[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]
=======================================================================
-----------------------------------------------------------------------
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 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\
---------------------------------------------------------------------------
\1\ See infra footnote 2.
---------------------------------------------------------------------------
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\
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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).
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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