdrawal symptoms observed following tramadol treatment versus buprenorphine treatment suggest apossible lower degree ofcross-dependence oftramadolto heroin versus cross-dependence ofbuprenorphine [C-Jll] to heroin (Tamaskar et al., 2003). Thesedata suggest that tramadol produces cross-dependence to opioids that is less than that of morphine [C-11] orbuprenorphine [C-111]. No studies were identified comparing cross dependence development to Schedule IV drugs. Dependence Information in Product Label for ULTRAM
The following statement is found in the "WARNINGS" section ofthe ULTRAM label approved September9, 2009:
Wtihdrawal symptoms may occur ifULTRAMis abruptly (.1·ee also DRUGABUSEANDDEPENDENCE). Reported.1ymptoms have includedanxiety. sweating. insomnia. rigors. pain. nausea, tremors. diarrhea, upper respiratory symptoms. piloerection, and rarely hallucinations. Other .1ymptoms that have heen reported lessfrequentlv ;vith ULTRAM discontinuation includepanic**attack~.** severe anxiety, andparesthesias. Clinical experience suggests that withdrawal symptoms may he avoidedhy tapering UrTRAM at the time of discontinuation. Dependence to Tramadol in Humans

- Documented Cases in the Medical Literature.

An examination ofthe medical literature reveals a variety ofarticles documenting dependence to tramadol in humans (Aknine et al., 2000; Anonymous, 2003; Anonymous 2005; Barsotti ct al., 2003; Brinker et al., 2002; Choong and Chiculcscu, 2008; Croissant et al, 2008; Ehrenreich and Poser, 1993; Freye and Levy, 1978; Jensen, 1997; Kabel and van Puijenbroek, 2005; Knisely et al., 2002; Leo et al., 2000; Liu et al., I999; Meyer et al., 1997; Naslund and Dahlqvist, 2003; Pollicc et al., 2008; Ripamonti ct al., 2004; Ritvo et al., 2007; Rodriguez Vallamanan ct al., 2000; Senayet al., 2003; Skipper et al., 2004; Soyka ct al., 2004; Stoehr et al., 2009; Thomas and Surish, 2000; Tjaderbom et al., 2009; Wang et al., 2008; Willaschek et al., 2008; Woody et al., 2003; and Yates et al., 2001). These reports include cases ofindividuals abusing large doses of tramadol as well as individuals taking prescribed doses. Also included are cases documenting psychological dependence to tramadol as assessed using DSM-IV criteria. Two ofthe articles document withdrawal in neonates delivered by mothers taking tramadol (Meyer et al., 1997; Willaschck et al., 2008).

59SummaryofRelevant Findings and Conclusions ofFactor 7

The information available indicates that tramadol produces physical dependence thereby supporting the scheduling ofthe drug.

The most current label for ULTRAM specifically states that tramadol maybe associated with development ofdependence ofthe morphine type (μ-opioid). A variety ofcase reports in the medical literaturedocument development ofdependence to tramadol. Both animal studies and a limited number ofclinical studies also provide supportthat tramadol induces an opioid-like dependence. The available information from animal and human studies suggest that the degree ofphysical dependence produced bytramadol is low, supporting placement oftramadol in a lower schedule such as Schedule IV.
With regard to animal studies, mild spontaneous withdrawal is observed in the Rhesus monkey following repeated tramadol treatment. In a rat study, signs ofspontaneous withdrawal from tramadol appear to be less than similar signs evoked by withdrawal ofbuprenorphine [C-III].

In a study using Rhesus monkeys, a mild opioid-like syndrome is precipitated following the administration ofnaloxoneto monkeys repeatedly treated with tramadol. In a study using rats, precipitated withdrawal scores for tramadol are similarto withdrawal scores for pentazocine (CIV], but less than those ofmorphine [C-II], methadone (C-11], orproproxyphene (C-IV]. Two studies looked at precipitated withdrawal evoked in mice receiving prolonged tramadol treatment. One studyrevealed minimal precipitated withdrawal signs in tramadoltreated mice compared to morphine [C-11] treated mice. The other study showed precipitated withdrawal behavior in tramadol treated mice similar to that found in mice treated with proproxyphene [CIV], but less than that seen in micetreated with codeine [C-11], methadone [C-II], and morphine [C-Il]. Theoverall data from the various animal studies show a dependence producing potential oftramadolthat is low, that is consistent with CSA Schedule IV.

Three clinical studies, as well as several casereports showthat tramadol produces some crossdependence to opioids including heroin [C-I], morphine [C-II], methadone [C-11] and buprenorphine [C-III]. Two ofthe studies provide information on the relative degree ofcross dependencedevelopment compared to other scheduled opioids. Thesetwo studies showed that tramadol produces cross-dependenceto opioids that is less than that ofmorphine (C-11) or buprenorphine [C-III]. Collectively, all ofthe data show that tramadol produces a modest level ofphysical dependence. Preclinical and clinical studies suggest a degree ofphysical dependence development less than that ofSchedule II and III opioids and similarto that ofSchedule IV opioids.

Factor 8: Whether tramadol is an immediate precursor ofa substance already controlled
Tramadol is not an immediate precursorofa substance already controlled.

60

### IV. Findings and recommendation

After consideration ofthe eight factors discussed above. FDA finds that tramadol, its isomers. and all mixtures, compounds and preparations oftramadol meet the three criteria for placing a substance in Schedule IV ofthe CSA, under 21 U.S.C. 812 (b).

I. Tramadol has apotential.fiJrahuse less than the drugs orothersuhstances in Schedule I I I.

The available information indicates that tramadol satisfies the criteria (indicators) set forth in the legislative history ofthe CSA for having apotential for abuse. Individuals taketramado1in the absence ofmedical supervision and in amounts sufficient to create ahazard to theirhealth as evidenced from case studies in the medical literature, nonmedical use DAWN data, nonmedical
use NSDUH data and

## rec data. Tramadol is diverted from legitimate sources as evidenced by
case reports in the medical literature, NFLIS data, DAWN and NSDUH nonmedical use data and 

## recdata. Clinical and preclinical studies show that tramadol, via its M 1metabolite, produces a variety ofeffects similarto that ofopioids known to have an abuse potential and to be controlled under the CSA. Collectively, the available information regarding tramadol supports an abuse potential that is less than that ofSchedule III and similarto that for Schedule IV. Preclinical self-administration studies show that tramadol produces limited reinforcing effects, consistent with a lower schedule. Clinical studies indicatethat tramadol can produce subjectivereinforcing effects similarto that ofmorphine [C-II] and approaching that ofoxycodonc [C-II] at high doses (supratherapeutic doses) but not at therapeutic doses. A similar dose dependency occurs with propoxyphenc [CIV], in which high dosesbut not therapeutic doses produce subjectivereinforcing effects. For bothtramadol and propoxyphene, the doses required to produce significant subjective reinforcing effects is in a range causing sufficient adverse effects. These observations indicatethat the subjective reinforcing effects, areflection ofabuse potential, oftramadol is less than that of morphine [C-II] oroxycodone [C-II], but similar to that ofpropoxyphene [C-IV]. Dependence is one ofthe driving forces in the abuse ofdrugs. As such, the development of dependence provides support for a drug having apotential ofabuse. A varietyofcase report studies document physical and psychological dependenceto tramadol resulting from abuse of suprathcrapeutic doses oftramadol. Clinical studies show that tramadol causes some opioid withdrawal suppressionthat is less than that produced bymorphine [C-II] orbuprcnorphinc [Cl!I]. The combined animal and human information available regarding dependence is supportive ofan abuse potential for tramadol less than that ofSchedule Ill drugs and similarto that of Schedule IV. Epidemiological data is also supportive ofan abuse potential for tramadol consistent with Schedule IV. TheNSDUH showsthat the numberofindividuals reporting lifetime misuse of tramadol was below that ofthe numberreporting lifetime misuse ofeitheroxycodone products [C-II] orhydrocodone combination products [C-III]. NSDUH supports the placement of tramadol in a schedule less restrictive than Schedule III. DAWN data show that the number or ED visits per I00,000 prescriptions is lower than that ofanumber ofopioids in Schedules II and

61llI and similar to that ofpropoxyphene [C-IV]. NFLIS data for 2008 show that the number of law enforcement encounters with tramadol was closeto the number for propoxyphene [C-IV], thereby supporting the same schedule (Schedule IV) for tramadol.

2. Tramadol has a currentlyacceptedmedical use in treatment in the UnitedStates.

The FDA approved tramadol for marketing for the management ofmoderateto moderately
severe pain in 1995. Since then, FDA has approved a number ofadditional products containing tramadol. As such, tramadolhas a currently accepted medical use in treatment in the U.S.

3. Ahuse o(Tramadolmay lead to limitedphysicaldependence orpsychologicaldependence relative to the drugs orothersuhstances in Schedule III.
Tramadol may lead to development ofphysical and psychological dependence as documented in information in current product labels for ULTRAM. In addition, a variety ofcase reports in the medical literature document development ofphysical and psychological dependence to tramadol. Both animal studies and a limited number ofclinical studies also provide support that tramadol induces an opioid-like dependence. The available information from animal and human studies suggest that the degree ofphysical dependence produced bytramadol is low, supporting placement oftramadol in Schedule IV.

Withregard to animal studies, mild spontaneous and precipitated withdrawals arc observed in the Rhesus monkey following repeated tramadol treatment. In a rat study, signs ofspontaneous withdrawal from tramadol are less severe than similar signs evoked bywithdrawal of buprenorphine [C-III]. In a study using rats, precipitated withdrawal scores for tramadol are similar to those for pentazocine [C-IV]. The precipitated withdrawal scores for tramadol were less than the withdrawal scores for morphine [C-11], methadone [C-11], orproproxyphene [C-IV]. Two studies looked at precipitated withdrawal oftramadol in mice. One studyrevealed minimal precipitated withdrawal signs compared to morphine [C-11]. The other study showed withdrawal behavior similarto that observed by withdrawal ofproproxyphenc [C-IV] but less than that of codeine [C-11], methadone [C-11], and morphine [C-11]. Theoverall data from the various animal studies show a dependenceproducing potential oftramadolthat is consistent with Schedule IV control.
Limited clinical studies suggest a dependence producing potential for tramadol less than that of Schedule Ill drugs. Three clinical studies, as well as several case reports, show that tramado1 produces some cross-dependenceto opioids including heroin [C-1], morphine [C-11], methadone [C-11], and buprenorphine [C-III]. The clinical studies provide information onthe relative degree ofcross dependence development compared to other scheduled opioids. Two studies showed that tramadol produces cross-dependenceto opioids that is less than that ofmorphine (C-11) or buprcnorphine [C-III].



### 62Recommendation

The scientific and medical evaluation oftramadol supports a recommendation ofthe Department ofHealth and 

### Human Services to the Drug Enforcement Administration for Schedule IV control oftramado

### l.

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