Schedules of Controlled Substances: Removal of 6β-naltrexol From Control

 
CONTENT
Federal Register, Volume 84 Issue 162 (Wednesday, August 21, 2019)
[Federal Register Volume 84, Number 162 (Wednesday, August 21, 2019)]
[Proposed Rules]
[Pages 43530-43536]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-17630]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-492]
Schedules of Controlled Substances: Removal of 6[beta]-naltrexol
From Control
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Notice of proposed rulemaking.
-----------------------------------------------------------------------
SUMMARY: The Drug Enforcement Administration (DEA) proposes to remove
(5[alpha],6[beta])-17-(cyclopropylmethyl)-4,5-epoxymorphinan-3,6,14-
triol (6[beta]-naltrexol) and its salts from the schedules of the
Controlled Substances Act (CSA). This scheduling action is pursuant to
the CSA which requires that such actions be made on the record after
opportunity for a hearing through formal rulemaking. 6[beta]-Naltrexol
is currently a schedule II controlled substance because it can be
derived from opium alkaloids. This action would remove the regulatory
controls and administrative, civil, and criminal sanctions applicable
to controlled substances, including those specific to schedule II
controlled substances, on persons who handle (manufacture, distribute,
reverse distribute, dispense, conduct research, import, export, or
conduct chemical analysis) or propose to handle 6[beta]-naltrexol.
DATES: Interested persons may file written comments on this proposal in
accordance with 21 CFR 1308.43(g). Electronic comments must be
submitted, and written comments must be postmarked, on or before
September 20, 2019. Commenters should be aware that the electronic
Federal Docket Management System will not accept comments after 11:59
p.m. Eastern Time on the last day of the comment period.
    Interested persons, defined at 21 CFR 1300.01 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),'' may file a request for
hearing or waiver of participation pursuant to 21 CFR 1308.44 and in
accordance with 21 CFR 1316.45, 1316.47, 1316.48, or 1316.49, as
applicable. 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 September 20, 2019.
ADDRESSES: To ensure proper handling of comments, please reference
``Docket No. DEA-492'' on all correspondence, including any
attachments.
[[Page 43531]]
     Electronic comments: The DEA encourages that all comments
be submitted through the Federal eRulemaking Portal, which provides the
ability to type short comments directly into the comment field on the
web page or to attach a file for lengthier comments. Please go to
http://www.regulations.gov and follow the online instructions at that
site for submitting comments. Upon completion of your submission you
will receive a Comment Tracking Number for your comment. Please be
aware that submitted comments are not instantaneously available for
public view on Regulations.gov. If you have received a comment tracking
number, your comment has been successfully submitted and there is no
need to resubmit the same comment.
     Paper comments: Paper comments that duplicate an
electronic submission are not necessary and are discouraged. Should you
wish to mail a comment in lieu of an electronic format, it should be
sent via regular or express mail to: Drug Enforcement Administration,
Attention: DEA Federal Register Representative/ODXL, 8701 Morrissette
Drive, Springfield, Virginia 22152.
     Hearing requests: All requests for hearing and waivers of
participation must be sent to: Drug Enforcement Administration, Attn:
Hearing Clerk/LJ, 8701 Morrissette Drive, Springfield, Virginia 22152.
FOR FURTHER INFORMATION CONTACT: Scott A. Brinks, Regulatory Drafting
and Policy Support Section, Diversion Control Division, Drug
Enforcement Administration; Mailing Address: 8701 Morrissette Drive,
Springfield, Virginia 22152; Telephone: (202) 598-8106.
SUPPLEMENTARY INFORMATION:
Posting of Public Comments
    Please note that all comments received in response to this docket
are considered part of the public record. They will, unless reasonable
cause is given, be made available by the DEA for public inspection
online at http://www.regulations.gov. Such information includes
personal identifying information (such as your name, address, etc.)
voluntarily submitted by the commenter. The Freedom of Information Act
(FOIA) applies to all comments received. 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 publicly available, you
must include the phrase ``PERSONAL IDENTIFYING INFORMATION'' in the
first paragraph of your comment. You must also place the personal
identifying information you do not want 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.
    Comments containing personal identifying information and
confidential business information identified as directed above will
generally be made publicly available in redacted form. If a comment has
so much confidential business information or personal identifying
information that it cannot be effectively redacted, all or part of that
comment may not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information
(such as name, address, and phone number) included in the text of your
electronic submission that is not identified as directed above as
confidential.
    An electronic copy of this document and supplemental information to
this proposed rule are available at http://www.regulations.gov for easy
reference. The DEA specifically solicits written comments regarding the
DEA's economic analysis of the impact of these proposed changes. The
DEA requests that commenters provide detailed descriptions in their
comments of any expected economic impacts, especially to small
entities. Commenters should provide empirical data to illustrate the
nature and scope of such impact.
Request for Hearing, Notice of Appearance at or Waiver of Participation
in Hearing
    Pursuant to 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) through (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 * * *.'' All requests for hearing and waivers
of participation must be sent to the DEA using the address information
above, on or before the date specified above.
Legal Authority
    The CSA provides that proceedings for the issuance, amendment, or
repeal of the 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 Department of Health and Human Services
(HHS),\1\ or (3) on the petition of any interested party. 21 U.S.C.
811(a). This action was initiated by two petitions to remove 6[beta]-
naltrexol from the list of scheduled controlled substances of the CSA,
and is supported by, inter alia, a recommendation from the Assistant
Secretary of the HHS and an evaluation of all relevant data by the DEA.
If finalized, this action would remove the regulatory controls and
administrative, civil, and criminal sanctions applicable to controlled
substances, including those specific to schedule II controlled
substances, on persons who handle or propose to handle 6[beta]-
naltrexol.
---------------------------------------------------------------------------
    \1\ As discussed in a memorandum of understanding entered into
by the Food and Drug Administration (FDA) and the National Institute
on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS
in carrying out the Secretary's scheduling responsibilities under
the CSA, with the concurrence of NIDA. 50 FR 9518, March 8, 1985.
The Secretary of the HHS has delegated to the Assistant Secretary
for Health of the HHS the authority to make domestic drug scheduling
recommendations. 58 FR 35460, July 1, 1993.
---------------------------------------------------------------------------
Background
    6[beta]-Naltrexol is the major metabolite of naltrexone. Naltrexone
and 6[beta]-naltrexol are reversible opioid receptor antagonists.
Opioid receptor antagonists are commonly used in the treatment of
[[Page 43532]]
opioid addiction and overdose. On December 24, 1974, naloxone, an
opioid receptor antagonist that works similarly to naltrexone, was
removed from all schedules for control under the CSA. Effective on
March 6, 1975, Title 21 of the Code of Federal Regulations was amended
to remove naltrexone from all schedules for control under the CSA. The
Administrator of the DEA found that both naltrexone and naloxone and
their salts have an accepted medical use for treatment in the United
States and that they do not have a potential for abuse to justify
continued control in any schedule under the CSA. In June 2003 and April
2008, the DEA received two separate citizen petitions to initiate
proceedings to amend 21 CFR 1308.12(b)(1) so as to decontrol 6[beta]-
naltrexol from schedule II of the CSA. These petitions complied with
the requirements of 21 CFR 1308.44(b) and were accepted for filing.
Both petitioners argue that 6[beta]-naltrexol has been characterized as
an opioid receptor antagonist, a class of drugs with no abuse
potential.
Proposed Determination To Decontrol 6[beta]-Naltrexol
    Pursuant to 21 U.S.C. 811(b), the DEA gathered the necessary data
on 6[beta]-naltrexol and forwarded the data, the sponsors' petitions,
and a request for scheduling recommendation on 6[beta]-naltrexol to the
Department of Health and Human Services (HHS) on August 11, 2009. On
July 21, 2017, the HHS provided to the DEA a scientific and medical
evaluation entitled ``Basis For The Recommendation To Remove (5[alpha],
6[beta])-17-(cyclopropylmethyl)-4,5-epoxymorphinan-3,6,14-triol
(6[beta]-naltrexol) And Its Salts From All Schedules Of Control Under
The Controlled Substances Act'' and a scheduling recommendation.
Following consideration of the eight factors and findings related to
the substance's abuse potential, legitimate medical use, and dependence
liability, the HHS recommended that 6[beta]-naltrexol and its salts be
decontrolled from all schedules of control of the CSA. The National
Institute on Drug Abuse (NIDA) concurred with the recommendation.
    The CSA requires the DEA to determine whether the HHS's scientific
and medical evaluation, scheduling recommendation, and all other
relevant data constitute substantial evidence that a substance should
be scheduled. 21 U.S.C. 811(b). The DEA reviewed the scientific and
medical evaluation and scheduling recommendation provided by the HHS,
and all other relevant data, and completed its own eight-factor review
document on 6[beta]-naltrexol pursuant to 21 U.S.C. 811(c). Included
below is a brief summary of each factor as analyzed by the HHS and DEA,
and as considered by the DEA in this proposal to remove 6[beta]-
naltrexol from the schedules of the CSA. 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-492.
1. The Drug's Actual or Relative Potential for Abuse
    The first factor that must be considered is the actual or relative
potential for abuse of 6[beta]-naltrexol. The term ``abuse'' is not
defined in the CSA. However, the legislative history of the CSA
suggests the following points in determining whether a particular drug
or substance has a potential for abuse:
    a. Whether there is evidence that individuals are taking the drug
or drugs containing such a substance in amounts sufficient to create a
hazard to their health or to the safety of other individuals or to the
community.
    According to HHS, there are no mentions of abuse of 6[beta]-
naltrexol in the National Survey on Drug Use and Health (NSDUH),\2\ a
survey sponsored by the Substance Abuse and Mental Health Services
Administration (SAMHSA). This survey provides national and state-level
data on tobacco, alcohol, and drug use, mental health and other health-
related issues in the United States. The Monitoring the Future (MTF)
\3\ survey did not provide any data on 6[beta]-naltrexol.
---------------------------------------------------------------------------
    \2\ The National Survey on Drug Use and Health, formerly known
as the National Household Survey on Drug Abuse (NHSDA), is conducted
annually by the Department of Health and Human Service's Substance
Abuse and Mental Health Services Administration (SAMHSA). It is the
primary source of estimates of the prevalence and incidence of
nonmedical use of pharmaceutical drugs, illicit drugs, alcohol, and
tobacco use in the United States. The survey is based on a
nationally representative sample of the civilian, non-
institutionalized population 12 years of age and older. The survey
excludes homeless people who do not use shelters, active military
personnel, and residents of institutional group quarters such as
jails and hospitals. The NSDUH provides yearly national and state
level estimates of drug abuse, and includes prevalence estimates by
lifetime (i.e., ever used), past year and past month abuse or
dependence.
    \3\ Monitoring the Future (MTF) is a national survey conducted
by the Institute for Social Research at the University of Michigan
under a grant from the National Institute on Drug Abuse (NIDA) that
tracks drug use trends among American students in the 8th, 10th, and
12th grades.
---------------------------------------------------------------------------
    b. Whether there is significant diversion of the drug or drugs
containing such a substance from legitimate drug channels.
    According to HHS, 6[beta]-naltrexol is not currently marketed in
any country. Availability is limited to research settings, and there is
no evidence of diversion from legitimate drug channels. The National
Forensic Laboratory Information System (NFLIS) is a DEA database that
collects scientifically verified data on analyzed drug samples in State
and local forensic laboratories.\4\ It also includes data from the
System to Retrieve Information from Drug Evidence (STRIDE), which
includes data on analyzed samples from DEA laboratories.\5\ There are
no records of 6[beta]-naltrexol drug cases or seized drug exhibits in
NFLIS. Thus, there is no evidence of significant diversion of 6[beta]-
naltrexol.
---------------------------------------------------------------------------
    \4\ The National Forensic Laboratory Information System (NFLIS)
represents an important resource in monitoring illicit drug abuse
and trafficking, including the diversion of legally manufactured
pharmaceuticals into illegal markets. NFLIS is a comprehensive
information system that includes data from forensic laboratories
that handle approximately 90% of an estimated 1.0 million distinct
annual State and local drug analysis cases. NFLIS includes drug
chemistry results from completed analyses only. While NFLIS data is
not direct evidence of abuse, it can lead to an inference that a
drug has been diverted and abused. See 76 FR 77330, 77332, Dec. 12,
2011.
    \5\ The System to Retrieve Information from Drug Evidence
database (STRIDE) reports the results of drug evidence analyzed at
DEA laboratories nationwide. These drug exhibits (or items) are
submitted to the laboratory as drug evidence from seizures and
undercover purchases. As of October 1, 2014, STARLiMS is the new
system of record for exhibits analyzed by DEA laboratories,
replacing STRIDE.
---------------------------------------------------------------------------
    c. Whether individuals are taking the drug or drugs containing such
a substance on their own initiative rather than on the basis of medical
advice from a practitioner licensed by law to administer such drugs in
the course of his professional practice.
    According to HHS, 6[beta]-naltrexol is only available in research
laboratories and is not currently marketed in any country. The DEA
notes that a review of scientific literature, STRIDE, STARLiMS, NFLIS,
NSDUH, and MTF databases revealed no history of abuse of 6[beta]-
naltrexol. Thus, there is no evidence that individuals are taking
6[beta]-naltrexol on their own initiative rather than on the basis of
medical advice from a practitioner licensed by law to administer the
same.
    d. Whether the drug or drugs containing such a substance are new
drugs so related in their action to a substance already listed as
having a potential for abuse to make it likely that it will have the
same potentiality for abuse as such drugs, thus making it reasonable to
assume that there may be significant diversions from legitimate
channels, significant use contrary to or
[[Page 43533]]
without medical advice, or that they have a substantial capability of
creating hazards to the health of the user or to the safety of the
community.
    According to HHS, actions of 6[beta]-naltrexol are not related to a
substance already listed as having a potential for abuse. In humans,
6[beta]-naltrexol is the major metabolite of naltrexone, which was
removed from all schedules for control under the CSA on March 6, 1975
(40 FR 10455).
2. Scientific Evidence of the Drug's Pharmacological Effects, If Known
    According to HHS, 6[beta]-naltrexol is formed when the 6-keto group
of naltrexone goes through a reduction process. It is the major
metabolite of naltrexone in humans, monkeys, and guinea pigs, but not
in rodents. It is a considerably weaker antagonist than naltrexone and
does not affect basal signaling of [micro]- and [delta]-opioid
receptors in opioid-na[iuml]ve and opioid-dependent states which
suggests that 6[beta]-naltrexol has neutral antagonist properties.
Binding affinities (Ki) of 6[beta]-naltrexol were 2.12 nM, 212 nM, and
7.42 nM at [micro]-opioid receptor, [delta]-opioid receptor, and
[kappa]-opioid receptor, respectively. A study found that the affinity
of 6[beta]-naltrexol for the [micro]-opioid receptor and [kappa]-opioid
receptor was 2- to 5-fold higher than that of naloxone and 2-fold lower
than naltrexone. 6[beta]-Naltrexol also inhibited the inverse agonist
effects of naloxone in pretreated membranes. The study thus concludes
that 6[beta]-naltrexol retained neutral antagonist activity. A previous
study in animal models indicates that 6[beta]-naltrexol appears to be
1/12th to 1/185th as potent as naltrexone. Though 6[beta]-naltrexol is
lower in potency than naltrexone, it contributes to the therapeutic and
adverse effects of naltrexone because it accumulates to a greater
extent than naltrexone especially in chronic dosing conditions. HHS
concludes that this may be attributed to 6[beta]-naltrexol's 10-fold
higher systemic exposure as compared to naltrexone. 6[beta]-naltrexol
has a longer half-life (12 to 14 hours) than that of naltrexone (4
hours).
    Although 6[beta]-naltrexol has weaker opioid receptor antagonistic
properties than naltrexone, it contributes significantly to the effects
of naltrexone after oral administration. 6[beta]-Naltrexol is
metabolized primarily through glucuronidation and renal secretion.
6[beta]-Naltrexol has a lower potency than naltrexone, and its longer
duration of action and higher plasma concentrations indicate that
6[beta]-naltrexol will contribute to the therapeutic and adverse
effects of naltrexone. The physiochemical properties of 6[beta]-
naltrexol suggest that it may have a preferential blockade of
peripheral over central opioid receptors following a systemic
administration. This selectivity for peripheral opioid receptors may
allow for co-formulation with an opioid, to attenuate the peripheral
side effects, such as opioid-induced changes in bowel function, and
immune functions.
    In the in vitro assay, the effect of 6[beta]-naltrexol to inhibit
morphine-induced reduction in twitch response in electrically
stimulated guinea pig ileum was assessed. Results of the study showed
that 6[beta]-naltrexol was 4.5-fold more potent than naloxone and 2.8-
fold more potent than naltrexone in preventing the morphine-induced
reduction of twitch height of stimulated guinea pig ileum. In the in
vivo analgesic test, naltrexone was 2 times as potent as naloxone and
185 times as potent as 6[beta]-naltrexol in inhibiting morphine-induced
antinociception in mice. Thus, 6[beta]-naltrexol is highly potent in
the guinea pig ileum in vitro, but much less so in vivo after an acute
dose. The potency of 6[beta]-naltrexol in vivo is also time-dependent
with a longer duration of action than naloxone and naltrexone. These
data are consistent with pharmacokinetic data for 6[beta]-naltrexol
with a longer terminal half-life and supports that 6[beta]-naltrexol is
likely to contribute to the efficacy of naltrexone in human subjects.
    Another study that compared the activity of naltrexone and naloxone
relative to 6[beta]-naltrexol in blocking fentanyl-induced analgesia
and lethality, and in precipitating withdrawal jumping in mice
dependent on fentanyl reported that the potency ratio in antagonizing
fentanyl-induced analgesia was 17:4:1 for naltrexone, naloxone, and
6[beta]-naltrexol, respectively. The corresponding ratio to attenuate
fentanyl-induced lethality was 13:2:1. In precipitating withdrawal, the
corresponding ratio was 1107:415:1. Additionally, 6[beta]-naltrexol
pre-treatment resulted in decreased naloxone withdrawal. Thus, 6[beta]-
naltrexol produced a lower efficacy antagonist activity by blocking
inverse agonist-mediated effects of naloxone. In a chronic mouse model
of dependence, 6[beta]-naltrexol was 30 and 100 times less potent than
naloxone and naltrexone, respectively. 6[beta]-Naltrexol at 1.0 mg/kg
dose did not produce a withdrawal response (e.g., jumping), but at 10
mg/kg dose it elicited withdrawal effect 8 hours after morphine
pretreatment. 6[beta]-Naltrexol was equipotent to naloxone in blocking
morphine's anti-nociceptive effect.
    In a study of developing neonatal abstinence syndrome (NAS) in
pregnant mice with opioid dependence, the result found that 6[beta]-
naltrexol passed through the placenta and through the blood brain
barrier (BBB) in fetal mice. A co-administration of 6[beta]-naltrexol
with morphine to postnatal mice (before day 14) inhibited withdrawal
behavior at doses 20- to 500-fold lower than those used to inhibit
anti-nociception in adult animals. Almost complete inhibition of
withdrawal symptoms was observed at the highest dose (1 mg/kg), which
correlated to 1/20th that of the morphine dose. These data support that
as a neutral antagonist, 6[beta]-naltrexol contributes through
suppressing fetal withdrawal symptom.
    Another study found that 6[beta]-naltrexol was only 1/85th as
potent as naltrexone in producing antagonism effects as oxymorphone-
induced loss of righting reflex in rats. Another test in a spinal dog
preparation showed that, 6[beta]-naltrexol had only 1/12th to 1/15th
the potency of naltrexone in producing withdrawal. 6[beta]-Naltrexol
was 1/56th as potent as naltrexone in preventing the loss of righting
reflex in rats, and was 1/26th as potent as naltrexone in preventing
morphine-induced Straub tail. As a weaker antagonist, 6[beta]-naltrexol
still retains moderate activity with a prolonged duration of activity
in rats and mice suggesting that 6[beta]-naltrexol may produce a longer
narcotic blockade observed in humans after naltrexone administration.
In another monkey study evaluating naltrexone and its metabolites of
the inverse agonist activity treated with morphine (3.2 mg/day), data
showed that naltrexone was 5- and 23-fold more potent than
6[alpha]naltrexol and 6[beta]-naltrexol without morphine pre-treatment,
while in monkeys with a morphine injection, naltrexone was 8- and 71-
fold more potent than 6[alpha]naltrexol and 6[beta]-naltrexol. The
results indicate that naltrexone and 6[alpha]naltrexol and 6[beta]-
naltrexol have qualitatively similar effects, and their potencies do
not vary significantly with opioid treatment. Another study to compare
the potency of naltrexone and 6[beta]-naltrexol in monkeys revealed
that naltrexone displayed 2-fold higher affinity and potency than
6[beta]-naltrexol for the mu-opioid receptor (MOR) binding in monkey
brain membranes and for MOR agonist-stimulated function, respectively.
Naltrexone (0.0032-0.032 mg/kg) and 6[beta]-naltrexol (0.32-3.2 mg/kg)
retained the same potency difference in precipitating withdrawal to a
similar degree. Furthermore, 6[beta]-naltrexol failed to block
naltrexone-precipitated withdrawal in morphine-dependent monkeys. These
results indicate that
[[Page 43534]]
naltrexone and 6[beta]-naltrexol display similar pharmacological
actions with a large in vivo potency difference in monkeys such that
6[beta]-naltrexol may play a minimal role in the therapeutic or
antagonist effects of naltrexone in primates.
Clinical Studies
    According to HHS, in a study involving 24 moderate-to-heavy
drinkers with an oral dose of 50 mg of naltrexone, and following 3
hours of administration, the urinary levels of 6[beta]-naltrexol were
10 times greater than those of naltrexone. A higher urine concentration
of 6[beta]-naltrexol correlated to the presence of subjective side
effects, such as nausea, headache, and anxiety. The subjective side
effects observed in this study are partially attributed to the effects
of alcohol in combination with naltrexone. Another study found that
6[beta]-naltrexol (ED50 ~3mg) significantly blocked the
effect of morphine-induced gastrointestinal slowing, which is
consistent with its opioid receptor antagonist pharmacology. It
supports that 6[beta]-naltrexol can block some peripheral effects of
morphine while not affecting the central nervous system (CNS) analgesic
effect induced by morphine. This may be because 6[beta]-naltrexol has a
difficulty in crossing the BBB and therefore has low in vivo CNS
activity.
    One clinical study of 6[beta]-naltrexol in affecting abuse and
constipation of opioids in four opioid dependent individuals on
methadone maintenance therapy found that an intravenous treatment of
6[beta]-naltrexol (0.05 mg-1.0 mg in ascending doses) through 15-minute
infusions produced significantly greater Visual Analog Scale (VAS)
scores of ``Any Drug Effect'' than placebo, and no significant effect
was found in any other VAS measure. There was also a dose-dependent
increase in gastrointestinal activity. Agonists of the [micro]-opioid
receptor, such as methadone, are known to decrease gastrointestinal
motor activity, leading to constipation. This study determined that
6[beta]-naltrexol blocked the [micro]-opioid receptor agonist activity
of methadone, causing an increase in locomotor activity in the
gastrointestinal system. The lack of withdrawal symptoms indicated
that, at these doses, 6[beta]-naltrexol did not cross the BBB and had
little effect in the CNS, thereby supporting that 6[beta]-naltrexol is
a peripherally acting [micro]-opioid receptor antagonist.
3. The State of Current Scientific Knowledge Regarding the Drug or
Other Substance
    The molecular formula of 6[beta]-naltrexol is
C20H25NO4 and the molecular weight is
343.42 g/mol. 6[beta]-Naltrexol is formed in vivo when the 6-keto group
of naltrexone goes through a reduction process. A structure affinity
analysis indicated that 6[beta]-naltrexol has reduced bonds in the six
position of its chemical structure, which may result in its neutral
antagonist activity.
    According to HHS, naltrexone through the in vivo metabolic
reduction metabolizes into two active metabolites, 6[alpha]-naltrexol
and 6[beta]-naltrexol. The metabolite, 6[alpha]-naltrexol, was found in
only trace amounts in two (monkey and guinea pig) of the seven species
tested. However, 6[beta]-naltrexol was detected in the urine of all of
the species tested, including humans. HHS states that 6[alpha]-
naltrexol is not present as a metabolite in humans and is of little
concern. Plasma concentration-time curve fit into a two compartment
model with absorption showing first-order kinetics. According to
another study, 6[beta]-hydroxy epimers have little or no
antinociceptive activity, while 6[alpha]-hydroxy epimers showed
significant antinociceptive activity similar to the report of
nalorphine and pentazocine. This study showed that 6[beta]-naltrexol
lacks analgesic activity suggesting that it does not have agonist or
partial agonist properties. As stated by HHS, single and multiple
administrations of 6[beta]-naltrexol do not change its plasma kinetics.
After one intramuscular injection of 6[beta]-naltrexol (0.2 mg/kg), the
time-curve of plasma concentration fits a two-compartment model with
first-order absorption and it remained consistent after multiple
intramuscular injections for 6[beta]-naltrexol for 7 days.
    According to HHS, naltrexone is converted to its active metabolite,
6[beta]-naltrexol through a stereospecific reduction by dihydrodiol
dehydrogenase enzymes (DD1, 2, and 4). Because of first-pass
metabolism, concentrations of 6[beta]-naltrexol are much higher than
its parent molecule following oral dosing. However, when 6[beta]-
naltrexol is administered intramuscularly, hepatic biotransformation is
avoided, and the arca under the curve (AUC) for 6[beta]-naltrexol is
only 2-fold higher than that of naltrexone. In contrast, following a
single and multiple oral dosing of naltrexone (50 mg), 6[beta]-
naltrexol exposure was over 20-fold greater than that of the parent
drug, naltrexone. In another cited study in patients with mild or
moderate hepatic impairment, following a single dose of long acting
naltrexone (190 mg), plasma concentrations of 6[beta]-naltrexol were 2-
fold greater than corresponding naltrexone concentrations. Thus mild or
moderate hepatic impairment affect the patient's exposure to either
6[beta]-naltrexol or naltrexone.
4. Its History and Current Pattern of Abuse
    According to HHS, based on chemical and pharmacological
similarities between 6[beta]-naltrexol and naltrexone, a [micro]-opioid
receptor antagonist that was removed from control under the CSA, it is
unlikely that 6[beta]-naltrexol would be abused. In addition, reports
from Monitoring the Future, Treatment Episode Data Set, the National
Survey on Drug Use and Health, poison control centers, the Drug Abuse
Warning Network, NFLIS, STRIDE, and STARLiMS had no mentions of use or
abuse of 6[beta]-naltrexol.
5. The Scope, Duration, and Significance of Abuse
    As mentioned in Factor 4, a comprehensive review and research on
available data performed by both HHS and DEA revealed no reports of
abuse of 6[beta]-naltrexol.
6. What, If Any, Risk There Is to the Public Health
    According to both HHS and DEA's data review and as stated in
Factors 4 and 5, there is no sufficient data to report any abuse of
6[beta]naltrexol or show the scope, duration, and significance of abuse
of 6[beta]-naltrexol. None of the available sources including
Monitoring the Future, Treatment Episode Data Set, the National Survey
on Drug Use and Health, poison control centers, the Drug Abuse Warning
Network, NFLIS, and STRIDE capture data that examine the use or abuse
of 6[beta]-naltrexol.
7. Its Psychic or Physiological Dependence Liability
    According to HHS, in a morphine dependent state, naloxone and
naltrexone act as inverse agonists by suppressing basal [micro]-opioid
receptor signaling thereby contributing to the presence of withdrawal
in an opioid dependent state. 6[beta]-Naltrexol exhibits neutral
antagonist properties and results in a less severe withdrawal state.
According to HHS, 6[beta]-naltrexol and naloxone are equipotent in
blocking acute morphine antinociception. In contrast, 6[beta]-naltrexol
was much less active than naloxone in eliciting withdrawal, both in
acute and chronic morphine-dependence models. Yet, given at equipotent
doses to naltrexone
[[Page 43535]]
and naloxone, 6[beta]-naltrexol afforded a similar time course of rapid
reversal of acute morphine-stimulated locomotion. Therefore, 6[beta]-
naltrexol does reach the receptor sites but fails to cause substantial
withdrawal; consistent with the hypothesis that suppression of basal
[micro]-opioid receptor signaling plays a significant role.
    The HHS review stated that 6[beta]-naltrexol has been shown to
produce minimal withdrawal jumping as compared to naltrexone. A dose of
0.2 mg/kg of naltrexone and 1.0 mg/kg 6[beta]-naltrexol are equipotent
in antagonizing anti-nociceptive effects of morphine 10 to 20 minutes
after administration. The 1 mg/kg dose of 6[beta]-naltrexol did not
elicit withdrawal jumping in the 72-hour time period following morphine
administration, whereas the 10 mg/kg dose of naltrexone caused a
withdrawal effect after 8 hours of morphine pretreatment. Another study
assessing the relative potency of two opioid receptor antagonists
(naltrexone and naloxone) and a neutral antagonist (6[beta]-naltrexol)
in blocking fentanylinduced analgesia and toxicity, and in
precipitating withdrawal revealed that the order of potency in
antagonizing analgesia and in precipitating withdrawal jumping was:
Naltrexone > naloxone > 6[beta]-naltrexol. Pretreatment with 6[beta]-
naltrexol reduced naloxone-precipitated withdrawal and supports that
6[beta]-naltrexol acts as an antagonist.
    Another HHS-cited study found that both 6[beta]-naltrexol (10 mg/
kg) and naloxone (10 mg/kg) were equipotent and 4.5- and 10-fold less
potent than naltrexone (l.0 mg/kg). 6[beta]-Naltrexol, unlike naloxone
and naltrexone, at high doses produced minimal withdrawal at in an
acute dependence Institute of Cancer Research (ICR) mice model. In this
assay, naloxone and naltrexone produced withdrawal jumping at doses
that blocked the acute effects of morphine, whereas 6[beta]-naltrexol
at 10 mg/kg (the dose that blocks the acute of effects of morphine) did
not precipitate withdrawal jumping. In the chronic dependence model,
6[beta]-naltrexol was 77-fold and 30-fold less potent than naltrexone
and naloxone in producing withdrawal.
    The ability of 6[beta]-naltrexol and naltrexone to produce
withdrawal in morphine-dependent and morphine-naive mice was compared.
This HHS-cited study showed that naltrexone had a 10-to 100-fold
greater potency than that of 6[beta]-naltrexol. Another study compared
the effects of naltrexone and 6[beta]-naltrexol on precipitated
withdrawal in morphine-dependent mice and reported that the low doses
of 6[beta]-naltrexol antagonized naltrexone precipitated withdrawal,
while high doses of 6[beta]-naltrexol were additive. This reduction in
withdrawal symptoms by low doses of 6[beta]-naltrexol is believed to be
due to its neutral antagonist properties which could attenuate inverse
agonist effects of naltrexone. These studies mentioned above show that
6[beta]-naltrexol produces significantly reduced incidence of
precipitated withdrawal in opioid-dependent animals compared to its
parent compound, naltrexone, as well as naloxone. It may be the result
of limited abilities of 6[beta]-naltrexol in crossing the blood-brain
barrier. Furthermore, there are no published reports assessing the
abuse liability of 6[beta]-naltrexol.
8. Whether the Substance Is an Immediate Precursor of a Substance
Already Controlled Under the CSA
    6[beta]-Naltrexol is not considered an immediate precursor of any
controlled substance.
Conclusion
    Based on the 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 demonstrate that 6[beta]-naltrexol
does not possess abuse or dependence potential. The data from in vitro,
in vivo animal studies, and clinical evidence indicate that 6[beta]-
naltrexol is a [mu]-opioid receptor antagonist and lacks abuse
potential. It should be understood that the lack of currently accepted
medical use in treatment in the United States is inconsequential where,
as here, the substance in question is determined to have insufficient
abuse potential and dependence liability to warrant control in any
schedule. HHS indicated that 6[beta]-naltrexol has no currently
accepted medical use in treatment in the United States. There are no
investigational new drugs and new drug applications for 6[beta]-
naltrexol. 6[beta]-naltrexol showed no physical or psychological
dependence in both non-clinical and clinical studies. Accordingly, the
DEA finds that 6[beta]-naltrexol does not meet the requirements for
inclusion in any schedule, and should be removed from control under the
CSA.
Regulatory Analyses
Executive Orders 12866, 13563, and 13771, Regulatory Planning and
Review, Improving Regulation and Regulatory Review, and Reducing
Regulation and Controlling Regulatory Costs
    In accordance with 21 U.S.C. 811(a), this 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.
    This final rule is not an Executive Order 13771 regulatory action
pursuant to Executive Order 12866 and OMB guidance.\5\
---------------------------------------------------------------------------
    \5\ Office of Mgmt.& Budget, Exec. Office of The President,
Interim Guidance Implementing Section 2 of the Executive Order of
January 30, 2017 Titled ``Reducing Regulation and Controlling
Regulatory Costs'' (Feb. 2, 2017).
---------------------------------------------------------------------------
Executive Order 12988, Civil Justice Reform
    This 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, Federalism
    This rulemaking does not have federalism implications warranting
the application of Executive Order 13132. The rule does not have
substantial direct effects on the States, on the relationship between
the Federal Government and the States, or the distribution of power and
responsibilities among the various levels of government.
Executive Order 13175, Consultation and Coordination With Indian Tribal
Governments
    This rule does not have tribal implications warranting the
application of Executive Order 13175. This rule does 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.
[[Page 43536]]
Regulatory Flexibility Act
    The Acting 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 rule is to remove 6[beta]-naltrexol from the list of schedules
of the CSA. This action will remove regulatory controls and
administrative, civil, and criminal sanctions applicable to controlled
substances for handlers and proposed handlers of 6[beta]-naltrexol.
Accordingly, it has the potential for some economic impact in the form
of cost savings.
    If finalized, the proposed rule will affect all persons who would
handle, or propose to handle, 6[beta]-naltrexol. 6[beta]-Naltrexol is
the major metabolite of naltrexone and is not currently available or
marketed in any country. Due to the wide variety of unidentifiable and
unquantifiable variables that potentially could influence the
distribution and dispensing rates, if any, of 6[beta]-naltrexol, the
DEA is unable to determine the number of entities and small entities
which might handle 6[beta]-naltrexol. In some instances where a
controlled pharmaceutical drug is removed from the schedules of the
CSA, the DEA is able to quantify the estimated number of affected
entities and small entities because the handling of the drug is
expected to be limited to DEA registrants even after removal from the
schedules. In such instances, the DEA's knowledge of its registrant
population forms the basis for estimating the number of affected
entities and small entities. However, the DEA does not have a basis to
estimate whether 6[beta]-naltrexol is expected to be handled by persons
who hold DEA registrations, by persons who are not currently registered
with the DEA to handle controlled substances, or both. Therefore, the
DEA is unable to estimate the number of entities and small entities who
plan to handle 6[beta]-naltrexol.
    Although the DEA does not have a reliable basis to estimate the
number of affected entities and quantify the economic impact of this
final rule, a qualitative analysis indicates that this rule is likely
to result in some cost savings. As noted above, the DEA is specifically
soliciting comments on the economic impact of this proposed rule. The
DEA will revise this section if warranted after consideration of any
comments received. Any person planning to handle 6[beta]-naltrexol will
realize cost savings in the form of saved DEA registration fees, and
the elimination of physical security, recordkeeping, and reporting
requirements.
    Because of these factors, DEA projects that this rule will not
result in 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 of 1995 (UMRA), 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.
Paperwork Reduction Act
    This action does not impose a new collection of information
requirement under the Paperwork Reduction Act, 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.
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), 956(b), unless otherwise
noted.
0
2. In Sec.  1308.12, revise the introductory text paragraph (b)(1) to
read as follows:
Sec.  1308.12   Schedule II.
* * * * *
    (b) * * *
    (1) Opium and opiate, and any salt, compound, derivative, or
preparation of opium or opiate excluding apomorphine, thebaine-derived
butorphanol, dextrorphan, nalbuphine, naldemedine, nalmefene,
naloxegol, naloxone, 6[beta]-naltrexol and naltrexone, and their
respective salts, but including the following:
* * * * *
    Dated: August 6, 2019.
Uttam Dhillon,
Acting Administrator.
[FR Doc. 2019-17630 Filed 8-20-19; 8:45 am]
 BILLING CODE 4410-09-P