[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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