[Federal Register Volume 67, Number 55 (Thursday, March 21, 2002)]
[Proposed Rules]
[Pages 13114-13116]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-6767]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR PART 1308

[DEA-225P]


Schedule of Controlled Substances: Proposed Rule: Rescheduling of 
Buprenorphine From Schedule V to Schedule III

AGENCY: Drug Enforcement Administration (DEA), Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: This proposed rule is issued by the Administrator of the Drug 
Enforcement Administration (DEA) to increase the regulatory controls 
placed on buprenorphine by rescheduling buprenorphine from a Schedule V 
narcotic to a Schedule III narcotic. This proposed action is based on a 
formal rescheduling recommendation by the Department of Health and 
Human Services (DHHS) and a DEA review indicating that buprenorphine 
meets the definition of a Schedule III narcotic. If finalized, this 
action will impose the regulatory controls and criminal sanctions of a 
Schedule III narcotic on those person who handle buprenorphine or 
products containing buprenorphine.

DATES: Comments must be received by April 22, 2002.

ADDRESSES: Comments should be submitted to the 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, (202) 307-7183.

SUPPLEMENTARY INFORMATION:

What Is Buprenorphine?

    Buprenorphine is a derivative of thebaine, a major constituent of 
opium, presently marketed in the United States as an injectable 
formulation under the brand name of Buprenex for the 
treatment of pain. It is classified as a narcotic agonist-antagonist, 
or partial agonist, with an analgesic potency far greater than morphine 
(generally reported to be about 20 to 30 times that of morphine sulfate 
in humans). DEA placed buprenorphine in Schedule V of the Controlled 
substances Act (CSA) in 1985 (50 FR 8104).
    Buprenorphine has also been investigated for the treatment of 
narcotic addiction. Two New Drug Applications (NDA) have been submitted 
to the Food and Drug Administration (FDA) for this indication. 
Applications for marketing approval for these high-dose sublingual 
tablet products remain pending at FDA. However, approvable letters have 
been issued for both products and they are likely to receive final 
marketing approval in 2002.

Why Is DEA Issuing This Notice?

    As part of the NDA review process for the high-dose sublingual 
tablet formulations for buprenorphine, the FDA reviewed and evaluated 
the scientific and medical data relating to scheduling under the CSA 
pursuant to 21 U.S.C. 811(b), (c), and (f). Since the original review 
conducted by the FDA in the early 1980s (prior to the marketing of 
Buprenex), a substantial amount of human experience with 
buprenorphine products as well as a number of scientific studies have 
provided new information. These data have prompted a reevaluation of 
buprenorphine's status under the CSA. The eight factors used to 
determine the appropriate placement of buprenorphine under the CSA 
include:
    (1) Its actual or relative potential for abuse;
    (2) Scientific evidence of its pharmacological effects;
    (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 physic or physiological dependence liability; and
    (8) Whether the substance is an immediate precursor of a substance 
already controlled under this subchapter.
    On December 4, 2001, the Assistant Surgeon General and Acting 
Principal Deputy Assistant Secretary for Health, Department of Health 
and Human Services (DHHS), Arthur J. Lawrence, signed and forwarded a 
letter to the DEA recommending that buprenorphine be rescheduled as a 
Schedule III substance. This recommendation was based on FDA's 
scientific and medical evaluation. After considering the FDA's 
evalaution and the DHHS scheduling recommendation and reviewing all the 
available relevant data regarding the eight factors determinative of 
control (21 U.S.C. 811(b)(c)), the DEA concludes that buprenorphine 
should be placed in Schedule III of the CSA.

Why Did DEA Conclude That Buprenorphine Should Be Placed in 
Schedule III of the Controlled Substances Act?

    The DEA found that buprenorphine met the definition of a Schedule 
III substance. In accordance with 21 U.S.C. 812(b):
    1. Buprenorphine has a potential for abuse less than the drugs or 
other substances in Schedule I or II.
    Buprenorphine is a long-acting partial agonist with a high affinity 
for and slow dissociation from opioid receptors.
    Buprenorphine produces effects similar to other pure mu agonists 
(like morphine or hydromorphone) including euphoria, drug liking, 
respiratory depression, pupillary constriction and sedation. It is 
recognized as morphine or heroin-like by experienced narcotic abusers.
    Little abuse or diversion of buprenorphine has been noted in the 
U.S. (reflecting very limited prescription, distribution and product 
formulation: only low-dose injectable buprenorphine has been marketed). 
However, significant abuse of buprenorphine has been reported in many 
countries where it has been more available and other formulations have 
been marketed. In those countries, buprenorphine has been abused via 
the intravenous, sublingual, intransasal and inhalation routes by many 
abuser populations. Buprenorphine products have been diverted from 
legitimate channels through theft, doctor shopping and fraudulent 
prescriptions. Significant amounts of buprenorphine have been 
trafficked across international borders and law enforcement authorities 
have seized large amounts of buprenorphine involved in these 
activities.
    The above data suggest that the abuse potential of buprenorphine is 
high and closely resembles other narcotics in Schedule II. However, 
buprenorphine effects are less dose-dependent than pure mu agonists and 
a ``ceiling effect''

[[Page 13115]]

has been demonstrated for many of the actions of buprenorphine. This 
attenuation in effects at high doses may have a blunting effect on the 
continued escalation in dose to obtain greater reinforcing effects. 
Although buprenorphine is capable of producing significant respiratory 
depression and numerous deaths have been associated with injection and 
abuse of high-dose sublingual tablets in combination with other 
psychoactive drugs in France, buprenorphine is a safer drug in overdose 
than other schedule II narcotics. Therefore, buprenorphine appears to 
have somewhat less abuse potential than Schedule I or II narcotic 
substances but more abuse potential than partial agonists in Schedule 
IV. Schedule IV partial agonists are less potent, less likely to 
produce pure mu agonists effects over a wide range of doses and are 
generally not recognized as heroin-like by experienced opioid abusers.
    2. Buprenorphine has a currently accepted medical use in treatment 
in the United States.
    Buprenex, a low-dose (0.3 mg/m1) buprenorphine product, 
is approved for use as a parenteral narcotic analgesic for pain 
management. Subutex and Subozone, high-dose (2 
and 8 mg) sublingual tablets for the treatment of narcotic addiction, 
have not, as yet, received final marketing approval in the U.S. If/When 
final approval is granted, they will have current accepted medical use 
in the United States.
    3. Abuse of buprenorphine may lead to moderate or low physical 
dependence or high psychological dependence.
    Data from a number of studies indicate that chronic use of 
buprenorphine is associated with a withdrawal syndrome that is of less 
intensity and, often, of longer duration than other opioids in Schedule 
I or II. The withdrawal effects have been characterized as mild to 
moderate. In addition, about 20 percent of babies born to mothers in 
treatment with buprenorphine substitution for opioid dependence have 
exhibited an abstinence syndrome severe enough to require treatment. 
Drug craving after discontinuation of buprenorphine use has been 
reported. Buprenorphine-dependent patients can easily return to heroin 
use and vice versa. These data suggest that buprenorphine produces low 
to moderate physical dependence and high psychological dependence.
    It is likely that the approval and marketing of high-dose 
buprenorphine sublingual tables (and any other buprenorphine products 
that may be marketed in the future) will increase the availability of 
buprenorphine in the United States. The Schedule V controls presently 
in effect for buprenorphine are insufficient to prevent the diversion 
and abuse of buprenorphine that is likely to occur with its increased 
availability. Both foreign data on buprenorphine and the U.S. 
experience with other drugs like buprenorphine have been viewed by both 
the DHHS and the DEA as significant and relevant to the control of 
buprenorphine under the CSA.
    According to the United Nations International Narcotics Control 
Board (UN/INCB), worldwide usage and availability of buprenorphine has 
increased substantially in recent years. Buprenorphine production has 
grown from 35 kg in 1980 to 460 kg in 1998. In France, imports 
increased from 5 kg in 1994 to 159 kg in 1998. The increased 
availability of buprenorphine in France coincides with the marketing of 
high-dose sublingual tablets and has been accompanied by increased 
diversion and abuse and over 100 buprenorphine-related deaths.
    In the United States, expansion in the use of mixed agonists-
antagonists or partial agonists has been accompanied by significant 
increases in their diversion, abuse and public health risks. For 
example, both pentazocine (Talwin) and butorphanol 
(Stadol) were initially marketed as injectable solutions for 
analgesia. The use of these products were limited and very few abuse-
related problems were identified. However, when pentazocine became 
available in a table formulation and a butorphanol nasal spray was 
introduced, these fewer formulations greatly increased the availability 
of these substances. Significant abuse and diversion of these products 
resulted in their control under the CSA.

What Is the Effect of This Notice?

    This proposed rule, if finalized, would specifically list 
buprenorphine as a Schedule III narcotic. All products containing 
buprenorphine or salts or buprenorphine would be subject to Schedule 
III narcotic regulatory requirements. The Schedule III placement will 
not prevent any future buprenorphine products approved by the FDA for 
the treatment of narcotic addiction from being used in office based 
treatment of narcotic addiction in accordance with the Drug Addiction 
Treatment Act of 2000 (Pub. L. 106-310). This Act amended the CSA to 
allow qualified physicians, under certification by the DHHS, to 
prescribe Schedule III-V narcotic drugs (FDA-approved for the 
indication of narcotic addiction treatment) to narcotic addicts outside 
the context of clinic-based narcotic treatment programs. The DEA 
recognizes the need to expand narcotic treatment and this factor was a 
consideration in proposing Schedule III placement for buprenorphine. 
However, buprenorphine's abuse potential and psychological dependence 
profile may result in significant abuse and diversion of the sublingual 
tablets once they are available for use in the U.S. Should this occur, 
the DEA will initiate action to further increase the regulatory 
controls on buprenorphine.
    This notice also provides an opportunity for interested persons to 
comment, in writing, with regard to any information they feel may have 
a bearing on this matter. 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 Administrator, Drug Enforcement Administration, Washington, DC 
20537. In the event that comments, objections, or requests for a 
hearing raise one or more questions that the Administrator finds 
warrants a hearing, the Administrator shall publish a hearing notice in 
the Federal Register summarizing the issues to be heard and setting the 
time for the hearing.

What Regulatory Requirements Will Be Applied to Handlers of 
Buprenorphine?

    Persons currently involved with the manufacture or handling of this 
substance are not expected to comply with DEA regulations applicable to 
a schedule III narcotic substance until such time as a final rule is 
published in the Federal Register. If/When a final rule is published in 
the Federal Register, persons who are currently engaged in 
manufacturing, distributing, dispensing, importing, exporting, storing 
or conducting research with buprenorphine will be provided with delayed 
dates for compliance with Federal regulation in order to avoid imposing 
any special hardship.

Regulatory Certifications

Regulatory Flexibility Act

    The Administrator hereby certifies that this rulemaking has been 
drafted in a manner consistent with the principles of the Regulatory 
Flexibility Act (5 U.S.C. 605(b)). It will not have a significant 
economic impact on a substantial number of small business entities. 
Buprenorphine is already controlled under the CSA. Individuals who are 
currently engaged in activities with buprenorphine are already 
registered to handle controlled substances and are subject to the 
regulatory requirements of the CSA.

[[Page 13116]]

Executive Order 12866

    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. The Administrator certifies that 
this proposed rulemaking has been drafted in accordance with the 
principles in Executive Order 12866, Section 1(b). DEA has determined 
that this is not a significant rulemaking action. Therefore, this 
action has not been reviewed by the Office of Management and Budget. 
Buprenorphine is already controlled under the CSA. Individuals who are 
currently engaged in activities with buprenorphine are already 
registered to handle controlled substances and are subject to the 
regulatory requirements of the CSA.

Executive Order 12988

    This proposed regulation meets the applicable standards set forth 
in Sections 3(a) and 3(b)(2) of the Executive Order 12988 Civil Justice 
Reform.

Executive Order 13132

    This proposed rulemaking does not preempt or modify any provision 
of state law; nor does it impose enforcement responsibilities on any 
state; nor does it diminish the power of any state to enforce its own 
laws. Accordingly, this rulemaking does not have federalism 
implications warranting the application of Executive Order 13132.

Unfunded Mandates Reform Act of 1995

    This proposed 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 will not 
significantly or uniquely affect small governments. Therefore, no 
actions were deemed necessary under the provisions of the Unfunded 
Mandates Reform Act of 1995.

Small Business Regulatory Enforcement Fairness Act of 1996

    This proposed 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 competition, employment, investment, productivity, 
innovation, or on the ability of United States-based companies to 
compete with foreign-based companies in domestic and export markets.

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 
201(a) of the CSA (21 U.S.C. 811(a)), and delegated to the 
Administrator of the DEA by the Department of Justice regulations (21 
CFR 0.100), the 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 1308.13 is proposed to be amended by revising paragraph 
(e) to read as follows:


Sec. 1308.13  Schedule III.

* * * * *
    (e) Narcotic drugs. Unless specifically excepted or unless listed 
in another schedule:

  (1) Any material, compound, mixture, or preparation containing
 any of the following narcotic drugs, or their salts calculated
 as the free anhydrous base or alkaloid, in limited quantities
 as set forth below:
  (i) Not more than 1.8 grams of codeine per 100 milliliters or     9803
 not more than 90 milligrams per dosage unit, with an equal or
 greater quantity of an isoquinoline alkaloid of opium..........
  (ii) Not more than 1.8 grams of codeine per 100 milliliters or    9804
 not more than 90 milligrams per dosage unit, with one or more
 active, nonnarcotic ingredients in recognized therapeutic
 amounts........................................................
  (iii) Not more than 300 milligrams of dihydrocodeinone            9805
 (hydrocodone) per 100 milliliters or not more than 15
 milligrams per dosage unit, with a fourfold or greater quantity
 of an isoquinoline alkaloid of opium...........................
  (iv) Not more than 300 milligrams of dihydrocodeinone             9806
 (hydrocodone) per 100 milliliters or not more than 15
 milligrams per dosage unit, with one or more active nonnarcotic
 ingredients in recognized therapeutic amounts..................
  (v) Not more than 1.8 grams of dihydrocodeine per 100             9807
 milliliters or not more than 90 milligrams per dosage unit,
 with one or more active nonnarcotic ingredients in recognized
 therapeutic amounts............................................
  (vi) Not more than 300 milligrams of ethylmorphine per 100        9808
 milliliters or not more than 15 milligrams per dosage unit,
 with one or more active, nonnarcotic ingredients in recognized
 therapeutic amounts............................................
  (vii) Not more than 500 milligrams of opium per 100               9809
 milliliters or per 100 grams or not more than 25 milligrams per
 dosage unit, with one or more active, nonnarcotic ingredients
 in recognized therapeutic amounts..............................
  (viii) Not more than 50 milligrams of morphine per 100            9810
 milliliters or per 100 grams, with one or more active,
 nonnarcotic ingredients in recognized therapeutic amounts......
  (2) Any material, compound, mixture, or preparation containing
 any of the following narcotic drugs or their salts, as set
 forth below:
    (i) Buprenorphine...........................................    9064
      (ii) [Reserved.]
 

* * * * *
    3. Section 1308.15 (b) introductory text is proposed to be revised 
and paragraph (b) (1) is proposed to be removed and reserved to read as 
follows:


Sec. 1308.15  Schedule V.

* * * * *
    (b) Narcotic drugs. Unless specifically excepted or unless listed 
in another schedule, any material, compound, mixture, or preparation 
containing any of the following narcotic drugs and their salts, as set 
forth below:
    (1) [Reserved]
* * * * *

    Dated: March 11, 2002.
Asa Hutchinson,
Administrator.
[FR Doc. 02-6767 Filed 3-20-02; 8:45 am]
BILLING CODE 4410-09-M