DEPARTMENT OF HEALTH AND HUMAN SERVICES Office of the Secretary 

The Honorable Michele Leonhart 

Acting Administrator 

Drug Enforcement Administration 

Lincoln Place- West 

700 Army Navy 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 of Health and Human Services is recommending that the substance tramadol 

be added to Schedule IV of the CSA. Tramadol is an opioid analgesic that produces its 

primary opioid-like action through an active metabolite reterred to as the M 1 metabolite 

(0-desmethyltramadol). Tramadol (50 mg/tablet), under the trade name of UL TRAM', 

was first approved for marketing in the United States in March 1995 as an immediatcrelease product for the treatment of moderate to moderately-severe pain. UL TRAC ET', 

an immediate-release, combination product, was approved in August 200 I. The first 

generic versions were approved in June 2002 and 2008. In September 2005, December 

2008, and May 2010, FDA approved the extended release tramadol products: UL TRAM" 

ER, RYZOL TTM, and tramadol hydrochloride extended-release capsules, respectively. 

According to drug abuse databases, tramadol abuse occurs in the United States. In 

addition, abuse and adverse events oftramadol are similar to those of other opioids 

currently controlled under the CSA. The data demonstrate that 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 conclude that tramadol should be controlled in Schedule IV. 

Enclosed is a document prepared by FDA's Controlled Substance Staff that 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 L-r,. - 7 ,l._ ··;'---../ : c_L, ~,> • t ?' \ ,«.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 of the 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 of the Controlled Substances Act (CSA). 

Tramadol is an opioid analgesic that produces its primary opioid-like action through an active 

metabolite, referred to below as the Ml metabolite (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 immediate-release product for the treatment of moderate to 

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 (UL TRACET). In 

September 2005, December 2008, and May 2010, FDA approved the extended-release tramadol 

products, UL TRAM ER, Ryzolt, and tramadol hydrochloride extended-release capsules, 

respectively. These products arc formulated to contain I 00, 200, and 300 mg oftramadol 

hydrochloride and are intended for once-daily treatment for management of moderate to 

moderately severe chronic pain requiring around-the-clock treatment for an extended period of 

time. 

This evaluation discusses the scientific and medical information relative to each of the eight 

factors determinative of control under the CSA, presents findings in the three required areas to 

recommend scheduling a substance in the CSA, and contains a reconunendation regarding 

scheduling. In determining the relative abuse potential oftramadol, FDA has evaluated all 

available abuse potential data from scientific and medical literature, animal and human 

laboratory and clinical trial data, as well as actual use data. 

According to drug abuse databases, tramadol abuse occurs in the United States. In addition, 

abuse and adverse events oftramadol arc similar to those of other opioids currently controlled 

under the CSA. The data demonstrate that public health and safety risks oftramadol result from 

its abuse as an opioid. The basis for the recommendation to schedule tramadol in Schedule IV of 

the CSA is described below. 

II. BACKGROUND 

Pursuant to 21 U.S.C. 811 (c) of the CSA, the Secretary of the Department of Health and Human 

Services (HHS) is required to consider, in a scientific and medical evaluation, eight factors 

determinative of control under the CSA. Following consideration of the eight factors, the 

Secretary must make three findings to recommend scheduling a substance in the CSA. These 

findings relate to the substance's abuse potential, legitimate medical use, and safety or 

dependence potential. 
The eight factors are: 

1. The drug's actual or relative potential for abuse 

2. Scientific evidence of the drug's pharmacological effects, if known 

3. The state of current scientific knowledge regarding the drug or substance 

4. Its history and current pattern of abuse 

5. The scope, duration, and significance of abuse 

6. What, if any, risk there is to the public health 

7. Its psychic or physiological dependence liability 

8. Whether the substance is an immediate precursor of a substance already controlled. 

The FDA performs the administrative responsibilities for evaluating a substance for control 

under the CSA, with concurrence of the National Institute on Drug Abuse (NIDA), as described 

in the Memorandum of Understanding (MOU) of March 8, 1985 (50 FR 9518-20). 

In October and November 2005, FDA accepted for filing five citizen petitions requesting that the 

Commissioner of Food and Drugs recommend scheduling tramadol and/or its extended-release 

formulation(s) under the CSA. Two petitioners requested that the Commissioner of Food and 

Drugs recommend designation of extended-release formulations oftramadol in Schedule Ill of 

the CSA. These petitioners also requested that FDA reevaluate the product labeling for 

extended-release formulations oftramadol based upon currently available safety information 

related to serotonin syndrome, and consider the potential for an increased risk of dose-dependent 

seizures or dose-dependent serotonin syndrome as an additional reason to require scheduling. 

Two other petitioners opined that available data would support scheduling oftramadol at the 

level of Schedule !II. A comment submitted to the public dockets for these citizen petitions on 

behalfofOrtho-McNeil, Inc., an affiliate of the new drug application holder for UL TRAM, took 

an opposite view 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 (from petitioners who also submitted citizen petitions to FDA) specifically 

requested the placement oftramadol in Schedule III, while the remaining petition did not specify 

a particular level of control. On July 3, 2006, the DEA formally accepted these petitions. Jn a 

letter dated April 25, 2007, and sent to the Assistant Secretary for 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 scheduling recommendation for tramado I. 

In evaluating the relative abuse potential oftramadol, FDA reviewed and evaluated all of the 

available data on the 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). 

2 
Regulatory 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, UL TRAM, an oral tablet dosage form containing 50 mg oftramadol, was approved and 

marketed in the United States as an analgesic. A combination product under the trade name 

UL TRACET (containing 37.5 mg tramadol hydrochloride and 325 mg acetaminophen) was 

approved for marketing in the United States on August 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 May 2010. 

At the time of approval of UL TRAM in 1995, little information on abuse potential oftramadol 

was known. Prior to this date, tramadol was marketed in the United Kingdom and Germany and 

other countries, but there was a lack of data 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 racemate has 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 

( + )-enantiomer was found to have 10-fold higher analgesic activity than the (-)-

enantiomer. 

This profile of activity is not typical of drugs of abuse or controlled substances. 

However, tramadol metabolizes to several metabolites of which the Ml metabolite, 0-

desmethyltramadol, has strong μ-opioid activity. In the view of the Sponsor of UL TRAM, the 

activity oftramadol was due to the 5-HT and NE activity and weakμ- opioid activity of the 

parent substance. The contribution of the Ml metabolite to the overall activity was not weighted 

very high. Human abuse potential studies in recreational opioid studies showed that compared to 

morphine or oxycodone, 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 comparator drugs. The 

occurrence of convulsions in one study was considered an adverse effect that could deter abuse. 

In addition, some preclinical studies assessing respiratory depression 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 were judged to be insufiicient for scheduling tramado 1 under the CSA at the time of 

approval. However, the FDA and the sponsor, Ortho-McNeil, agreed to an extensive postmarketing surveillance plan to monitor abuse of the drug post approval. The sponsor set up a 

3 
scientific advisory panel to provide advice on the 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 of new warnings. A "Dear Healthcare Provider" letter issued 

by Ortho-McNeil on March 20, 1996, warned of drug abuse as well as seizures and 

anaphylactoid reactions. This letter stated "115 spontaneous domestic reports of adverse events 

described as drug abuse, dependence, withdrawal, or intentional overdose have been received. 

This does not include cases of accidental overdose. Patients with a past or present history of 

addiction or dependence on opioids account for the majority of these reports. UL TRAM 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 UL TRAM. The FDA asked the DAAC for recommendations on 

what data the agency should require in making a decision on scheduling and whether the 

Committee was of the opinion that reports of abuse and pharmacological features of UL TRAM 

are "similar to other opioids which are scheduled." Ortho-McNeil maintained that although the 

drug produces opioid-like effects, a delayed onset makes abuse of UL TRAM unlikely. 

Both the parent substance (tramadol) and the Ml metabolite contribute to the drug's efficacy as 

an analgesic. Efficacy relates to the plasma concentration of each, and their relativeμ- opioid 

receptor affinities and efficacies. The metabolism oftramadol (a relatively weakμ- opioid) to 

Ml (a strongμ- opioid) is an important contributor to theμ- opioid activity oftramadol. 

The DAAC responded with the following proposals: 

1. More monitoring of abuse of UL TRAM is needed to determine whether it should be 

categorized as an opioid. 

2. Scheduling should remain an option. 

3. Future analyses should depend not only on reports from the Sponsor, but also on changes in 

abuse trends. 

4. Comparison of data with other opioid drugs is needed. 

5. Abuse reports of three or four other drugs that are in the same pharmacological class or used 

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 of sources have been obtained. Reports of abuse, 

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. These reports and studies, as well as other 

studies, have improved our understanding oftramadol's mechanism of action, particularly as 

applied to the consequences oftramadol use including opioid abuse and dependence. In 

addition, several years of data related to drug abuse/misuse, diversion and safety have been 

obtained from the Drug Abuse Warning Network, National Survey of Drug Use and Health 

(NS DUH), National Forensic Laboratory Information System (NFLIS), the American 

4 
Association of Poison Control Centers' National Poison Data System, and the Florida 

Department of Law 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 on prescribing and 

dispensing and criminal sanctions are applied. A partial listing of the countries that have such 

restrictions for tramadol is provided in Table I. 

5 
Table 1. International Special Prescribing Requirements (Source: Grunenthal USA, Inc. April 

27, 2007) 

Country Requirement 

Austria Psychotropic, Category IV 

Bahrain a Restricted Prescription a , Special Prescription Fonn 

Belarus 0 Under special governmental control according to the "List of Strong Acting 

Substances", not listed as narcotic b 

Bulgaria Narcotic 

Estonia Listed as psychotropic, not listed as narcotic: not more than 3 g tramadol 

per prescription 

Finland Listed as psychotropic, not listed as narcotic: separate, original 

prescription, prescription is kept by the pharmacy after the hand-over of the 

first package of the prescription 

Greece Category C (products belonging in this category are prescribed by special 

prescription for narcotics (with two lines), legalized by Prefecture, kept for 

3 years (for continual 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 . ussra o Under special governmental control according to the "List of Strong Acting 

Sb u stances "I'd .b , not 1ste as narco!Ic 

Ukraine 0 Under special governmental control according to the "List of Strong 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' is not 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. lbe doctor has to handle 

prescription paperwork and the prescriber should be a specialist. The nutnber of possible prescriptions per period is 

limited. The pharmacist should identify the patient or relative when dispensing and take the si!,'llalure. Quarterly 

follow-ups should be conducted by the physician. 

b 

In Russia and the former Commonwealth of Independent States (CIS)-countries, the trarnadol dosage tOrms 

(except T ramal suppositories and Tramal Retard) are classified in the "List of Strong Acting Substances and 

Poisons". Pharmacists may be subject to severe penalties if they 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 containing not more than 100 mg of 

drug per dosage unit and with a concentration of not 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 of codeine in Jordan. 

6 
Five Citizen Petitions were filed with the FDA in October and November 2005. Petitioners 

requested that the Commissioner of Food and Drugs recommend scheduling tramadol and/or the 

extended-release formulation(s) oftramadol under the CSA. Two petitioners requested that the 

Commissioner of Food and Drugs recommend designation of extended-release formulations of 

tramadol in Schedule III of the CSA. These petitioners also requested that FDA reevaluate the 

product labeling for extended-release formulations oftramadol based upon currently available 

safety information related to serotonin syndrome, and consider the potential for an increased risk 

of dose-dependent seizures or dose-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 of Schedule III. A comment submitted to the public dockets for these 

citizen petitions on behalfofOrtho-McNeil, Inc., an affiliate of the NOA holder for UL TRAM, 

took an opposite view and recommended that tramadol not be scheduled. 

The current labeling states that tramadol is a centrally-acting synthetic opioid analgesic. The 

UL TRAM labeling approved September 9, 2009, describes the drug's activity further, as 

follows: 

" ... its mode of action is not completely understood, from animal tests, at least two 

complementary mechanisms appear applicable: binding o/parent and MI metabolite to 

μ-opioid receptors and weak inhibition o/reuptake o/norepinephrine and serotonin. 

Opioid activity is due to both low affinity binding o/the parent compound and higher 

affinity binding(}/ the 0-demethylated metabolite MI to μ-opioid receptors. Jn animal 

models, M 1 is up to 6 times more potent than tramadol in producing analgesia and 200 

times more potent in μ-opioid binding. Tramadol-induced analgesia is only partialZv 

antagonized by the opiate antagonLl·t naloxone in several animal tests. The relative 

contribution of both tramadol and M 1 to human analgesia is dependent upon the plasma 

concentrations ol each compound (see CLINICAL PHARMACOLOGY, 

Pharmacokinetics.) 

Tramadol has been shown to inhibit re uptake ol norepinephrine and serotonin in vitro, as 

have some other opioid analgesics. These mechanisms may contribute independentlv to 

the overall analgesic profile of UL TRAM. Analgesia in humans begins approximately 

within one hour afier administration and reaches a peak in approximately f\1.o to three 

hours. 

Apart.from analgesia, ULTRAM administration may produce a constellation <Jf 

.1ymptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) 

similar to that of other opioids. Jn contrast to morphine, tramadol has not been shown to 

cause histamine release. At therapeutic doses, ULTRAM has no e[/ect on heart rate, lefiventricularfunction or cardiac index. Orthostatic hypotension has been observed." 

As the public health risks oftramadol that 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. 

7 
HI. EVALUATING TRAMADOL UNDER THE EIGHT FACTORS 

Factor 1: Tramadol's Actual or Relative Potential for Abuse 

"Abuse" is not defined in the CSA. However, the legislative history of the CSA 1 describes the 

potential for abuse of a particular drug or substance by the following indicators: 

a) Individuals are taking the substance in amounts sufficient to create a hazard to their 

health or to the safety of other individuals or to the community; 

b) There is significant diversion of the drug or substance from legitimate drug channels; 

c) Individuals are taking the substance on their own initiative rather than on the basis of 

medical advice from a practitioner licensed by law 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 same potential for abuse as such 

substance, thus making it reasonable to assume that there may be significant diversions 

from legitimate channels, significant use contrary to or without medical advice, or that it 

has a substantial capability of creating hazards to the health of the user or to the safety of 

the community. 

When assessing the abuse potential of a substance, the Secretary considers multiple factors. data 

sources, and analyses. No single test, by itself; provides a complete characterization of a 

substance's abuse potential. The prevalence, frequency, and manner of use by the general public 

and specific subpopulations, the amount of material that is available for abuse, as well as the 

evidence of particular risks are all considered. 

Animal, human, and epidemiological data are useful in assessing a substance's abuse potential. 

A comprehensive scientific evaluation of the relative abuse potential of a substance includes 

consideration of the receptor binding affinity, preclinical pharmacology, reinforcing effects, 

discriminative stimulus effects, dependence producing potential, pharmacokinetics/metabolism 

and routes of administration, toxicities, assessment of the clinical efficacy-safety database 

relative to actual abuse, human abuse potential studies, and the public health risks after 

marketing. Epidemiological data, as well as evidence of clandestine production and illicit 

trafficking, are also important indicators of abuse potential. The above four indicators of abuse 

potential are discussed in more detail as they relate to tramadol below. 

I. Individuals are taking the substance in amounts sufficient to create a hazard to their 

health or to the safety of other individuals or to 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 tramado I in 

amounts sufficient to create a hazard to their health and to the safety of other individuals or to 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; Stoehr et al., 2009; Tjaderbom et al., 

2009; and Yates et al., 200 l ). These publications, many of which are recent, demonstrate that 

abuse oflarge doses oftramadol occurs on a daily 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 of the use oftramadol in 

amounts sufficient to cause harm. DAWN data on tramadol are discussed in detail under Factor 

4. In 2007 and 2008, the estimated national, annual number of emergency department (ED) 

visits related to the nonmcdical use

2 oftramadol was 8,039 and 11,850, respectively. For 2007 

and 2008, with respect to nomnedical ED visits involving tramadol products alone (in the 

absence of other drugs present), 1,819 and 788, respectively, resulted from "overmedication"2 

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

design, the "other"2 category captures most of the documented drug abuse cases. 

The American Association of Poison Control Centers' National Poison Data System, discussed in 

detail under Factor 4, 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, or intentional abuse. Although the numbers of cases under 

each category for reason of exposure are not specified, it is probable that some of the cases 

involved the use of elevated doses oftramadol resulting in adverse effects. This is supported by 

the behavioral effects oftramadol at large doses, as described in Factor 2, below. 

2. There is significant diversion o/the drug or substance.from legitimate drug channels. 

The DEA National Forensic Laboratory Infonnation System (NFLIS) provides data on tramadol 

containing exhibits encountered in the course of state and local law enforcement investigations. 

Drug exhibits are analyzed in state and local forensic laboratories. Under Factor 4, there is a 

detailed examination oftramadol data in the NFLIS database. The data show that for each of the 

years from 2000 through 2008, tramadol was present in drug exhibits seized in the course of law 

, 

~ Nonn1edical use of pharmaceuticals includes prescription and OTC pharmaceuticals in ED visits that are of the 

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. 

Afalicious puisoning--TI1is category was designed to capture cases of drug use in which the patient was 

administered a drug by another person for a malicious purpose. Drug-facilitated sexual assault is one type 

of malicious poisoning, but other types of malicious 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 any of the other 

seven types. By design, most cases of documented drug abuse will fall into this category. 

9 
enforcement activity. In 2008, forensic laboratories analyzed 1,093 such exhibits. This number 

is greater than the number of exhibits shown to contain pentazocine [C-IV) or butorphanol [CIV], but less than the number of exhibits found to contain hydrocodone [C-111), codeine [C-11, III, 

VJ, and buprcnorphine [C-111). The number oftramadol exhibits is close to the number of 

exhibits for propoxyphene [C-IV). These exhibits were seized in the course of criminal 

investigations involving drugs and provide evidence of the 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 of Drug Use and Health (NS DUH) data 

indicating nonmedical use oftramadol; and 3) American Association of Poison 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 oftramadol by individuals who do not have a valid prescription 

for the drug, thereby suggesting the possibility of diversion from legitimate sources. These 

databases are discussed in detail under Factor 4. 

The possibility ofdivcrsion oftramadol is mentioned in the UL TRAM label that was last 

approved on September 9, 2009. Under the heading of"Physical Dependence and Abuse" is the 

following statement: 

Dependence and abuse. including drug-seeking behavior and taking illicit 

actions to obtain the drug, are not limited to those patients v.ith prior history 

of'opioid dependence. 

Knisely et al. (2002) observed in a postmarketing surveillance study oftramadol use among 

health care professionals that among 140 participants, who had a least one positive 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 over the period of January 

2002 through March 2004, as reported by drug diversion investigators from police agencies in all 

50 states. During the first quarter, 42 cases involved tramadol diversion. During each of the 

remaining eight quarters, approximately 30 cases oftramadol diversion were noted. The number 

oftramadol diversion cases was less than the number of diversion cases for other controlled 

substances such as hydrocodone products (C-III) and oxycodonc (C-ll). 

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

medical advice from a practitioner licensed by law to administer such substances. 

Evidence exists indicating that individuals take tramadol on their own initiative rather than on 

the basis of medical advice from a practitioner licensed by law to prescribe tramadol. This 

evidence includes case reports of abuse and dependence to tramadol in the medical literature. 

Epidemiological data (DAWN, NSDUH and AAPCC) also suggest tramadol use in the absence 

of medical supervision. These databases arc discussed in detail under Factor 4. 

Cases oftramadol use by individuals on their own initiative rather than on the basis of medical 

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 of the DAWN data shows that over the period of2004 through 2008, the 

national annual estimates of ED visits related to nonmedical use, including abuse, oftramadol 

and its combinations increased from approximately 4,800 to over 11,800. Upon normalization of 

the number ofnonmedical ED visits relative to I 00,000 prescriptions dispensed, the rate of ED 

visits for tramadol/combinations was found similar to the rates for codeine/combinations [C-11, 

III, VJ primarily) and proproxpyhene products (C-IV], but lower than the rates ofhydrocodone/ 

combinations [C-lll], buprenorphine/combinations [C-Ill], and ofa number of Schedule II 

opioids. 

According to 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 

of any pain reliever use during the past year, also reported nonmedical use oftramadol. Both 

lifetime nonmedical use, as well as nonmedical use over the past 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 of Knisely 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 of appropriate 

medical supervision. 

4. The substance is so related in its action to a substance alreadv listed as having a 

potentialfiJ1· abuse to make it hkelv that it will have the same potential.for abuse as 

such substance, thus making it reasonable lo assume that there may be significant 

diversions.fi'om legitimate channels, significant use contrwy to or without medical 

advice, or that it has a substantial capability of creating hazards to the health of the 

user or to 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 of medical supervision and to represent a safety 

concern to the community. 

The opioid activity oftramadol is primarily due to its metabolite, 0-desmethyltramadol, 

commonly known 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 of action compared to other opioids, 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 indicate that tramadol produces some, but limited, reinforcing effects. Animal 

studies, discussed under Factor 7, show that repeated administration oftramadol results in 

dependence development, characterized by a withdrawal syndrome similar in intensity to 

pentazocine [C-IV] or propoxyphene [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 or V. These studies indicate 

that tramadol produces some reinforcing subjective effocts at high (supratherapeutic) doses. A 

similar dose 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 comparator drug for tramadol with respect to producing 

reinforcing effects. Tramadol and propoxyphene, as well as other opioids, have a greater 

probability of eliciting adverse effects at higher doses. These studies and separate studies 

examining propoxyphene abuse potential indicate that the subjective reinforcing effect of 

tramadol is less than that of Schedule II opioids and more comparable to that ofpropoxyphene 

[C-IV]. Clinical studies evaluating the abuse potential oftramadol are discussed in detail under 

Factor 2. 

Summary of Relevant Findings and Conclusions from Factor 1. 

An evaluation of the accumulated information demonstrates that the indicators of a drug's 

potential for abuse, as described in the legislative history of the CSA, are present for tramadol. 

Individuals take tramadol in the absence of medical supervision and in amounts sufficient to 

create a hazard to their health. Tramadol is diverted from legitimate sources. Tramadol 

produces effects similar to 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 of Schedule 

III drugs and similar to that of drugs in Schedule IV. Preclinical self-administration studies show 

that tramadol produces limited reinforcing effects, consistent with a lower schedule. Clinical 

studies indicate that tramadol produces subjective reinforcing effects similar to that of morphine 

(C-ll] and approaching that of oxycodone [C-Il] at high (supratherapeutic doses) but not at 

therapeutic doses. A similar dose dependency occurs with propoxyphene [C-IV]. These 

observations indicate that the subjective reinforcing effects, a reflection of abuse potential, of 

tramadol is less than that of morphine [C-11] or oxycodone (C-11], but similar to that of 

propoxyphene [C-IV]. 

Dependence is one of the driving forces in the abuse of drugs. As such, the development of 

dependence to a drug can contribute to its abuse potential. Animal studies indicate that tramadol 

causes a mild to moderate level of dependence as evidenced by a withdrawal syndrome similar to 

that produced by pentazocine [C-IV] and propoxyphene [C-IV]. A small number of clinical 

studies indicate the occurrence of dependence in pain patients taking therapeutic doses of 

tramadol; however, a variety of case report studies document dependence to tramadol resulting 

from supratherapeutic doses oftramadol. Clinical studies show that tramadol can cause 

suppression of opioid withdrawal that is quantitatively less than that produced by morphine [C12 
II] or buprenorphine [C-III]. The information available regarding dependence is supportive of an 

abuse potential for tramadol less than that of Schedule III drugs and similar to that of Schedule 

IV. 

Epidemiological data also support an abuse potential for tramado 1 that is consistent with drugs in 

Schedule IV. NSDUH shows that the number of individuals reporting lifetime misuse of 

tramadol is less than that of the number reporting lifetime misuse of either oxycodone products 

[C-II] or hydrocodone combination products [C-lll]. NSDUH supports the scheduling of 

tramadol in the CSA and the placement oftramadol in a less restrictive schedule than Schedule 

Ill. DAWN data show that the number of ED visits per 100,000 prescriptions is lower than that 

ofopioids in Schedules II and Ill, but similar to that ofpropoxyphene [C-lV]. NFLIS data for 

2008 show that the number oflaw enforcement encounters with tramadol was close to the 

number for propoxyphene [C-IV]. These data support the placement oftramadol in Schedule IV. 

Factor 2: Scientific Evidence of Tramadol's Pharmacological Effects 

General Pharmacology of Tramadol 

An examination of the general pharmacology, including behavioral pharmacology, oftramadol 

reveals that tramadol produces many pharmacological effects similar to those of opioids, and as 

such can be considered an opioid. Opioids are drugs of abuse that are controlled in various 

schedules under the Controlled Substances Act. At the same time, however, in contrast to many 

opioids that act directly without requiring metabolism to produce opioid like effects, the opioid 

pharmacology oftramadol primarily 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 some opioids, but not most opioids, in having the additional 

pharmacological effects ofblocking the reuptake ofnorepinephrine and serotonin. 

This section presents the fu1dings on the pharmacology for tramadol and its Ml metabolite. 

Collectively, these findings show that although the pharmacological profile oftramadol does 

differ is some ways (i.e., primary opioid 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 receptor binding activity oftramadol and 0-desmethyltramadol {Ml) [not scheduled] 

has been examined in a number of studies (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 of comparison, Table 2, adapted from Frink et al. (1996), shows 

μ-opioid receptor binding of morphine [C-11] and codeine (C-11]; the opioid antagonist naloxonc 

[not scheduled]; and tramadol and its Ml metabolite. The affinity of morphine [C-11] to theμopioid receptor is approximately 10-100 times greater than Ml and 300 times greater than 

tramadol. Although the affinity of codeine [C-II] to the μ-opioid receptor is less than that of 

racemic M 1 and (+)-Ml, it is noted that codeine activity is largely attributed to its 

biotransformation to its active metabolite, morphine (Frink et al., 1996). 

13 
Table 2. Inhibition of Specific Opioid Receptor Ligand Binding to Rat Brain. (Adapted from 

Frink et al., 1996.) 

Ki values (moles/liter; tnean of3 or n1ore determinations) 

Drug or Metabolite Opioid Receptor Binding Assays 

[

3H]DAMGO [ 3 H]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-V dependent 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 of either [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. For blocking μ-opioid binding, tramadol was approximately IO-fold less 

potent than codeine [C-11], 60-fold weaker than d-proproxyphene [C-IVJ, I 000-fold weaker than 

methadone [C-ll], and 6000-fold weaker than morphine [C-11]. 

Gillen et al. (2000) demonstrated very low affinity ofracemic tramadol, but high affinity of(+)-

M I, to the human opioid receptor in CHO-Kl cells. Competitive binding 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 ofracemic tramadol and(+) Ml were 

approximately 3,800 and 5.5-fold less than that of morphine, 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 of agonists to stimulate [

35S]GTPyS binding in isolated membranes (Hilf et al., 1989). 

Gillen et al. (2000) used this assay to determine the potency and relative efficacy, that is, the 

ability compared to other substances to cause transduction of the receptor, of morphine, fontanyl, 

tramadol, and tramadol metabolites Ml, M2, M3, M4 and M5. For this study, cloned human 

opioid receptors were inserted into the membranes of Chinese hamster ovary cells. Racemic (±)-

tramadol was found to have little intrinsic efficacy at the opioid receptor, a finding consistent 

with a very low affinity for binding to the receptor. In addition, the M2, M3 and M4 metabolites 

had no atlinity for the human 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 the human opioid receptor that was between the relative intrinsic efficacies 

of morphine [C-11] and fentanyl [C-11]. Based on the high binding affinity and intrinsic efficacy 

14 
of the Ml metabolite forthe human opioid receptor, the authors concluded that the Ml 

metabolite accounts for the μ-opioid component of the analgesic effects oftramadol (Gillen et 

al., 2000). More recently, Nakamura et al. (2008) using the [3 5

S]GTPyS binding and morphine 

binding assays, showed that Ml, but not tramadol, had functional activity at opioid receptors in 

mo use brain. 

Inhibition of Serotonin and Norepinephrine Reuptake 

Studies have shown that 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 of serotonin (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 of serotonin 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 of preclinical animal models of pain (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 vocalization tests in rats; tail-flick, hotplate, and 

abdominal constrict ion 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 of either tramadol or Ml produced dose-dependent analgesia. When the authors 

compared this analgesic activity to other opioids, the following descending order of analgesic 

activity was found: hydromorphone [C-11] > hydrocodone [C-JI] >morphine [C-JI] > Ml > 

codeine [C-11] = tramadol. Animal studies showed that naloxone only partially antagonizes 

antinociceptive effects oftramadol, indicating the involvement of additional mechanisms (i.e. 

inhibition ofnorepinephrine and serotonin reuptake) in the analgesic effects oftramadol (see 

above) (Kayser et al., 1991; Raffa et al. 1992). Studies indicate a role for both opioid receptor 

stimulation and inhibition of norepinephrine 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 number of clinical studies demonstrate the analgesic effects oftramadol in various pain 

states in humans (for review see Grond and Sablotzki, 2004, Prommer, 2005; Reeves and Burke, 

2008; Rhoda Lee et al., 1993; Sunshine, 1994). This analgesic effect involves both opioid 

mechanisms, via the Ml metabolite, and the mechanism ofnorepinephrine and serotonin 

reuptake blockade. In clinical studies with tramadol, the production of analgesia is consistent 

15 
with M 1 formation, commencing within one hour of administration and peaking 2 to 3 hours 

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 genetically polymorphic nature of the 

enzyme, CYP206, which is involved in, among other things, the conversion oftramadol to the 

Ml metabolite (for review: Rollason et al., 2008). As a result of this 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 demonstrate that 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 correlate to the presence of the 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 either hydrocodone/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 of acute musculoskeletal pain caused by minor trauma. Thirty-three patients received 

tramadol (I 00 mg orally) and an equal number received hydrocodone 5 mg/acetaminophen 500 

mg. Tramadol was significantly less effective than treatment with hydrocodone/acetaminopben 

[C-lll]. 

Richter et al. (1981) compared the analgesic effects of orally administered tramadol (50 mg) to 

pcntazocine (50 mg) [C-IV] and placebo in a multicenter, double-blind trial with patients in 

acute pain. Tramadol displayed an analgesic effect similar to that of pentazocine 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 of placebo 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 superior to 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 of tramadol (75 - 150 mg) had analgesic efficacy 

equivalent to combinations of acetaminophen 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 of the pupils (Reisine and Pasternak, 

I 996). In clinical studies, tramadol was also shown to cause pupillary restriction, the onset of 

which is delayed several hours following tramadol administration (Fliegert et al., 2005; Krueger 

and Muller-Limmroth, 1978; Knaggs et al., 2004; Slanar et al., 2007). This delayed miotic effect 

results from the delayed formation of the tramadol MI metabolite. Additional support for the 

importance of the 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 of morphine therapy 

catherization may be 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 UL TRAM, tramadol can also depress respiration, particularly in cases of overdose or 

when combined with other central nervous system depressants. 

Teppema et al. (2003) showed that tramadol causes a dose-dependent respiratory depression in 

cats in the dosage range of I to 4 mg/kg. Naloxone treatment prevented more than 50% of the 

respiratory depression suggesting a role of the opioid receptor in causing respiratory depression. 

Considering that naloxone did not completely block 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 respiratory depression following administration oftramadol, 

100 mg four times daily, in a patient with impaired renal function. The respiratory depression 

was reversed with administration ofnaloxone. Stamer et al. (2008) recently documented the 

occurrence ofrespiratory depression 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 oftramadol to the active Ml metabolite, which was 

considered the cause of respiratory depression. 

Antitussive Effect 

Morphine [C-11] and other opioids suppress the cough reflex (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 stimulation of the cough reflex). Tramadol suppressed cough in cats (Nosalova et 

al., 1991 ). Hennies et al (1988) showed that both tramadol 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]. 

17 
N auseant and Emetic Effects 

Nausea and vomiting are typically unpleasant side effects associated with the use of opioids 

(Reisine and Pasternak, 1996 ). Nausea and vomiting are common side effects seen with 

tramadol treatment (for review, see Radbruch et al., 1996). In the label approved September 9, 

2009, for UL TRAM, nausea and vomiting are listed as significant adverse effects associated with 

use of the product in clinical trials. 

Intestinal Effects 

Bowel dysfunction leading to constipation is a common effect produced by opioids (Pappagallo, 

2001; Bell et al., 2008). Opioids tend to reduce the propulsive contractions (peristalsis) of the 

small and large intestines (Reisine and Pasternak, 1996). This action, along with increases in 

anal sphincter tone, 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 guinea pig (Herbert et al., 2007). In the mouse, tramadol had 

a weak inhibitory effect on colonic propulsive motility, with the ( + )-enantiomer being more 

potent than the racemic or (-)-enantiomer (Raffa et al., 1993). In the rat, tramadol was 

approximately 38 times less potent than morphine [C-II] in inhibiting gastrointestinal transit time 

(Planas et al., 2003). In the guinea pig, Ml (0-desmethyltramadol), as well as tramadol, 

inhibited intestinal peristalsis, with the former having greater potency (Herbert et al., 2007). 

Naloxone blocked the inhibitory effects oftramadol and 0-desmethyltramadol thereby indicating 

an opioid mechanism of action. 

The effect oftramadol on gastrointestinal motility in humans is suggested by the fact that 

constipation is a problem with the use oftramadol. As evidenced by the labeling for UL TRAM, 

constipation is one of the 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 colonic transit, which may account for its constipating effects 

(Maurer et al., 1996; Wilder-Smith and Bettiga, 1997 and Freye and Latasch, 2000). 

Preclinical Abuse Potential Studies. 

Drug discrimination and intravenous self-administration studies are important animal studies that 

help in the assessment of the abuse potential of a drug. Drug discrimination studies are of value 

in discerning the class or classes of drugs to which a test drug belongs, based on similar stimulus 

clues. Intravenous self-administration studies evaluate the reinforcing effects of a drug. 

Tramadol was evaluated in a limited number of drug discrimination studies using rats and selfadministration studies using the Rhesus monkey. Those studies are described below. 

18 
Drug Discrimination Studies 

Several drug discrimination studies using rats indicate that 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 of stimulus 

generalization oftramadol relative to other opioids, including those in Schedules III and IV, arc 

not reported. However, studies demonstrate the lack of generalization oftramadol to 

methamphetamine [C-ll central nervous system stimulant) and selected antidepressant drugs 

(norepinephrine reuptake blockers). Tramadol also does not generalize to the alpha-adrenergic 

agonist, flupirtine and the 5-HTI b agonist, anpirtoline. These studies indicate that the 

discriminative stimulus cues oftramadol are typical of classical 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 oftramadol to morphine [C-Il). Rats were trained to discriminate morphine (4 

mg/kg s.c.) from saline using a fixed ratio (FRI 0) schedule of food reinforcement. Once training 

was completed, test doses of either morphine (0.56- 10 mg/kg s.c.) ortramadol (3.2-56 mg/kg 

s.c.) were evaluated for generalization to morphine. Full generalization was achieved with 

morphine at doses of2.37 mg/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 was blocked 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 study demonstrated that tramadol shares 

interoceptive cues with the opioid, morphine [C-Il], but not with the central nervous system 

stimulant, methamphetamine [C-Il]. Blockade of the cues demonstrates the opioid nature of the 

interoceptive cues evoked by tramadol and morphine and are further demonstrated by the 

blockade of these cues by naltrexonc. 

In a study by Filip et al. (2004), tramadol was evaluated for generalization to morphine [C-ll], 

naloxone [not scheduled] and a number of antidepressants [not scheduled]. Rats were trained to 

distinguish tramadol (20 mg/kg s.c.) from saline using a two-choice water-reinforcement 

paradigm. Test drugs were administered intraperitoneally (i.p.). The non-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 prior to testing. Of the drugs tested, only morphine ( 1 - 3 mg/kg) showed generalization 

to tramadol. Concomitant naloxone (0.1 - 1 mg/kg) administration attenuated the stimulus 

effects oftramadol (20 mg/kg) as well as the substitution evoked by morphine (2 mg/kg). The 

effects of morphine and naloxone were obtained without altering the animals' response rates. Of 

the antidepressants studied, only milnacipram (I 0 mg/kg) and reboxetine (I 0 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 by noradrencrgic 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 

19 
further demonstrated by the lack of stimulus 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 shock termination 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 generalize to flupirtine, a non-scheduled analgesic which acts via an 

alpha-adrenergic mechanism, and not an opioid mechanism. In a separate study by 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 other drugs in this study, the authors concluded that the 

discriminative stimulus effocts of anpirtoline primarily involved agonistic actions at serotonin I B 

(5-HTl b) 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 

other opioids. In various drug discrimination studies using rats, morphine displays high 

specificity of the 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 of the drug discrimination 

data generated for both morphine and for tramadol provide support that tramadol produces 

opioid-like effects. 

Drug Self-Administration Studies 

Yanagita (1978) provides the sole report documenting the intravenous self-administration of 

tramadol in animals. To evaluate the reinforcing effects of tramado l, Yanagita ( 1978) conducted 

three intravenous self-administration studies using Rhesus monkeys. In the first study, tramado l 

supported self-administration behavior nonstatistically, 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. The third study was a progressive ratio study demonstrating 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 initially trained to self-administer 0.1 mg/kg/injection of 

lefetamine [C-1!] at a rate of greater than 100 injections within a 4-hour period on consecutive 

days. This was followed by saline substitution for lefetamine and continued until the daily 

number of injections fell below 20. The lefetamine-saline procedure was repeated so that 

monkeys came to discriminate the effects and extinguish or restart self-administration, 

20 
immediately (or within 24 hours at the most) of starting saline or lefotamine, respectively. Once 

training was completed, test drug was administered 4 hours per day for three consecutive days. 

The order of treatment 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 of injections taken during each test period was detennined and data 

was expressed in terms of the percentage oflefetamine responding. 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 of both groups were not statistically significantly 

different. At a unit dose of0.06 mg/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 significance was observed. The author concluded that this study 

demonstrated a non-significant trend oftramadol toward producing reinforcement of drug 

seeking behavior, particularly at the 0.25 mg/kg dose. However, this effect was less than that 

previously shown in separate studies by the author for either pentazocine [C-IV) or codeine [C11) (Yanagita et al., 1975). 

In a second study, Yanagita (1978) evaluated tramadol for initiation of self:administration in two 

drug naive monkeys and in two monkeys with previous drug selt:administration experience. 

Initiation of self-administration did not occur when monkeys received access for 4 to 6 weeks to 

tramadol at a unit dose ofO. l mg/kg/injection. However, increasing the unit dose ten-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 of the first two weeks, the average number of daily 

injections for the four monkeys was 97.0, 48.1, 39.9 and 188.9. By the end of 6 weeks, one 

monkey died and the number of average 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 of spontaneous motility, mydriasis, anorexia, nausea, and vomiting. At 

weeks 2 and 4 of the 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) study examined the reinforcing effects oftramadol. For this study, a 

progressive ratio test oflow rate was performed on two of the Rhesus monkeys that had initiated 

tramadol self:administration in the previous study. The number oflever presses 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 a ratio of 64: I on the second day after initiation of the test, but 

thereafter, the animal began to extinguish self-administration. The second monkey reached a 

ratio of 32: I on the 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 similarity that tramadol has to opioids in Schedules ll - V, and supports 

the scheduling of the drug. Yanagita (1978) did not use a positive opioid control; however, the 

results of this study indicate a limited reinforcing effect as compared to opioids in ll and Ill, 

thereby indicating placement oftramadol in a lower schedule. 

21 
Human Abuse Potential Studies - Subjective Reinforcing Effects of Tramadol 

Evaluation of the subjective positive reinforcing effects of drugs in human subjects provides 

important information regarding the drug's abuse potential. Four clinical studies evaluating the 

subjective reinforcing effects oftramadol are described below. Two of the studies submitted to 

the FDA under NOA 20-281 demonstrate that at high, greater than therapeutic doses, tramadol 

produces subjective positive reinforcing effects when given orally or intravenously to nondependent, opioid experienced subjects. A similar pattern of dose 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 of intravenous tramadol was compared to that of intravenous morphine in a 

study submitted after approval of UL TRAM. Subjects were non-dependent, opioid experienced 

male volunteers enrolled into a single inpatient site. There were two segments to the study. In 

each segment, self and observer-rated subjective, behavioral, and physiological effects were 

measured. Instruments were the 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!] or placebo, in random order, followed by each of the tramadol doses (I 00, 200, 300, and 400 

mg) administered in ascending order. At least 48 hours separated treatments. Various 

measurements were taken at 15 minutes prior to dosing and at various intervals following dosing 

up to 24 hours. Quantitation consisted of determining the 24-hour area-under-the-curve (AUC) 

and maximum effect observed. Two of the SDRQ questions included "Like the Effect?" and 

"How High Are You?" For both questions, the 24-hour AUC for 20 mg morphine was larger 

than that for 400 mg tramadol, though the peak effect score was higher for 400 mg tramadol 

compared to morphine. The larger 24-hour AUC values of morphine 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 of an opiate?" The larger 24-hour AUC for morphine compared to all 

doses oftramadol indicated that subjects were less likely to identify tramadol, 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 

surpassing the 20 mg morphine dose. Overall, this initial single-blind study showed that at the 

higher intravenous dose of 400 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 oftramadol were less effective in producing these effects. In light 

of the high doses oftramadol relative to morphine, required to produce reinforcing effects, 

tramado I has an abuse potential but it is less than that of morphine. 

22 
The second segment of the study utilized a five-treatment, double-blind, single-dose, LatinSquare crossover design in which I 0 non-dependent, opioid experienced subjects received 

tramadol ( l 00 and 200 mg), morphine (l 0 mg and 20 mg) [C-Jl], and placebo, intravenously. 

The original intent to evaluate the 400 mg dose oftramadol was terminated as seizures 

developed in one of the subjects receiving this dose. Measurements of subjective, behavioral, 

and physiological effects were similar to those described above in the initial single-blind 

segment. For the various abuse parameters, the Sponsor plotted effects as a function of time and 

generated 12-hour AUC values. Data analysis included generation of data of maximum 

response, time of maximum response, and time to return to baseline. For the SDRQ questions of 

"Feel the Effect?", "Like the Effect", and "How High Are You", the 12-hour AUC results of 

morphine 20 mg dose clearly were higher than for other treatments. The morphine 10 mg and 

tramadol 200 mg 12-hour AUC scores for these questions were similar, primarily due to the 

longer duration of action oftramadol. Tramadol at a dose of 100 mg consistently scored only 

slightly greater than that of placebo. Across the three questions, the morphine 20 mg and often 

even the morphine l 0 mg doses consistently peaked to a larger extent than did tramado l 200 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 of euphoria, both morphine doses scored higher 

than did tramadol (100 or 200 mg). Also, based on the LSD subscale of the ARC!, tramadol 

produced more dysphoria than did morphine. The overall results of this second segment indicate 

that tramadol at intravenous doses of 100 mg and 200 mg has a low abuse potential, certainly 

lower than that of intravenous morphine [C-ll] at doses of 10 mg and 20 mg. 

A second study submitted after approval of UL TRAM compared the abuse potential of oral 

tramadol to that of oral oxycodone [C-ll] using non-dependent, opioid experienced volunteers. 

Sec published abstract by Jasinski et al. (1993). The study consisted of two segments. The first 

segment was a single-blind escalating dose detcnnination of the highest safo single-dose of 

tramadol in six former addicts. All were required to be able to distinguish oral oxycodonc from 

placebo. Subjects were first given oxycodone 40 mg or placebo. 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 evaluate the subjective effects of each treatment. 

The test was given 15 minutes prior to treatment and at various intervals up to 24 hours posttreatment. Effects were analyzed as a function to time. Questions of primary importance on the 

DRQS were "How much do you feel the drug?", "How much do you like the effects of the 

drug?", "How much do you dislike the drug?", and "How high are you now9" A general 

examination of the time response curves for these questions show that 40 mg oxycodone and 

tramadol, in a dose-dependent manner, produced "liking" and a "high" significantly above that of 

placebo. At a dose 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 superior to the doses oftramadol, 

particularly in the early time 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 of tramadol 

were slower in onset and oflonger duration compared to effects produced by oxycodone. Peak 

effects of oxycodone occurred within a couple of hours, while peak effects oftramadol occurred 

at 5+ hours. 

23 
The second part of the study was a completely randomized double-blind crossover test of 

tramadol (175 mg, 375 mg and 750 mg), oxycodone (20 mg and 40 mg) and placebo. The 

methodology used was similar to that found in the first segment (dose ranging study) of the study 

except that twelve subjects (non-dependent, opioid experienced) were used instead of six. 

Similar results as found in the first segment of the 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 substantially greater than placebo. Tramadol 175 mg produced placebo-like effects. 

For "feel the drug effect", tramadol 750 mg produced a larger response than did oxycodone 20 

mg but slightly less response compared to oxycodone 40 mg. This effect oftramadol was slower 

in onset and longer in duration. Tramadol 750 mg also produced "liking" which was slower in 

onset and of!onger duration than that produced by oxycodone. 

Both segments of the 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 lower relative abuse potential. 

Subjective Reinforcing Effects of Propoxyphene - Dose Dependency Similar to Tramadol 

Tramadol at higher than therapeutic doses produces subjective reinforcing effects similar to or 

approaching those of morphine [C-II] and oxycodone [C-11]. Examination of the 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 l 00 

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 similar to the reinforcing effects produced 

by pentazocine [C-IV] (Fraser and Rosenberg, 1963). At still higher doses, specifically 420 mg 

and 620 mg proproxyphene HCI [C-lV] and 620 mg and 700 mg proproxyphene napsylate [Cl VJ), significant subjective reinforcing effects ofpropoxyphene were comparable to morphine 

[C-1!] or methadone [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 greater than the recommended therapeutic doses. At supratherapeutic doses, 

they each can produce reinforcing effects similar to other controlled substances. 

Conclusions: Subjective Reinforcing Effects as Related to Abuse Potential ofTramadol 

Studies show that tramadol, at single doses above the therapeutically prescribed single doses, 

produces subjective reinforcing effects that are significantly greater than those of placebo and arc 

similar to 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 of experiencing seizures. By contrast, at single therapeutic doses oftramadol, 

subjective reinforcing effects are not generally observed. These results support the placement of 

tramadol in a CSA schedule less restrictive than that of Schedule II. No clinical abuse liability 

studies have been identified that evaluated tramadol's subjective reinforcing effects relative to a 

Schedule lII or IV positive control. However, the dose dependency oftramadol for producing 

subjective reinforcing effects is similar to 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 or methadone. This similarity between 

tramadol and propoxyphene suggests tramadol is appropriate for Schedule JV placement. 

Summary of Relevant Findings and Conclusions for Factor 2 

Tramadol is an opioid. Receptor binding and efficacy studies indicate that tramadol primarily 

acts via its Ml metabolite to interact with the μ-opioid receptor to produce qualitatively a variety 

of pharmacological effects commonly produced by opioids that are listed in Schedules II-IV. 

There tends to be a time delay in the appearance of these effocts, indicating the importance of the 

Ml metabolite in evoking the effects. Generalization to the morphine stimulus cue provides 

additional support indicating that tramadol produces effects similar to 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 which to place tramadol. 

In three intravenous selt:administration studies in Rhesus monkeys, tramadol produced some 

reinforcing effocts, thereby showing qualitatively another similarity to that ofopioids. The 

reinforcing effect oftramadol was limited. No animal self-administration studies utilizing an 

opioid positive control in schedules II, III, IV or V have 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 show that tramadol, at single doses greater than therapeutically prescribed, 

produces subjective reinforcing effects that are significantly greater than those of placebo and arc 

similar to or approach those produced by morphine [C-11] and oxycodone [C-Il], respectively. 

The higher doses may contribute to the seizure risk. Lower doses, 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 similar to those of 

morphine [C-11] and methadone [C-11] at therapeutic doses. This similarity between tramadol 

and propoxyphene provides support for a similar abuse potential and placement oftramadol into 

Schedule IV. 

25 
Factor 3. The State of Current Scientific Knowledge Regarding Tramadol 

Chemistry 

The chemical name of tramadol hydrochloride is(±) cis-2-[(dimethylamino) methyl)-1-(3-

methoxyphenyl)-cyclohexanol hydrochloride. The drug is also known chemically as(±) cis-2-

[(dimethylamino )methyl)-1-(m-methoxyphenyl)-cyclohexanol hydrochloride and as (I RS; 2RS)-

2-(dimcthylamino-methyl)-l-(m-methoxyphenyl)-cyclohcxanol hydrochloride. Tramadol is a 4-

phenyl-piperidine analogue of codeine resulting in chemical similarities to codeine. Tramadol 

has two chiral centers, and the drug is marketed as the (±)-cis racemate. 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 powder that is readily soluble in 

water and ethanol and has a pKa of9.41. The water/n-octanol partition coefficient is 1.35 at pH 

7. 

Pharmacokinctics 

The pharmacokinetics oftramadol was 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 UL TRAM tramadol products. Information 

on the human pharmacokinetics oftramadol taken from the approved labeling (September 9, 

2009) for UL TRAM is provided below. 

The analgesic activity of' UL TRAM® is due to both parent drug and the MI metabolite 

(5ee CUN/CAL PHARMACOLOGY, Pharmacodvnamics). Tramadol is administered as a 

racemate and both the [-J and [+jf(Jrms of'hoth tramadol and Ml are detected in the 

circulation. Linear pharmacokinetics have been observed.following multiple doses of' 50 

and 100 mg to steady-state. 

Absorption 

Racemic tramadol is rapidly and almost completely absorbed afier oral administration. 

The mean absolute bioavailahility ofa JOO mg oral dose is approximately 75%. The 

mean peak plasma concentration of' racemic tramadol and MI occurs at two and three 

hours, respectively, afier administration in healthy adults. Jn general, both enantiomers 

ol tramadof and M 1 follow a parallel time course in the hodyfollowing single and 

multiple doses although small differences (- 10%) exist in the absolute amount of each 

enantiomer present. Steady-state plasma concentrations ofhoth tramadol and MI are 

achieved within two days with four times per day dosing. There is no evidence ofself 

induction. 

Distribution 

The volume of' di.1trihution of tramadol was 2. 6 and 2. 9 liters/kg in male andfemale 

subjects, respectively, fiJ/lov.,ing a 100 mg intravenous dose. The binding of tramadol to 

human plasma proteins is approximately 20% and binding also appears to he 

26 
independent of concentration up to 1 () μglmL. Saturation of plasma protein fanding 

occurs only at concentrations outside the clinical~v relevant range. 

Metabolism 

Tramadol is extensively metabolized afier oral administration. Approximately 30% of"the 

dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as 

metabolites. The remainder is excreted either as unidentified or as unextractable 

metabolites. The major metabolic pathways appear to he N- and 0-demethylation and 

glucuronidation or sulfation in the liver. One metabolite (0-desmethyltramadol, denoted 

M 1) is pharmacologically active in animal models. Formation of M 1 is dependent on 

CYP2D6 and as such is subject to inhibition, which may (lffect the therapeutic response 

(5ee PRE CA UTJONS, Drug Interaction). 

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of 

cytochrome P-45(). These individuals are "poor metaholizers" of dehrisoquine, 

dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population 

PK analysis of"Phase I studies in healthy subjects, concentrations of" tramadol were 

approximately 20% higher in "poor metabolizers" versus "extensive 1netaholizers", H'hile 

M 1 concentrations were 4()% lower. Concomitant therapy with inhibitors ofCYP2D6 

such as.fluoxetine, paroxetine and quinidine could result in significant drug interactions. 

In vitro drug interaction studies in human liver microsomes indicate that inhibitors of 

CYP2D6 such asfluoxetine and its metabolite norfluoxetine. amitriptvline and quinidine 

inhibit the metabolism (Jf tramadol to various degrees. suggesting that concomitant 

administration ol these compounds could result in increases in tramadol concentrations 

and decreased concentrations ofM I. Thefi11! pharmacological impact of these 

alterations in terms of either efficacy or safety is unknown. Concomitant use of 

SEROTONIN re-uptake INHIBITORS and MAO JNHIBJTORS may enhance the risk of 

adverse events, including seizure (.vee WARNINGS) and serotonin syndrome. 

Elimination 

Tramadol is eliminated primarilv through metabolism by the liver and the metabolites 

are eliminated primarily by the kidneys. The mean terminal plasma elimination halflives 

ofracemic tramadol and racemic MI are 6. 3 ± I. 4 and 7. 4 ± 1.4 hours, respectively. The 

plasma elimination halflife ofracemic tramadol increasedfrom approximately six hours 

to seven hours upon multiple dosing. 

Other routes for administering tramadol to 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 of intranasal tramadol administration has not been examined in humans, but 

was recently documented using rats (Zhao et al., 2008). In this study, the phannacokinetics 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 higher than that achieved following oral administration, but less than 

following intravenous administration. The time to reach peak plasma levels following intranasal 

27 
administration was less than that following oral administration. Elimination was also fast 

fo !lowing intranasal application. 

Summary of Relevant Findings and Conclusions for Factor 3. 

The chemical structures oftramadol and the Ml metabolite share similarities with the chemical 

structure of the opioid, codeine [C-ll, C-IIJ and C-V for products]. This similarity is consistent 

with the findings of pharmacology studies that demonstrate the 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, with both enantiomers as well 

as the M 1 metabolite found in the blood following administration. Tramadol is also readily 

absorbed via subcutaneous, intramuscular and rectal routes of administration. One study, 

conducted in rats, suggests that nasal application may be a very effective means of administering 

tramadol resulting in rapid plasma levels oftramadol. 

Tramadol undergoes extensive metabolism to a number of metabolites including the Ml 

metabolite which is primarily responsible for the opioid activity oftramadol. This extensive 

metabolism, in part, provides for possible interactions between tramadol and a variety of other 

drugs that undergo metabolism by the CPY2D6 enzyme. 

Factor 4. Tramadol's History and Current Pattern of Abuse 

FDA approved UL TRAM, tramadol immediate-release oral tablets, in 1995 for the treatment of 

moderate to moderately severe pain. Since that time, a variety of other tramadol products 

including immediate release products, combination products and extended release products have 

been approved for marketing in the United States. A detailed regulatory history oftramadol is 

provided under the "Background" section of the Introduction. 

Since 1995, new data has been collected regarding the pharmacology, safety, diversion and 

misuse and abuse oftramadol. These data are discussed under various Factors including Factors 

I, 2, 4, 5, 6 and 7. Abuse data from epidemiological databases is specifically discussed below 

(Factor 4). 

History and Current Patterns ofTramadol Abuse. 

Epidemiological Databases 

In order to assess the significance of abuse oftramadol, data from the Drug Abuse Warning 

Network (DAWN), the National Survey of Drug Use and Health (NS DUH), and Annual Reports 

of the American Association of Poison Control Centers' National Poison Data System are 

compiled along with law enforcement data from the National Forensic Laboratory Information 

System (NFLIS). Detailed information on these databases, as well as on annual prescription data 

(SDI), are provided below. Collectively, these data support placement oftramadol into Schedule 

IV. 

28 
Prescription Data Regarding Tramadol 

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 of annual prescriptions dispensed over the period of2003 to 2008. In 2007 

and 2008, more prescriptions were written for tramadol than for any other opioid other than 

hydrocodone [C-IIIJ and oxycodone [C-IJJ. The annual number of prescriptions for tramadol 

surpassed the annual number of prescriptions ofproproxyphene [C-IVJ and codeine (C-11, Ill, VJ 

in 2007 and 2008. 

Table 3. Annual Number of Retail Prescriptions for Opioid Analgesics for 2003 to 2008. 

(Source: SDI) 

Drug" Number of Prescriptions 

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 

H vdromorphonc 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 of methadone for treatinent of 

opioid addiction in drug abuse treatment clinics. 2 Buprenorphine is primarily prescribed and dispensed for treatment of opioid 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 tramado 1 over the 

period of2003 to 2008, there was a consistent reduction in annual prescriptions for 

proproxyphene [C-IV], butorphanol [C-IVJ and pentazocine [C-IVJ over the same period. 

Whereas there was a slight rise in the number of prescriptions in 2008, there has been a 

consistent reduction in annual prescriptions for codeine (C-11, III, VJ over the period from 2003 

to 2007. Over each of the five years, there has been a consistent multi-fold greater number of 

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 Warning Network (DAWN) 

The Drug Abuse Warning Network (DAWN) is a public health surveillance system that monitors 

drug-related visits to hospital emergency departments (ED) and drug-related deaths reported to 

DAWN by participating medical examiners and coroners to track the impact of drug 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 the beginning of2003. These changes were the result of 

a redesign that, among other changes, altered most of DA WN's core features, including the 

design of the hospital sample and the cases eligible for DAWN. These changes resulted in a 

permanent disruption in trends for the time period prior to 2003. As a result, 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 year between the two DAWN systems. Below arc data on 

tramadol and other opioids 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 from 45 (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, or an csti1nate v.·ith an RSE greater 

than 50o/r) has hcen suppressed. 

DAWN (2003 - 2008) 

DAWN is currently designed 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-counter phannaceuticals, dietary supplements, nonpharmaceutical inhalants, alcohol 

when it is combined with another drug and, for patients under age 21, ED visits where alcohol is 

30 
the only substance. Measures provided by DAWN ofnonmedical use ofa particular drug 

resulting in a drug-related ED visit involve at least one of the following: 

1) Taking more than the prescribed dose of a prescription pharmaceutical 

2) Taking more than the recommended dose of an OTC pharmaceutical supplement 

3) Taking a pharmaceutical prescribed for another individual 

4) Deliberate poisoning with a pharmaceutical by another person: or 

5) Documented misuse or abuse of a prescription or OTC pharmaceutical or dietary 

supplement. Nonmedical use of pharmaceuticals may involve pharmaceuticals 

alone or pharmaceuticals in combination with illicit drugs or alcohol. 

National estimated annual ED visits for the period of2004 through 2008 resulting from the 

nonmedical use oftramadol and other opioids, including their combination products, are 

provided in Table 5. Over this period, the number of estimated ED visits from nonmedical use 

oftramadol/combinations showed a continuous increase from approximately 4,800 ED visits to 

over 11,800 ED 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 of the 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 over the period of2004 through 2008, the national estimated 

annual ED visits oftramadol/combinations were more closely in the range of those 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 of ED visits in 2008 compared to in 2007. In 2008, the annual ED visits for 

tramadol/combinations ( 11,850) was somewhat higher than that of codeine/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 of Selected Opioids for 2004 

Through 2008. (Source: SAMHSA, Office of Applied 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; 4

Schedulc IV; 5Not Scheduled 

31 
The rates of estimated nonmedical ED visits docwnented in DAWN per 100,000 prescriptions 

dispensed for tramadol/combinations as well as other selected opioids are shown in Table 6. 

Over the period of2004 through 2007, the annual rates oftramadol/combination ED visits 

ranged between 28.4 and 33.9. In 2008, there was a substantial increase in rate of ED visits of 

tramadol/combinations to 45.8 ED visits per 100,000 prescriptions. Over the five year period 

(2004-2008), annual rates oftramadol ED visits were substantially below that of rates 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 of2004 through 2008, the rates of estimated nonmedical ED visits for 

tramadol/combinations, were more closely in the range for the rates of codeine/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 of ED visits in 2008 compared to 2007. In 2008, the rate of nonmedical 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 100,000 prescriptions). 

Table 6. Rates of DAWN Estimated Annual Nonmedical ED Visits for Selected Opioids for 

2004 Through 2008. Rates Calculated as Estimated Annual Number of ED Visits Per 100,000 

Prescriptions. (Source: DAWN data is from SAMSHA, Office of Applied Studies. Prescription 

data comes from SDI and is found in Table 3 in Factor 4) 

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 1 I 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 

32 
For 2007 and 2008, with respect to nonmedical ED visits involving tramadol/combinations alone 

(in the absence of other drugs present), 1,819 and 788, respectively, resulted from 

"overmedication" while 1,476 and 2,016, respectively, of visits were placed under the category 

of"other." By design, it is the "others" category that captures most of the documented drug 

abuse cases. 

Approximately 54 % of the visits for tramadol involved women. Nonmedical ED visits for 

tramadol involved individuals across a wide range of age groups. Of the total ED visits (11,850), 

21.4 %, 21. 7 %, 26.4 % , and 16.3 % of the visits involved individuals in the age ranges of 18 to 

20, 21 to 29, 30 to 44, and 45 to 64, respectively. 

In summary, examination of the DAWN data indicates that abuse related and nonmedical use of 

tramado 1 products result in ED visits. The DAWN data prior to 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 data documents ED visits resulting from the 

nonmedical use oftramadol that include, but are not limited to, ED visits resulting from abuse of 

tramadol. Both the national estimates ofnonmedical related ED visits and the rates of 

nonmedical ED visits calculated based on 100,000 prescriptions are lower for 

tramadol/combinations compared to a number of the Schedule II opioids. This is also true when 

tramadol/combinations is compared to the Schedule III drug. buprenorphine, and to hydrocodone 

combinations. With respect to both national estimates ofnonmcdically related ED visits and to 

rates of these 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 

of Schedule II and Ill substances and products most similar to that ofpropoxyphene (Schedule 

IV). 

National Survey on Drug Use and Health (NSDUH) 

The National Survey on Drug Use and Health (NS DUH), operated by SAMHSA, provides 

information on the nonmedical use of drugs in the general United States population age 12 and 

older. Yearly national and state level estimates of alcohol, tobacco, illicit drug, as well as forthe 

nonmedical use of prescription drugs, are obtained. 

The NSDUH provides annual estimates on the lifetime nonmedical use of pain relievers. FDA 

has received from SAMHSA for each of the years from 2002 through 2007 specific estimates of 

lifetime nonmedical use ofhydrocodone products [C-lll], oxycodone products [C-IIJ, and 

tramadol products. As used in the NS DUH, lifetime nonmedical use of any pain reliever by an 

individual means any use ever, even once, of a pain reliever that was not prescribed to an 

individual or that the individual took only for the experience or feeling that the pain reliever 

caused. 

As seen from Table 7, the number of individuals who used tramadol products nonmedically at 

least once in their lifetime increased from approximately 994,000 in 2002 to 1,559,000 in 2007. 

For each year surveyed, the absolute number of individuals reporting lifetime nonmedical use of 

tramadol was lower than that of individuals reporting lifetime nonmedical use ofhydrocodone 

33 
products [C-III] or oxycodone products [C-Il]. For example, in 2007 the estimated number of 

individuals reporting lifetime nonmedical use ofhydrocodone products [C-lll] and oxycodone 

products [C-Il] were 21,335,000 and 13,055,000, respectively, compared to 1,559,000 estimated 

individuals having reported lifetime nonmedical use oftrarnadol products. 

Table 7. Estimated Lifetime Nonmedical Use of Selected Pain Relievers, Age 12 and Older. 

(Source: SAMS HA, Office of Applied 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 

Oxycodone Products' I 0, 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 

2

Includes Percocet®, Percodan® or Tylox®, and OxyContin® in Schedule II 

'Includes Iramadol and UL TRAM® 

20,755 

12,858 

1,352 

2007 

21,335 

13,055 

1,559 

The NS DUH also provided data on the number of individuals who reported 1) initiation of the 

use of any pain reliever within the past year and 2) nonrnedical use of either hydrocodone 

products [C-111], oxycodone products [C-Il], ortramadol products within the same period (one 

year). The data is presented in Table 8 below. For each of the years over the period of2002 to 

2007, the estimated number of individuals who initiated use of pain relievers and reported 

nonmcdical use oftramadol was less than 100,000 (with the highest at 95,000 in 2003 and the 

lowest at 22,000 in 2006). By contrast, for each of the years 2002 to 2007, the number of past 

year initiates for use of any pain reliever who also used hydrocodonc products(> 1,200,000) and 

oxycodone products(> 450,000) nonmedically was greater than for the nonmcdical use of 

tramadol 

Table 8. Past YearNonmedical Use of Selected Pain Relievers According to Past Year Initiates 

of Any Pain Reliever, Age 12 and Older. (Source: SAMS HA, Office of Applied Studies, 2002-

2007 National Survey on 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. 

2

illcludes Percocet®, Percodan® or Tylox®, and OxyContin® 

'Includes tramadol and UL TRAM® 

1,314 1,315 

455 546 

46 22 

2007 

1,285 

592 

57 

In summary, the NSDUH data indicate that there is nonmedical use oftramadol and that such use 

is on the rise. Both lifetime nonmedical use as well as nonmedical use over the past year, that is 

the last 12 months since the date that 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 

34 
tramadol 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 Laboratory Information System (NFLIS) is a program of the Drug 

Enforcement Administration (DEA), Office of Diversion 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 quantity of drug (controlled or noncontrolled) seized in the course oflaw enforcement activity 

and subsequently sent to and analyzed by a state or local forensic laboratory. For each exhibit, a 

variety of related information is provided, including time and date of drug seizure, location of 

drug seizure and identification ofindividual(s) who possessed the exhibit when it was seized. 

Analyzed exhibits may be 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 Control website. 

The NFLIS expands each year with recruitment of additional state and local laboratories. 

According to the 2007 NFLIS Annual Report, as of April 2008 NFLIS includes 45 state 

laboratory systems, 95 local or municipal laboratories and one territorial laboratory, representing 

276 individual laboratories and handling over 88% of the nation's annual state and local drug 

analysis cases. According to the 2001 NFLIS Annual Report, there were only 32 state laboratory 

systems and 45 local laboratories, representing 174 individual laboratories participating in 

NFLIS. As a result of this growth, data provided in NFLIS cannot be trended over the years. 

However, NFLIS may be useful in demonstrating that a substance has been encountered by law 

enforcement laboratories and the number of such 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. 

35 
Table 9. Number of Exhibits in NFLIS ofTramadol and Other Opioids Analyzed by State and 

Local Laboratories Annually from 2000-2007. (Source: NFLIS Annual Reports found at 

ww_w,deag ivers ion. usdo j. gov Intl is/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 

Ox ymorphone· 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 other selected opioids. Tramadol is the only 

drug listed that is not controlled in the CSA. In 2008, the tramadol-containing exhibits were 

close in number to that of exhibits for proproxyphene [C-IV]. For each year, the number of 

tramadol exhibits was less than the number of exhibits of the Schedule II substances, oxycodone, 

methadone, morphine and hydromorphone, and hydrocodone [C-III] and codeine [C-II, Ill, VJ. 

For the years 2006 - 2008, the number oftramadol exhibits was less than the number of exhibits 

ofbuprenorphinc [C-III] seized. 

Further examination of Table 9 shows that for most years, the number oftramadol exhibits 

exceeded that of exhibits for the Schedule II drugs, meperidine, oxymorphone and fentanyl and 

for the Schedule IV drugs pentazocine and butorphanol. The higher numbers oftramadol 

exhibits may reflect the more limited availability of these 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 

probable that the numbers oftramadol exhibits analyzed by the state and local laboratories and 

documented in NFLIS is considerably lower than the actual number of exhibits involving 

tramadol submitted to state and local laboratories. As noted by the DEA, while tramadol is 

seized during law enforcement action, tablets may not be analyzed if identified as being an 

uncontrolled pharmaceutical product. It should also be noted that the NFLIS system may 

underreport the diversion of such drugs as the schedule IV drugs butorphanol, pentazocine, 

proproxyphene, and codeine products [C-11-V]. Being in lower schedules, these drugs may 

receive lower priority with respect to law enforcement investigations, as well as with respect to 

36 
submission and analysis in the forensic laboratory of exhibits suspected of containing these 

drugs. 

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

Poison Control Center data demonstrate that from 2004 through 2008, the number of human 

poison exposures to tramadol increased annually. This data indicates tramadol represents a 

growing risk to the public. 

Data on cases of human poison exposure to tramadol and other opioid analgesics were collected 

from the Annual Reports of the 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 by 61 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 a human exposure to a substance. All cases were closed, meaning that the 

Poison Control Center reporting the case determined that no further information is available or 

no further follow-up recommendations will be made. Calls only requesting information, 

including drug identification, were not included. 

The annual number of poison exposure cases oftramadol and other opioids for the period 2004 

to 2008 is provided in Table 10. Over the period of2004 to 2008, the annual number of case 

mentions for tramadol continuously increased from 3,769 to 9,623, though remaining less than 

the case mentions ofhydrocodone combination products [C-III] or oxycodone products [C-ll]. 

In 2007 tramadol ranked third behind hydrocodone combination products and oxycodonc 

products, in terms of number of opioid case mentions. When looked at in terms of rates, the 

number of case mentions per I 00,000 prescriptions for tramadol increased from 22 in 2004 to 37 

in 2008. Over the period of2004 through 2007, the poison control center rates oftramadol case 

mentions were higher than 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 of oxycodone [C-II] case mentions but was less than the rate of case 

mentions for methadone [C-II] and morphine [C-11]. For the 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 of case 

mentions and rates of case mentions. 

37 
Table 10. Number of Case Mentions (Exposures) to Selected Opioids Reported in the Annual 

Reports of the American Association of Poison Control Centers (AAPCC) Toxic Exposure 

Surveillance System (NPDS) for 2004 - 2008. (These reports are available at 

www.aapcc.org/DNN/.) 

Drug Total No. of Case Mentions' 

(No. of Case 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, l 65 (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. Does not include calls JUSt for 1nformat1on. 

2

Ratcs were determined using annual retail prescription data provided by SDI and tabulated in Table 3. 

·~('onsists ofhydrocodonc combination products in Schedule III. 4

Schedule II 5

Schedules II. III. Y. In 2005, 71 °/o of cases involved codeine in combination with acetaminophen or aspirin, 

suggesting Schedule III or V control. In 2004, 2006 and 2007, there were 82o/o, 81°;{i and 84?;;) of cases 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" exposure to tramadol alone. These cases included suicides, 

intentional misuse, intentional abuse and unknown. The specific breakdown of the number of 

cases under each of these four categories was not provided. Intentional misuse is defined as 

exposure resulting from the intentional improper or incorrect use of a substance for reasons other 

than the pursuit of a psychotropic or euphoric effect. Intentional abuse was drug exposure 

resulting from the intentional improper or incorrect use of a substance where the victim was 

likely attempting to achieve a euphoric or psychotroplic effect. Although specific case numbers 

are not provided this data suggest that at least some of the case mentions documented by the 

AAPCC database involved poison episodes due to the intentional abuse or misuse oftramadol 

alone. 

Summary of Relevant Findings and Conclusions of Factor 4 

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

progressive increase in the availability oftramadol containing products. In 2007, more than 23.7 

million prescriptions were issued for tramado 1 products. 

Data from DAWN indicates that the nonmedical use, including abuse, oftramadol is associated 

with visits to the emergency department. 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 of estimated annual nonmedical ED visits per I 00,000 prescriptions resulting from 

nonmedical use, including abuse, oftramadol is in the same range as that for proproxyphene 

products [C-IV]; greater than that for meperidine products [C-11]; and lower than that for 

buprenorphine products [C-III] (2006 and 2007 only), hydrocodone combination products [CIII], and a number of Schedule II opioid products. 

Overall, the annual data from the NSDUH for the period of2002 through 2007 indicates that a 

smaller number of individuals reported using tramadol products nonmedically compared to the 

number of individuals reporting nonmcdical use ofC-III or C-11 opioid products. This includes 

data for estimated lifetime nonmedical use or for past-year nonmedical use by past year initiates 

of any pain reliever. 

Poison Control Center data show that from 2004 to 2008, tramadol exposure cases reported have 

increased substantially. The reporting rate for tramadol (number of case mentions per 100,000 

prescriptions) increased to a greater extent than other opioids, from 22 in 2004 to 37 in 2008. 

From 2004 through 2007, the rates (per 100,000 prescriptions) oftramadol case mentions was 

higher than for hydrocodone combination products [C-Ill] but lower than for oxycodone [C-11], 

morphine [C-II] and methadone [C-ll) products. For the years 2004 through 2006, the rates of 

tramadol case mentions were similar to the rates ofpropoxyphene case mentions. In 2007, the 

rate oftramadol case mentions was similar to codeine [C-ll, Ill, VJ and a little greater than 

propoxyphene [C-IV). Jn 2008, the rate oftramadol case mentions was equal to that of the rate 

of case mentions for oxycodone and surpassed that of the rates of case mentions for either 

codeine or propoxyphene case mentions. 

Data obtained from DAWN, NS DUH, NFLIS and the AAPCC database collectively demonstrate 

the misuse, abuse, and diversion oftramadol. The data are comparable to other substances 

(opioids) controlled in the CSA. With respect to both the rates ofnonmedical ED visits found in 

DAWN and the number of law enforcement encounters found in NFLIS, and the increasing rates 

of poison control center reporting, particularly over the period of2004 to 2007, tramadol data 

most closely resembles that ofpropoxyphene [C-IV). Data from the NSDUH also support a 

schedule less than that of Schedule III. 

Factor 5. The Scope, Duration, and Significance of Abuse of Tramadol 

An assessment of the scope, duration, and significance oftramadol abuse is made by 

examination of databases that document abuse, as described in Factor 4, review of studies of 

abuse potential that are documented in Factor 2, and consideration of the case reports described 

below (Factor 5). Preclinical studies that demonstrate positive reinforcing and discriminative 

stimulus effects oftramadol similar to 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 of post-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 of a patient's drug-seeking behavior, as 

evidenced by its nonmedical use and reports of withdrawal symptoms when the drug is 

suddenly withdrawn. Withdrawal symptoms of tramadol are typical of opioids. 

Approximately I 5 years of post-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 of other 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 of the CSA. 

Case Reports from The Medical Literature 

Case reports in the medical literature provide information on patterns of abuse oftramadol when 

prescribed for treatment of pain. The case reports describe abuse oftramadol for its 

euphorigenic and sedating etfocts. Development of iatrogenic addiction to tramadol is also 

described. 

Ehrcnreich and Poser ( 1993) reported the case of a 39-year-old female nurse who was urged by 

her superiors at work to enter the psychiatric clinic for treatment oftramadol dependence. At the 

time of intiating treatment, she was using tramadol for more than 6 years. Urinalyses suggested 

that she did not use other drugs. The patient initially received treatment with tramadol for a 

toothache. She learned to appreciate the feeling of well-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 trauma ward 

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 stop tramadol 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, I 07, 515, and 326 tramadol abuse calls in 

1995, 1996, 1997 and 1998, respectively. The Cincinnati police documented diversion of7,258 

doses oftramadol from September 1997 to December 1997 and 11,385 doses in 1998. Tramadol 

was listed in both the Cincinnati Police top I 0 diverted prescription drugs and the DPIC top 20 

prescription drugs abused lists for 1997. Reasons for abuse included: prevention of withdrawal 

40 
from other opioids when unable to get the narcotic of choice, easier availability due to lack of 

control status, and exclusion from urinalysis screening for drugs of abuse. 

Bozic et al. (1999) reported seizures associated with tramadol abuse occurring in 17 nonepileptic adolescents. General tonic-clonic seizures were associated with high doses of single (at 

least 250 mg) or repeated tramadol intake. The authors noted that tramadol was a popular 

substance of abuse among adolescents and was associated with significant neurologic and 

hepatic toxicity in overdoses. About 20-30% of subjects use tramadol alone and 70% use it in 

combination with beer, cannabis, or glue. 

Leo et al. (2000) described the case ofa 46-year old woman who became addicted to tramadol 

after being prescribed the drug for severe pain from an orthopedic problem. She started 

increasing tramadol doses above that prescribed. In order to maintain her supply oftramadol, the 

woman made visits to the local hospital emergency room and various doctors' offices. Her use 

oftramadol continued after the orthopedic problem was corrected. Prior to presentation at a 

detoxification unit, she admitted to taking 30 (50 mg) tramadol tablets per day. Initially, 

tramadol abuse was associated with feelings of mild 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 of a 35-year old male with a history of intravenous heroin 

abuse and bromazepam and alcohol abuse. After being initially prescribed tramadol at a dose of 

300 mg per day, he soon escalated the dose to about 600 mg daily to experience feelings of well 

being and decreased heroin craving. At the time of detoxification, he was taking tramadol at 

daily doses ranging from 100 to 1,000 mg per day. 

Yates et al. (2001) describe the case of a 29-year-old woman who became addicted to tramadol 

while receiving the drug for a medical condition. Initially, she took the prescribed dose of one 

50 mg tablet every 4 to 6 hours. Gradually, she increased the dose such that after 3 years she 

was taking about 30 50-mg tablets 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., a bruised face). 

Reeves and Liberto (2001) describe the case ofa 28-year old woman who was abusing tramadol 

in combination with carisoprodol. The woman had a history of alcohol and benzodiazepine 

abuse. She was prescribed carisoprodol for treatment ofparavertebral muscle spasms. She said 

that two friends with histories of narcotic abuse introduced her to the combination of 

carisoprodol and tramadol. She subsequently began on her own initiative to take larger doses of 

carisoprodol and eventually requested tramadol from her doctor to treat headaches. When she 

was confronted with her misuse of carisoprodol, she admitted that she was seeing different 

physicians to obtain carisoprodol and tramadol. She took the medications together (one or two 

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 1 male-to-female transsexual) with physical dependence to 

tramadol were admitted to the addiction ward of the psychiatric hospital of the University of 

Munich. Two of the pain patients had a history of alcohol abuse and two other patients had drug 

abuse histories. Mean daily tramadol dosage was 745 mg with the maximum being 2.5 grams. 

The average length oftramadol consumption was 4.9 years ranging from 3 months to 15 years. 

Seventeen of the 20 patients had initially received tramadol for chronic nonmalignant pain. Nine 

of the patients had experienced seizures prior to admission. The authors noted that it was 

difficult to treat these patients. Twelve of the 20 patients (60%) left the hospital before 

completion of detoxification against medical advice despite gradual tapering of medication and 

concomitant psychopharmacological and psychotherapeutic treatment. The authors concluded 

that abuse or dependence to opioid analgesics such as tramadol may be more frequent than 

previously thought in chronic nonmalignant pain and not exclusively limited to patients with 

alcohol or polysubstance 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 she obtained enough tramadol to take up to 1200 mg per day. Use of 

tramado I continued 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 1500 mg/day. She continued abuse oftramadol despite 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 after her husband discovered $7,000.00 in Internet 

pharmacy charges for tramadol on his credit card statement. 

Stoehr ct al. (2009) described two cases of abuse and dependence to tramadol. The first case 

involved a 38-year-old male physician who entered addiction treatment for dependence to 

tramadol. Four years earlier, he first started using tramadol daily for headaches. He used 

hydrocodone and oxycodone preparations intermittently but preferred tramadol because of the 

euphoria and increased energy level he experienced after taking the drug. The physician 

obtained tramadol via drug samples and Internet purchases. He attempted to stop tramadol 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 of his addiction, the physician was taking 27 tablets (50 

mg per tablet) oftramadol daily. He completed 6 weeks of inpatient 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 of presentation, she admitted to using tramadol 300 

mg five to six times daily for the past 3 months. She purchased tramadol from Mexico. She 

42 
expressed a desire to stop taking tramadol but could not do so without assistance. When 

attempting to stop tramado 1 use she experienced rhinorrhea, sweats, myoclonic twitching, and 

anxiety. The woman had a 30-year history of intermittent substance abuse including abuse of i. 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 counselor for assistance on her abuse; she 

was encouraged to participate in 12-step meetings (i.e., Pills Anonymous). 

Summary of Case Reports of Abuse and Dependence. 

The above described published case reports provide information on characteristics and patterns 

oftramadol abuse with the development of dependence. Abuse is primarily by the oral route. 

Escalation oftramadol dosing is observed resulting in the use of very high doses oftramadol, 

well outside of appropriate and recommended clinical dosing regimens and in the absence of 

medical supervision. Seeking the effects of euphoria, well-being and increased energy, as well 

as preventing the experience of withdrawal symptoms are reasons given for taking tramadol. In 

order to obtain sufficient supplies oftramadol, individuals may doctor-shop (approach multiple 

doctors for prescriptions), make multiple visits to the emergency room, purchase tramadol over 

the Internet, or purchase tramadol in Mexico. 

The above cases provide documentation of the actual abuse oftramadol. In these cases, abuse is 

via the oral route of administration. Currently, marketed tramado 1 products 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 of abusing prescription opioids (Havens et al., 2007; Recs 

Davis and Johnson, 2008; Butler et al., 2008). 

Study oflmpaired Health Professionals 

Impaired health care professionals (N = 1,601) who were participants in treatment programs in 

four states were recruited for a study to detennine the incidence oftramadol abuse (Knisely ct 

al., 2002). Impaired health professionals in treatment programs were selected because they 

comprise a high risk and accessible population for drug abuse. In addition, they were considered 

to be highly knowledgeable about a drug's pharmacology and the relative ease of availability of 

noncontrolled versus controlled substances. Individuals not selected included those with an 

abuse history or preference for tramadol. Most of the individuals who turned out to be abusers of 

tramadol had previous histories of opioid 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) of the impaired health care professionals in the study 

had at least one urine sample that was positive for tramadol. 

2. Eighty-seven of the 140 trarnadol-exposed population (62.1 percent) did not have a 

legitimate prescription and experimented with the drug. 

43 
3. Twenty-four subjects (1.5 percent of total sample; 14.9 percent oftramadol-exposcd 

population) met study criteria defined as "extensive experimentation." 

4. Of the 24 "extensive experimenters," 15 met criteria for abuse/dependence, that is, they 

found tramadol to be superior to other drugs they had abused, or they felt that it was a 

drug that could easily avoid detection because it was not scheduled in the CSA. 

5. When tramadol was abused, it was typically taken without other drugs of abuse. 

6. By way of comparison, hydrocodone-containing products (C-III) (calculated N = 196) 

was the most abused opiate by this population. 

Potential Routes of Administration for Purposes of Abuse 

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 hydrochloride has the potential for abuse by a number of routes of administration, 

including oral, intranasal and rectal, as well as by intravenous, intramuscular or 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 by these various routes of administration. Studies show that prescription 

opioids are abused by a number of routes of administration 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 of nonmedical ED visits from 2004 ( 4,849 

visits) through 2008. With normalization of the visits per 100,000 prescriptions dispensed, the 

rate of nonmedical ED visits for tramadol is similar to that of codeine/combinations (Schedule Il, 

lll, IV) and proproxyphene/combinations (Schedule IV). The rate of nonmedical ED visits for 

tramadol was lower than the rates of ED visits for hydrocodone/combinations (Schedule III), 

buprenorphine (Schedule III) and a number of Schedule II opioids either alone or in combination 

products. For 2007 and 2008, 1,819 and 788, respectively, ofnonmedical ED visits involving 

tramadoVcombinations alone (in the absence of other drugs present) were categorized as 

"overmedication",2 while 1,476 and 2,016, respectively, oftramadol combination visits were 

categorized as "other." By design of DAWN, the "others"2 category captures most of the 

documented drug abuse cases. Approximately 54 % of the visits for tramadol involved women. 

Of the total nonmedical ED visits (11,850) in 2008, 21.4 %, 21. 7 %, 26.4 % and 16.3 % of the 

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 Factor 4 for a more detailed description of DAWN data. 

National Survey of Drug Use and Health (NSDUH) 

The NSDUH, discussed in detail in Factor 4, also provides evidence of the nonmcdical use of 

tramadol products. In 2007, an estimated 1,559,000 individuals used tramadol products 

nonmedically during their lifetime. Such use is defined in the survey as any use ever, even once, 

44 
oftramadol products that were not prescribed to the individual or that the individual took only 

for the experience or feeling that the tramadol product(s) caused. As can be seen from Table 7 in 

Factor 4, the absolute estimated number oflifetime nonmedical users oftramadol for 2007 was 

less than that of oxycodone 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. 

Summary of Relevant Findings and Conclusions of Factor 5 

Case reports from the medical literature provide information on patterns oftramadol abuse. 

The physicochemical properties oftramadol, as well as the available pharmacokinetic data on 

tramadol suggest that tramadol has the potential for abuse by a variety of routes 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. For NSDUH data for each year from 2002-2007, the number of 

individuals reporting either lifetime nonmedical use or past-year nonmedical use oftramadol was 

lower than the number of individuals reporting lifetime or past-year nonmedical use of 

hydrocodonc products (C-III) or oxycodone products (C-II), thereby suggesting an abuse 

potential less than that of Schedule III . Overall, the data provided in Factor 5 supports the 

scheduling oftramadol and is consistent with Schedule IV control. 

Factor 6. What, If Any, Risk to the Public Health 

The information collected from a variety of sources shows that there is a risk to public health 

associated with use and abuse oftramadol. Tramadol produces adverse effects similar to those 

of other opioids. In addition, it is associated with seizure formation, serotonin syndrome, and 

drug interactions. N onmedical use of tramado 1 is associated with emergency room visits. Over 

the last four years, there has been a substantial increase in the number of exposure cases reported 

by Poison Control Centers in the United States. Data from several sources show that tramadol is 

associated with deaths. 

In order to assess the risk to the public health associated with tramadol, a number of information 

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 

examiner reports; 4) data from the American Association of Poison Control Centers; and 5) data 

from drug-related death reports from the Florida Medical Examiner's Office. 

Adverse Effects - Information Documented in Labeling for UL TRAM 

Adverse effects associated with the use oftramadol are documented in the label approved 

September 9, 2009 for UL TRAM. Adverse effects occurring with tramadol are consistent with 

adverse effects associated with other opioids. 

45 
Table 11. Cumulative Incidence of Adverse Reactions for UTRAM in Chronic Trials of 

Nonmalignant Pain (N=427). (Source: Label approved September 9, 2009, for UL TRAM) 

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 incidence rate of the most frequent adverse reactions (5% or 

more by 7 days) reported following 7, 30, and 90 days of treatment with UL TRAM. This data 

was generated during double-blind or open-label extension periods in U.S. studies looking at the 

use ofULTRAM for treating chronic nonmalignant pain in a total of 550 patients. Some of the 

most frequently reported adverse effects included dizziness, nausea, constipation, headache, and 

vomiting, all of which are also seen with use of other opioids. Evident in Table 11 is the 

increased incidence ofreported adverse effocts as time of therapy increases. The overall 

incidence rates of adverse effects in the trials were similar for UL TRAM 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]. 

Seizures Associated with Tramadol 

According to the UL TRAM labeling, approved September 9, 2009: 

Seizures have been reported in patients receiving UL TRAM tt·ithin the 

recommended dosage range. Spontaneous postmarketing reports indicate 

that seizure risk is increased with doses of ULTRAM above the recommended 

range. Concomitant use of UL TRAM increases the seizure risk in patients 

taking: selective serotonin reuptake inhibitors (SSR! antidepressants or 

anorectic1), tricyclic antidepressants (TCAs), and other tricyclic 

compound1· (e.g. cyclobenzaprine, promethazine, etc.), or other opioid., 

Administration of ULTRAM may enhance the seizure risk in patients taking: 

MA 0 inhibitors, neuroleptics, or other drugs that may reduce the seiwre threshold.. 

Risk of convulsions may also increase in patients with epilepsy. those ttith a 

hist01y ofseizures, or in patients with a recognized risk for seizure (.rnch 

46 
as head trauma, metabolic disorders, alcohol and drug withdrawal and CNS 

infections}. In ULTRAM overdose, naloxone administration may increase risk 

of seizure. 

Serotonin Syndrome 

According to label approved September 9, 2009, for UL TRAM: 

The development ofa potentially life-threatening serotonin syndrome may occur with the 

use oftramadol products, including ULTRAM, particularly ·with concomitant use of 

serotonergic drugs such as SSRls, SNRls, TCAs, MAO/s, and triptans, with drugs ·which 

impair metabolism !!{serotonin (including MAOls}, and with drugs which impair 

metabolism of tramadol (CYP2D6 and CPY3A4 inhibitors). This may occur 11ithin the 

recommended dose (.1·ee CLINICAL PHARMACOLOGY, Pharmacokinetics). 

Serotonin .1yndrome may include mental-status changes (e.g., agitation, hallucinations, 

coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), 

neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal 

symptoms (e.g., nausea, vomiting. diarrhea). 

Tramadol has been associated with numerous case reports in the scientific and medical literature 

involving the generation of the serotonin syndrome. The vast majority of these cases involved 

tramadol administered concomitantly with other drugs that interact with the serotonergic system. 

(Adverse Drug Reactions Advisory Committee, 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 UL TRAM: 

Administer UL TRAM cautiously in patients at risk.fin· respiratory depression. 

In these patients alternative non-opioid analgesics should he considered. When 

large doses of ULTRAM are administered with anesthetic medications or 

alcohol, respiratory depression may result. Respiratory depression should he 

treated as an overdose. 

Overdose 

The UL TRAM label approved September 9, 2009, notes the following with regard to overdose 

with tramado 1: 

47 
A cute overdosage >eith tramadol can be manifested hy respiratory depression, 

somnolence progressing to stupor or coma, skeletal muscle.flaccidity, cold and 

clamm_v skin. constricted pupils, seizures, hradvcardia, hypotension, cardiac 

arrest, and death. 

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., l 997). In a prospective study of 

tramadol toxicity from seven U.S. poison centers, 126 cases of overdose involving tramadol 

single entity were reported between October 1995 and August 1996. individuals' ages ranged 

from 1 to 86 years, with a mean and median of26.8 and 25 years, respectively. There were 10 

overdose cases in children 6 years of age or younger. 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 much toxicity of 

tramadol appears to be attributable to the MAO uptake inhibition. Agitation, tachycardia, 

confusion, and hypertension suggested a possible mild serotonin syndrome. This study found 

significant neurologic toxicity, without serious cardiovascular toxicity (Spiller et al., 1997) 

DAWN Data 

DAWN data arc discussed in depth under Factor 4. The DAWN data show that the nonmedical 

use oftramadol, as well as other opioids, leads to emergency department (ED) visits. Rates of 

ED visits, expressed per 100,000 prescriptions, for tramadol have been similar to that of 

propoxyphcne [C-IV] but lower than that of Schedule II and III opioids. The DAWN data 

demonstrate a risk to the public health associated with the nonmedical use oftramadol that is 

similar to that ofpropoxyphene [C-IV]. See Factor 4 for a more detailed description of DAWN 

data. 

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

Data from the American Association of Poison Control Center's National Poison Data System 

(NPDS) shows that over the period of2004 to 2008, there was an increasing public health risk 

associated with tramadol. The data are discussed in detail under Factor 4. Over the period from 

2004 to 2008, annual poison case mentions of actual 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 of the number of poison case mentions of 

opioids. Over this period, the rates of case mentions per 100,000 prescriptions for tramadol 

increased from 22 to 37. Over the period of2004 through 2007, the poison control center rates 

oftramadol case mentions was higher than for hydrocodone combination products [C-III] but 

lower than for oxycodone [C-11], morphine [C-11] and methadone [C-11] products. In 2008, the 

rate oftramadol case mentions equaled that ofoxycodone [C-11] case mentions but was less than 

the rate of case mentions for methadone [C-11] and morphine [C-11]. For the years 2004, 2005, 

and 2006, the rates oftramadol case mentions were similar to the rates ofpropoxyphene [C-IV] 

case mentions. In 2007 and 2008, tramadol surpassed codeine and propoxyphene in the number 

48 
of case mentions and rates of case mentions. See Factor 4 for a more detailed description of 

AAPCC data. 

Information on Tramadol Related Deaths Obtained From the Labeling for UL TRAM 

The following statement is taken verbatim from the section entitled "Risk ofOverdosage" in the 

labeling approved on September 9, 2009 for UL TRAM: 

Patients taking tramadol should he warned not to exceed the dose 

recommended hy their physician. Tramadol products in excessive doses 

either alone or in comhination v.'ith other CNS depressants. including 

alcohol, are a cause oldntg-related deaths. 

Tramadol Related Deaths Mentioned in the Medical Literature 

A number ofreports in the medical literature have documented deaths associated with tramadol 

(Bynum et al., 2005; Clarkson et al., 2004; Claro! et al., 2003a; Claro! et al., 2003b; De Decker et 

al., 2008; Goeringer et al., 1997; Levine et al., 1997; Loughery et al., 2003; Lusthof and 

Zwcipfenning, 1998; Michaud et al., 1999; Moore et al., 1999; Musshoff and Madea, 2001; 

Ripple et al., 2000; Tajaderborn et al., 2007). Some of these reports describe tramadol alone 

being the cause of death (Lusthof and Zweipfenning, 1998; Moore ct al., 1999; Musshoff and 

Madea, 2001; Loughrey et al., 2003; De Decker et al., 2004). Other reports 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. The drug abuse deaths do not represent the U.S. as a 

whole, nor do they necessarily represent the total number of deaths in which drug abuse was a 

causal or contributing factor. Rather, DAWN cases reflect the number of drug abuse deaths 

reviewed, identified, and reported by the participating medical examiners and coroners in 

selected areas. A total of395 tramadol abuse-related deaths were reported to DAWN from 1997 

to 2002. The number oftramadol-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. 

49 
Table 12. Drug Abuse Warning Network (DAWN)': Drug Abuse-Related Deaths Involving 

Tramadol from a Consistently Reporting PaneI1 of Medical Examiners: 1997-2002 

Drug 1997 1998 1999 2000 2001 2002 

Tramadol 45 46 58 72 86 88 

1 Deaths reported by a consistent panel of medical examiners in 28 metropolitan areas. Consistent panels include 

only those jurisdictions that reported at least I 0 months of data each year from 1997-2002. The panel does not 

include New York City (which did not submit data for 2001) or Los Angeles (which did not submit data for 2002). 

'source: Suhstance Ahuse and Mental Health Services Administration, Office (?f Applied Studies, Drug Ahuse 

rvarning NetttYJrk. 

Table 13. Drug Abuse Warning Network (DAWN)': Drug Abuse-Related Deaths Involving 

Tramado I from Two Panels: a Consistently Reporting PaneI1 of Medical Examiners and a 5-State 

Panel (2003 - 2004) 

DRUG 2003 2004 

NAME Number of Number of 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 by the Florida Department of Law Enforcement 

The Florida Department of Law Enforcement (FDLE) collects information on drug-related 

deaths as reported by medical examiner offices across the state of Florida. This information is 

disseminated in interim and annual Florida Medical Examiner Commission Reports that are 

available for viewing at the FDLE website. Additional information for this document was 

obtained from staff of the FDLE, Medical Examiner's Commission. 

Total annual deaths involving selected opioids as determined by medical examiners in Florida 

for each year over the period of 2003 to 2008 are shown in Table 14. The number of deaths 

involving tramadol increased from I 06 in 2003 to 235 in 2008. Based on communications with 

staff from the FDLE Medical Examiners' Commission, the vast majority of deaths involving 

tramadol also involved other drugs. In the small number of cases in which tramadol only was 

50 
found, the deaths tended to be suicides. Tramadol-related deaths were higher than heroin [C-1] 

related deaths in 2005, 2006, 2007, and 2008. For each of the years, the number of deaths 

involving tramadol was less than the number of deaths 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 of deaths involving mcperidine [C-II] and 

hydromorphone [C-11] (except for 2007). 

Table l 4. Total Annual Drug-Related Deaths Involving Selected Opioids As Identified by 

Florida Medical Examiners and Collected by the Florida Department of Law 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 Opio ids 1 120 194 230 318 368 307 l Codeine, oxymorphone and, rarely, other op101ds. Majortty arc codeine. 2

Schcdu!e I: 'Schedule II; 4Schedule III Combination Products of Hydrocodone; 5Schedule IV; 6Not Scheduled 

Table 15 provides a breakdown of selected opioid related deaths over the period of2005 to 2008 

based on whether the opioid actually contributed to causing the death or simply was identified in 

the deceased. The determination of whether the opioid contributed to the death was made by 

medical examiners. The opioid could either be the cause of death on its own or be a contributing 

factor to the death caused by a combination of drugs. Over the four-year period the percentage 

of annual deaths in which tramadol was detennincd to be a cause of death, compared to the total 

number of deaths in which tramadol was present, ranged from 18% to 26%. This was a little 

higher than the range found for meperidinc (I 0% to 23%). A similar percentage range was 

found regarding proproxyphene [C-IV] (22% to 27%) and hydromorphone [C-II] (20% to 22%) 

as a cause of death. For each of the years, tramadol was determined to be a cause of death in a 

lower percentage of total related deaths than was heroin [C-1], fentanyl [C-11], hydrocodone [CIll], methadone [C-11], morphine [C-11], and oxycodone [C-11]. 

51 
Table 15. Opioid-Related Deaths Identified by Florida Medical Examiners and Collected by the 

Florida Department of Law Enforcement (FDLE). Identification of Death 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 

lleroin1 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 

Summary of Relevant Findings and Conclusions of Factor 6 

The available data from a number of sources indicates that tramadol presents risks to the public 

health and, as such, supports the scheduling oftramadol. 

Reports in the medical literature and information available in the latest approved label for 

ULTRAM provide evidence that tramadol produces a variety of adverse effects, many of which 

arc similar to those produced by opioids 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 or in 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 data demonstrate a public health risk associated with the nonmedical use oftramadol. 

Examination of rate data (number of ED visits per 100,000 prescriptions) suggests that this risk 

is similar to that from propoxyphenc [C-IV] and less than that of Schedule II and III opioids. 

Data from the American Association of Poison Control Centers demonstrate that unintentional 

and intentional exposure to tramado 1 are risks to the public health. From 2004 to 2008, there was 

a continuous increase in the annual number of case mentions (poison exposures) for tramadol. 

This increase was such that with respect to opioid analgesics in 2007 tramadol ranked third 

behind hydrocodone combination products and oxycodone in terms of the number of case 

mentions to poison control centers The number (rate) of case mentions per 100,000 

prescriptions of tramadol increased from 22 in 2004 to 37 in 2008. In 2006, the rate of case 

mentions for tramadol was similar to that for codeine [C-II, III and VJ and propoxyphene [C-IV]. 

52 
In 2007, the rate of case mentions for tramadol was close to that of codeine but higher than that 

for propoxyphene. 

As with all opioids, tramadol overdose can result in death. According to the latest approved 

label for UL TRAM, 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 examiner data documents deaths involving tramadol over the period of 1997 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 oftramadol with other selected drugs. Death can also occur in the course of 

tramado I abuse. 

Data from Florida Medical Examiners Offices and collected by the FDLE indicate that tramadol 

is ruled as contributing to deaths in approximately 18% to 26% of the total death cases in which 

tramadol is found to be present. This percentage was considerably lower compared to heroin [CI], fentanyl [C-Il], hydrocodone [C-lll], methadone [C-II], morphine [C-Il], and oxycodone [Cl!], but similar to the percentages found for proproxyphene [C-!V], meperidine [C-Il], and 

hydromorphone [C-1!]. The data indicate that tramadol is less likely to be a contributor to the 

cause of death than are heroin [C-I], fentanyl [C-II], hydrocodonc combinations [C-lll], 

methadone [C-11, morphine [C-II], or oxycodone [C-II] when these drugs are detected in 

deceased indivduals. This may suggest a lower 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 other opioids, as seen from 

the Florida Medical Examiner's Office, also suggest a lower schedule for tramado I, 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 tramado 1 results in dependence 

development as evidenced by mild to a moderate withdrawal syndrome following either abrupt 

tennination of treatment or administration of an opioid antagonist (precipitated withdrawal). 

Precipitation withdrawal studies suggest a degree of dependence to tramadol similar to that 

produced by propoxyphene [C-IV] and pentazocine [C-IV]. The second section notes that in the 

most recently approved UL TRAM label, withdrawal symptoms may occur following tcnnination 

oftramadol treatment. The third section discusses approximately 30 literature articles 

documenting numerous cases of physiological and physical dependence to tramadol. 

Preclinical Studies 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 

of physical dependence as evidenced by spontaneous or precipitated withdrawal. These studies 

53 
suggest that the degree of dependence development oftramadol is less than that of Schedule Ill, 

but similar to that of Schedule IV drugs such as propoxyphene and pentazocine. 

Preclinical Studies of Spontaneous Withdrawal 

Y anagita (1978) examined for spontaneous withdrawal in Rhesus monkeys given repeated s.c. 

injections oftramadol. Eight drug naive monkeys were divided into two b>roups. One group, 

designated the low dose group, was given injections oftramadol four times daily under the 

schedule of 8 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 of 8 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 of 8 weeks, tramadol administration was 

terminated and monkeys were observed for signs of withdrawal for 5 days. The severity of 

withdrawal signs were graded according to criteria established by Seevers ( 1936) for opiate 

withdrawal in morphine dependent monkeys. Body weight did not change during spontaneous 

withdrawal in either group. However, three monkeys each in the low and high dose tramadol 

groups displayed "mild" withdrawal signs, while in the high dose group one additional monkey 

displayed "intermediate" withdrawal signs. Mild signs of withdrawal included apprehension. 

continual yawning, rhinorrhea, lacrimation, hiccup, shivering, perspiration on face, chattering, 

and quarreling and fighting. Intermediate signs of withdrawal included tremor, anorexia, 

pilomotor activity, muscle twitching, 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 per treatment) 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 of the week for 40 days. On the seventh day of each 

week, dosing was omitted. For purposes of evaluating physical dependence, body weight was 

measured twice daily. In addition, animals were observed for other typical withdrawal signs 

such as diarrhea, Straub tail, convulsions, changes in respiratory rate, pupil diameter, and body 

temperature. Over the 40-day treatment period, there was a slower rise in body weight observed 

in rats treated with either tramadol, codeine [C-11], or buprenorphine [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 specific days in which drug was withdrawn, the fluctuation in 

body weight was less for tramadol compared to either codeine or buprenorpbine, thereby 

indicating a milder withdrawal with termination oftramadol versus termination of either codeine 

(C-11] or buprenorphine [C-lll]. In addition, compared to buprenorphine withdrawal, tramadol 

withdrawal was generally associated with a lower level of other withdrawal effects, such as 

diarrhea, Straub tail, convulsions, changes in respiratory rate, pupil diameter, and changes in 

body temperature. 

Preclinical Studies of Precipitated Withdrawal 

Yanagita (1978) examined Rhesus monkeys given repeated subcutaneous injections oftramadol 

for precipitated withdrawal. Eight drug naive monkeys were divided into two groups. One 

group, designated the low dose group, was given injections oftramadol four times daily under 

54 
the 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 tramado 1 

at unit doses of 8 mg/kg for the first two weeks, 16 mg/kg for the third and fourth weeks, and 24 

mg/kg for a final four weeks. At the end of2, 4, 6, and 8 weeks of administration, a precipitation 

test was conducted by s.c. injection of 1.0 mg/kg naloxone. As one measure of withdrawal, body 

weight reductions were measured following naloxone challenge. Slight weight loss occurred in 

some monkeys in both groups suggestive of a withdrawal syndrome. Monkeys were also 

observed for other withdrawal signs. These other signs were observed in the precipitated 

withdrawal test at 42 and 56 weeks of treatment only in three monkeys from the high dose group. 

The withdrawal in all three monkeys was mild based on a classification of withdrawal signs in 

morphine dependent monkeys established by Seevers (1936). Under this classification, mild 

signs of withdrawal included apprehension, continual yawning, rhinorrhea, lacrimation. hiccup, 

shivering, perspiration on face, chattering, and quarreling and fighting. Y anagita ( 1978) 

concluded that tramadol has some physical dependence potential as evidenced by naloxoneprecipitated withdrawal. 

Friderichs et al. ( 1978) evaluated tramado I in the withdrawal jumping test with mice, with 

comparison to other opioids 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/kg to 75 mg/kg over two consecutive days. Following this treatment, mice received 

an intraperitoneal injection of 30 mg/kg naloxone and were observed for jumping behavior. 

Mice receiving repeated treatments oftramadol displayed only limited withdrawal jumping in 

response to naloxone injection. The number of jumps in tramadol-treated animals was 

comparable with that obtained after the administration ofpropoxyphene [C-lV] and lower than 

after codeine, methadone [C-ll], and morphine [C-ll]. The naloxone precipitated jumping assay 

indicated that tramadol produced a degree of physical dependence similar to that of 

proproyphene [C-IV]. 

Wakasa et al. (! 994) evaluated precipitated withdrawal in rats receiving short-term frequent 

intravenous infosions of various opioids. Rats fitted with jugular catheters received by infusion a 

fixed dose of a 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 8 mg/kg), loperamide (1or2 mg/kg), pentazocinc [C-IV] (4 mg/kg), 

ethylketocyclazocine (0.25 or 0.5 mg\kg), buprenorphine (4 or 8 mg/kg), and thcbaine (I or 2 

mg/kg). Rats given saline (0.25 ml/kg) served as controls. Thirty minutes following the final 

infosion, naloxone ( 4 mg/kg, s.c.) was administered and rats were observed for one hour for 

signs of precipitated withdrawal. The severity of withdrawal signs was scored based on a 

behavioral (unusual posture, hyperirritability, teeth chattering) sign score, autonomic 

(lacrimation, diarrhea, salivation) sign score, and body weight loss score. 

The morphine [C-ll] treatment group displayed the highest total withdrawal score. Other groups 

showing total withdrawal scores significantly greater than that of saline included those treated 

with methadone [C-11], propoxyphene [C-IV], tramadol, and pentazocine [C-IV], but not those 

involving treatment with buprenorphine [C-III] or thebaine [C-11]. When looking at individual 

withdrawal sign category scores, the behavioral sign scores tended to be higher than the other 

two scores in the drugs showing relatively low but significant total scores such as with tramado I, 

55 
pentazocine [C-IV], and ethylketocyclazocine [not scheduled]. In contrast, the scores of 

autonomic signs and of body weight 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 either 4 or 8 mg/kg tramadol displayed a significant 

reduction in body weight 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 of either morphine [C-11] (I 00 and 1.05 mg/kg) or tramadol ( 100 or 

39.1 mg/kg) to mice three times daily for five consecutive days. 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 occurrence ofdifforent signs 

(seizures, wet-dog shakes, urination, diarrhea, pilocrcction, jumps, and tachypnea) induced by 

the intraperitoneal administration of naloxone (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 of tramadol and challenged with naloxone showed only diarrhea, urination and 

piloerection in one out of six animals. In mice pretreated with 39.1 mg/kg tramadol, naloxone 

administration evoked wet-dog shakes and piloercction in only one out of six animals. By 

contrast, when challenged with naloxone, all (six out of six) mice pretreated with I 00 mg/kg 

morphine displayed jumps, wet-dog shakes, tachypnea and piloerection while five of the 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 of withdrawal as evidenced 

by three out of six animals showing wet-dog shakes, piloerection and tachypnea. This study 

demonstrated that under the treatment conditions examined, tramado 1 produced only a lesser 

degree of physical dependence than morphine. In contrast, morphine pretreatment produced a 

more robust level of physical dependence. 

Dependence to Tramadol in Humans 

Under this section are several studies looking at dependence development in pain patients treated 

with tramadol and a number of studies looking at cross dependence development between 

tramadol and other opioids. ln studies of cross dependence, tramadol produces a modest 

suppression of withdrawal in subjects dependent on other opioids. This suppression appears less 

than that produced by morphine [C-Il] or buprenorphine [C-111]. The available studies show that 

tramado I shows some cross dependence to heroin, methadone, morphine and buprenorphine. 

Clinical Studies and Case Reports Demonstrating Cross Dependence Between Tramadol and 

Other Opio ids 

A number of studies examined the ability oftramadol to substitute for other opioids in 

individuals who are opioid dependent. These studies are discussed below. 

Tamaskar et al. (2003) conducted a retrospective cohort control study in order to compare the 

effectiveness oftramadol versus buprenorphine in the treatment of opiate 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 

56 
as defined by their use ofless than ten bags of heroin daily. The tramadol detoxification group 

received treatment with tramadol I 00 mg orally every 4 hours for 24 hours, then I 00 mg every 

six hours for 24 hours, and then 50 mg four times a day and 50 mg three times a day for 24 hours 

each. The buprenorphine detoxification group received treatment with buprcnorphine 0.4 mg, 

0.3 mg, 0.2 mg and 0.1 mg subcutaneously six times a day in the first, second, third, and fourth 

days, respectively. Both groups received clonidine 0.05 to 1.0 mg orally every two to four hours, 

as needed for breakthrough withdrawal symptoms. Clonidine is a non-scheduled drug that is 

approved for treatment of hypertension but is reportedly also used to reduce anxiety, produce 

sedation, and to treat drug withdrawal (Cregoretti et al., 2009). Other drugs given as needed 

were hydroxyzine [not scheduled] for anxiety and dicyclomine [not scheduled] for abdominal 

cramps or nausea. Endpoints of the study included improvements of withdrawal symptoms, as 

measured by the Clinical Institute Narcotic Assessment (CINA), length of stay 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 or buprenorphine. 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 opposed to the tramadol group 

left the program prior to 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 oftramadol to that of 

clonidine for management of acute heroin [C-I] withdrawal. Fifty-nine patients were detoxified 

using tramadol and 85 using clonidine [not scheduled]. Tramadol protocol involved tramadol 

I 00 mg orally every four hours for one day, every six hours of one day and every eight hours for 

one day. This dosage was followed with 50 mg tramadol orally every six hours for one day, 

every eight hours for one day 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, every eight hours for one 

day and every twelve hours for one day. For each day in detoxification, the magnitude of 

withdrawal symptoms was estimated on a scale ofO to 3, with 0 being no detectable withdrawal 

and 3 being severe withdrawal symptoms. Patients remaining in the detoxification program were 

also monitored. Patients detoxified with tramadol had a 23% risk oflcaving the program against 

medical advice relative to patients detoxified with clonidine (I 00%) and scored an average of 

0.24 points lower than clonidine on the withdrawal symptom scale. This study provides 

evidence that tramadol does display some cross-dependence development 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 

moderate degree of opioid physical dependence. Spontaneous opioid withdrawal oceun-ed 

following substitution of placebo for scheduled morphine doses 17.5 hours before experimental 

sessions that occun-ed twice weekly. Acute effects of placebo, 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 

57 
intramuscularly) were tested under double-blind, double-dummy, randomized conditions. 

Participants completed visual analog scales (VAS) and a drug class, identification questionnaire. 

Drug treatments were assessed for agonist and antagonist effects using both participant and 

observer measures. Tramadol at doses of 50 and I 00 mg were without any effect and the 7.5 mg 

morphine dose did not produce consistent effects compared to placebo. On the observer-rated 

antagonist adjective scale, both morphine and tramadol produced evidence of withdrawal 

suppression that continued through the 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 due to the oral 

administration oftramadol and to the metabolism oftramadol to the Ml metabolite. On the 

participant rated antagonist scale, tramado I at 400 mg, 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 severity of withdrawal symptoms. Again, the 

withdrawal suppression by tramadol was significantly delayed compared to that produced by 

morphine. Based upon the results from the study, the authors concluded that tramadol produced 

a modest suppression of opioid withdrawal in subjects with a mild to moderate degree of opioid 

physical dependence. This suggests cross dependence development between tramado 1 and other 

opioids, such as morphine. 

In addition to clinical studies, there are several case reports in the published literature that 

provide evidence of cross dependence development between tramadol and opioids, as seen by 

suppression of withdrawal symptoms upon termination of extended 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-year old female who had a history of taking 

up to 30 (50 mg) tablets oftramadol in divided doses daily. Upon attempting to stop tramadol 

use, she presented to the emergency room with symptoms of anxiety, dysphoria, restlessness, 

irritability, abdominal cramping, and lower extremity cramping. 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 I 0 mg dose that did mitigate the symptoms. The 

methadone [C-ll] dosing was reduced over eight successive days by 2.5 mg daily. Significant 

reductions occurred in subjective symptoms of opiate withdrawal. 

Ritvo et al (2007) provided two case reports documenting the use ofbuprenorphinc/naloxone [ Clll] to alleviate withdrawal symptoms caused by prolonged use of high doses oftramadol. One 

case involved a 34-year old female who was abusing 1200 mg/day oftramadol obtained by 

doctor shopping and purchases oftramadol over the Internet. Upon attempting to stop tramadol 

use, she presented for treatment oftramadol withdrawal, including symptoms of restless pain, 

muscle stiffuess, joint soreness, anxiety and lethargy. She was subsequently titrated to a dose of 

32 mg/8 mg buprenorphine/naloxone [C-lll], after which time withdrawal symptoms 

disappeared. The second case involved a 44-year old fomale who admitted to using 1500 mg/day 

oftramadol purchased over the Internet. Upon attempting to cease tramadol use, she developed 

symptoms of withdrawal successfully treated with buprenorphine/naloxone [C-lll] (32mg/8mg). 

58 
Both of these 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) demonstrate tramadol cross-dependence to heroin [C-1], 

morphine [C-11], methadone [C-11] and buprenorphine. Only the studies ofLotwall et al. (2007) 

and Tamaskar et al. (2003) provide information on the relative degree of cross dependence 

development compared to other scheduled opioids. LofWall et al. (2007) notes the "modest" 

suppression of opioid withdrawal in comparison to morphine [C-11]. The increased number of 

breakthrough opioid withdrawal symptoms observed following tramadol treatment versus 

buprenorphine treatment suggest a possible lower degree of cross-dependence oftramadol to 

heroin versus cross-dependence ofbuprenorphine [C-Jll] to heroin (Tamaskar et al., 2003). 

These data suggest that tramadol produces cross-dependence to opioids that is less than that of 

morphine [C-11] or buprenorphine [C-111]. No studies were identified comparing cross 

dependence development to Schedule IV drugs. 

Dependence Information in Product Label for UL TRAM 

The following statement is found in the "WARNINGS" section of the UL TRAM label approved 

September 9, 2009: 

Wtihdrawal symptoms may occur if UL TRAM is abruptly (.1·ee 

also DRUG ABUSE AND DEPENDENCE). Reported .1ymptoms have 

included anxiety. sweating. insomnia. rigors. pain. nausea, tremors. diarrhea, 

upper respiratory symptoms. piloerection, and rarely hallucinations. Other 

.1ymptoms that have heen reported lessfrequentlv ;vith ULTRAM 

discontinuation include panic attack~. severe anxiety, and paresthesias. 

Clinical experience suggests that withdrawal symptoms may he avoided hy 

tapering Ur TRAM at the time of discontinuation. 

Dependence to Tramadol in Humans - Documented Cases in the Medical Literature. 

An examination of the medical literature reveals a variety of articles 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., I 999; 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; Senay et 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 of individuals 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 of the articles 

document withdrawal in neonates delivered by mothers taking tramadol (Meyer et al., 1997; 

Willaschck et al., 2008). 

59 
Summary of Relevant Findings and Conclusions of Factor 7 

The information available indicates that tramadol produces physical dependence thereby 

supporting the scheduling of the drug. 

The most current label for UL TRAM specifically states that tramadol may be associated with 

development of dependence of the morphine type (μ-opioid). A variety of case reports in the 

medical literature document development of dependence to tramadol. Both animal studies and a 

limited number of clinical studies also provide support that tramadol induces an opioid-like 

dependence. The available information from animal and human studies suggest that the degree 

of physical dependence produced by tramadol 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 of spontaneous 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 ofnaloxone to monkeys repeatedly treated with tramadol. In a study using rats, 

precipitated withdrawal scores for tramadol are similar to withdrawal scores for pentazocine (CIV], but less than those of morphine [C-II], methadone (C-11], or proproxyphene (C-IV]. Two 

studies looked at precipitated withdrawal evoked in mice receiving prolonged tramadol 

treatment. One study revealed minimal precipitated withdrawal signs in tramadol treated 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 mice treated with codeine [C-11], methadone [C-II], and morphine 

[C-Il]. The overall data from the various animal studies show a dependence producing potential 

oftramadol that is low, that is consistent with CSA Schedule IV. 

Three clinical studies, as well as several case reports show that tramadol produces some crossdependence to opioids including heroin [C-I], morphine [C-II], methadone [C-11] and 

buprenorphine [C-III]. Two of the studies provide information on the relative degree of cross 

dependence development compared to other scheduled opioids. These two studies showed that 

tramadol produces cross-dependence to opioids that is less than that of morphine (C-11) or 

buprenorphine [C-III]. 

Collectively, all of the data show that tramadol produces a modest level of physical dependence. 

Preclinical and clinical studies suggest a degree of physical dependence development less than 

that of Schedule II and III opioids and similar to that of Schedule IV opioids. 

Factor 8: Whether tramadol is an immediate precursor of a substance already controlled 

Tramadol is not an immediate precursor ofa substance already controlled. 

60 
IV. Findings and recommendation 

After consideration of the 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 of the CSA, under 21 U.S.C. 812 (b). 

I. Tramadol has a potential.fiJr ahuse less than the drugs or other suhstances in 

Schedule I I I. 

The available information indicates that tramadol satisfies the criteria (indicators) set forth in the 

legislative history of the CSA for having a potential for abuse. Individuals take tramado 1 in the 

absence of medical supervision and in amounts sufficient to create a hazard to their health 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 NS DUH nonmedical use data and 

rec data. Clinical and preclinical studies show that tramadol, via its M 1 metabolite, produces a 

variety of effects similar to 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 of Schedule III and similar to that for Schedule IV. Preclinical self-administration 

studies show that tramadol produces limited reinforcing effects, consistent with a lower schedule. 

Clinical studies indicate that tramadol can produce subjective reinforcing effects similar to that 

of morphine [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 doses but not therapeutic doses produce subjective reinforcing effects. For 

both tramadol and propoxyphene, the doses required to produce significant subjective reinforcing 

effects is in a range causing sufficient adverse effects. These observations indicate that the 

subjective reinforcing effects, a reflection of abuse potential, oftramadol is less than that of 

morphine [C-II] or oxycodone [C-II], but similar to that of propoxyphene [C-IV]. 

Dependence is one of the driving forces in the abuse of drugs. As such, the development of 

dependence provides support for a drug having a potential of abuse. A variety of case report 

studies document physical and psychological dependence to tramadol resulting from abuse of 

suprathcrapeutic doses oftramadol. Clinical studies show that tramadol causes some opioid 

withdrawal suppression that is less than that produced by morphine [C-II] or buprcnorphinc [Cl! I]. The combined animal and human information available regarding dependence is supportive 

of an abuse potential for tramadol less than that of Schedule Ill drugs and similar to that of 

Schedule IV. 

Epidemiological data is also supportive of an abuse potential for tramadol consistent with 

Schedule IV. The NS DUH shows that the number of individuals reporting lifetime misuse of 

tramadol was below that of the number reporting lifetime misuse of either oxycodone products 

[C-II] or hydrocodone 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 I 00,000 prescriptions is lower than that ofa number of opioids in Schedules II and 

61 
llI and similar to that of propoxyphene [C-IV]. NFLIS data for 2008 show that the number of 

law enforcement encounters with tramadol was close to the number for propoxyphene [C-IV], 

thereby supporting the same schedule (Schedule IV) for tramadol. 

2. Tramadol has a currently accepted medical use in treatment in the United States. 

The FDA approved tramadol for marketing for the management of moderate to moderately 

severe pain in 1995. Since then, FDA has approved a number of additional products containing 

tramadol. As such, tramadol has a currently accepted medical use in treatment in the U.S. 

3. Ahuse o(Tramadol may lead to limited physical dependence or psychological dependence 

relative to the drugs or other suhstances in Schedule III. 

Tramadol may lead to development of physical and psychological dependence as documented in 

information in current product labels for UL TRAM. In addition, a variety of case reports in the 

medical literature document development of physical and psychological dependence to tramadol. 

Both animal studies and a limited number of clinical studies also provide support that tramadol 

induces an opioid-like dependence. The available information from animal and human studies 

suggest that the degree of physical dependence produced by tramadol is low, supporting 

placement oftramadol in Schedule IV. 

With regard to animal studies, mild spontaneous and precipitated withdrawals arc observed in the 

Rhesus monkey following repeated tramadol treatment. In a rat study, signs of spontaneous 

withdrawal from tramadol are less severe than similar signs evoked by withdrawal 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], or proproxyphene [C-IV]. 

Two studies looked at precipitated withdrawal oftramadol in mice. One study revealed minimal 

precipitated withdrawal signs compared to morphine [C-11]. The other study showed withdrawal 

behavior similar to that observed by withdrawal ofproproxyphenc [C-IV] but less than that of 

codeine [C-11], methadone [C-11], and morphine [C-11]. The overall data from the various animal 

studies show a dependence producing potential oftramadol that 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 tramado 1 

produces some cross-dependence to opioids including heroin [C-1], morphine [C-11], methadone 

[C-11], and buprenorphine [C-III]. The clinical studies provide information on the relative degree 

of cross dependence development compared to other scheduled opioids. Two studies showed 

that tramadol produces cross-dependence to opioids that is less than that of morphine (C-11) or 

buprcnorphine [C-III]. 

62 
Recommendation 

The scientific and medical evaluation oftramadol supports a recommendation of the Department 

of Health and Human Services to the Drug Enforcement Administration for Schedule IV control 

of tramado l. 

63 
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