Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules 65923 

essential to, or that yields information 

that is essential to, the restoration or 

continuation of a bodily function 

important to the continuation of human 

life. 

Meaningful disruption means a 

change in production that is reasonably 

likely to lead to a reduction in the 

supply of a biological product by a 

manufacturer that is more than 

negligible and affects the ability of the 

manufacturer to fill orders or meet 

expected demand for its product, and 

does not include interruptions in 

manufacturing due to matters such as 

routine maintenance or insignificant 

changes in manufacturing so long as the 

manufacturer expects to resume 

operations in a short period of time. 

Significant disruption means a change 

in production that is reasonably likely 

to lead to a reduction in the supply of 

blood or blood components by a 

manufacturer that substantially affects 

the ability of the manufacturer to fill 

orders or meet expected demand for its 

product, and does not include 

interruptions in manufacturing due to 

matters such as routine maintenance or 

insignificant changes in manufacturing 

so long as the manufacturer expects to 

resume operations in a short period of 

time. 

Dated: October 28, 2013. 

Leslie Kux, 

Assistant Commissioner for Policy. 

[FR Doc. 2013–25956 Filed 10–31–13; 11:15 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1308 

[Docket No. DEA–351] 

Schedules of Controlled Substances: 

Placement of Tramadol Into Schedule 

IV 

AGENCY: Drug Enforcement 

Administration, Department of Justice. 

ACTION: Notice of proposed rulemaking. 

SUMMARY: The Drug Enforcement 

Administration (DEA) proposes to place 

the substance 2- 

((dimethylamino)methyl)-1-(3- 

methoxyphenyl)cyclohexanol, its salts, 

isomers, salts of isomers, and all 

isomeric configurations of possible 

forms including tramadol (the term 

‘‘isomers’’ includes the optical and 

geometric isomers) into Schedule IV of 

the Controlled Substances Act (CSA). 

This proposed action is based on a 

recommendation from the Assistant 

Secretary for Health of the Department 

of Health and Human Services (HHS) 

and an evaluation of all other relevant 

data by the DEA. If finalized, this action 

would impose the regulatory controls 

and administrative, civil, and criminal 

sanctions applicable to Schedule IV 

controlled substances on persons who 

handle (manufacture, distribute, 

dispense, import, export, engage in 

research, conduct instructional 

activities, or possess) or propose to 

handle tramadol. 

DATES: Interested persons may file 

written comments on this proposal 

pursuant to 21 CFR 1308.43(g). 

Electronic comments must be 

submitted, and written comments must 

be postmarked, on or before January 3, 

2014. Commenters should be aware that 

the electronic Federal Docket 

Management System will not accept 

comments after midnight Eastern Time 

on the last day of the comment period. 

Interested persons, defined as those 

‘‘adversely affected or aggrieved by any 

rule or proposed rule issuable pursuant 

to section 201 of the Act (21 U.S.C. 

811),’’ 21 CFR 1300.01, may file a 

request for hearing pursuant to 21 CFR 

1308.44 and in accordance with 21 CFR 

1316.45 and 1316.47. Requests for 

hearing, notices of appearance, and 

waivers of an opportunity for a hearing 

or to participate in a hearing must be 

received on or before December 4, 2013. 

ADDRESSES: To ensure proper handling 

of comments, please reference ‘‘Docket 

No. DEA–351’’ on all electronic and 

written correspondence. The DEA 

encourages that all comments be 

submitted electronically through the 

Federal eRulemaking Portal, which 

provides the ability to type short 

comments directly into the comment 

field on the Web page or attach a file for 

lengthier comments. Go to http://

www.regulations.gov and follow the online instructions at that site for 

submitting comments. An electronic 

copy of this document and 

supplemental information to this 

proposed rule are also available at the 

http://www.regulations.gov Web site for 

easy reference. Paper comments that 

duplicate electronic submissions are not 

necessary. All comments submitted to 

http://www.regulations.gov will be 

posted for public review and are part of 

the official docket record. Should you, 

however, wish to submit written 

comments in lieu of electronic 

comments, they should be sent via 

regular or express mail to: Drug 

Enforcement Administration, Attention: 

DEA Federal Register Representative/

ODW, 8701 Morrissette Drive, 

Springfield, Virginia 22152. All requests 

for hearing must be sent to Drug 

Enforcement Administration, Attention: 

Hearing Clerk/LJ, 8701 Morrissette 

Drive, Springfield, Virginia 22152. 

FOR FURTHER INFORMATION CONTACT: 

Ruth A. Carter, Chief, Policy Evaluation 

and Analysis Section, Office of 

Diversion Control, Drug Enforcement 

Administration, 8701 Morrissette Drive, 

Springfield, Virginia 22152; Telephone 

(202) 598–6812. 

SUPPLEMENTARY INFORMATION: Posting of 

Public Comments: Please note that 

comments received in response to this 

NPRM are considered part of the public 

record and will be made available for 

public inspection and posted at http:// 

www.regulations.gov and in the DEA’s 

public docket. Such information 

includes personal identifying 

information (such as your name, 

address, etc.) voluntarily submitted by 

the commenter. 

If you want to submit personal 

identifying information (such as your 

name, address, etc.) as part of your 

comment, but do not want it to be made 

public, you must include the phrase 

‘‘PERSONAL IDENTIFYING 

INFORMATION’’ in the first paragraph 

of your comment. You must also place 

all of the personal identifying 

information you do not want to be made 

publicly available in the first paragraph 

of your comment and identify what 

information you want redacted. 

If you want to submit confidential 

business information as part of your 

comment, but do not want it to be made 

publicly available, you must include the 

phrase ‘‘CONFIDENTIAL BUSINESS 

INFORMATION’’ in the first paragraph 

of your comment. You must also 

prominently identify confidential 

business information to be redacted 

within the comment. If a comment has 

so much confidential business 

information that it cannot be effectively 

redacted, all or part of that comment 

may not be made publicly available. 

Comments containing personal 

identifying information and confidential 

business information identified and 

located as set forth above will be made 

available in redacted form. The Freedom 

of Information Act (FOIA) applies to all 

comments received. If you wish to 

personally inspect the comments and 

materials received or the supporting 

documentation the DEA used in 

preparing the proposed action, these 

materials will be available for public 

inspection by appointment. To arrange 

a viewing, please see the FOR FURTHER

INFORMATION CONTACT paragraph, above. 


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1See infra footnote 2. 

2For simplicity’s sake, from this point forward in 

the document, ‘‘tramadol’’ is used to refer to 2- 

((dimethylamino)methyl)-1-(3- 

methoxyphenyl)cyclohexanol, its salts, isomers, 

salts of isomers, and all isomeric configurations of 

possible forms. 

Request for Hearing, Notice of 

Appearance at or Waiver of 

Participation in Hearing 

Pursuant to the provisions of the CSA 

(21 U.S.C. 811(a)), this action is a formal 

rulemaking ‘‘on the record after 

opportunity for a hearing.’’ Such 

proceedings are conducted pursuant to 

the provisions of the Administrative 

Procedure Act (APA) (5 U.S.C. 551– 

559). 21 CFR 1308.41–1308.45, and 21 

CFR part 1316 subpart D. In accordance 

with 21 CFR 1308.44(a)–(c), requests for 

hearing, notices of appearance, and 

waivers of an opportunity for a hearing 

or to participate in a hearing may be 

submitted only by interested persons, 

defined as those ‘‘adversely affected or 

aggrieved by any rule or proposed rule 

issuable pursuant to section 201 of the 

Act (21 U.S.C. 811).’’ 21 CFR 1300.01. 

Such requests or notices must conform 

to the requirements of 21 CFR 

1308.44(a) or (b), and 1316.47 or 

1316.48, as applicable, and include a 

statement of the interest of the person in 

the proceeding and the objections or 

issues, if any, concerning which the 

person desires to be heard. Any waiver 

must conform to the requirements of 21 

CFR 1308.44(c) and 1316.49, including 

a written statement regarding the 

interested person’s position on the 

matters of fact and law involved in any 

hearing. 

Please note that pursuant to 21 U.S.C. 

811(a), the purpose and subject matter 

of a hearing is restricted to ‘‘(A) 

find[ing] that such drug or other 

substance has a potential for abuse, and 

(B) mak[ing] with respect to such drug 

or other substance the findings 

prescribed by subsection (b) of section 

812 of this title for the schedule in 

which such drug is to be placed. * * *’’ 

Requests for hearing, notices of 

appearance at the hearing, and waivers 

of an opportunity for the hearing or to 

participate in the hearing should be 

submitted to the DEA using the address 

information provided above. 

Legal Authority 

The DEA implements and enforces 

titles II and III of the Comprehensive 

Drug Abuse Prevention and Control Act 

of 1970, as amended. Titles II and III are 

referred to as the ‘‘Controlled 

Substances Act’’ and the ‘‘Controlled 

Substances Import and Export Act,’’ 

respectively, but they are collectively 

referred to as the ‘‘Controlled 

Substances Act’’ or the ‘‘CSA’’ for the 

purposes of this action. 21 U.S.C. 801– 

971. The DEA publishes the 

implementing regulations for these 

statutes in title 21 of the Code of Federal 

Regulations (CFR), parts 1300 to 1321. 

The CSA and its implementing 

regulations are designed to prevent, 

detect, and eliminate the diversion of 

controlled substances and listed 

chemicals into the illicit market while 

providing for the legitimate medical, 

scientific, research, and industrial needs 

of the United States. Controlled 

substances have the potential for abuse 

and dependence and are controlled to 

protect the public health and safety. 

Under the CSA, controlled substances 

are classified in one of five schedules 

based upon their potential for abuse, 

their currently accepted medical use, 

and the degree of dependence the 

substance may cause. 21 U.S.C. 812. The 

schedules of controlled substances 

established by Congress are found at 21 

U.S.C. 812(c), and the current list of 

scheduled substances is published at 21 

CFR part 1308. Pursuant to 21 U.S.C. 

811(a)(1), the Attorney General may, by 

rule, ‘‘add to such a schedule or transfer 

between such schedules any drug or 

other substance if he (A) finds that such 

drug or other substance has a potential 

for abuse, and (B) makes with respect to 

such drug or other substance the 

findings prescribed by subsection (b) of 

section 812 of this title for the schedule 

in which such drug is to be placed 

* * *.’’ Pursuant to 28 CFR 0.100(b), 

the Attorney General has delegated this 

scheduling authority to the 

Administrator of the DEA, who has 

further delegated this authority to the 

Deputy Administrator of the DEA. 28 

CFR 0.104. 

The CSA provides that scheduling of 

any drug or other substance may be 

initiated by the Attorney General (1) on 

his own motion; (2) at the request of the 

Secretary of the HHS; or (3) on the 

petition of any interested party. 21 

U.S.C. 811(a). This proposed action is 

based on a recommendation from the 

Assistant Secretary for Health of the 

HHS and on an evaluation of all other 

relevant data by the DEA. If finalized, 

this action would impose the regulatory 

controls and administrative, civil, and 

criminal sanctions of Schedule IV 

controlled substances on persons who 

handle (manufacture, distribute, 

dispense, import, export, engage in 

research, conduct instructional 

activities, or possess) or propose to 

handle tramadol.1

Background 

Tramadol is an opioid analgesic that 

produces its primary opioid-like action 

through an active metabolite, referred to 

as the ‘‘M1’’ metabolite (Odesmethyltramadol). Since March 1995, 

tramadol has been available as a noncontrolled and centrally acting opioid 

analgesic under the trade name 

ULTRAM® approved by the Food and 

Drug Administration (FDA) in the 

United States. Subsequently, the FDA 

approved generic, combination, and 

extended release products of tramadol. 

Because of its chemical structure, 2- 

((dimethylamino)methyl)-1-(3- 

methoxyphenyl)cyclohexanol can exist 

as different isomeric forms. Thus, 

various prefixes can be associated with 

the name. Some examples of these 

prefixes include dextro, levo, d, l, R, S, 

cis, trans, erythro, threo, (+), (¥), 

racemic, and may include combinations 

of these prefixes sometimes with 

numerical designations. Any such 

isomer is, in fact, 2- 

((dimethylamino)methyl)-1-(3- 

methoxyphenyl)cyclohexanol. Tramadol 

is typically formulated as a racemic 

mixture identified as (±)-cis-2- 

((dimethylamino)methyl)-1-(3- 

methoxyphenyl)cyclohexanol 

hydrochloride.2

Proposed Determination To Schedule 

Tramadol 

The DEA received four petitions 

between October and November 2005 

requesting that tramadol be controlled 

as a scheduled substance under the 

CSA. Three of these petitions 

specifically requested the placement of 

tramadol into Schedule III; the 

remaining petition did not specify a 

schedule for control. One of the 

petitioners stated that ‘‘tramadol has 

significant abuse potential, consistent 

with its pharmacology. This abuse has 

significant public health policy 

implications.’’ 

Pursuant to 21 U.S.C. 811(b) of the 

CSA, the DEA gathered the necessary 

data on tramadol and, on April 25, 2007 

submitted it to the Assistant Secretary of 

the HHS with a request for a scientific 

and medical evaluation and the 

Secretary’s recommendation as to 

whether or not tramadol should be 

added as a controlled substance, and, if 

so, in which schedule. On September 

16, 2010, the HHS provided to the DEA 

a written scientific and medical 

evaluation and scheduling 

recommendation entitled ‘‘Basis for the 

Recommendation to Schedule Tramadol 

in Schedule IV of the Controlled 

Substances Act.’’ In this 

recommendation, the HHS presented its 

eight-factor analysis as required under 

21 U.S.C. 811(b), and recommended that 


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3As defined by the DAWN glossary, non-medical 

use of pharmaceuticals includes prescription and 

over-the-counter pharmaceuticals in ED visits that 

are of the following types of cases: 

Overmedication—Patient took too much of his/ 

her prescription medication. 

Malicious poisoning—Drug use in which the 

patient was administered a drug by another person 

for a malicious purpose. 

Other—This category includes all drug-related ED 

visits that could not be assigned into any of the 

other classifications used by DAWN (suicide, 

attempt, seeking detox, alcohol only (under 21), 

adverse reaction, overmedication, malicious 

poisoning, and accidental ingestion). 

Non-medical use may involve pharmaceuticals 

alone or pharmaceuticals in combination with illicit 

drugs or alcohol. 

4Because the primary focus of law enforcement 

agencies (with respect to drugs) is on investigating 

the unlawful distribution of drugs, the incidents in 

which tramadol has been seized in the course of 

law enforcement investigations supports a finding 

that the drug is being abused and/or diverted from 

legitimate channels. Moreover, because tramadol is 

not controlled in most states there is reason to 

believe that many laboratories may not report those 

incidents in which they have identified a substance 

as tramadol. This suggests that tramadol would 

likely rank substantially higher in NFLIS data were 

it controlled nationally. 

5While NFLIS data is not direct evidence of 

abuse, it can lead to an inference that a drug has 

been diverted or abused. 76 FR 77330, 77332, Dec. 

12, 2011. 

tramadol be added to Schedule IV of the 

CSA. In response, the DEA reviewed the 

scientific and medical evaluation and 

scheduling recommendation provided 

by the HHS and all other relevant data, 

and completed an eight-factor review 

document pursuant to 21 U.S.C. 811(c) 

in February 2011. Included below is a 

brief summary of each factor as 

analyzed by the HHS in its 2010 

transmittal and the DEA in its 2011 

analysis, and as considered by the DEA 

in its proposed scheduling decision. 

Please note that both the DEA and HHS 

analyses are available in their entirety 

under ‘‘Supporting and Related 

Material’’ of the public docket for this 

rule at http://www.regulations.gov 

under docket number ‘‘DEA–351.’’ Full 

analysis of, and citations to, information 

referenced in the summary may also be 

found in the supporting material. 

1. The Drug’s Actual or Relative 

Potential for Abuse: Data gathered by 

the DEA and HHS indicate that since 

the initial marketing of tramadol in 

1995, tramadol has been, and currently 

is, abused for its opioid effects. The 

DEA has considered all relevant data 

and found that: 

a. Individuals Are Taking Tramadol in 

Amounts Sufficient To Create a Hazard 

to Their Health or to the Safety of Other 

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 

a hazard to their health, to the safety of 

other individuals, and to the 

community. Tramadol abuse is 

associated with serious adverse events 

including death, drug dependence, drug 

withdrawal symptoms, seizures, 

serotonin syndrome, and other serious 

medical problems. 

DAWN is a database, managed by the 

Substance Abuse and Mental Health 

Services Administration (SAMHSA), 

which collects data on drug-related 

emergency department (ED) visits from 

a nationally representative sample of 

hospitals in the United States and a 

selection of metropolitan areas. The 

HHS reviewed and analyzed DAWN 

data from 2004 through 2008 and found 

that the estimated annual non-medical 3

Emergency Department (ED) visits from 

non-medical use of tramadol and its 

combinations (hereinafter ‘‘tramadol/

combinations’’) continually increased 

from 4,849 ED visits to 11,850 ED visits. 

The DEA also evaluated more recent 

DAWN data and found that this 

increasing trend for tramadol continued 

in 2009 and 2010 (15,349 and 16,251 ED 

visits, respectively). 

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 United States. The NPDS 

collects information from the poison 

centers across the United States. The 

HHS reviewed the NPDS data 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. The DEA 

reviewed the more recent NPDS data 

and found that in 2009, 2010, and 2011, 

the number of reported tramadol poison 

exposures, alone and in combination 

with other drugs, totaled 10,255; 11,225; 

and 12,424, respectively. Of these totals, 

intentional exposures to tramadol alone 

(i.e., exposures not including tramadol/ 

combinations or tramadol in 

combination with any other substances) 

were 2,677; 2,867; and 3,170, resulting 

in four deaths in 2009, three deaths in 

2010, and six deaths in 2011. 

b. There Is a Significant Diversion of 

Tramadol From 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 

of the years from 2000 through 2012, 

tramadol was present in drug exhibits 

seized in the course of law enforcement 

activity.4 The tramadol exhibits seized 

by law enforcement involving drug 

abuse indicate the diversion of tramadol 

in the United States 5 Tramadol exhibits 

increased from a total of 82 in 2000 to 

1,806 in 2012 (NFLIS data). In 2010, this 

number was greater than the number of 

exhibits shown to contain pentazocine 

(96, Schedule IV), but less than the 

number of hydrocodone (45,627, 

Schedule III), codeine (3,679, Schedules 

II, III, V), and buprenorphine (10,167, 

Schedule III) exhibits (NFLIS data). The 

number of tramadol exhibits is similar 

to that of propoxyphene (1,320, 

Schedule IV) (2010 NFLIS data). 

However, the reduced number of 

propoxyphene exhibits (561) in 2011 is 

significantly less than that of tramadol 

(1,704) due to the FDA’s 

recommendation to withdraw 

propoxyphene from the United States 

market. 

A post-marketing study published in 

2002 and cited by the HHS’s review 

document 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. Another study referred to in 

the HHS review noted that from January 

2002 through March 2004 there were 72 

cases involving the diversion of 

tramadol from all 50 state law 

enforcement agencies. However, the 

number of tramadol diversion cases was 

less than the number of diversion cases 

associated with hydrocodone and 

oxycodone. 

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 

The DEA’s evaluation found that 

current evidence indicates that 

individuals take tramadol on their own 

initiative without medical consultation. 

This evidence includes case reports of 

abuse and dependence on tramadol in 

the medical literature, national drug 

abuse monitoring systems, and 

epidemiological data (DAWN, NFLIS, 

STRIDE, AAPCC, and the National 

Survey on Drug Use and Health 

(NSDUH)). 

DAWN data show that from 2004 to 

2010, the national annual estimates of 

ED visits related to non-medical use or 


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6Since 2004, DAWN has defined ‘‘drug misuse or 

abuse’’ as a group of ED visits including all visits 

associated with the non-medical use of 

pharmaceuticals. 

abuse 6 of tramadol/combinations 

increased from 4,849 to 16,251. Upon 

normalization of the number of nonmedical ED visits relative to 100,000 

prescriptions dispensed, the rate of ED 

visits for tramadol/combinations was 

found similar to the rates for 

propoxyphene. 

The NSDUH, operated by 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 non-medical use of 

opioids and pain relievers. The 

estimated number of individuals who 

have used tramadol products nonmedically at least once in their lifetime 

increased from 994,000 in 2002 to 

2,614,000 in 2011. 

The NPDS from AAPCC reported that 

the number of tramadol exposures 

increased each year between 2004 

(3,769 cases) and 2011. In 2011, the 

number of reported tramadol poison 

exposures totaled 12,424. Of these total 

poison exposures in 2011, the 

intentional exposures to tramadol alone 

(i.e., not tramadol/combinations or in 

combination with other substances) 

were 3,170—six of which resulted in 

death. These findings indicate that 

tramadol poses a significant threat to the 

public health. 

d. Tramadol is so Related in Its Action 

to a Drug or Other 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 

According to the HHS review, 

tramadol shares many similar 

pharmacological activities with some 

opioids scheduled under the CSA. As 

such, the abuse potential of tramadol 

would be expected to be related to its 

opioid properties. As a result, tramadol 

would be expected to be diverted from 

legitimate sources, be used without 

medical supervision, and consequently 

be a safety concern to individuals and 

the community. 

The opioid activity of tramadol is 

primarily due to the ‘‘M1’’ metabolite. 

Compared to other opioids, tramadol 

showed a longer onset of action due to 

accumulation of the active metabolite 

and its effects include analgesia, 

respiratory depression, miosis, cough 

suppression, and inhibition of bowel 

motility. Preclinical studies demonstrate 

that tramadol, like other opioids in 

Schedules I through IV, exhibits 

complete generalization to morphine 

and is able to produce some reinforcing 

effects. Repeated administration of 

tramadol in animals caused dependence 

development, evidenced by a 

withdrawal syndrome similar in 

intensity to pentazocine (Schedule IV) 

or propoxyphene (Schedule IV). Human 

studies reveal that tramadol produces 

some reinforcing subjective effects at 

high doses. A similar dose response 

pattern at high doses with 

propoxyphene 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 the 

HHS review, several studies examining 

chemical abuse potential suggest that 

the subjective reinforcing effect of 

tramadol is less than that of Schedule II 

opioids and more comparable to that of 

propoxyphene. 

In summary, the abuse potential of 

tramadol is similar to that of substances 

in Schedule IV (such as propoxyphene) 

of the CSA. The accumulated 

information demonstrates that 

individuals take 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 CSAcontrolled opioids known to have an 

abuse potential. Furthermore, the 

available information regarding 

reinforcing effects and drug dependence 

shows that the abuse potential of 

tramadol is less than that of morphine 

(Schedule II), oxycodone (Schedule II), 

or buprenorphine (Schedule III), but 

similar to that of propoxyphene 

(Schedule IV). Additionally, 

epidemiological data also support an 

abuse potential for tramadol that is 

similar to substances in Schedule IV of 

the CSA. These data suggest that 

tramadol has an abuse potential 

warranting control under the CSA. 

The DEA and HHS believe that 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. Obtained or diverted from 

legitimate sources, individuals take 

tramadol in the absence of medical 

supervision and in amounts sufficient to 

create a hazard to their health. Tramadol 

produces effects similar to opioids 

known to have an abuse potential and 

that are controlled under the CSA. 

2. Scientific Evidence of the Drug’s 

Pharmacological Effects, if Known: The 

DEA and HHS recognize tramadol as an 

opioid analgesic with monoaminergic 

activity that contributes to its analgesic 

effects. The M1 metabolite of tramadol 

contributes to its opioid effects and may 

be the cause of the delayed and 

prolonged activity associated with 

tramadol administration. Tramadol can 

block the reuptake of norepinephrine 

and serotonin, effects also produced by 

such opioids as meperidine (Schedule 

II), methadone (Schedule II), and 

levorphanol (Schedule II). 

Preclinical animal studies found that 

tramadol demonstrated a dose-related 

anti-nociceptive effect. Its analgesic 

effects were compared to other Schedule 

III and IV opioid analgesics. In clinical 

trials for treatment in human subjects, 

tramadol was less effective than 

hydrocodone/acetaminophen (Schedule 

III), but displayed an analgesic effect 

similar to that of pentazocine (Schedule 

IV), and superior or similar to the 

propoxyphene/acetaminophen 

combination (Schedule IV) in relieving 

postoperative pain. 

Tramadol produces abuse liabilityrelated effects in various animal models 

and humans. It has been selfadministered by monkeys, producing 

reinforcing effects which qualitatively 

show a similarity to opioids. In a drug 

discrimination study using rats, 

tramadol was shown to produce 

systematic generalization to morphine. 

Similar to other opioids in Schedules II 

through IV, tramadol fully substituted 

for discriminative effects of morphine 

and morphine fully substituted for 

tramadol. Drug discriminative studies 

showed that tramadol is comparable to 

other Schedule III and IV opioids. 

Physical dependence of tramadol has 

been demonstrated in studies on 

animals and humans. 

Most adverse effects are related to 

tramadol’s opioid activity including 

sedation, nausea, vomiting, 

constipation, and respiratory 

depression. However, a small but 

significant portion of individuals who 

use tramadol will experience seizures. 

The risk of seizures increases with dose 

and is relatively common among 

tramadol abusers. Further, clinical 

studies show that tramadol, at a single 

dose greater than the therapeutically 

prescribed-dose, produces subjective 

reinforcing effects that are significantly 

greater than those of placebos, and are 

similar to or approach those produced 

by morphine and oxycodone. A similar 

dose dependency in producing 

subjective reinforcing effects was also 


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7The various studies cited throughout this rule 

interchangeably use the terms ‘‘hydrocodone 

products,’’ ‘‘hydrocodone combinations,’’ and 

‘‘hydrocodone combination products’’ to refer to the 

controlled substance hydrocodone combined with 

one or more active ingredients (Schedule III). The 

DEA uses the term ‘‘hydrocodone combination 

products’’ to refer to these controlled substances. 

8 DAWN was redesigned in early 2003, which 

resulted in a permanent disruption in trends for the 

years prior to 2003. Therefore, comparisons cannot 

be made between the previous DAWN system 

(before 2002) and the current DAWN system. 

Additionally, before 2002, DAWN collected data on 

‘‘drug abuse cases’’ whereas now it collects data on 

all types of ‘‘drug-related’’ ED visits’’ (i.e., ‘‘nonmedical visits’’). 

9Only data from 2006 to 2008 was available for 

buprenophrine/combinations. 

observed with propoxyphene at doses 

greater than the therapeutically 

prescribed dose. This similarity between 

tramadol and propoxyphene provides 

support for a similar abuse potential and 

placement of tramadol into Schedule IV. 

3. The State of Current Scientific 

Knowledge Regarding the Drug or Other 

Substance: The chemical name of 

tramadol hydrochloride is (±)-cis-2- 

[(dimethylamino)methyl]-1-(3- 

methoxyphenyl) cyclohexanol 

hydrochloride. Tramadol hydrochloride 

has a molecular formula of C16H25NO2

HCl with a molecular weight of 299.84. 

Because of tramadol’s chemical 

structure, it can exist as different 

isomeric forms. Thus, various prefixes 

can be associated with the name. Some 

examples of these prefixes include 

dextro, levo, d, l, R, S, cis, trans, 

erythro, threo, (+), (-), racemic, and may 

include combinations of these prefixes 

sometimes with numerical designations. 

Any such isomer is, in fact, 2- 

[(dimethylamino) methyl]-1-(3- 

methoxyphenyl)cyclohexanol. It is 

typically formulated as a racemic 

mixture identified as (±)-cis-2- 

[(dimethylamino)methyl]-1-(3- 

methoxyphenyl) cyclohexanol 

hydrochloride. Tramadol hydrochloride 

is a white, crystalline, and odorless 

powder soluble in water and ethanol. 

Tramadol is readily absorbed from the 

gastrointestinal tract, with both 

enantiomers as well as the M1 

metabolite found in the blood following 

administration. Tramadol undergoes 

extensive metabolism in the liver, while 

90 percent of tramadol and its 

metabolites are excreted via the kidneys. 

Approximately 10 to 30 percent of the 

parent drug is excreted un-metabolized 

with an elimination half-life of about 5.5 

hours. This extensive metabolism, in 

part, provides for possible interactions 

between tramadol and a variety of other 

drugs that undergo metabolism by the 

CPY2D6 enzyme. 

4. Its History and Current Pattern of 

Abuse: Tramadol has been abused since 

its marketing approval in 1995 by a 

wide spectrum of individuals of 

different ages, alone and in combination 

with other psychoactive substances. 

Data from Surveillance Data, Inc. (SDI)’s 

prescription database comparing 

tramadol and other analgesics in terms 

of annual prescriptions dispensed show 

that in 2007 and 2008, more 

prescriptions were written for tramadol 

than for any other opioid other than 

hydrocodone combination products 7

(Schedule III) and oxycodone (Schedule 

II). The annual number of prescriptions 

for tramadol surpassed the annual 

number of prescriptions for 

propoxyphene (Schedule IV) and 

codeine (Schedules II, III, V) in 2007 

and 2008. Over each of the five years 

from 2003 to 2007, there was a 

consistent multi-fold greater number of 

prescriptions written for tramadol 

compared to such analgesics as 

morphine (Schedule II), fentanyl 

(Schedule II), methadone (Schedule II), 

hydromorphone (Schedule II), 

buprenorphine (Schedule III), 

meperidine (Schedule II), butorphanol 

(Schedule IV), pentazocine (Schedule 

IV), and oxymorphone (Schedule II). 

Updated information from another 

major national prescription database, 

IMS Health’s National Prescription 

Audit PlusTM, demonstrated a similar 

trend from 2009 to 2011: more 

prescriptions were written for tramadol 

than for any other opioid other than 

hydrocodone and oxycodone. 

According to the HHS, abuse-related 

ED visits involving tramadol as reported 

in DAWN increased from 1995 (645 

cases) to 2002 (1,714 cases), peaking in 

2001 (2,329 cases).8 Tramadol abuserelated deaths increased from 45 cases 

in 1997 to 88 cases in 2002. Over the 

period of 2004 through 2008, the 

number of estimated ED visits from nonmedical use of tramadol/combinations 

showed a continuous increase from 

4,849 ED visits to 11,850 ED visits. The 

DEA further reviewed the DAWN data 

for 2009 and 2010 and found that the 

national annual ED visits involving 

tramadol increased to 15,349 in 2009 

and 16,251 in 2010. 

The 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. The HHS found that from 2004 

to 2007, the annual rates of non-medical 

tramadol/combination ED visits ranged 

between 28.4 and 33.9. In 2008, there 

was a substantial increase in the rate of 

ED visits of tramadol/combinations to 

45.8 ED visits per 100,000 prescriptions. 

Over the five year period (2004 to 2008), 

annual rates of tramadol ED visits were 

substantially below that of rates for 

oxycodone/combinations (Schedule II), 

methadone (Schedule II), 

hydromorphone (Schedule II), morphine 

(Schedule II), fentanyl/combinations 

(Schedule II), meperidine/combinations 

(Schedule II), hydrocodone/

combinations (Schedule III), and 

buprenorphine/combinations (Schedule 

III).9 Over the period of 2004 through 

2008, the rates of estimated non-medical 

ED visits for tramadol/combinations 

were more closely in the range for the 

rates of codeine/combinations 

(Schedules II, III, V) and 

proproxyphene/combinations (Schedule 

IV). For example, in 2008, the rate of 

non-medical 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). 

Overall, these data suggest that the 

abuse potential of tramadol is less than 

that of Schedule II and III substances 

and most similar to that of 

propoxyphene (Schedule IV). 

According to the annual NSDUH 

report, the number of individuals who 

used tramadol non-medically at least 

once in their lifetime increased from 

approximately 994,000 in 2002 to 

2,614,000 in 2011. For each year 

surveyed, the absolute number 

regarding tramadol was lower than that 

of hydrocodone combination products 

or oxycodone products. Additionally, 

for each of the years from 2002 to 2007, 

the estimated number of individuals 

who initiated use and reported nonmedical use of tramadol 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 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) non-medically 

was greater than that of tramadol. The 

DEA further analyzed the updated 

NSDUH data and found that the 

estimated number of individuals who 

have used tramadol products nonmedically 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 lower than that of 

oxycodone (Schedule II) and 

hydrocodone combination products 

(Schedule III). Collectively, the 

information from NSDUH shows that 

tramadol is used non-medically and 

supports placement of tramadol in a 


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schedule less restrictive than Schedule 

III. 

NFLIS and STRIDE databases provide 

evidence that tramadol has been 

diverted from legitimate use and 

encountered by law enforcement 

personnel. Furthermore in 2010, 

forensic laboratories analyzed 1,485 

such exhibits and the tramadolcontaining exhibits were close in 

number to that of exhibits for 

propoxyphene (Schedule IV) (1,320). 

The relative lower number of 

propoxyphene exhibits in 2011 and 

2012 is because in November 2010, the 

FDA recommended that propoxyphene 

be withdrawn from the United States 

market due to the risk of cardiac 

toxicity. These exhibits from criminal 

investigations involving tramadol 

provide evidence of the significant 

diversion and non-medical use of 

tramadol in the United States. 

The NPDS demonstrates that from 

2004 to 2011, the number of human 

poison exposures to tramadol increased 

annually from 3,769 to 12,424. 

However, the number of exposures for 

tramadol is also less than the number of 

exposures for hydrocodone combination 

products (Schedule III) or oxycodone 

(Schedule II). The HHS calculated the 

number of case mentions per 100,000 

prescriptions for tramadol and several 

other opioids and found that the 

tramadol case mentions per 100,000 

prescriptions increased from 22 in 2004 

to 37 in 2008. The HHS also found that 

from 2004 to 2007, the NPDS rates of 

tramadol case mentions per 100,000 

prescriptions were lower than for 

oxycodone (Schedule II), morphine 

(Schedule II), and methadone (Schedule 

II). For the years 2004, 2005, and 2006, 

the rates of tramadol cases were similar 

to that of propoxyphene (Schedule IV). 

In 2007 and 2008, tramadol surpassed 

codeine (Schedules II, III, V) and 

propoxyphene (Schedule IV) in the 

number and rate of case mentions. 

These data indicate that tramadol 

represents a significantly growing risk to 

the public. 

Collectively, data from DAWN, 

NSDUH, NFLIS, STRIDE, and AAPCC– 

NPDS databases demonstrate the 

misuse, abuse, and diversion of 

tramadol in the United States. With 

respect to the rates of non-medical ED 

visits found in DAWN, the number of 

NFLIS exhibits, and the increasing rates 

of AAPCC’s NPDS reporting, tramadol 

data most closely resembles that of 

propoxyphene (Schedule IV). 

5. The Scope, Duration, and 

Significance of Abuse: The scope, 

duration, and significance of tramadol 

abuse is evidenced by findings of 

national monitoring databases for drug 

abuse, review of studies of abuse 

potential, and clinical case reports. The 

HHS concluded its 15 years of postmarketing epidemiologic abuse-related 

data in the scientific literature and from 

the adverse events reporting system 

(AERS) since tramadol’s commercial 

availability in the United States. The 

case reports describe abnormal behavior 

that demonstrates an addiction liability 

of 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 

physicians in order to obtain more 

prescriptions for tramadol. 

Approximately 15 years of postmarketing history now show that 

tramadol can be, and is being, abused 

both in the United States and other 

countries. 

Clinical case reports in the medical 

literature provide information on 

patterns of tramadol abuse when 

prescribed for clinical pain 

management. The case reports listed by 

the HHS review describe abuse of 

tramadol 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 reported. 

The NSDUH data, discussed in detail 

in Factor 4, also provides evidence of 

the non-medical use of tramadol. 

According to the NSDUH data, the 

estimated number of individuals who 

have used tramadol products nonmedically at least once in their lifetime 

increased from 994,000 in 2002 to 

2,614,000 in 2011. For each year from 

2002 to 2007, the number of individuals 

reporting either lifetime non-medical 

use or past-year non-medical use of 

tramadol was lower than the number of 

that of hydrocodone or oxycodone. The 

estimated number of individuals who 

have used tramadol products nonmedically at least once in their lifetime 

increased from 2008 to 2011, but these 

numbers for tramadol are still lower 

than that of oxycodone (Schedule II) 

and hydrocodone combination products 

(Schedule III). 

According to DAWN data, in 2010, an 

estimated 16,251 ED visits nationally 

were for non-medical use of tramadol. 

There is an increasing annual trend of 

non-medical ED visits from 2004 

through 2010. Furthermore, the HHS 

reviewed the national estimates of ED 

visits related to non-medical use and to 

rates of these visits per 100,000 

prescriptions from 2004 to 2008, and 

found tramadol most closely compares 

to propoxyphene (Schedule IV) and to 

codeine (Schedules II, III, V). 

Collectively, the data shows that 

tramadol has less abuse potential than 

other pure mu-receptor agonists 

currently controlled in Schedule II. As 

evaluated by the HHS and the DEA, the 

DAWN data indicates tramadol most 

closely compares to propoxyphene 

(Schedule IV) and codeine (Schedules 

II, III, V). The NSDUH data from 2002 

to 2007, cited by the HHS, also indicates 

the number of individuals reporting 

non-medical use of tramadol was lower 

than that of individuals using 

hydrocodone combination products 

(Schedule III) and oxycodone (Schedule 

II) products, suggesting an abuse 

potential less than that of Schedule III. 

Tramadol’s similarity to other 

controlled opioids and clear evidence of 

significant non-medical use and abuse, 

accompanied by serious adverse events, 

indicate that tramadol has sufficient 

abuse potential and incidence of drug 

dependence and addiction to warrant 

control as a Schedule IV controlled 

substance under the CSA. 

6. What, if any, Risk There is to the 

Public Health: The DEA analysis 

indicates that there are numerous risks 

to the public health that may result from 

tramadol abuse. Tramadol and its M1 

metabolite are opiate agonists devoid of 

opioid antagonist activity. Adverse 

effects occurring with tramadol are 

consistent with adverse effects 

associated with other opioids. The 

incidence of reported adverse effects 

increased as the time of tramadol 

therapy increased. The overall 

incidence rates of adverse effects of 

tramadol were similar to that of codeine 

containing drugs. Other adverse effects 

associated with tramadol included 

seizures, serotonin syndrome, and 

respiratory depression. Case studies of 

tramadol overdoses from United States 

poison centers reported that tramadol 

overdoses presented multiple systematic 

symptoms ranging from cardiovascular 

toxicity to significant neurologic 

toxicity including lethargy, nausea, 

tachycardia, agitation, seizures, coma, 

hypertension, and respiratory 

depression. The toxic mechanism of 

tramadol overdose is closely related to 

its m-opioid receptor activity and its 

monoamine oxidase inhibition activity. 

Information from the DAWN database 

shows that the rates of ED visits due to 

non-medical use of tramadol have been 


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similar to that of propoxyphene 

(Schedule IV) but lower than that of 

Schedule II and III opioids from 2004 to 

2008. The HHS reviewed DAWN data 

and found that a total of 395 tramadol 

abuse-related deaths were reported to 

DAWN from 1997 to 2002 in selected 

areas. The result demonstrates a risk to 

the public health associated with the 

non-medical use of tramadol that is 

similar to that of propoxyphene 

(Schedule IV). 

An increased number of exposure and 

death cases were reported by the 

AAPCC’s NPDS database. It showed that 

from 2004 to 2011, annual tramadol 

exposures increased from 3,769 to 

12,424. The HHS found that tramadol 

ranked third behind hydrocodone 

combination products (Schedule III) and 

oxycodone (Schedule II) in terms of the 

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 for oxycodone (Schedule II), 

morphine (Schedule II), and methadone 

(Schedule II). For the years 2004, 2005, 

and 2006, the rates of tramadol case 

mentions were similar to that of 

propoxyphene (Schedule IV). 

The labeling information approved by 

the FDA states that tramadol in 

excessive doses, alone or in 

combination with other central nervous 

system depressants, including alcohol, 

is a cause of drug-related deaths. Deaths 

associated with tramadol were also 

documented in the medical literature. 

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 of 

tramadol-related deaths reported by 

medical examiners in the DAWN 

database gradually increased from 1997 

to 2004. 

Reports of tramadol associated deaths 

from the Florida Department of Law 

Enforcement (FDLE) were also reviewed 

by the HHS and it was found 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-related deaths between 

2005 and 2008. For each of those years, 

the number of deaths involving 

tramadol was less than the number of 

deaths involving hydrocodone 

combination products (Schedule III), 

fentanyl (Schedule II), morphine 

(Schedule II), oxycodone (Schedule II), 

methadone (Schedule II), and 

propoxyphene (Schedule IV). The DEA 

reviewed the data for the years 2009 to 

2011, and found that tramadol-related 

deaths continued to increase. There 

were 268 tramadol-related deaths in 

2009, 275 tramadol-related deaths in 

2010, and 379 tramadol-related deaths 

in 2011. 

In summary, the collected data from 

a number of sources indicate that 

tramadol presents risks to the public 

health and, as such, supports the 

scheduling of tramadol. The DAWN, 

AAPCC, and FDLE data suggest a lower 

schedule for tramadol than Schedule III. 

7. Its Psychic or Physiological 

Dependence Liability: The HHS 

reviewed available information from 

pre-clinical and clinical studies and 

found that repeated dosing with 

tramadol resulted in dependence 

development, and withdrawal 

syndromes resulted from termination of 

tramadol treatment. Additionally, 

medical literature also documents 

numerous case reports of physiological 

and physical dependence to tramadol. 

Preclinical studies using monkeys and 

rats found that the tested animals 

displayed withdrawal signs after the 

termination of tramadol. Tramadol’s 

potential to produce physical 

dependence was evidenced by naloxone 

precipitated withdrawal in observed 

animals. The results also supported that 

tramadol produced a degree of physical 

dependence similar to that of 

propoxyphene (Schedule IV). Infusion 

of tramadol in rats found that the total 

withdrawal scores of tramadol were 

lower than that of morphine (Schedule 

II) following naloxone administration. 

By comparing physical dependence 

development resulting from repeated 

subcutaneous administration of either 

morphine or tramadol to mice, another 

study concluded that tramadol 

produced a lesser degree of physical 

dependence than morphine. These 

findings suggest that tramadol can 

produce mild to moderate levels of 

physical dependence and the degree of 

dependence of tramadol is less than that 

of Schedule II, but similar to that of 

Schedule IV drugs such as pentazocine 

and propoxyphene. 

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 of 

tramadol versus buprenorphine 

(Schedule III) in the treatment of opiate 

withdrawal and found that tramadol 

and buprenorphine effectively managed 

acute opioid withdrawal syndrome 

displayed by patients with mild to 

moderate addiction to heroin. Another 

study compared the use of tramadol to 

that of clonidine (not controlled under 

the CSA) for management of acute 

heroin (Schedule I) withdrawal and 

found that tramadol was more effective 

in managing withdrawal than clonidine. 

One study revealed a cross dependence 

development between tramadol and 

morphine (Schedule II) in opioiddependent adults. A modest 

suppression of opioid withdrawal 

produced by tramadol was also reported 

in subjects with a mild to moderate 

degree of opioid physical dependence 

and this finding was also supported by 

several published case reports. 

According to the HHS review, as of 

September 9, 2009, ‘‘Withdrawal 

symptoms may occur’’ was documented 

in the ‘‘Warning’’ section of the label for 

a tramadol containing product. 

Combining studies of cross dependence, 

tramadol produces a modest 

suppression of withdrawal in subjects 

dependent on other opioids and this 

suppression appears less than that 

produced by morphine (Schedule II) or 

buprenorphine (Schedule III). 

In conclusion, the HHS states that 

collectively the data shows tramadol 

can produce a modest level of physical 

dependence, with the studies suggesting 

a degree of physical dependence 

development less than that of Schedule 

II and III opioids but similar to opioids 

in Schedule IV. 

8. Whether the Substance is an 

Immediate Precursor of a Substance 

Already Controlled Under the CSA: 

Both the HHS and DEA state that 

tramadol is not an immediate precursor 

of any substance already controlled 

under the CSA. 

Conclusion: Based on consideration of 

the scientific and medical evaluation 

and accompanying recommendation of 

the HHS, and based on the DEA’s 

consideration of its own eight-factor 

analysis, the DEA finds that these facts 

and all relevant data constitute 

substantial evidence of potential for 

abuse of tramadol. As such, the DEA 

hereby proposes to schedule tramadol as 

a controlled substance under the CSA. 

Proposed Determination of Appropriate 

Schedule 

The CSA outlines the findings 

required to place a drug or other 

substance in any particular schedule (I, 

II, III, IV, or V). 21 U.S.C. 812(b). After 

consideration of the analysis and 

recommendation of the Assistant 

Secretary for Health of the HHS and 

review of all available data, the Deputy 

Administrator of the DEA, pursuant to 

21 U.S.C. 812(b)(4), finds that: 

1. Tramadol has a low potential for 

abuse relative to the drugs or substances 

in Schedule III. The abuse potential of 


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tramadol is comparable to the Schedule 

IV substance propoxyphene; 

2. Tramadol has a currently accepted 

medical use in treatment in the United 

States. Tramadol and other tramadolcontaining products were approved for 

marketing by the FDA to manage 

moderate to moderately severe pain; and 

3. Abuse of tramadol may lead to 

limited physical dependence or 

psychological dependence relative to 

the drugs or other substances in 

Schedule III. 

Based on these findings, the Deputy 

Administrator of the DEA concludes 

that tramadol [2- 

((dimethylamino)methyl)-1-(3- 

methoxyphenyl)cyclohexanol, its salts, 

isomers, salts of isomers, and all 

isomeric configurations of possible 

forms including tramadol, warrant 

control in Schedule IV of the CSA (21 

U.S.C. 812(b)(4)). 

Requirements for Handling Tramadol 

If this rule is finalized as proposed, 

persons who handle tramadol would be 

subject to the CSA’s Schedule IV 

regulatory controls and administrative, 

civil, and criminal sanctions applicable 

to the manufacture, distribution, 

dispensing, import, export, research, 

and conduct of instructional activities, 

including the following: 

Registration. Any person who handles 

(manufactures, distributes, dispenses, 

imports, exports, engages in research 

with, or conducts instructional activities 

with) tramadol, or who desires to 

handle tramadol would need to be 

registered with the DEA to conduct such 

activities, pursuant to 21 U.S.C. 822, 

823, 957, and 958, and in accordance 

with 21 CFR parts 1301 and 1312. Any 

person who handles tramadol, and is 

not registered with the DEA, would 

need to be registered with the DEA to 

conduct such activities by the effective 

date of the final rule. 

Security. Tramadol would be subject 

to Schedules III–V security 

requirements and would need to be 

handled and stored in accordance with 

21 CFR 1301.71–1301.93 pursuant to 21 

U.S.C. 821, 823, and 871(b). 

Labeling and Packaging. All labels 

and labeling for commercial containers 

of tramadol distributed on or after 

finalization of this rule would need to 

be in accordance with 21 CFR 1302.03– 

1302.07, pursuant to 21 U.S.C. 825, and 

958(e). 

Inventory. Every DEA registrant who 

possesses any quantity of tramadol on 

the effective date of the final rule would 

be required to take an inventory of all 

stocks of tramadol on hand as of the 

effective date of the rule, pursuant to 21 

U.S.C. 827, 958(e), and in accordance 

with 21 CFR 1304.03, 1304.04, and 

1304.11(a) and (d). Any person who 

becomes registered with the DEA after 

the effective date of the final rule would 

be required to take an initial inventory 

of all stocks of controlled substances 

(including tramadol) on hand at the 

time of registration, pursuant to 21 

U.S.C. 827, 958(e), and in accordance 

with 21 CFR 1304.03, 1304.04, and 

1304.11(a) and (b). After the initial 

inventory, every DEA registrant would 

be required to take a biennial inventory 

of all controlled substances (including 

tramadol) on hand, pursuant to 21 

U.S.C. 827, 958(e), and in accordance 

with 21 CFR 1304.03, 1304.04, and 

1304.11. 

Records. All registrants would be 

required to maintain records for 

tramadol or products containing 

tramadol pursuant to 21 U.S.C. 827, 

958(e), and in accordance with 21 CFR 

parts 1304 and 1312, including reports 

to Automation of Reports and 

Consolidated Orders System (ARCOS). 

Prescriptions. All prescriptions for 

tramadol or prescriptions for products 

containing tramadol would be required 

to be issued pursuant to 21 U.S.C. 829 

and in accordance with 21 CFR part 

1306. 

Importation and Exportation. All 

importation and exportation of tramadol 

would need to be done in accordance 

with 21 CFR part 1312, pursuant to 21 

U.S.C. 952, 953, 957, and 958. 

Liability. Any activity with tramadol 

not authorized by, or in violation of, the 

CSA, occurring on or after finalization 

of this proposed rule would be 

unlawful, and may subject the person to 

administrative, civil, and/or criminal 

sanctions. 

Regulatory Analyses 

Executive Orders 12866 and 13563 

In accordance with 21 U.S.C. 811(a), 

this proposed scheduling action is 

subject to formal rulemaking procedures 

done ‘‘on the record after opportunity 

for a hearing,’’ which are conducted 

pursuant to the provisions of 5 U.S.C. 

556 and 557. The CSA sets forth the 

criteria for scheduling a drug or other 

substance. Such actions are exempt 

from review by the Office of 

Management and Budget (OMB) 

pursuant to Section 3(d)(1) of Executive 

Order 12866 and the principles 

reaffirmed in Executive Order 13563. 

Executive Order 12988 

This proposed regulation meets the 

applicable standards set forth in 

Sections 3(a) and 3(b)(2) of Executive 

Order 12988 Civil Justice Reform to 

eliminate drafting errors and ambiguity, 

minimize litigation, provide a clear legal 

standard for affected conduct, and 

promote simplification and burden 

reduction. 

Executive Order 13132 

This proposed rulemaking does not 

have federalism implications warranting 

the application of Executive Order 

13132. The proposed rule will not have 

substantial direct effects on the States, 

on the relationship between the national 

government and the States, or the 

distribution of power and 

responsibilities among the various 

levels of government. 

Executive Order 13175 

This proposed rule will not have 

tribal implications warranting the 

application of Executive Order 13175. 

The proposed rule will not have 

substantial direct effects on one or more 

Indian tribes, on the relationship 

between the Federal Government and 

Indian tribes, or on the distribution of 

power and responsibilities between the 

Federal Government and Indian tribes. 

Regulatory Flexibility Act 

The Deputy Administrator, in 

accordance with the Regulatory 

Flexibility Act (5 U.S.C. 601–612) 

(RFA), has reviewed this proposed rule 

and by approving it certifies that it will 

not have a significant economic impact 

on a substantial number of small 

entities. The purpose of this proposed 

rule is to place tramadol, including its 

salts, isomers, salts of isomers, and all 

isomeric configurations of possible 

forms, into Schedule IV of the CSA. No 

less restrictive measures (i.e., noncontrol or control in Schedule V) would 

enable the DEA to meet its statutory 

obligations under the CSA. 

This proposed rule affects 

approximately 1.5 million DEA 

registrants. If finalized, the proposed 

rule on the placement of tramadol into 

Schedule IV of the CSA will affect all 

persons who handle, or propose to 

handle, tramadol. Tramadol handlers 

primarily include: manufacturers, 

distributors, pharmacies, individual 

practitioners, mid-level practitioners, 

and hospital/clinics. For the purpose of 

this analysis, the DEA assumes all 

legally operating manufacturers, 

distributors, importers/exports, 

pharmacies, individual practitioners, 

mid-level practitioners, and hospitals/

clinics that handle tramadol are 

registered with the DEA and all 

distributors, importers/exporters, 

pharmacies, individual practitioners, 

mid-level practitioners, and hospital/

clinics registered with the DEA are 

tramadol handlers. While the number of 


EMCDONALD on DSK67QTVN1PROD with PROPOSALS
Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules 65931 

DEA registrations forms the basis of the 

number of businesses affected by this 

rule, the number of manufacturers 

affected by this rule is based on industry 

data. Other than manufacturers, the 

DEA-estimated ‘‘Business-to-Registrant 

Ratio’’ is used to estimate the number of 

businesses represented by DEA 

registrants, and the ‘‘Percent of Business 

Below SBA Size Standard’’ is used to 

determine the number of businesses that 

are below the Small Business 

Administration (SBA) size standard (or 

number of businesses represented by 

DEA registrants that are small 

business.’’ The DEA estimates that 

approximately 367,046 of these to be 

small entities. When there are no special 

considerations for ‘‘substantial number’’ 

or criteria prescribed by external 

sources, the DEA uses a general criteria 

based on percentage. For the purposes 

of this analysis, a ‘‘substantial number’’ 

is defined as greater than 30 percent. 

Therefore, the DEA has determined that 

this proposed rule will not have an 

impact on a substantial number of small 

entities. 

In accordance with the RFA, the DEA 

evaluated the impact of this proposed 

rule on small entities. Specifically, the 

DEA examined the registration, storage, 

inventory and recordkeeping, and 

disposal requirements for the 367,046 

small businesses estimated to be 

affected by the proposed rule. (While 

approximately 1.5 million DEA 

registrations are estimated to be affected 

by this rule, 273,485 registrations are in 

the 10 states that currently control 

tramadol as a Schedule IV controlled 

substance under state law, with 

requirements that meet or exceed the 

DEA’s requirements for Schedule IV 

controlled substances. These states 

include Arkansas, Illinois, Kentucky, 

Mississippi, New Mexico, New York, 

North Dakota, Oklahoma, Tennessee, 

and Wyoming. Therefore, only 

approximately 1.2 million registrations 

are estimated to be economically 

impacted by this rule.) The DEA 

estimates that 298,354 small businesses 

total (across all States) would be 

economically impacted by this rule. 

When there are no special 

considerations for ‘‘significant economic 

impact’’ or criteria prescribed by 

external sources, the DEA uses one of 

two general criteria, revenue-based or 

profit based. The revenue-based criteria 

are widely used, while the profit-based 

criteria can be used for some high-profit 

industries. For the purposes of this 

analysis the revenue-based general 

criteria is used, where if the cost of the 

rule is greater than one percent of 

annual revenue, the rule has a 

‘‘significant’’ economic impact of the 

business. To estimate the number of 

businesses ‘‘significantly’’ impacted by 

the proposed rule, the DEA first 

estimated the revenue level associated 

with the 1 percent criteria for each 

North American Industry Classification 

System (NAICS) code associated with 

the affected entities. Then, using the 

revenue profile from the 2007 Economic 

Census, estimated the number of 

businesses where the cost of the rule is 

one percent or more than the revenue. 

This methodology was applied to all 

NAICS codes, except manufacturers. 

The estimate of small business 

manufacturers with significant 

economic impact is based on publically 

available data for annual sales data. The 

DEA estimates that the proposed rule 

would have a significant economic 

impact on 573 small businesses (0 

manufacturers, 47 distributors/

importers/exporters, 74 pharmacies, and 

452 practitioners). Based on the DEA’s 

estimate of 376,904 businesses to be 

affected by the proposed rule, and 

367,046 of these estimated to be small 

businesses, including businesses located 

in states where tramadol is controlled as 

Schedule IV under state law, 573 (0.2 

percent) of the 367,046 small businesses 

affected by the proposed rule are 

estimated to be significantly impacted 

economically. 

The DEA examined the 

disproportionality of the economic 

impact. The DEA did not have a basis 

for differentiating costs for different 

business sizes, thus one cost estimate 

was made for each of the registrant 

business activities. The estimate 

suggests disproportionality, where 

smaller (of the small) businesses will 

bear a larger economic impact as a 

percentage of revenue. However, the 

DEA believes that the disproportionality 

will be mitigated by business volume. A 

smaller business will handle a lower 

volume of tramadol, thus requiring less 

secure storage. 

Based on the DEA’s understanding of 

its registrants’ operations and facilities, 

the DEA estimates a non-recurring 

expense for system modification and 

initial inventory of $172.24 for all 

businesses and an additional $10,000 

for secure storage for 50 percent of 

distributors, importers, and exporters. 

(Fifty percent of distributors, importers, 

and exporters are estimated to meet the 

requirements of the proposed rule 

without the need to expand secure 

storage area.) The DEA estimates these 

costs will have significant economic 

impact on 0 percent of small business 

manufacturers, 3.3 percent of small 

business distributors, 0.1 percent of 

small business pharmacies, and 0.1 

percent of practitioners (other than 

pharmacies), totaling 0.2 percent of all 

businesses if the proposed rule were 

finalized. The percentage of small 

businesses with significant economic 

impact is below the 30 percent 

threshold for all registrant categories. 

The annual economic effect on the 

economy is the annual cost per business 

times the number of affected businesses. 

The DEA estimated that 306,375 

businesses, in States where tramadol is 

not controlled, were economically 

affected by the proposed rule. The 

annual cost of $974.39 is applied to the 

assumed 50 percent (588) of 1,175 

Distributor/Importer/Exporters affected 

by the proposed rule. Annual cost of 

$30.46 is applied to remaining 

businesses affected by the proposed 

rule: 51 Manufacturer, 587 Distributor/ 

Importer/Exporter, 40,797 Pharmacy, 

and 264,352 businesses that employ or 

hold Individual Practitioner, Mid-level 

Practitioner, and/or Hospital/Clinic 

registrations. To be conservative in 

analysis, the higher values for annual 

costs of $974.39 and $30.46 at 7 percent 

discount and interest rates is used rather 

than the annual costs of $698.22 and 

$26.06 at 3 percent discount and 

interest rates. The total annual cost is 

estimated to be $9,887,561. 

The DEA’s assessment of economic 

impact by size category indicates that 

the proposed rule will not have a 

significant economic impact on a 

substantial number of small entities. 

Unfunded Mandates Reform Act of 1995 

On the basis of information contained 

in the ‘‘Regulatory Flexibility Act’’ 

section above, the DEA has determined 

and certifies pursuant to the Unfunded 

Mandates Reform Act (UMRA) of 1995 

(2 U.S.C. 1501 et seq.), that this action 

would not result in any federal mandate 

that may result ‘‘in the expenditure by 

State, local, and tribal governments, in 

the aggregate, or by the private sector, of 

$100,000,000 or more (adjusted for 

inflation) in any one year[. . . .]’’ 

Therefore, neither a Small Government 

Agency Plan nor any other action is 

required under provisions of UMRA of 

1995. 

Paperwork Reduction Act of 1995 

This action does not impose a new 

collection of information under the 

Paperwork Reduction Act of 1995, 44 

U.S.C. 3501–3521. This action would 

not impose recordkeeping or reporting 

requirements on State or local 

governments, individuals, businesses, or 

organizations. An agency may not 

conduct or sponsor, and a person is not 

required to respond to, a collection of 

information unless it displays a 

currently valid OMB control number. 


EMCDONALD on DSK67QTVN1PROD with PROPOSALS
65932 Federal Register / Vol. 78, No. 213 / Monday, November 4, 2013 / Proposed Rules 

List of Subjects in 21 CFR Part 1308 

Administrative practice and 

procedure, Drug traffic control, 

Reporting and recordkeeping 

requirements. 

For the reasons set out above, 21 CFR 

part 1308 is proposed to be amended to 

read as follows: 

PART 1308—SCHEDULES OF 

CONTROLLED SUBSTANCES 

■ 1. The authority citation for 21 CFR 

part 1308 continues to read as follows: 

Authority: 21 U.S.C. 811, 812, 871(b) 

unless otherwise noted. 

■ 2. Amend § 1308.14 by adding a new 

paragraph (b)(3) to read as follows: 

§ 1308.14 Schedule IV. 

* * * * * 

(b) * * * 

(3) Tramadol [2- 

((dimethylamino)methyl)-1-(3- 

methoxyphenyl)cyclohexanol, its salts, 

optical and geometric isomers and salts 

of these isomers]—9752 

* * * * * 

Dated: October 25, 2013. 

Thomas M. Harrigan, 

Deputy Administrator. 

[FR Doc. 2013–25933 Filed 11–1–13; 8:45 am] 

BILLING CODE 4410–09–P 

DEPARTMENT OF THE TREASURY 

Internal Revenue Service 

26 CFR Part 300 

[REG–144990–12] 

RIN 1545–BL37 

User Fees for Processing Installment 

Agreements and Offers in 

Compromise; Hearing Cancellation 

AGENCY: Internal Revenue Service (IRS), 

Treasury. 

ACTION: Cancellation of a notice of 

public hearing on proposed rulemaking. 

SUMMARY: This document cancels a 

public hearing on proposed regulations 

that amend the provider user fees for 

installment agreements and offers in 

compromise. 

DATES: The public hearing originally 

scheduled for October 1, 2013 at 10 a.m. 

is cancelled. 

FOR FURTHER INFORMATION CONTACT: 

Oluwafunmilayo Taylor of the 

Publications and Regulations Branch, 

Legal Processing Division, Associate 

Chief Counsel (Procedure and 

Administration) at (202) 622–7180 (not 

a toll-free number). 

SUPPLEMENTARY INFORMATION: A notice 

of proposed rulemaking and a notice of 

public hearing that appeared in the 

Federal Register on Friday August 30, 

2013 (78 FR 53702) announced that a 

public hearing was scheduled for 

October 1, 2013, at 10 a.m. in the IRS 

Auditorium, Internal Revenue Building, 

1111 Constitution Avenue NW., 

Washington, DC. The subject of the 

public hearing is under sections 6159 

and 7122 of the Internal Revenue Code. 

The public comment period for these 

regulations expired on September 30, 

2013. The notice of proposed 

rulemaking and notice of public hearing 

instructed those interested in testifying 

at the public hearing to submit a request 

to speak and an outline of the topics to 

be addressed. The hearing was not held 

on October 1, 2013, due to the closure 

of the Federal Government. As of 

October 17, 2013, the date of the 

reopening of the Federal Government, 

there were no requests to speak. 

Therefore, the public hearing scheduled 

for October 1, 2013, is cancelled and 

will not be rescheduled. 

Martin V. Franks, 

Chief, Publications and Regulations Branch, 

Legal Processing Division, Associate Chief 

Counsel, (Procedure and Administration). 

[FR Doc. 2013–26280 Filed 11–1–13; 8:45 am] 

BILLING CODE 4830–01–P 

DEPARTMENT OF LABOR 

Occupational Safety and Health 

Administration 

29 CFR Parts 1910 and 1926 

[Docket No. OSH–2013–0005] 

RIN No. 1218–AC77 

Updating OSHA Standards Based on 

National Consensus Standards; 

Signage 

AGENCY: Occupational Safety and Health 

Administration (OSHA), Department of 

Labor. 

ACTION: Proposed rule; withdrawal. 

SUMMARY: With this notice, OSHA is 

withdrawing the proposed rule that 

accompanied its direct final rule 

revising its signage standards for general 

industry and construction. 

DATES: Effective November 4, 2013, 

OSHA is withdrawing the proposed rule 

published June 13, 2013 (78 FR 35585). 

FOR FURTHER INFORMATION CONTACT: 

General information and press 

inquiries: Contact Frank Meilinger, 

Director, OSHA Office of 

Communications, Room N–3647, U.S. 

Department of Labor, 200 Constitution 

Avenue NW., Washington, DC 20210; 

telephone: (202) 693–1999; email: 

meilinger.francis2@dol.gov. 

Technical information: Contact Ken 

Stevanus, Directorate of Standards and 

Guidance, Room N–3609, OSHA, U.S. 

Department of Labor, 200 Constitution 

Avenue NW., Washington, DC 20210; 

telephone: (202) 693–2260; fax: (202) 

693–1663; email: stevanus.ken@dol.gov. 

SUPPLEMENTARY INFORMATION: 

Copies of this Federal Register notice: 

Electronic copies of this Federal 

Register notice are available at http://

www.regulations.gov. This Federal 

Register notice, as well as news releases 

and other relevant information, also is 

available at OSHA’s Web page at 

http://www.osha.gov. 

Withdrawal of the proposal: On June 

13, 2013, OSHA published a companion 

proposed rule (NPRM) along with the 

direct final rule (DFR) (see 78 FR 35585) 

updating its signage standards for 

general industry and construction. In 

the DFR, OSHA stated that it would 

withdraw the companion NPRM and 

confirm the effective date of the DFR if 

it received no significant adverse 

comments to the DFR by the close of the 

comment period, July 15, 2013. OSHA 

received eight favorable and no adverse 

comments on the DFR by that date (see 

ID: OSHA–2013–0005–0008 thru –0015 

in the docket for this rulemaking). 

Accordingly, OSHA is withdrawing the 

proposed rule. In addition, OSHA is 

publishing two separate Federal 

Register notices, one confirming the 

effective date of the DFR, and the other 

making minor, nonsubstantive additions 

and corrections to 29 CFR 1910.6, 

1926.6, and 1926.200(b) and (c). 

List of Subjects in 29 CFR Parts 1910 

and 1926 

Signage, Occupational safety and 

health, Safety. 

Authority and Signature 

David Michaels, Ph.D., MPH, 

Assistant Secretary of Labor for 

Occupational Safety and Health, U.S. 

Department of Labor, 200 Constitution 

Avenue NW., Washington, DC 20210, 

authorized the preparation of this 

document. OSHA is issuing this 

document pursuant to 29 U.S.C. 653, 

655, and 657, 5 U.S.C. 553, Secretary of 

Labor’s Order 1–2012 (77 FR 3912), and 

29 CFR part 1911. 


EMCDONALD on DSK67QTVN1PROD with PROPOSALS