[Federal Register Volume 78, Number 213 (Monday, November 4, 2013)]
[Proposed Rules]
[Pages 65923-65932]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-25933]


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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.

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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 on-line 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.

[[Page 65924]]

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\
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    \1\ See infra footnote 2.
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Background

    Tramadol is an opioid analgesic that produces its primary opioid-
like action through an active metabolite, referred to as the ``M1'' 
metabolite (O-desmethyltramadol). Since March 1995, tramadol has been 
available as a non-controlled and centrally acting opioid analgesic 
under the trade name ULTRAM[supreg] 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\
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    \2\ For 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.
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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

[[Page 65925]]

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).
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    \3\ As 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.
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    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.
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    \4\ Because 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.
    \5\ While 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.
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    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

[[Page 65926]]

abuse \6\ of tramadol/combinations increased from 4,849 to 16,251. Upon 
normalization of the number of non-medical ED visits relative to 
100,000 prescriptions dispensed, the rate of ED visits for tramadol/
combinations was found similar to the rates for propoxyphene.
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    \6\ Since 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.
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    The NSDUH, operated by SAMHSA, provides information on the non-
medical 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 non-medically 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 
non-medically 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 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 liability-related effects in various animal 
models and humans. It has been self-administered 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

[[Page 65927]]

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 Plus\TM\, demonstrated a similar trend from 2009 to 
2011: more prescriptions were written for tramadol than for any other 
opioid other than hydrocodone and oxycodone.
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    \7\ The 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.
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    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 abuse-related 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 non-medical 
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.
---------------------------------------------------------------------------

    \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., 
``non-medical visits'').
---------------------------------------------------------------------------

    The HHS reviewed DAWN data and calculated the rates of estimated 
non-medical 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).
---------------------------------------------------------------------------

    \9\ Only data from 2006 to 2008 was available for buprenophrine/
combinations.
---------------------------------------------------------------------------

    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 non-medical 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 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 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

[[Page 65928]]

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 tramadol-containing 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 post-marketing 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 post-marketing 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 non-medically 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 non-medically 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 [micro]-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

[[Page 65929]]

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 opioid-
dependent 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

[[Page 65930]]

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 tramadol-containing 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., 
non-control 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

[[Page 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.

[[Page 65932]]

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

0
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.

0
2. Amend Sec.  1308.14 by adding a new paragraph (b)(3) to read as 
follows:


Sec.  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