[Federal Register Volume 62, Number 132 (Thursday, July 10, 1997)]
[Proposed Rules]
[Pages 37004-37007]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-17961]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
[DEA No. 166P]
21 CFR Part 1308
Schedules of Controlled Substances: Proposed Placement of
Butorphanol into Schedule IV
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Notice of proposed rulemaking.
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SUMMARY: This proposed rule is issued by the Acting Deputy
Administrator of the Drug Enforcement Administration (DEA) to place the
substance butorphanol, including its salts and optical isomers, into
Schedule IV of the Controlled Substances Act (CSA). This proposed
action is based on a recommendation from the Assistant Secretary for
Health of the Department of Health and Human Services (DHHS) that
butorphanol be added to Schedule IV and on an evaluation of the
relevant data by the DEA. If finalized, this action will impose the
regulatory controls and criminal sanctions of Schedule IV on
[[Page 37005]]
those who handle butorphanol and products containing butorphanol.
DATES: Comments, objections and requests for a hearing must be
submitted on or before August 11, 1997.
ADDRESSES: Comments, objections and requests for a hearing should be
submitted in quintuplicate to the Acting Deputy Administrator, Drug
Enforcement Administration, Washington, DC 20537; Attention: DEA
Federal Register Representative/CCR.
FOR FURTHER INFORMATION CONTACT:
Frank Sapienza, Chief, Drug and Chemical Evaluation Section, Drug
Enforcement Administration, Washington, DC 20537, Telephone: (202) 307-
7183.
SUPPLEMENTARY INFORMATION: Butorphanol, currently a non-controlled
substance is classified as an opioid agonist-antagonist analgesic that
is marketed as a prescription drug under the trade name
Stadol for the relief of moderate to severe pain in humans.
It is also marketed as a veterinary product under the trade names
Torbugesic and Torbutrol for use in horses and
dogs. It was first marketed as an injectable product in 1979. Although
there was limited abuse of the injectable product among certain
populations, significant abuse was not observed until after the nasal
spray was introduced in 1992.
The Acting Deputy Administrator of the DEA received a letter dated
September 30, 1996, from the Assistant Secretary for Health, on behalf
of the Secretary of the DHHS, recommending that the drug product,
Stadol NS Nasal Spray, be placed into Schedule IV of the CSA. Enclosed
with the September 30, 1996 letter from the Assistant Secretary was a
scientific and medical evaluation prepared by the Food and Drug
Administration (FDA). The document contained a review of the factors
which the CSA requires the Secretary to consider [21 U.S.C. 811(b)].
Correspondence from the Acting Assistant Secretary for Health dated
June 19, 1997, confirmed that the DHHS recommendation included the
substance butorphanol and its salts and isomers.
The factors considered by the Assistant Secretary for Health and
the DEA with respect to butorphanol were:
(1) Its actual or relative potential for abuse;
(2) Scientific evidence of its pharmacological effect;
(3) The state of current scientific knowledge regarding the drug;
(4) Its history and current pattern of abuse;
(5) The scope, duration, and significance of abuse;
(6) What, if any, risk there is to the public health;
(7) Its psychic or physiological dependence liability; and
(8) Whether the substance is an immediate precursor of a substance
already controlled under this subchapter.
The following are summaries of the abuse potential and actual abuse
of butorphanol based on the information reviewed by the DEA, including
the scientific and medical evaluation of the DHHS.
Summary of Abuse Potential
Butorphanol's profile of effects resembles that of an opioid with
either mixed agonist-antagonist actions or partial agonist effects,
rather than full mu agonist effects, like morphine. Butorphanol's
actions are mediated via three different opioid receptor subtypes: mu,
kappa, and delta opioid receptors, showing a 12:1 mu:kappa and 34:1
mu:delta selectivity. Butorphanol's selectivity for mu receptors is
consistent with its mu agonist discriminative stimulus, self-
administration and antinociceptive profile of effects which are similar
to those of morphine, codeine and fentanyl, all Schedule II controlled
substances. Butorphanol's selectivity for kappa receptors is consistent
with its sedation and respiratory depression which are similar to those
of kappa agonists such as pentazocine, a Schedule IV substance under
the CSA.
Preclinical and clinical studies show that butorphanol produces
reinforcing effects that are less than those of morphine. Butorphanol
administered transnasally, intramuscularly, or intravenously in either
normal volunteers or former opioid abusers produces positive mood and
reinforcing effects in humans (i.e., high, drug-liking). In both
opiate-abusing and normal volunteer subjects, butorphanol's subjective
effects differ from those of full mu opiate agonists. Compared to an
equivalent dose of morphine, butorphanol produces equivalent positive
subjective effects, but greater aversive or dysphoric effects,
including greater disruption of behavior, sedation, confusion, and
difficulty concentrating. Butorphanol administered transnasally or
intramuscularly produces similar onsets of effects, rates of
elimination, and profiles of effects, however, the magnitudes of
effects were greater after intramuscularly administered butorphanol.
These studies show that the abuse potential of butorphanol does not
differ depending upon the route of administration or preparation, and
that the abuse potential of butorphanol is lower than that of morphine
and similar to that of pentazocine.
Butorphanol can induce physical and psychological dependence in
animals and humans. There is evidence that use of butorphanol produces
tolerance and dependence, results in drug-seeking and craving, and its
abrupt discontinuation produces an opioid-like withdrawal syndrome.
During clinical trials, three percent of the 161 patients who used
butorphanol for two months or longer reported behavioral symptoms
suggesting possible abuse, and approximately one percent of these
patients reported significant overuse. Chronic use of butorphanol
results in reports of abuse and self-reported addiction and
discontinuation results in a mild withdrawal syndrome. Withdrawal such
as anxiety, agitation, and diarrhea are observed. The physical
dependence and withdrawal syndrome produced by butorphanol are similar
to those observed after long term administration of pentazocine.
Consistent with its partial antagonist effects, butorphanol can
precipitate withdrawal in animals and humans maintained on mu agonists.
Summary of Actual Abuse and Diversion
For about a decade after butorphanol was first approved for
marketing as an injectable product in the United States, reports of
abuse were received only occasionally. This was likely due to its
limited availability and therapeutic indication. However, following the
introduction of the nasal spray product in the United States in 1992,
abuse dramatically increased. Many of the abuse reports came from state
authorities. At their November 1996 annual meeting, the National
Association of State Controlled Substances Authorities (NASCA)
recognized that the increasing abuse and diversion of butorphanol
warranted its scheduling. Furthermore at this meeting, NASCA passed a
resolution urging FDA and DEA to expeditiously place butorphanol into
Schedule III of the CSA.
Butorphanol has been a source of increasing incidents of abuse and
diversion since 1992. DEA has received reports from 44 states
indicating that butorphanol is being abused, diverted and trafficked.
These reports have been received from DEA Diversion Investigators,
physicians, State Boards of Pharmacies, the National Association of
State Controlled Substances Authorities, and State Drug Enforcement
officials. They show that butorphanol is stolen from retail and
hospital
[[Page 37006]]
pharmacies and is diverted through forged and altered prescriptions,
improper prescribing and inappropriate dispensing, doctor shopping, and
requests for early refills. Additionally, butorphanol abuse is
associated with escalating use and drug seeking behavior.
In response to increasing reports of abuse and diversion, six U.S.
states and Canada have administratively scheduled butorphanol, and
several other states have proposals pending to schedule butorphanol.
Some individual hospital pharmacies handle butorphanol as a controlled
substance requiring the same recordkeeping, change of shift audits, and
security as though the products were already scheduled. In many cases,
the initial use of butorphanol is for pain relief, however, escalation
of dose and drug seeking of butorphanol have been reported.
In 1994 the FDA, in consultation with the DEA, conducted a survey
of State Drug Program Directors, Boards of Pharmacy, and Drug
Enforcement officials to provide information on the abuse, trafficking,
and diversion of butorphanol. The results of the FDA's survey of the
states on the ``Abuse, Misuse, Diversion of Stabol Injectable and
Stadol Nasal Spray'' confirm the reports of increasing abuse of
butorphanol. State Boards of Pharmacy, State Drug Program Directors,
and State Drug Enforcement officials from 46 states and Guam responded
to the survey. In November 1995, the FDA issued a final report on this
survey. Eighty-three percent of the respondents stated that they were
aware of non-medical use, diversion or abuse of butorphonol in their
state. Fifteen percent of the states have attempted to regulate
butorphanol as a controlled substance, and 44 percent of the states
reported that non-regulatory entities, such as hospitals, nursing
homes, and clinics have found it necessary to institute special
controls beyond those of normal prescription drugs to limit access to
the drug. Of the states that responded, 74 percent reported that the
nasal spray was abused and 52 percent reported that the injectable was
abused. Approximately 60 percent of the states cited that the drug's
source was from overprescribing, 55 percent from forged or altered
prescriptions and six percent from ``the street''. Twenty-five percent
of the states were aware of excessive prescription refill data from
health insurance payment plans. Forty-eight percent of the states were
aware of thefts of butorphanol and 11 percent of the states reported
product tampering. The survey provided information that butorphanol
abusers crossed all socioeconomic levels.
Relying on the scientific and medical evaluation and the
recommendation of the Assistant Secretary for Health, received in
accordance with section 201 (b) of the Act (21 U.S.C. 811 (b)), and the
independent review of the DEA, the Acting Deputy Administrator of the
DEA, pursuant to sections 201(a) and 201(b) of the Act (21 U.S.C.
811(a) and 811(b)), finds that:
(1) Based on information now available, butorphanol has a low
potential for abuse relative to the drugs or other substances in
Schedule III;
(2) Butorphanol has a currently accepted medical use in treatment
in the United States; and
(3) Abuse of butorphanol may lead to limited physical dependence
and psychological dependence relative to the drugs or other substances
in Schedule III.
Based on these findings, the Acting Deputy Administrator of the DEA
concludes that butorphanol, including its salts and isomers, warrants
control in Schedule IV of the CSA.
Interested persons are invited to submit their comments, objections
or requests for a hearing, in writing, with regard to this proposal.
Requests for a hearing should state, with particularity, the issues
concerning which the person desires to be heard. All correspondence
regarding this matter should be submitted to the Acting Deputy
Administrator, Drug Enforcement Administration, Washington, D.C. 20537.
Attention: DEA Federal Register Representative/CCR. In the event that
comments, objections, or requests for a hearing raise one or more
issues which the Acting Deputy Administrator finds warrants a hearing,
the Acting Deputy Administrator shall other a public hearing by notice
in the Federal Register, summarizing the issues to be heard and setting
the time for the hearing.
In accordance with the provisions of the CSA (21 U.S.C. 811(a)),
this action is a formal rulemaking ``on the record after opportunity
for a hearing.'' Such proceedings are conducted pursuant to the
provisions of 5 U.S.C. 556 and 557 and, as such, are exempt from review
by the Office of Management and Budget pursuant to Executive Order
(E.O.) 12866, section 3(d)(1). The Acting Deputy Administrator, in
accordance with the Regulatory Flexibility Act (5 U.S.C. 605(b)), 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-business entities. Butorphanol products are prescription drugs
used to treat moderate to severe pain. Handlers of butorphanol also
handle other opiate analgesics which are controlled substances and are
already subject to the regulatory requirements of the CSA.
This rule will not result in the expenditure by State, local and
tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more in any one year, and it will not significantly or
uniquely affect small governments. Therefore, no actions were deemed
necessary under provisions of the Unfunded Mandates Reform Act of 1995.
This rule is not a major rule as defined by section 804 of the
Small Business Regulatory Enforcement Fairness Act of 1996. This rule
will not result in an annual effect on the economy of $100,000,000 or
more; a major increase in costs or prices; or significant adverse
effects on competitions, employment, investment, productivity,
innovation, or on the ability of the United States-based companies to
compete with foreign-based companies in domestic and export markets.
This rule will not have substantial direct effects on the States,
on the relationship between the national government and the States, or
on the distribution of power and responsibilities among the various
levels of government. Therefore, in accordance with E.O. 12612, it is
determined that this rule, if finalized, will not have sufficient
federalism implications to warrant the preparation of a Federalism
Assessment.
List of Subjects in 21 CFR Part 1308
Administrative practice and procedure, drug traffic control,
narcotics, prescription drugs.
Under the authority vested in the Attorney General by section
210(a) of the CSA [21 U.S.C. 811(a)], and delegated to the
Administrator of the DEA by the Department of Justice regulations (28
CFR 0.100) and redelegated to the Acting Deputy Administrator pursuant
to 28 CFR 0.104, the Acting Deputy Administrator hereby proposes that
21 CFR part 1308 be amended as follows:
PART 1308--[AMENDED]
1. The authority citation for 21 CFR part 1308 continues to read as
follows:
Authority: 21 U.S.C. 811, 812, 871(b) unless otherwise noted.
2. Section 1308.14 is proposed to be amended by adding a new
paragraph (f)(2) to read as follows:
[[Page 37007]]
Sec. 1308.14 Schedule IV.
* * * * *
(f) * * *
(2) Butorphanol (including its optical isomers).
* * * * *
Dated: July 2, 1997.
James S. Milford,
Acting Deputy Administrator, Drug Enforcement Administration.
[FR Doc. 97-17961 Filed 7-9-97; 8:45 am]
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