[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]


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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.

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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.
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    \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.
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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.
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    \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.
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    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.
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    \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.
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    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