U.S. Department ofJustice

Drug Enforcement Administration

Schedules of Controlled Substances: Placement of Tramadol into

Schedule IV

Background, Data, and Analysis:

Eight Factors Determinative of Control

and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by

Office of Diversion Control, Drug and Chemical Evaluation Section

Washington, D.C. 20537

May 2013
I. Background

In October and November 2005, the Drug Enforcement Administration (DEA)

received four citizen petitions requesting that 21 CFR §1308.13 be amended so that

tramadol be controlled as a scheduled substance under the Controlled Substances Act

(CSA). Three ofthese petitions specifically requested the placement oftramadol in

schedule III, while the remaining petition did not specify a particular level of control.

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

an active metabolite, O-desmethyltramadol, referred to below as the Ml metabolite. It

was originally synthesized by Grunenthal Research Laboratories in 1962 and first

marketed in West Germany for the treatment of moderate to moderately severe pain in

1977. In March 1995, the Food and Drug Administration (FDA) approved tramadol as a

non-controlled, non-traditional, centrally acting analgesic under the trade name

ULTRAM® (50 mg tramadol) for marketing in the United States. Since then several

other tramadol formulations were approved for marketing as immediate-release, extended

release products and as generic products and extended release products.

Pursuant to 21 U.S.C. § 811(a) and (b), DEA gathered the available data on tramadol

and in April 2007, DEA requested that the Department of Health and Human Services

(HHS) provide a scientific and medical evaluation ofthe available information and a

scheduling recommendation for tramadol, in accordance with 21 U.S.C. § 811(b).

On September 16, 2010, pursuant to 21 U.S.C. § 811(c), the HHS provided to the

DEA a scientific and medical evaluation entitled "Basis for the Recommendation to

Schedule Tramadol In Schedule IV ofthe Controlled Substances Act" and a scheduling

recommendation (HHS review, 2010). Following consideration ofthe eight factors and

findings related to the substance's abuse potential, legitimate medical use, and

dependence liability, HHS recommended that tramadol be controlled in schedule IV of

the CSA under 21 U.S.C. § 812 (b).

The CSA requires DEA, as delegated by the Attorney General, to determine whether

the HHS' scientific and medical evaluation and scheduling recommendation and all other

relevant data constitute substantial evidence that the substance should be scheduled (21

U.S.C. § 811(b)). This document contains an explanation ofthe relevant data that DEA

considered. Pursuant to 21 U.S.C. § 811(c), the DEA reviews the facts and all other

relevant data. This document is a summarized review ofthe relevant data, law

enforcement information and a determination to place tramadol into schedule IV ofthe

CSA.

'28 CFR0.100(b)

DEA/OD/ODE Page 2 of 21 May 2013
II. Eight Factors Determinative of Control

Pursuant to 21 U.S.C. § 811(c), DEA must consider eight factors in making any finding

ofsubstantial evidence of potential for abuse, including the data and law enforcement

information relevant to. The information contained in this document is organized according

to the eight factors as specified in 21 U.S.C. § 811 (c).

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

The term "Abuse" is not defined in the CSA. However, the legislative history ofthe

CSA suggests using the following four prongs in determining whether a particular drug

orsubstance has a potential for abuse2:

• There is evidence that individuals are taking the drug or other substance in

amounts sufficient to create a hazard to their health or to the safety of other

individuals or to the community; or

• There is significant diversion ofthe drug or other substance from legitimate drug

channels; or

• Individuals are taking the drug or substance on their own initiative rather than on

the basis of medical advice from a practitioner licensed by law to administer such

drugs; or

• The drug is a new drug so related in its action to a drug or other substance already

listed as having a potential for abuse to make it likely that the drug substance will

have the same potential for abuse as such drugs, 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 ofthe user or to the safety ofthe community.

Of course, evidence of actual abuse of a substance is indicative that a drug has a potential

for abuse. The above mentioned four prongs as applied to tramadol are discussed below.

In addition to the information HHS provided in their scientific and medical evaluation

document for tramadol, DEA considered all other relevant data and found that:

a. Individuals are taking tramadol in amounts sufficient to create a hazard to their

health or to the safety ofother individuals or to the community.

Published case reports, case series, and data from databases such as the Drug Abuse

Warning Network (DAWN) suggest that individuals are taking tramadol in amounts

sufficient to create hazard to their health, to the safety of other individuals or to the

community. Tramadol abuse is associated with serious adverse events including deaths,

drug dependence, drug withdrawal symptoms, seizures, serotonin syndrome, and other

serious medical problems.

2Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong.,

Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601.

DEA/OD/ODE Page 3 of 21 May 2013
The Drug Abuse Warning Network (DAWN) is a Substance Abuse and Mental

Health Services Administration (SAMHSA) database which collects data on drug-related

emergency department (ED) visits from a nationally representative sample of hospitals in

the U.S. and a selection of metropolitan areas. HHS reviewed and analyzed DAWN data

from 2004 through 2008 and found that the estimated annual nonmedical ED visits from

nonmedical use oftramadol/combinations continually increased from 4,849 ED visits to

11,850 ED visits. DEA further evaluated the updated DAWN data and found that this

increasing trend for tramadol continued in 2009 and 2010 (15,349 and 16,251 ED visits

respectively). There was a significant increase of 37% for tramadol from 2008 (11,850

visits) to 2010 (16,251 visits). However, these annual numbers for

tramadol/combinations were less than those for fentanyl/combinations (Schedule II or

C-II), methadone (C-II), morphine/combinations (C-II), oxycodone/combinations (C-II),

hydrocodone/combinations (C-III) during this period. These numbers for

tramadol/combinations were closer to the corresponding numbers for hydromorphone

(C-II), buprenorphine/combinations (C- III), codeine/combinations (C-II, -III, and -V)

and propoxyphene/combinations (C-IV).

The American Association of Poison Control Centers (AAPCC) manages the

National Poison Data System (NPDS), which is the only near real-time comprehensive

poisoning surveillance database in the U.S. The NPDS collects information from

participating poison centers across the United States. HHS reviewed and analyzed the

NPDS reports and found that annual number oftramadol exposures increased from 3,769

in 2004 to 9,623 in 2008. In 2008, intentional exposures to tramadol alone were 2,476.

DEA further reviewed the recent NPDS data and found that the number oftramadol

exposures continued to increase each year from 2009 through 2011. The numbers of

human toxic exposures to tramadol were 10,255, 11,225 and 12,424 in 2009, 2010 and

2011, respectively. Ofthese totals, intentional exposures to tramadol alone were 2,677,

2,867 and 3,170 resulting in 4, 3 and 6 deaths in 2009, 2010 and 2011, respectively. The

numbers of exposures for tramadol during the years from 2009 to 2011 are less than the

numbers of exposures for hydrocodone (27, 753, 28,310 and 30,792, respectively) or

oxycodone (18, 396, 19,363 and 19,424 respectively) products.

b. There is a significant diversion oftramadolfrom legitimate drug channels.

The National Forensic Laboratory Information System (NFLIS) is a DEA database

that collects scientifically verified data on analyzed samples in state and local forensic

laboratories. It also includes data from the System to Retrieve Information from Drug

Evidence (STRIDE), which includes data on analyzed samples from DEA laboratories.

The data show that for each ofthe years from 2000 through 2012, tramadol was present

in drug exhibits seized in the course oflaw enforcement activity. Tramadol exhibits

increased from a total of 82 in 2000 to 1,806 in 2012. The tramadol exhibits seized by

law enforcement confirm the diversion oftramadol in the United States (U.S.). From

2008 to 2012, data from NFLIS and STRIDE show that the number oftramadol exhibits

is greater than the pentazocine exhibits, but less than the corresponding numbers for

hydrocodone, codeine, and buprenorphine. Data from both NFLIS and STRIDE also

show that the annual number oftramadol exhibits during 2008 to 2010 is similar to that

DEA/OD/ODE Page 4 of 21 May 2013
of propoxyphene exhibits(Table 1). The numberof propoxyphene exhibits(561) in

2011 is significantly less than that oftramadol exhibit (1.704) and this reduction is

because in November 2010, FDA recommended that propoxyphene (Schedule IV or

C-IV) be withdrawn from the U.S. market due to the risk of cardiac toxicity. (Data

queried as of March, 2013, from NFLIS and STRIDE database, Office of Diversion

Control, DEA).

Table 1. Data Sources: NFLIS (State and Local Laboratories) and STRIDE (DEA/Federal

Laboratories), queried03/18/2013, bydate ofsubmission, all drugs reported.

Tramadol Exhibits

2008 2009 2010 2011 2012

NFLIS 1,148 1,255 1,450 1,632 1,754

STRIDE 22 31 35 72 52

TOTAL 1,170 1,286 1,485 1,704 1,806

Buprenorphine Exhibits (Schedule III)

2008 2009 2010 2011 2012

NFLIS 4,702 7,355 10,033 10,285 9,588

STRIDE 52 123 134 176 98

TOTAL 4,754 7,478 10,167 10,461 9,686

Codeine Exhibits (Schedule II, III,V)

2008 2009 2010 2011 2012

NFLIS 3,373 3,531 3,462 3,318 2,752

STRIDE 172 147 217 134 115

TOTAL 3,545 3,678 3,679 3,452 2,867

Hydrocodone Exhibits (Schedule III)

2008 2009 2010 2011 2012

NFLIS 37,943 43,430 45,003 42,603 34,808

STRIDE 481 651 624 689 450

TOTAL 38,424 44,081 45,627 43,292 35,258

Methadone Exhibits (Schedule II

2008 2009 2010 2011 2012

NFLIS 8,228 8,639 8,354 7,670 6,064

STRIDE 178 146 129 115 80

TOTAL 8,406 8,785 8,483 7,785 6,144

Morphine Exhibits (Schedule II)

2008 2009 2010 2011 2012

NFLIS 5,496 6,919 7,151 7,675 7,612

STRIDE 295 240 318 155 136

TOTAL 5,791 7,159 7,469 7,830 7,748

Oxycodone Exhibits (Schedule II)

2008 2009 2010 2011 2012

NFLIS 33,532 44,977 57,821 55,376 45,899

STRIDE 1,126 1,618 2,412 2,473 1,452

TOTAL 34,658 46,595 60,233 57,849 47,351

Pentazocine Exhibits (Schedule IV)

DEA/OD/ODE Page 5 of21 May 2013
2008 2009 2010 2011 2012

NFLIS 82 94 94 96 88

STRIDE 2 1 2 19 8

TOTAL 84 95 96 115 96

Propoxyphene Exhibits (Schedule IV)

2008 2009 2010 2011 2012

NFLIS 1,331 1,426 1,301 542 280

STRIDE 34 30 19 19 4

TOTAL 1,365 1,456 1,320 561 284

HHS review also suggeststhe possibility of diversion of tramadol by referencing

updated information for the ULTRAM label that was approved on September 9, 2009.

Under the heading of "Physical Dependence and Abuse" is the following statement:

Dependence andabuse, including drug-seeking behavior and taking illicit

actions to obtain thedrug, are notlimited to those patients with prior history

ofopioid dependence.

A post-marketingstudy published in 2002 cited by HHS review reported that among

140 health care professionals, who had at least one positive tramadol urine specimen, 87

cases were associated with illegal prescriptions for obtaining tramadol. According to

another study cited by HHS review, diversion investigators from police agencies in all 50

states reported 42 cases oftramadol diversion in the first quarter and approximately 30

cases each in the remaining quarters during the period ofJanuary 2002 through March

2004. However, the number oftramadol diversion cases was less than the number of

diversion cases associated with hydrocodone (C-III) and oxycodone (C-II) products.

c. Individuals are taking tramadol on their own initiative rather than on the basis of

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

HHS and DEA's evaluation found that current evidence indicates that individuals are

taking tramadol on their own initiative without medical consultation. This evidence

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

well as from epidemiological data (DAWN, NSDUH and AAPCC).

HHS reviewed the DAWN data and found that over the period of 2004 through 2008,

the national annual estimates of ED visits related to nonmedical use oftramadol and its

combinations increased from 4,849 to over 11,850. DEA further collected the DAWN

data of 2009 and 2010, and found that the national annual estimates of ED visits

increased to 15,349 in 2009 and 16,251 in 2010, respectively.

The National Survey on Drug Use and Health (NSDUH), operated by Substance

Abuse and Mental Health Services Administration (SAMHSA), provides information on

the nonmedical use of drugs in the United States population age 12 and older and its

database provides annual estimates on the lifetime nonmedical use of opioids and pain

relievers. HHS reviewed the NSDUH results and found that an estimated 1,559,000

DEA/OD/ODE Page 6 of21 May 2013
individuals had used tramadol nonmedically at least once in their lifetime in 2007. In

addition, 57,000 individuals reporting initiation of any pain reliever use during the past

year also had nonmedical use oftramadol. The 2007 result also revealed that both

lifetime nonmedical use and nonmedical use over the past year among new initiates of

pain reliever use, islower fortramadol products when compared to oxycodone products

(C-II), or to hydrocodone products (C-III). DEA further analyzed the updated NSDUH

data and found that the estimated number of individuals who have used tramadol

products non-medically at least once in their lifetime are 1,990,000; 2,181,000; 2,282,000

and 2,614,000 in 2008, 2009, 2010 and 2011, respectively. Furthermore, these numbers

are lowerthan that of oxycodone (C-II) and hydrocodone products (C-III).

AAPCC manages the National Poison Data System (NPDS), which is the only near

real-time comprehensive poisoning surveillance database in the U.S. HHS reviewed the

NPDS reports and found that for 2006, 2007, and 2008, there were 1,482, 1,847, and

2,476, respectively, case mentions involving intentional exposure to tramadol alone.

DEA further evaluated the NPDS data and found that in 2009, 2010 and 2011, the

number of reported tramadol poison exposures totaled 10,255, 11,225 and 12,424,

respectively. Of these totals, intentional exposures to tramadol alone were 2,677, 2,867

and 3,170 resulting in 4, 3 and 6 deaths in 2009, 2010 and 2011, respectively. The

number of exposures fortramadol in 2011 was less than the number of exposures for

hydrocodone (C-III) or oxycodone (C-II). These findings indicate thattramadol poses a

significant threat to the public health.

d. Tramadol is so related in its action toa drug or other substance already listed as

having apotentialfor abuse to make itlikely that itwill have the same potentialfor abuse

assuch substance, thus making itreasonable to assume that there may be significant

diversionsfrom legitimate channels, significant use contrary to or without medical

advice, or that ithas a substantial capability of creating hazards to the health ofthe user

or to the safety ofthe community.

According to HHS review, tramadol shares many similarpharmacological activities

with some opioids thatwere scheduled under the CSA. Assuch, the abuse potential of

tramadol would be expected to be related to its opioid properties. Therefore, tramadol

would be expected to be diverted from legitimate sources and be used without medical

supervision, and would subsequently represent a safety concern to individuals and the

community.

According to HHS review, the opioid activity of tramadol is primarilydue to its

metabolite, O-desmethyltramadol or "Ml." Compared to other opioids,tramadol showed

a longer onset of action due to accumulation ofthe active metabolite and its effects

include analgesia, respiratory depression, miosis, cough suppression, and inhibition of

bowel motility. Preclinical studies demonstrate that tramadol, as other opioids in

schedules I through IV, exhibits complete generalization to morphine (C-II) and be able

to produce some reinforcing effects. Repeated administration oftramadol in animals

caused dependence development, evidenced by a withdrawal syndrome similar in

intensity to pentazocine (C-IV) or propoxyphene (C-IV). Human studies reveal that

tramadol produces some reinforcing subjective effects at high doses. A similar dose

DEA/OD/ODE Page 7 of 21 May 2013
response pattern at high doses with propoxyphene (C-IV) to produce reinforcing

subjective effects was also observed. Thereby, propoxyphene may serve as an

appropriate comparator drug for tramadol with respect to generating reinforcing effects.

According to HHS review, several studies examining abuse potential suggest that the

subjective reinforcing effect oftramadol is less than that ofschedule II opioids and more

comparable to that of propoxyphene (C-IV).

In summary, the abuse potential oftramadol is similar to that ofsubstances in

schedule IV (such as propoxyphene) ofthe CSA. The accumulated information

demonstrates that individuals are taking tramadol nonmedically and in amounts sufficient

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

produces effects similar to other CSA-controlled opioids known to have an abuse

potential. Furthermore, the available information regarding reinforcing effects and drug

dependence shows that the abuse potential oftramadol is less than that of morphine

(C-II), oxycodone (C-II) or buprenorphine (C-III), but similar to that of propoxyphene

(C-IV). Additionally, epidemiological data also support an abuse potential for tramadol

that is similar with substances in schedule IV ofthe CSA.

Factor 2: Scientific Evidence of Tramadol's Pharmacological Effects

According to HHS review, tramadol is an opioid analgesic and produces opioid-like

effects primarily due to its metabolite, O-desmethyltramadol or "Ml" (not scheduled).

HHS found that tramadol, similar to some CSA-controlled opioids, produces many

pharmacological effects which are listed below:

Receptor Binding: The primary receptor binding site oftramadol and Odesmethyltramadol (Ml) is the tr-opioid receptor. The affinity of morphine (C-II) is

approximately 10-100 times greater than Ml and 300 times greater than tramadol.

Tramadol was approximately 10-fold less potent than codeine (C-II), 1000-fold weaker

than methadone (C-II), and 6000-fold weaker than morphine (C-II). The Ml metabolite

had a high intrinsic efficacy at the human opioid receptors and it was between the relative

intrinsic efficacies ofmorphine (C-II) and fentanyl (C-II). HHS concluded that Ml

metabolite primarily accounts for the u-opioid component ofthe analgesic effects of

tramadol.

Inhibition of Serotonin and Norepinephrine Reuptake: Studies have shown that

tramadol inhibits in vitro neuronal reuptake of norepinephrine and serotonin.

O-desmethyltramadol (Ml) is effective in both blocking reuptake and blocking release of

norepinephrine and serotonin. Tramadol, with the concomitant use ofserotonergic drugs

such as serotonin re-uptake inhibitors and monoamine oxidase inhibitor (MAO) inhibitors

may enhance the risk of adverse events, including seizure and serotonin syndrome.

Similar to tramadol, other opioids such as methadone (C-II), meperidine (C-II), and

levorphanol (C-II) inhibit serotonin and norepinephrine reuptake (HHS review, 2010).

Analgesia: Preclinical studies found that in animals with painful stimulation,

tramadol demonstrated a dose-related anti-nociceptive effect. The animal models

DEA/OD/ODE Page 8 of 21 May 2013
included tail-pressure, paw-pressure, and electrically induced vocalization tests in rats;

tail-flick, hot-plate, and abdominal constriction tests in mice and rats; and the electrical

tooth-pulp stimulation test in rabbits. In a HHS cited study, the intravenous

administration of either tramadol or Ml produced dose-dependent analgesia and the

following descending order of analgesic activity was found: hydromorphone (C-II) >

hydrocodone (C-II) > morphine (C-II) > Ml > codeine (C-II) = tramadol. According to

the HHS review, many clinical studies demonstrate the analgesic effects oftramadol

when treating various pain states in humans. The analgesic effect oftramadol involves

both opioid mechanisms, via the Ml metabolite, and the mechanism of norepinephrine

and serotonin reuptake blockade. The production of analgesia is consistent with Ml

formation, which commences within one hour of post-administration and peaks at 2 to 3

hours later. The analgesic effects oftramadol were compared to opioid analgesics in

schedules III and IV. In several large clinical trials for treatment of acute pain, tramadol

was significantly less effective than that of hydrocodone/acetaminophen (C-III), but

displayed an analgesic effect similar to that of pentazocine (C-IV) or, superior or similar

to proproxyphene/acetaminophen combination (C-IV) in relieving postoperative pain.

Miotic Effect: As stated in the HHS review, like morphine and most p-opioid

agonists, tramadol was also shown to cause pupillary restriction, but the onset of which is

delayed several hours following tramadol administration.

Urinary Effect: Tramadol and morphine (C-II) caused urinary retention in rats via a

similar mechanism of activating p-opioid receptors since a pretreatment with naloxone

blocked this effect. Human urinary retention induced by tramadol was also reported in

the medical literature (HHS review, 2010).

Respiratory Effect: Similar to other opioids that depress respiration, tramadol causes

a dose-response respiratory depression both in laboratory animals and patients.

Considering that naloxone partially blocks the respiratory depression caused by tramadol,

it was suggested that both monoaminergic and opioid mechanisms contributed to the

respiratory effects oftramadol (HHS review, 2010).

Other Effects: Other effects oftramadol including anti-tussive effect, nauseant and

emetic effects and intestinal effects were also reported extensively in medical literature

referenced by HHS review.

Several pre-clinical and clinical studies evaluating tramadol's abuse liability in

laboratory animals and human were documented in the HHS review and summarized

below:

Drug Discrimination Studies: Several drug discrimination studies using rats indicate

that tramadol displays symmetrical generalization to morphine (C-II). A study using rats

reported that a full generalization was achieved with morphine at doses of 2.37 mg/kg or

higher and with tramadol at doses of 32 mg/kg or higher. The generalizations by

morphine and tramadol were blocked by the concomitant administration of naltrexone

(0.01 - 0.05 mg/kg). Another study cited by HHS confirmed that tramadol generalized to

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morphine (C-II) through a p-opioid receptor mechanism. These studies indicate that the

discriminative stimuluscues of tramadol are typical of classical opioids like morphine.

Drug Self-Administration Studies: According to HHS review, there are published

reports documentingthe intravenous self-administration of tramadol in Rhesus monkeys.

Based on review of these studies, HHS stated that tramadol produces limited reinforcing

effects as compared to schedule II and III opioids, thereby supporting placement of

tramadol in a lower schedule level.

Human Abuse Potential Studies - Subjective Reinforcing Effects of Tramadol

In post-approval studies of a tramadol containing product, the abuse potential of

intravenous tramadol was compared to that of intravenous morphine. One single-blind

study showed that at the higher intravenous dose of 400 mg, tramadol produced opiate

like effects, including "liking" and a euphoric "high", that transiently surpassed that

produced by 20 mg morphine. Lower doses oftramadol were less effective in producing

these effects. According to HHS review, in light ofthe high doses oftramadol relative to

morphine required to produce reinforcing effects, tramadol has an abuse potential but it is

less than that of morphine (C-II). Another double-blind, single-dosed study found that

tramadol at intravenous doses of 100 mg and 200 mg has a lower abuse potential, than

that of intravenous morphine (C-II) at doses of 10 mg and 20 mg in non-dependent,

opioid experienced subjects. When comparing the abuse potential of oral tramadol to that

of oral oxycodone (C-II) in non-dependent, opioid experienced volunteers, the results

indicated that the effect oftramadol was slower in onset and longer in duration.

Tramadol (750 mg) also produced "liking" which was slower in onset and of longer

duration than that produced by oxycodone (C-II). Both studies provided support that

tramadol, particularly at the higher doses, produces subjective reinforcing effects, thereby

indicating an abuse potential for tramadol. According to HHS review, tramadol at high

doses produces subjective reinforcing effects similar to or approaching those of morphine

(C-II) and oxycodone (C-II).

In summary, pharmacological and efficacy studies indicate that tramadol primarily

acts via its Ml metabolite to interact with the p-opioid receptor to produce a variety of

pharmacological effects commonly produced by CSA-controlled opioids listed in

schedules II-IV. There tends to be a time delay in the appearance ofthese effects,

indicating the importance ofthe Ml metabolite in evoking the effects. Generalization to

the morphine stimulus cue provides additional support indicating that tramadol produces

effects similar to opioids (C-II, -III, and -IV). Additionally, tramadol can block the

reuptake of norepinephrine and serotonin and similar effects are also produced by such

opioids as meperidine (C-II), methadone (C-II) and levorphanol (C-II). 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 self-administration

studies suggest placement oftramadol in a schedule less restrictive than morphine(C-II).

Clinical studies also show that tramadol, at single high doses, produces subjective

reinforcing effects that are significantly greater than those of placebo and are similar to or

DEA/OD/ODE Page 10 of 21 May 2013
approach those produced by morphine (C-II) and oxycodone (C-II), respectively. A

similar dose response in producing subjective reinforcing effects occurs with

propoxyphene (C-IV) at elevated doses and this fact provides support for a similar abuse

potential and placement oftramadol into schedule IV ofCSA.

Factor 3: The State of Current Scientific Knowledge Regarding Tramadol

The chemical name oftramadol hydrochloride is (±) c/s-2-((dimethylamino) methyl)-

l-(3-methoxyphenyl)-cyclohexanol hydrochloride. Tramadol hydrochloride has a

molecular formula of C16H25NO2 HC1 with a molecular weight of 299.84. Because ofits

chemical structure, it can exist as different isomeric forms. Thus, various prefixes can be

associated with the name. Some example ofthese prefixes include dextro, levo, d, 1, R,

S, cis, trans, erythro, threo, (+), (-), Racemic, and may include combinations ofthese

prefixes sometimes with numerical designations. Using a prefix that identifies an

isomeric form in the name does not change the fact that it is 2-((dimethylamine)-mefhyl)-

l-(3-methoxyphenyl)-cyclohexano. Tramadol is typically identified as (±) cis-2-

((dimefhylamino) methyl)-l-(3-methoxyphenyl)-cyclohexanol hydrochloride. Registry

numbers for tramadol are CAS-36282-47-0 (hydrochloride salt) and CAS-27203-92-5

(base). Tramadol hydrochloride is a white, bitter, crystalline and odorless powder soluble

in water and ethanol.

According to HHS review, a linear pharmacokinetic pattern oftramadol has been

observed following multiple doses of 50 mg and 100 mg to a steady-state. Racemic

tramadol is rapidly and almost completely absorbed after oral administration. The mean

absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak

plasma concentration ofracemic tramadol and Ml occurs at two and three hours,

respectively, after administration in healthy adults. The volume of distribution of

tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100

mg intravenous dose. The binding oftramadol to human plasma proteins is

approximately 20% and the binding capability also appears to be independent of

concentration up to 10 pg/mL. Tramadol is extensively metabolized after oral

administration. Approximately 30% ofthe dose is excreted in the urine as unchanged

drug, whereas 60% ofthe dose is excreted as metabolites. The major metabolic pathways

appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One

metabolite (O-desmethyltramadol, or denoted Ml) is pharmacologically active in animal

models. Formation of Ml is dependent on cytochrome P450 2D6 (CYP2D6) and as such

is subject to inhibition, which may affect the therapeutic response. Tramadol is

eliminated primarily through metabolism by the liver and the metabolites are eliminated

primarily by the kidneys. The mean terminal plasma elimination half-lives ofracemic

tramadol and racemic Ml are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. Tramadol is

rapidly absorbed with a high bioavailability following rectal administration and

intramuscular injection.

In summary, tramadol hydrochloride is readily absorbed from the gastrointestinal

tract, or via subcutaneous, intramuscular and rectal routes. As the primary metabolite of

tramadol, Ml is primarily responsible for the opioid activity oftramadol. The

DEA/OD/ODE Page 11 of 21 May 2013
metabolism oftramadol, in part, may interact with other drugs that undergo metabolism

by the CYP2D6 enzyme.

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

FDA approved ULTRAM® (immediate-release oral tablets oftramadol) in 1995 for

the treatment ofmoderate to moderately severe pain. Since that time, a variety of other

tramadol products including immediate release forms, combination products and

extended release products have been approved for marketing in the U.S.

HHS collected and analyzed the data regarding tramadol prescriptions in the United

States and it included tramadol as an active ingredient in both immediate-release and

extended-release pharmaceutical products. HHS performed a comparison between

tramadol and other analgesics in terms of annual prescriptions dispensed over the period

of 2003 to 2008 from SDI prescription database. It was found that in 2007 and 2008,

more prescriptions were written for tramadol than for any other opioid other than

hydrocodone (C-III) and oxycodone (C-II). The annual number of prescriptions for

tramadol surpassed the annual number of prescriptions of proproxyphene (C-IV) and

codeine products (C-II, -III, and -V) in 2007 and 2008. In contrast to the consistent

incremental rise in annual prescriptions seen for tramadol over the period of 2003 to

2008, there was a consistent reduction in annual prescriptions for proproxyphene,

butorphanol (C-IV) and pentazocine (C-IV) 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 products (C-II, -III, and -V) over the period from 2003 to

2007. Over each ofthe 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 (C-II), methadone (C-II), hydromorphone (C-II), buprenorphine (C-III),

meperidine (C-II), butorphanol (C-IV), pentazocine (C-IV), and oxymorphone (C-II).

DEA further collected and analyzed updated data from IMS Health's National

Prescription Audit Plus , another major national prescription database and found a

similar trend from 2009 to 2011, as revealed by HHS's document, that more prescriptions

were dispensed for tramadol than for any other opioid other than hydrocodone (C-III) and

oxycodone (C-II).

DAWN managed by SAMHSA is a public health surveillance system that monitors

drug-related visits to hospital emergency departments (ED). HHS reviewed DAWN data

and found that abuse-related ED visits involving tramadol increased from 1995 (645

cases) to 2002 (1714 cases) peaking in 2001 (2329 cases). Tramadol abuse-related deaths

increased from 45 cases (1997) to 88 cases (2002). Over the period of 2004 through

2008, the number of estimated ED visits from nonmedical use oftramadol/combinations

showed a continuous increase from 4,849 ED visits to 11,850 ED visits. For each ofthe

years from 2004 through 2008, the annual nonmedical ED visits for

tramadol/combinations were well below that for fentanyl/combinations (C-II),

hydrocodone/combinations (C-III), morphine/combinations (C-II), and

oxycodone/combinations (C-II). DEA further collected the DAWN data of 2009 and

2010, and found that the national annual ED visits increased to 15,349 in 2009 and

16,251 in 2010, respectively.

DEA/OD/ODE Page 12 of 21 May 2013
HHS reviewed DAWN data and calculated the rates of estimated nonmedical ED

visits per 100,000 prescriptions dispensed for tramadol/combinations as well as other

selected opioids. HHS found that over the period of 2004 through 2007, the annual rates

oftramadol/combination ED visits ranged between 28.4 and 33.9 per 100,000

prescriptions. 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-II), methadone (C-II), hydromorphone (C-II),

morphine (C-II), fentanyl/combinations (C-II), meperidine/combinations (C-II),

hydrocodone combinations (C-III) and buprenorphine/combinations (C-III) (2006-2008

only). Over the period of 2004 through 2008, the rates of estimated nonmedical ED visits

for tramadol/combinations were more closely in the range for the rates of

codeine/combinations (C-II, -III, and -V) 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 100,000 prescriptions of

tramadol/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).

HHS reviewed the annual NSDUH report and found that the number of individuals

who used tramadol 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 regarding tramadol was lower than that of hydrocodone or oxycodone.

Additionally, for each ofthe years over the period of 2002 to 2007, the estimated number

of individuals who initiated use and reported nonmedical 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 ofthe years from 2002 to 2007, the number of past year initiates for use

of any pain reliever who also used hydrocodone (> 1,200,000) and oxycodone (>

450,000) nonmedically was greater than that oftramadol. In summary, the information

from the NSDUH shows that tramadol is used nonmedically. The lifetime nonmedical

use and past year nonmedical use oftramadol among new initiates of pain reliever use is

lower than that for oxycodone products (C-II) and hydrocodone products (C-III) and

supports placement oftramadol in a schedule less restrictive than schedule III .

As stated in Factor 1, the DEA-managed NFLIS and STRIDE databases provide

evidence that tramadol has been diverted and encountered by law enforcement personnel.

Such as in 2010, forensic laboratories analyzed 1,485 such exhibits and the tramadolcontaining exhibits were approximately similar in number to that of propoxyphene (Table

1). For each year, the number oftramadol exhibits was less than that ofthe schedule II

substances, oxycodone, methadone, morphine, hydromorphone, hydrocodone, and

codeine (C-II, -III, and -V). The relatively lower numbers of propoxyphene exhibits in

2011 and 2012 is because in November 2010, FDA recommended that propoxyphene (CIV) be withdrawn from the United States market due to the risk of cardiac toxicity.

DEA/OD/ODE Page 13 of 21 May 2013
These exhibits from criminal investigations involving tramadol provide evidence ofthe

significant diversion and nonmedical use oftramadol in the U.S.

HHS reviewed toxic exposure calls data from the National Poison Data System

(NPDS), a database ofthe American Association of Poison Control Centers (AAPCC),

and found that the number of case mentions of human toxic exposures to tramadol during

2004 through 2008 increased annually from 3,769 to 9,623. These are less than the case

mentions oftoxic exposures to hydrocodone (C-III) or oxycodone (C-II). Of 5,965,

7,500 and 9,623 total case mentions for tramadol in 2006, 2007, and 2008, respectively,

1,482, 1,847, 2,476 involved "intentional" exposure to tramadol alone. DEA further

reviewed the recent NPDS data and found that in 2009, 2010 and 2011, the number of

reported tramadol poison exposures totaled 10,255, 11,225 and 12,424, respectively. Of

these totals, intentional exposures to tramadol alone were 2,677, 2,867 and 3,170

resulting in 4, 3 and 6 deaths in 2009, 2010 and 2011, respectively. Furthermore, the

numbers oftoxic exposures for tramadol in 2009, 2010 and 2011 are also less than the

corresponding numbers for hydrocodone or oxycodone. HHS further found that the rates

oftoxic exposures calculated as number of case mentions per 100,000 prescriptions for

tramadol increased from 22 in 2004 to 37 in 2008. These rates oftoxic exposures for

tramadol during the period of 2004 through 2007 were lower than the corresponding rates

for oxycodone (C-II), morphine (C-II) and methadone (C-II). For the years 2004, 2005,

and 2006, the rates oftoxic exposures to tramadol were similar to that of propoxyphene

(C-IV). In 2007 and 2008, tramadol surpassed codeine (C-II, -III, and -V) and

propoxyphene (C-IV) in the number and rate oftoxic exposures. These data indicate that

tramadol represents a significantly growing risk to the public health.

Overall, data from DAWN, NSDUH, NFLIS, STRIDE and AAPCC-NPDS databases

collectively demonstrate the abuse, and diversion oftramadol in the U.S. With respect to

both the rates of nonmedical ED visits as reported in DAWN and the number of forensic

drug exhibits, and the rates oftoxic exposures, tramadol data most closely resembles that

of propoxyphene (C-IV). Data from the NSDUH also supports a schedule less restrictive

than that ofschedule II or 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, review ofstudies of abuse potential, and

consideration ofthe case reports described in HHS review document.

HHS stated that there is almost 15 years of post-marketing epidemiologic abuserelated data in the scientific literature and from the adverse events reporting system

(AERS) since tramadol's commercial availability in the U.S. The case reports describe

abnormal behavior that demonstrates an addiction liability oftramadol: 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

physicians in order to obtain more prescriptions for tramadol. Approximately 15 years of

post-marketing history now show that tramadol can and is being abused both in the

DEA/OD/ODE Page 14 of 21 May 2013
United States and other countries. The increasing 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.

Case reports in the medical literature provide information on patterns oftramadol

abuse when prescribed for clinical pain management. The case reports listed by HHS

review describe abuse oftramadol for its euphorigenic and sedating effects. The depicted

behavior illustrates an addiction to tramadol: drug craving, increasing the tramadol dose,

inflicting 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. These reports provide information on characteristics and

patterns of actual tramadol abuse with the development of dependence. Development of

iatrogenic addiction to tramadol due to medical treatments is also described in HHS

review.

The NSDUH data, discussed in detail in Factor 4, also provides evidence of the

nonmedical use oftramadol. According to the updated NSDUH data analyzed by DEA,

the estimated number of individuals who have used tramadol products non-medically at

least once in their lifetime increased from 1,990,000 in 2008 to 2,614,000 in 2011. For

each year from 2002 to 2011, the number of individuals reporting lifetime nonmedical

use oftramadol resulting from the NSDUH survey was lower than the corresponding

numbers for hydrocodone or oxycodone.

According to DAWN data, in 2008, an estimated 11,850 ED visits nationally were for

nonmedical use oftramadol. There is an increasing trend of annual nonmedical ED visits

from 2004 through 2008. With regard to the national estimates of ED visits of

nonmedical use and the rates ofthese visits per 100,000 prescriptions, the rate for

tramadol is similar to propoxyphene/combination and codeine/combination. DEA further

found that the national annual estimates of ED visits involving tramadol in 2009 and

2010 increased to 15,349 and 16,251 respectively.

These data from several databases collectively suggest that tramadol has abuse

potential and it adversely affects the public health. These data further support the

scheduling oftramadol with a schedule IV control of CSA.

Factor 6: What, If Any, Risk to the Public Health

According to HHS review, information from a variety ofsources and medical

literature shows that there is a risk to public health associated with the abuse oftramadol

due to its adverse effects similar to other opioids.

As stated in the HHS review, adverse effects associated with the use oftramadol

are documented in the label of a tramadol containing product approved by FDA in

September 9, 2009. Adverse effects occurring with tramadol are consistent with adverse

effects associated with other opioids. The incidence ofreported adverse effects increased

as the time oftramadol therapy increased. The overall incidence rates of adverse effects

DEA/OD/ODE Page 15 of 21 May 2013
oftramadol were similar with codeine containing drugs such as codeine phosphate 30 mg

with acetaminophen 300 mg (C-III). and codeine phosphate 30 mg with aspirin 325 mg

(C-III). Other adverse effects associated with tramadol included seizures, serotonin

syndrome, and respiratory depression. In a study oftramadol overdose from seven U.S.

poison centers over the period from October 1995 through August 1996, 126 cases of

overdosed tramadol presented multiple systematic symptoms ranging from cardiovascular

toxicity to significant neurologic toxicity including lethargy, nausea, tachycardia,

agitation, seizures, coma , hypertension and respiratory depression. The mechanism

underlying tramadol overdose toxicity is closely related to its p-opioid receptor activity

and its monoamine oxidase inhibitor (MAOI) activity.

Information from DAWN database shows that the rates of ED visits due to

nonmedical use oftramadol have been similar to that of propoxyphene (C-IV) but lower

than that ofschedule II and III opioids during the period of 2004 - 2008. HHS reviewed

the number of drug abuse deaths from DAWN database reported by the participating

medical examiners and coroners in selected areas and found a total of 395 tramadol

abuse-related deaths were reported to DAWN from 1997 to 2002. The DAWN data

demonstrates a risk to the public health associated with the nonmedical use oftramadol

that is similar to that of propoxyphene (C-IV).

The HHS reviewed the AAPCC's NPDS data and found that there was an increasing

public health risk associated with tramadol. Annual tramadol exposures increased from

3,769 in 2004 to 9,623 in 2008. DEA further reviewed the recent NPDS data and found

that the number oftramadol exposures continued to increase each year from 2009

through 2011. The numbers of human toxic exposures to tramadol were 10,255, 11,225

and 12,424 in 2009, 2010 and 2011, respectively. Ofthese totals, intentional exposures

to tramadol alone were 2,677, 2,867 and 3,170 resulting in 4, 3 and 6 deaths in 2009,

2010 and 2011, respectively. The HHS found that tramadol ranked third behind

hydrocodone (C-III) and oxycodone (C-II) in terms ofthe number of poison case

mentions of opioids in 2007 and 2008. Over this period, the rates of case mentions per

100,000 prescriptions for tramadol increased from 22 to 37. In addition, the rate of

tramadol case mentions was lower than that for oxycodone (C-II), morphine (C-II) and

methadone (C-II). In 2008, the rate oftramadol case mentions was less than that of

methadone (C-II) and morphine (C-II). For the years 2004, 2005, and 2006, the rates of

tramadol case mentions were similar to that of propoxyphene (C-IV).

The labeling information approved by FDA states that tramadol in excessive doses

either alone or in combination with other central nervous system depressants, including

alcohol, are a cause of drug-related deaths. Furthermore, a number ofreports in the

medical literature have documented deaths associated with tramadol. Other reports

document tramadol as a contributing factor to deaths in combination with other drugs

such as, but not limited to, benzodiazepines, serotonergic drugs and other antidepressants.

The annual number oftramadol-related deaths reported by medical examiners in the

DAWN database gradually increased from 1997 to 2004.

DEA/OD/ODE Page 16 of 21 May 2013
The HHS also reviewed tramadol associated mortality from the Florida Department

of Law Enforcement (FDLE). FDLE collects information on drug-related deaths as

reported by medical examiner offices across the state of Florida. The number of deaths

involving tramadol increased from 106 in 2003 to 235 in 2008. According to FDLE's

data, tramadol-related deaths were higher than heroin (C-I) related deaths in years from

2005 to 2008. For each ofthe years, the number of deaths involving tramadol was less

than the number of deaths involving hydrocodone (C-III), fentanyl (C-II), morphine (CII), oxycodone (C-II), methadone (C-II), and propoxyphene (C-IV), but higher than the

number of deaths involving meperidine (C-II) and hydromorphone (C-II) (except for

2007). DEA further reviewed the data for the recent years 2009, 2010 and 2011 and

found that tramadol-related deaths continued to increase. There were 268, 275, 379

tramadol-related deaths in 2009, 2010 and 2011, respectively.

In summary, the above mentioned data from a number ofsources indicate that

tramadol presents risks to the public health and, as such, supports the scheduling of

tramadol as a schedule IV substance under the CSA.

Factor 7: Tramadol's Psychic or Physiological Dependence Liability

According to HHS review, current information from pre-clinical and clinical studies

demonstrates that the repeated dosing with tramadol resulted in dependence development

as well as withdrawal syndrome following either abrupt termination oftramadol

treatment or administration of opioid antagonist. Furthermore, medical literature also

documents numerous case reports of physiological and physical dependence to tramadol.

As stated in HHS review document, a preclinical study ofspontaneous withdrawal of

tramadol in Rhesus monkeys found that the tested animals displayed "mild" or

"intermediate" withdrawal signs after the termination oftramadol administration for 8

weeks. This study demonstrated that tramadol has the potential to produce some physical

dependence as evidenced by naloxone precipitated withdrawal. Another finding in rats

cited by the HHS review indicating milder withdrawal signs with termination oftramadol

also confirmed that a physical dependence could be developed following repeated oral

administration oftramadol. In a withdrawal jumping test with mice, the results showed

that the number ofjumps in tramadol-treated animals was comparable with that of

propoxyphene (C-IV) and lower than that of codeine (C-II), methadone (C-II), and

morphine (C-II). Another naloxone precipitated jumping assay indicated that tramadol

produced a degree of physical dependence similar to that of propoxyphene (C-IV).

Furthermore, a short-term frequent intravenous infusion oftramadol in rats found that the

total withdrawal scores oftramadol were lower than that of morphine (C-II) following

naloxone administration. By comparing physical dependence development resulting

from repeated subcutaneous administration of either morphine (C-II) (100 and 1.05

mg/kg) or tramadol (100 or 39.1 mg/kg) to mice, another study concluded that tramadol

produced a lesser degree of physical dependence than morphine. These HHS-referenced

preclinical studies show that repeated exposure to tramadol results in mild to moderate

levels of physical dependence as evidenced by spontaneous or precipitated withdrawal.

These data also suggest that the degree of dependence development oftramadol is less

DEA/OD/ODE Page 17 of 21 May 2013
than that ofschedule II and schedule III, but similar to that ofschedule IV drugs such as

pentazocine (C-IV) and propoxyphene (C-IV).

According to HHS review, a number of clinical studies examined the ability of

tramadol to substitute for other opioids in individuals who are opioid dependent. A study

compared the effectiveness oftramadol versus buprenorphine in the treatment of opiate

withdrawal and reported that tramadol and buprenorphine (C-III) effectively managed

acute opioid withdrawal displayed by patients with mild to moderate addiction to heroin

(C-I). Another study compared the use oftramadol to that of clonidine for management

of acute heroin (C-I) withdrawal and found that tramadol was more effective in managing

withdrawal than clonidine (not scheduled), and may be useful in outpatient

detoxification. In examining tramadol for opioid withdrawal suppression in opioiddependent adults, one study revealed a cross dependence development between tramadol

and other opioids, such as morphine. A modest suppression of opioid withdrawal

produced by tramadol was also reported in subjects with a mild to moderate degree of

opioid physical dependence.

The HHS review cites several published case reports that provide evidence of cross

dependence development between tramadol and opioids, as seen by suppression of

withdrawal symptoms upon termination of extended tramadol treatment. Such as, one

case report indicated a cross-dependence development oftramadol to methadone (C-II)

and another study documented that the use of buprenorphine/naloxone (C-III) to alleviate

withdrawal symptoms caused by prolonged use of high doses oftramadol.

According to HHS review, as of September 9, 2009, 'Withdrawal symptoms may

occur" was documented in the "Warning" section ofthe label for a tramadol containing

product. Combining 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-II) or buprenorphine (C-III). The

available studies indicate that tramadol shows some cross dependence to heroin,

methadone, morphine and buprenorphine.

Collectively, all ofthe preclinical and clinical data show that tramadol produces a

modest level of physical dependence. These studies also suggest a degree of physical

dependence development less than that ofschedule II and III opioids and similar to that

ofschedule IV opioids.

Factor 8: Whether Tramadol Is an Immediate Precursor of a Substance Already

Controlled

Tramadol is not an immediate precursor of a substance already controlled.

III. Findings for Schedule Placement Pursuant to 21 U.S.C. 812(b)

DEA/OD/ODE Page 18 of 21 May 2013
21 U.S.C. § 812(b) requires the evaluation of a substance's abuse potential, accepted

medical use, and safety for use under medical supervision for placement in the CSA as a

controlled substance. After consideration ofthe above eight factors determinative of

control of a substance (21 U.S.C. § 811(c)), and a review ofthe scientific and medical

evaluation and scheduling recommendation provided by the HHS, DEA finds that

tramadol meets the following criteria for placement in schedule IV ofthe CSA, under 21

U.S.C. §812 (b)(4).

1) Tramadol has a potential for abuse less than the drugs or other substances in

Schedule III.

The collected information suggests that tramadol meets the criteria and indicators set

forth in the legislative history ofthe CSA for having an abuse potential. Individuals take

tramadol without medical supervision and in amounts sufficient to create a hazard to their

health as evidenced from various study reported in the medical literature, nonmedical use

in databases from DAWN, NSDUH and AAPCC. Tramadol has been diverted from

legitimate sources as evidenced by numerous reports in the medical literature as well as

in epidemiology and legal databases including NFLIS, STRIDE, DAWN, NSDUH and

AAPCC. Both pre-clinical and clinical studies show that tramadol, via its Ml metabolite,

produces a variety of pharmacological and toxicological effects similar to that of CSAcontrolled opioids known to have an abuse potential.

Collectively, the available information regarding tramadol supports an abuse potential

that is less than that ofschedule III and similar to that for schedule IV. Preclinical selfadministration studies show that tramadol produces limited reinforcing effects, consistent

with a lower schedule. Tramadol can produce subjective reinforcing effects similar to

that of morphine (C-II) and approaching that of oxycodone (C-II) at supra-therapeutic

doses. A similar dose dependency occurs with propoxyphene (C-IV), 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 are in a range causing sufficient adverse effects. These observations indicate that

the subjectivereinforcing effects, a reflection of abuse potential, of tramadol is less than

that of morphine or oxycodone, but similar to that of propoxyphene.

Dependence is one of the driving forces leadingto the tramadol abuse and scientific

information related to tramadol dependence provides evidence for tramadol's potential of

abuse. Several case reports describe physical and psychological dependence to tramadol

resulting from human abuse of high dosesof tramadol. Opioid withdrawal suppression

caused by tramadol was indicated in several clinical investigationsand the degree was

less than that produced by morphine or buprenorphine (C-III). The current clinical

studies on tramadol dependence suggest its abuse potential lower than that of schedule III

drugs, but similar to that of schedule IV.

Scientific evidence for indicating an abuse potential for tramadol at a level of

schedule IV is also supported by collected data from several epidemiological databases.

The NSDUH data indicates that the number ofindividuals reporting lifetime misuse of

DEA/OD/ODE Page 19 of 21 May 2013
tramadol was below that ofthe number of either oxycodone or hydrocodone. The

NSDUH result supports a scheduled level for tramadol less restrictive than schedule III.

The DAWN data also shows that the rate of ED visits related to tramadol is lower than

that of opioids in schedules II and III, but similar to that of propoxyphene. The 2008

NFLIS data demonstrate that the number ofseized tramadol by law enforcement agencies

was close to that of propoxyphene, thereby supporting a schedule IV control for

tramadol.

2) 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 United States.

3) Abuse of tramadol may lead to limited physical dependence or psychological

dependence relative to the drugs or other substances in schedule III.

Tramadol may lead to development of physical and psychological dependence as

documented in current product labels. In addition, several clinical case reports indicate

the development of physical and psychological dependence to tramadol. Both animal and

clinical studies also provide support that tramadol induces an opioid-like dependence.

The available information regarding reinforcing effects and drug dependence suggests

that the degree of physical dependence produced by tramadol is low, supporting

placement oftramadol in schedule IV.

DEA/OD/ODE Page 20 of 21 May 2013
References

j.

Department of Health and Human Services, FDA Review (2010): Basis for the

Recommendation to Schedule Tramadol In Schedule IV ofthe Controlled

Substances Act.

Data queried for tramadol (March, 2013),The National Forensic Laboratory

Information System (NFLIS), Office of Diversion Control, DrugEnforcement

Administration.

Dataqueried fortramadol (March, 2013), The System to Retrieve Information

from Drug Evidence (STRIDE), Office of Diversion Control, DrugEnforcement

Administration.

DEA/OD/ODE Page 21 of 21 May 2013