[Federal Register Volume 67, Number 194 (Monday, October 7, 2002)]
[Rules and Regulations]
[Pages 62354-62370]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-25293]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR part 1308

[DEA-225F]


Schedules of Controlled Substances: Rescheduling of Buprenorphine 
From Schedule V to Schedule III

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

ACTION: Final rule.

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SUMMARY: This final rule is issued by the Deputy Administrator of the 
Drug Enforcement Administration (DEA) to reschedule buprenorphine from 
a Schedule V narcotic to a Schedule III narcotic under the Controlled 
Substances Act (CSA). This action is based on a rescheduling 
recommendation by the Department of Health and Human Services (DHHS) 
and a DEA review indicating that buprenorphine meets the criteria of a 
Schedule III narcotic. The DEA published a proposed rule to reschedule 
buprenorphine on March 21, 2002 (67 FR 13114). The comment period was 
extended for an additional 30 days until May 22, 2002 (67 FR 20072). 
The DEA received ten comments but no requests for hearings.
    This final action will impose the regulatory controls and criminal 
sanctions of a Schedule III narcotic on those persons who handle 
buprenorphine or products containing buprenorphine.

DATES: Effective Date: October 7, 2002. Compliance to some regulatory 
requirements may be delayed as noted in the Regulatory Requirements 
section of this document.

FOR FURTHER INFORMATION CONTACT: Frank Sapienza, Chief, Drug and 
Chemical Evaluation Section, Drug Enforcement Administration, 
Washington, DC 20537, (202) 307-7183.

SUPPLEMENTARY INFORMATION: 

Background

    Buprenorphine is a semisynthetic opioid. As a derivative of 
thebaine, buprenorphine was controlled in Schedule II of the CSA in 
1970 and remained in Schedule II during its research and development 
for marketing. In 1981, buprenorphine hydrochloride (Buprenex[reg]) was 
approved for marketing in the United States as an injectable 
formulation (0.3 mg/ml) for the treatment of moderate to severe pain. 
The DEA proposed placement of buprenorphine in Schedule V of the CSA 
after receiving a medical and scientific evaluation and a Schedule V 
recommendation from the DHHS. However, buprenorphine was not placed in 
Schedule V of the CSA until April 1, 1985 (50 FR 8104, February 28, 
1985) due to a hearing requested by the manufacturer of buprenorphine, 
Reckitt & Coleman (now Reckitt Benckiser). Since 1985, Buprenex[reg] 
has remained in Schedule V. As an injectable analgesic, this product 
has had limited use outside hospital and clinic settings and is the 
only buprenorphine product presently marketed in the United States.
    In December 2001, the DHHS forwarded a recommendation to reschedule 
buprenorphine to Schedule III of the CSA. This recommendation was based 
on a reevaluation of buprenorphine's abuse potential and dependence 
profile in light of numerous scientific studies and years of human 
experience with this drug. The DHHS compared buprenorphine with other 
drugs that share similar pharmacological properties and/or medical 
utility and considered both foreign and domestic data especially in 
regard to formulations of buprenorphine that are likely to become 
available for use in the United States. Two New Drug Applications (NDA) 
have been submitted to the Food and Drug Administration (FDA) for high 
dose sublingual (under the tongue) tablets. These potential addiction 
treatment products include: (1) Subutex[reg], a mono or single entity 
buprenorphine product (2 and 8 mg tablets), and (2) Suboxone[reg], a 
combination product in a 4:1 ratio of buprenorphine to naloxone (2: 0.5 
and 8: 2 mg tablets). The Subutex[reg] and Suboxone[reg] NDAs remain 
pending at the FDA but approvable letters have been issued for both 
products and they are likely to receive final marketing approval in 
2002. Low dose sublingual tablets (0.1 , 0.2 and 0.4 mg) have been 
available in numerous countries throughout the world and, in recent 
years, high dose sublingual tablets (2 and 8 mg) have been introduced 
in many countries for the treatment of opioid dependence.
    After consideration of the DHHS scientific and medical evaluation 
and Schedule III recommendation, the DEA completed an independent eight 
factor analysis that included the following factors in accordance with 
21 U.S.C. 811(c):
    (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 psychic or physiological dependence liability; and
    (8) Whether the substance is an immediate precursor of a substance 
already controlled under this subchapter.
    On March 21, 2002, the DEA published a proposed rule to place 
buprenorphine in Schedule III of the CSA (67 FR 13114). This notice 
will

[[Page 62355]]

finalize that proposed rule. Schedule III control requires the DEA to 
make the following findings in accordance with 21 U.S.C. 812 (b):
    1. Buprenorphine has a potential for abuse less than the drugs or 
other substances in Schedules I and II.
    2. Buprenorphine has a currently accepted medical use in treatment 
in the United States.
    3. Abuse of buprenorphine may lead to moderate or low physical 
dependence or high psychological dependence.

Comments to the Proposed Rule

    The DEA received comments from ten interested parties. Two 
commenters were in support of the proposed rule, seven commenters were 
in opposition to the proposed rule and one individual requested that 
the DEA be mindful of possible conflicts of interest by individuals/
organizations responding to this proposed rule. One commenter felt that 
Schedule II more accurately reflected the abuse potential and 
dependence profile of buprenorphine while another commenter felt that 
the evidence suggests that buprenorphine should remain in Schedule V. 
Five commenters support differential scheduling of buprenorphine 
products and contend that the buprenorphine/naloxone product under 
development has less abuse potential. The following is a listing of all 
commenters and a brief summary of their comments:
    1. The Medical Director of the American Psychiatric Association 
(APA) commented on behalf of this organization. He stated that the APA 
supports the proposed rule to reschedule this drug. However, once 
buprenorphine has been approved for use in opioid substitution 
treatment, the APA recommends that the DEA study and evaluate the 
actual abuse over a three-year period to more accurately determine 
whether placement in Schedule III is appropriate.
    2. The President of the American Association for the Treatment of 
Opioid Dependence (AATOD) submitted comments on behalf of the Board of 
Directors of AATOD in support of a Schedule III narcotic classification 
for buprenorphine and its products.
    3. The Chair Committee for the Treatment of Opioid Dependence of 
the California Society of Addiction Medicine (CSAM) and the President 
of CSAM recommended less restrictive scheduling of the buprenorphine/
naloxone combination product (Suboxone[reg]) compared to the mono 
buprenorphine product (Subutex[reg]) should they be approved for 
marketing. They believe it is important to convey the message to 
physicians about the lower risk of abuse and diversion of the combined 
formulation. They believe that differential scheduling would encourage 
physicians to appropriately choose the combination product for 
treatment of addicted patients. No data was provided in support of 
their contentions.
    4. A member of the Board of Directors of the American Academy of 
Addiction Psychiatry (AAAP) commented on behalf of this organization. 
The AAAP contends that the available literature and research on 
buprenorphine do not support the DEA recommendation and recommends 
differential scheduling of buprenorphine products. Because 
Buprenex[reg] has been in Schedule V and has not been associated with 
widespread diversion and abuse, they believe there is no compelling 
reason to reschedule this medication. Further, they believe there are 
substantial differences between the two sublingual products intended 
for addiction treatment. They contend that the buprenorphine/naloxone 
product is being developed specifically to prevent diversion and 
illicit injection use. They believe that buprenorphine diversion in 
other countries has been limited to use by out-of-treatment, opioid 
dependent, injection drug users. Should both products be placed in 
Schedule III, they believe that there will be no incentive for 
physicians to differentially make use of one product. They recommend 
Schedule V for Buprenex[reg] and Suboxone[reg] and Schedule III for 
Subutex[reg]. No data was submitted to the DEA in support of these 
comments.
    5. The President of the American Society of Addiction Medicine 
(ASAM) commented on behalf of this organization. His views also 
represent those of the Chairmen of ASAM's Medication Development 
Committee and the Opioid Agonist Treatment Committee. They contend that 
placing all buprenorphine-containing products into the same schedule is 
not consistent with the pharmacology and the intended clinical use of 
the buprenorphine/naloxone sublingual tablets. They believe that 
sufficient evidence currently exists to support a lower parenteral 
abuse potential of the combination product as compared to the mono 
product. They feel that differentially scheduling these addiction 
medications would encourage physicians to prescribe the naloxone 
combination product in preference to the mono-product. No data was 
submitted to the DEA in support of these comments.
    6. The President of the College on Problems of Drug Dependence 
(CPDD) commented on behalf of this organization. This commenter 
requests that the DEA consider differential scheduling for the 
potential addiction treatment medications, Suboxone[reg] and 
Subutex[reg]. She believes there is strong evidence to support 
differential scheduling: the combination product will lead to lower 
abuse liability and less parenteral abuse by individuals who are 
currently dependent on opioids because the naloxone will precipitate 
withdrawal. The mono-product will not precipitate withdrawal. No data 
was submitted to the DEA in support of these comments.
    7. The President of Reckitt Benckiser Pharmaceuticals, the 
manufacturer of Buprenex[reg] and the sponsor of the two NDAs for 
buprenorphine products in the treatment of opioid dependence, does not 
support the proposed rule for the following reasons:
    (a) Little diversion or abuse of buprenorphine has been noted in 
the United States in the 15 years the product has been marketed.
    (b) The DEA has disregarded data on the development of the naloxone 
combination product that shows significantly less potential for 
diversion and abuse.
    (c) The DEA disregards the additional controls imposed on these 
newer products by the Drug Addiction Treatment Act of 2000 (DATA).
    (d) The Schedule III control for all formulations of buprenorphine 
would thwart company efforts to ensure that the combination product, if 
approved, is the primary medication that should be utilized for 
addiction treatment. By not differentially scheduling these products, 
the DEA is removing the incentive for physicians to prescribe the 
combination product rather than the single entity product.

The company feels that Buprenex[reg] should be left in Schedule V, and 
the addiction medications, if approved, should be placed in Schedule 
IV. Or, as an alternative, the substance, buprenorphine, should be 
placed in Schedule III (which would include Subutex[reg]), 
Suboxone[reg] should be placed in Schedule IV and buprenorphine 
products with less than 1 mg/ml should be placed in Schedule V. No data 
was provided to the DEA in support of these comments.
    8. The law offices of Hogan & Hartson submitted comments on behalf 
of a client. Hogan & Hartson requests that DEA enter an order 
immediately placing buprenorphine and all products containing 
buprenorphine under Schedule II based on their contention that:
    (a) Buprenorphine has a high potential for abuse consistent with 
the

[[Page 62356]]

abuse potential of Schedule II drugs. The partial agonist activity, 
including safety in overdose, is not supported and, even if true, does 
not warrant a change from the conclusion that buprenorphine has a high 
potential for abuse.
    (b) Safety in overdose is not a relevant factor in deciding if a 
drug has less abuse potential than other similar drugs.
    (c) The DEA failed to consider that the illusion of safety may 
result in greater potential for abuse.
    (d) Scheduling under the CSA is a relative analysis and depends on 
aligning a drug with the closest set of comparators. Hogan and Hartson 
believe that the closest set of comparators are Schedule II.
    (e) Buprenorphine is a gateway drug which compounds public health 
risks.
    (f) The DEA failed to give adequate weight to the fact that 
buprenorphine is administered by many routes of administration and in 
combination with other drugs.
    (g) The DEA has not been consistent in its decision making process 
and has failed to meet the non-arbitrary agency action requirements. 
The finding that buprenorphine has a potential for abuse less than 
Schedule I or II substances is arbitrary and capricious and not 
supported by the underlying administrative record.
    (h) The DEA position that buprenorphine most closely resembles 
Schedule III substances with respect to physical and psychological 
dependence is contrary to the evidence (even if true, DEA must give 
greater weight to the abuse potential).
    (i) The DEA erred in considering that buprenorphine be available 
for office-based use as it is not a relevant factor in the scheduling 
analysis.
    (j) Placement of buprenorphine in Schedule III to make it available 
for office based care will have a significant impact on opioid 
treatment programs. The DEA is required to analyze this issue and 
follow the mandate of the Regulatory Flexibility Act.
    (k) The CSA requires DEA to make a reasonable predictive judgment 
about a drug and should not take a reactive posture by stating ``should 
significant abuse or diversion of buprenorphine occur, DEA will 
initiate actions to increase its regulatory control.''

In support of these comments, Hogan & Hartson referred to various legal 
citations and statements made by DEA and FDA in the scheduling review 
documents on buprenorphine. No new scientific data was submitted.
    9. The law offices of Hyman, Phelps & McNamara, P.C. commented on 
behalf of Purdue Pharma. After reviewing the information that the FDA 
and the DEA relied upon in order to reach a decision to propose 
Schedule III placement for buprenorphine, they contend that:
    (a) The DEA has not presented an adequate basis for the proposed 
rulemaking.
    (b) The proposed rule has not adequately described the pharmacology 
of the drug substance buprenorphine or the drug products that would be 
affected by this rule.
    (c) Many facts cited by the DEA and FDA in their conclusions have 
been removed from their proper scientific context. This is particularly 
evident in the description of buprenorphine and in the basis for the 
DEA conclusion that buprenorphine may cause high psychological 
dependence.
    (d) The DEA and FDA have not explained why data generated since the 
original scheduling action for buprenorphine in 1985 would alter the 
original conclusions that buprenorphine has a low potential for abuse 
and low potential for physical and psychological dependence.
    (e) The DEA and FDA have inadequately described the conditions of 
use of Subutex[reg] in France and the impact of such use on either the 
mortality associated with heroin addiction or the frequency of abuse of 
buprenorphine. It is asserted without supporting data that the 
conditions of use that will apply to Suboxone[reg] and Subutex[reg], 
should they be approved for use in the United States, will inevitably 
lead to significant abuse of buprenorphine. There is no discussion of 
how the proposed use of Subutex[reg] in the United States may differ 
from the use of this product in France. There is not an acknowledgment 
in the proposed rule that one of the products under development, which 
is not available in France, contains naloxone which is expected to 
deter intravenous abuse.
    (f) The additional controls that would be provided by moving 
buprenorphine to Schedule III are not described and no rationale is 
provided for the assertion that the Drug Addiction Treatment Act will 
not provide adequate safeguards for the public health.
    (g) The overwhelming scientific and medical evidence demonstrates 
that buprenorphine should not be rescheduled. If buprenorphine is 
rescheduled it should not be placed any higher than Schedule IV.

Hyman, Phelps & McNamara relied on data from the World Health 
Organization (WHO), United Nations (UN), International Narcotics 
Control Board (INCB) statistics, emergency department mentions in the 
Drug Abuse Warning Network (DAWN), DEA forensic laboratory data, 
literature cited in FDA and DEA review documents on buprenorphine and 
case law.
    1. The Director of the Edmond de Rothschild Foundation, Chemical 
Dependency Institute of Beth Israel Medical Center in New York City, 
urged the DEA to assess possible conflict of interest of individuals/
organizations submitting comments on the proposed rule to place 
buprenorphine in Schedule III of the CSA.

DEA Response to Comments

    The DEA has thoroughly reviewed, analyzed and considered all the 
comments submitted in response to the proposed rule to place 
buprenorphine into Schedule III of the CSA. Most commenters averred 
that the DEA failed to consider data that demonstrates that 
buprenorphine has a lower (or higher) abuse potential/dependence 
profile than Schedule III substances. In most instances, no data was 
provided to support these contentions. Two commenters, however, 
provided data that they relied upon in opposing the proposed rule. The 
relevant data cited by these commenters were available to and 
considered by DHHS and DEA in deliberations regarding the proposal to 
reschedule buprenorphine. In several cases, the same medical, 
scientific and other data cited by FDA and/or DEA in scheduling review 
documents are interpreted differently by the commenters.
    Fundamental to all of the comments in opposition to the proposed 
rule is the belief that buprenorphine and/or products containing 
buprenorphine have an abuse potential and dependence profile other than 
Schedule III. The following is a brief summary of the data used by the 
DEA to conclude that the most appropriate placement for buprenorphine 
and products containing buprenorphine is in Schedule III of the CSA 
classified as a narcotic. Following this summary (under the headings of 
Abuse Potential of Buprenorphine and Dependence Profile of 
Buprenorphine), specific questions or comments raised by the commenters 
are addressed.

Abuse Potential of Buprenorphine

    The evaluation of the abuse potential of any substance considers a 
number of factors including (but not limited to) its chemistry 
(including ease of synthesis and evidence of clandestine production), 
pharmacology (including routes of administration, profile of effects 
under various conditions and populations, duration of action, drug 
interactions), intended use, populations at-risk of abuse and actual 
abuse data.

[[Page 62357]]

The subjective effects (alterations in mood, feeling and thinking) 
produced by a drug may lead to reinforcement of drug-taking behavior 
and abuse (Jasinski, 1991). The abuse potential criteria under the CSA 
is a relative one with Schedule I and II requiring substances to have a 
high abuse potential and Schedule III, IV and V substances having 
progressively lower abuse potentials. This necessitates the comparison 
of the abuse potential of the substance under review with other 
substances. Morphine, a Schedule II substance with high abuse 
potential, is often used as a standard for comparing the effects 
produced by other opiates; the more an opiate/opioid is morphine-like 
as perceived by the user, the more likely the substance, if available, 
will be abused.
    Buprenorphine is a semi-synthetic opioid derived from thebaine. It 
has high affinity for, low intrinsic activity at, and slow dissociation 
from opioid receptors (for review see Johnson & McCagh, 2000). These 
properties contribute to its protracted occupancy at opioid receptors.
    Buprenorphine is a partial agonist (activator) at the mu-opioid 
receptor and an antagonist (blocker) at the kappa-opioid receptor 
(Richards and Sadee, 1985; Sadee et al., 1982). Mu receptor activation 
is associated with analgesia, miosis (pupillary constriction), 
respiratory depression, euphoria, reduced gastrointestinal motility and 
dependence. Kappa receptor activation produces analgesia, miosis, 
sedation, dysphoria and psychotomimetic effects including 
disorientation and/or depersonalization. As a partial agonist at the mu 
receptor, buprenorphine produces effects similar to pure mu agonists 
(like morphine) but effects are less dose-dependent producing a 
``ceiling effect'' on both physiological and psychological properties: 
dose increases above the ``ceiling dose'' do not produce greater 
effects (Pickworth et al., 1993; Walsh et al., 1994, 1995). Various 
effects produced by buprenorphine have different ceiling doses. At 
clinically relevant doses, the ``ceiling'' for some effects produced by 
buprenorphine administration may not be reached. As a consequence, 
buprenorphine may act more like a pure mu agonist (depending on dose, 
effect being measured and individual variability) and may produce 
significant dose-related euphoria, drug liking, respiratory depression 
and sedation over a wide range of doses (see citations below). However, 
buprenorphine's unique pharmacology results in greater safety (less 
respiratory depression at very high doses), less physical dependence 
and greater flexibility in dose scheduling than pure mu agonists such 
as morphine (Johnson & McCagh, 2000).
    Although poorly available by the oral route due to poor absorption 
and extensive metabolism in the small intestine and liver, 
buprenorphine can be taken sublingually (Walter et al., 1996). As a 
drug of abuse, tablets have been crushed and snorted, smoked and placed 
in aqueous solutions and injected (for example: Strang, 1985, 1991; 
Gruer et al., 1993; Kintz, 2001). The absolute bioavailability of 
sublingual tablets is approximately 30 percent when the extent of 
absorption of a sublingual solution is compared to an intravenous dose 
(Mendelson et al., 1997a). Dissolving buprenorphine in aqueous alcohol 
enhances sublingual absorption: the bioavailability of the tablet is 
about 50 percent that of a sublingual aqueous alcohol solution 
containing equivalent amounts of buprenorphine (Nath et al., 1999; 
Schuh et al., 1999a). This difference in the bioavailability of 
sublingual aqueous alcohol solutions and sublingual tablets of 
buprenorphine may account for some of the variability in data involving 
dose effects. Data generated using animal models suggest that 
buprenorphine may have relatively high bioavailability in humans by the 
intranasal route (Brewster et al., 1981; Lindhardt et al., 2000).
    The more ways a drug can be administered by various populations of 
abusers increases its likelihood to be abused. Individuals that only 
abuse pharmaceuticals by swallowing tablets or liquids (like most 
abusers of hydrocodone products) would be less likely to abuse 
buprenorphine. At the same time, the lack of oral bioavailability 
increases the likelihood that buprenorphine will be abused in a manner 
that enhances its reinforcing effects. Abuse data indicates that 
buprenorphine is often injected. While heroin addicts and experienced 
narcotic abusers have been the primary abusers of buprenorphine, data 
from England, France, Scotland, and Ireland demonstrate that, if 
available, buprenorphine is abused by young, non-dependent drug abusers 
(Coggans et al., 1991; Forsyth et al., 1993; Frischer, 1992; 
Hammerseley et al., 1990; O'Connor et al., 1988).
    The DEA has no evidence that buprenorphine is clandestinely 
produced; diverted pharmaceutical products are the only source of this 
drug for those who would choose to abuse it. Like all substances with 
abuse potential, the greater the availability of buprenorphine (greater 
use due to new dosage forms and new indications) the more likely it 
will be abused. High-dose, sublingual tablets intended for narcotic 
treatment and utilized outside the constraints of traditional narcotic 
treatment programs increases the risk that these products will be 
diverted, trafficked and abused. Simply stated, providing an abusable 
substance to known drug abusers imparts enhanced risks. While little 
diversion and abuse of the injectable formulation, Buprenex[reg], has 
occurred in the United States, the circumscribed use (few prescriptions 
and primary use in hospital settings) has limited the availability of 
this substance for abuse purposes. Recent increases in the use of 
Buprenex[reg] may be related to the use of this product for narcotic 
treatment and detoxification: IMS National Disease and Therapeutic 
Index data and DEA field office reports indicate that many doctors are 
illegally using Buprenex[reg] for narcotic treatment and 
detoxification. The Drug Addiction Treatment Act of 2000 (DATA) does 
not apply to Buprenex[reg] as it has not been approved by the FDA for 
use in narcotic treatment.
    Drug discrimination studies are among the most rigorous laboratory 
procedures for assessing the substitutability of psychoactive drugs and 
provide valuable information about the subjective effects produced by a 
drug (Schuster & Johanson, 1988). In drug discrimination studies, 
buprenorphine generally substitutes for mu agonists across several 
animal species including humans (for example: Leander, 1983; France et 
al., 1984; Young et al, 1984; France & Woods, 1985; Hoffmeister, 1988; 
Picker & Dykstra, 1989; Negus et al., 1990; Preston et al., 1989, 1992; 
Bigelow and Preston, 1992; Paronis & Holtzman, 1994; Walker et al., 
1994). These studies suggest that buprenorphine shares more similar 
effects with pure mu agonists than with prototypic partial agonists 
(like butorphanol and pentazocine that are in Schedule IV of the CSA). 
For example, Preston & Bigelow (2000) conducted a drug discrimination 
study in adult males with histories of opioid abuse (but not physically 
dependent at time of study) trained to discriminate hydromorphone (a 
Schedule II pure mu agonist) from placebo (saline). Of the partial 
agonists tested (buprenorphine, butorphanol, pentazocine and 
nalbuphine) only buprenorphine fully substituted for hydromorphone and 
produced dose-related increases in hydromorphone-appropriate responses. 
Pentazocine showed an inverted U-shaped dose-response curve while 
butorphanol and nalbuhine did not

[[Page 62358]]

substitute for hydromorphone at any dose tested.
    The subjective effects of buprenorphine, with or without naloxone, 
have been studied under a wide range of conditions including study 
subjects, dose ranges, routes of administration and timing intervals. 
In addition, opiate or naloxone challenge in buprenorphine maintained 
clients vary significantly with study conditions. Despite the 
methodological differences in these studies, certain conclusions can be 
made regarding the abuse potential of buprenorphine (with or without 
naloxone) in different populations of users. The following represents a 
sampling of those studies.
    Studies conducted in non-drug abusers (for example: Manner et al., 
1987; Saarialho-Kere et al., 1987; MacDonald et al., 1989; Fullerton et 
al., 1991; Zacny et al., 1997) indicate that buprenorphine, like 
morphine, produces dose related impairment of psychomotor performance, 
euphoria, miosis, respiratory depression, somnolence and nausea. In 
studies with non-dependent, opioid-experienced subjects, the most 
consistent finding with buprenorphine administration (sublingual, 
intravenous, intramuscular, subcutaneous) is a dose-related increase in 
``drug liking'' and ``good drug effects'' over a wide range of doses 
(for example: Jasinski et al., 1978; Preston et al., 1992; Weinhold et 
al., 1992; Pickworth et al., 1993; Preston and Bigelow, 1994; Foltin 
and Fischman, 1996; Greenwald et al., 1999; Strain et al., 2000; Comer 
et al., 2002). In opioid dependent subjects, buprenorphine can 
substitute for heroin. Clinical data indicate that when equipotent 
doses of buprenorphine and methadone are used, buprenorphine is as 
effective as methadone in suppressing opioid withdrawal (Bickel et al., 
1988; Johnson et al., 1992). Jasinski et al. (1978) reported that 
chronic subcutaneous administration of a daily dose of 8 mg of 
buprenorphine produces morphine-like subjective effects and euphoria 
equivalent to 30 mg of morphine sulfate administered four times daily. 
In a sample of experienced detoxified opiate abusers, Bedi et al (1998) 
examined the abuse liability of 0.6 mg of buprenorphine, 16 mg morphine 
and 30 mg pentazocine. Buprenorphine produced significant euphoria and 
was identified as heroin rather than pentazocine. In a study with 
opiate-dependent heroin abusers, intravenous administration of 2 mg of 
buprenorphine produced potent opiate agonist effects (Mendelson et al., 
1996). Seven of eight subjects estimated that this dose of 
buprenorphine had a street value between $5 and $20 but of lesser value 
than heroin. In subjects maintained on daily sublingual buprenorphine 
(8 mg), intramuscular injections of buprenorphine (4, 8, 16 mg) 
produced opioid agonist-like effects (Strain et al., 1997). 
Collectively, these data suggest that buprenorphine has abuse potential 
in a wide spectrum of individuals. Vulnerable populations include drug 
naive individuals (new drug abusers), opiate experienced individuals 
and opiate dependent individuals.
    Many of the comments to the proposed rule for buprenorphine 
rescheduling expressed concern about placing the buprenorphine/naloxone 
combination product in the same schedule as single entity products. 
They contend that the combination product has significantly less abuse 
potential warranting lesser control. However, the data regarding 
naloxone and buprenorphine/naloxone administration in various 
populations of users does not support a lower schedule.
    Naloxone is an opioid antagonist that acts competitively at opioid 
receptors. It is used to reverse opioid central depression, including 
respiratory depression (the leading cause of death in narcotic 
overdoses), and has been given intravenously to precipitate withdrawal 
symptoms in the diagnosis of opioid dependence. It is generally 
injected and has a short duration of action. Taken sublingually, 
naloxone has little bioavailability.
    The buprenorphine/naloxone combination product was specifically 
developed to inhibit intravenous abuse by heroin addicts. In theory, 
the injection of buprenorphine/naloxone combination in opioid-dependent 
subjects should precipitate a moderate to severe withdrawal syndrome 
similar to abrupt withdrawal from opioids. This withdrawal syndrome 
develops within minutes of injection and subsides in one to two hours. 
However, a substantial percentage of individuals currently abusing 
heroin or other opiates do not show any evidence of withdrawal when 
challenged with naloxone. Between 34 and 61 percent of patients 
applying for methadone maintenance may have minimal or no response to 
intravenous or intramuscular naloxone in doses ranging from 0.2-1.2 mg 
(Blachly, 1973; Judson et al., 1980; Kanof et al., 1991; Peachy and 
Lei, 1988; Zilm and Sellers, 1978). While addicts that seek treatment 
may have very high levels of psychological dependence, this data 
suggest that they may not have high levels of physical dependence on 
narcotics.
    The extent of withdrawal associated with injection of 
buprenorphine/naloxone combination, should it occur, is directly 
related to the buprenorphine/naloxone dose and the level of dependence 
of the subjects. For example, individuals maintained on 30-60 mg of 
methadone (Strain et al., 1995; Mendelson et al., 1997) or 60-120 mg 
intramuscular morphine (Mendelson et al., 1999; Fudala et al., 1998; 
Schuh et al., 1996), opiate doses likely to produce significant 
physical dependence, experience an unpleasant opioid withdrawal 
syndrome after injection of low doses of naloxone or buprenorphine/
naloxone. Mendelson et al. (1999) studied the effects of three 
intravenous buprenorphine and naloxone combinations on agonist effects 
and withdrawal signs in 12 opiate-dependent subjects. Following 
stabilization on a daily dose of 60 mg morphine intramuscularly, 
subjects were challenged with buprenorphine alone (2 mg intravenously) 
or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, 
and 0.25 mg of naloxone). Buprenorphine alone did not precipitate 
withdrawal and produced effects similar to morphine. Dose-dependent 
increases in withdrawal signs and symptoms and a decrease in opioid 
agonist effects occurred after all naloxone combinations. At the 4:1 
ratio (that which has been chosen for the marketing of the combination 
product), opioid agonist effects were attenuated by about 50 percent 
and unpleasant effects were observed for about 30 minutes. These data 
suggest that injection of the combination buprenorphine/naloxone 
product has less abuse potential in non-buprenorphine opiate-dependent 
addicts.
    In New Zealand, the only country that has marketed a buprenorphine/
naloxone combination product, extensive intravenous abuse of the 0.2 mg 
buprenorphine tablet among opiate abusers led to the 1991 reformulation 
of buprenorphine to include 0.17 mg of naloxone. Robinson et al. (1993) 
conducted two separate surveys among narcotic addicts presenting for 
treatment before and after the launch of the naloxone combination 
product. In 1990, 81 percent of the patients reported intravenous 
buprenorphine abuse in the previous 4 weeks, 50 percent reported 
exclusive use of buprenorphine and 65 percent tested positive for the 
drug. In 1991, 57 percent reported intravenous abuse of the combination 
tablet and 43 percent tested positive for the combination. One third of 
the patients that used the combination product intravenously reported 
instances of withdrawal symptoms. Only one patient

[[Page 62359]]

reported exclusive use (by injection) of buprenorphine/naloxone and 
experienced no adverse withdrawal effects. The authors concluded that 
the combination product did act as a deterrent for some drug abusers 
but did not stop injection practices. In addition, the authors noted 
that the injection of the combination product would not produce 
withdrawal symptoms (act as a deterrent) in individuals who were not 
physically dependent on narcotics or those who were physically 
dependent on buprenorphine.
    Injection of buprenorphine/naloxone in opioid naive individuals, 
non-dependent opioid abusers or buprenorphine maintained addicts will 
likely result in opioid agonist effects. For example, intramuscular 
administration of buprenorphine alone (0.4 and 0.8 mg/70 kg) or in 
combination with naloxone (0.4 and 0.8 mg/70 kg) was examined in seven 
non-physically dependent opioid abuser volunteers (Weinhold et al, 
1992). In subjective measures of drug effects, buprenorphine alone 
produced dose dependent increases in ``drug liking'', ``high'', and 
agonist ratings. Administration of 0.4 mg buprenorphine in combination 
with 0.4 mg naloxone produced positive subjective opiate effects 
greater than 0.4 mg of buprenorphine alone and a greater percentage of 
subjects identified the naloxone-buprenorphine combination as an opiate 
when compared to buprenorphine treatment alone. However, increasing the 
naloxone concentration to 0.8 mg (twice the concentration of 
buprenorphine) significantly reduced opioid agonist effects.
    In another study with opioid-dependent volunteers stabilized on 8 
mg/day sublingual buprenorphine, intravenous buprenorphine (8 mg) with 
naloxone (4 or 8 mg) produced subjective effects similar to 8 mg 
sublingual buprenorphine and did not precipitate withdrawal (Harris et 
al., 2000). Buprenorphine's high affinity for opioid receptors prevents 
naloxone from displacing buprenorphine already bound to these sites. In 
some populations of buprenorphine-maintained clients, extremely high 
intravenous doses of naloxone are required to even partially displace 
buprenorphine from opioid receptors (Koston et al., 1990).
    In non-dependent opioid abusers, sublingual administration of 
buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg) produced 
opioid agonist-like effects (Strain et al., 2000).
    The data suggest that the buprenorphine/naloxone combination 
products will likely produce an unpleasant withdrawal when injected by 
heroin-dependent subjects. However, this combination drug product will 
not be a serious deterrent to injection by marginally or non-physically 
dependent users or by individuals stabilized on this medication for 
addiction treatment (those individuals that will probably have the 
greatest access to this drug) or by injecting addicts who are abusing 
and dependent on buprenorphine. In addition, this combination product, 
taken sublingually, is not a deterrent for abuse by most populations. 
Studies on snorting and smoking this combination are not available.
    One of the many objectives of opioid replacement therapy for 
addiction treatment is to deter addicts from the continued use of 
heroin or other opiates. Chronic buprenorphine dosing produces cross-
tolerance to other opioids (Jasinski et al., 1978; Bickel et al., 1988) 
and may limit the magnitude of effects produced by supplemental 
challenges of other opioids.
    In subjects maintained on a sublingual dose of 8 mg/day of 
buprenorphine, acute supplemental intramuscular doses of buprenorphine 
(4, 8 and 16 mg) or hydromorphone (9 and 18 mg) administered 16 hours 
after the buprenorphine daily dose produced opioid agonist effects 
although there was a lack of graded dose-effects for hydromorphone 
(Strain et al., 1997). The addition of naloxone to the maintenance dose 
of buprenorphine does not impart greater blockade (Strain et al., 
2002).
    In a study to determine what dose of buprenorphine would 
effectively block the reinforcing effects of intravenous heroin (Comer 
et al., 2001), both 8 and 16 mg of sublingual buprenorphine maintenance 
dosing failed to block the effects of 12.5 mg or 25 mg of heroin. These 
data indicate that buprenorphine maintenance (even at relatively high 
maintenance doses) may not serve as a deterrent for patients who chose 
to continue their illicit use of heroin or other opiates.
    Buprenorphine has been diverted, trafficked and abused in many 
countries throughout the world. Starting in the late 1970s, low-dose 
buprenorphine sublingual tablets and injectable solutions were approved 
for marketing in many countries. High-dose buprenorphine for narcotic 
treatment gained marketing approval in France in 1996 and has since 
been approved in several other countries.
    Buprenorphine abuse was detected in many countries soon after it 
was approved for marketing. The initial profile of low abuse liability 
and high therapeutic index (safety) fueled decisions that allowed the 
initial marketing of buprenorphine without any significant restrictions 
or regulatory controls. Its easy accessibility and acceptability by a 
wide spectrum of drug abusers, including heroin addicts, resulted in 
substantial abuse (for example: Levelle et al., 1991; Rainey, 1986; 
Strang, 1995,1991; Tracqui et al., 1998; Kintz, 2001; Basu, 1998; 
Robinson et al., 1993; Dore et al., 1997, Singh et al., 1992; Chowdhury 
et al., 1998). Austria, Australia, Belgium, Germany, France, India, New 
Zealand, Norway and Sweden have all increased the regulatory controls 
on buprenorphine. In 1988 the World Health Organization (WHO) 
recommended that buprenorphine be placed in Schedule III of the 
Psychotropic Convention. This action was taken by the United Nations in 
1989.
    A number of factors have contributed to the illicit use of 
buprenorphine. In areas where heroin has been less available or of low 
quality, buprenorphine's low cost, easy accessibility, high purity and 
substantial morphine-like effects have contributed to its popularity on 
the illicit market. Doctor shopping and forged prescriptions are 
important sources of this drug and, according to the International 
Narcotics Control Board (INCB), large quantities of buprenorphine have 
been trafficked across international borders.
    While extensive diversion, trafficking and abuse have been 
documented for both the sublingual tablets and injectable formulations, 
the sublingual tablet has a greater appeal to a wider range of drug 
abusers. The variety of routes of administration may account for this 
preference. The tablets can be abused by the sublingual route or they 
can be crushed and snorted or the powder can be solubilized and 
injected.
    In summary, unlike Schedule IV partial mu agonists, buprenorphine 
is recognized as morphine-like in many drug discrimination studies and 
produces effects similar to morphine over a wide range of doses. 
Significant abuse has been documented in many countries although 
various factors, including the lack of regulatory controls placed on 
buprenorphine and the scarcity of high purity heroin, have played a 
role in contributing to this abuse. Buprenorphine's partial agonist 
effects make buprenorphine less desirable than pure mu agonists in 
Schedule I or II. The extent to which buprenorphine is able to produce 
euphoria and ``good drug'' effects limits its use by opiate tolerant 
abusers. While buprenorphine can substitute for heroin,

[[Page 62360]]

it is rarely preferred over high quality heroin. In addition, the 
reduced respiratory depressant effects of buprenorphine (as a 
consequence of its ``ceiling effect'') imparts greater safety in 
overdose than other pharmaceutical narcotics controlled in Schedule II.
    In reviewing all the data relevant to the abuse potential, 
including the comments and the DHHS evaluation, the DEA concludes that 
buprenorphine has an abuse potential less than narcotics in Schedule I 
or II of the CSA but greater than Schedule IV narcotics.

Dependence Profile of Buprenorphine

    In addition to having abuse potential, most drugs controlled under 
the CSA are capable of producing dependence, either physical 
(physiological) or psychological. Physical dependence refers to the 
physiological changes produced by repeated use of a drug that 
necessitates the continued administration of the drug to prevent a 
withdrawal syndrome. Psychological dependence refers to the need or 
craving for a drug that compels an abuser to continue drug use.
    Chronic buprenorphine administration is associated with physical 
dependence (for example see: Jasinski et al., 1978; Kosten et al., 
1988, 1990; San et al., 1992; Eissenber et al., 1996). The extent of 
physical dependence, as measured by an abstinence syndrome, has been 
characterized as mild to moderate in intensity and of long duration. 
The profile of withdrawal effects/duration varies with buprenorphine 
dose, route of administration and duration of chronic use. While some 
aspects of the abstinence syndrome approach those which occur with pure 
mu agonists, generally the withdrawal is reported as less intense and 
may not require pharmaceutical intervention for relief of adverse 
withdrawal effects.
    Jasinski et al. (1978) conducted the original clinical abuse 
liability studies evaluating buprenorphine's abuse potential. 
Buprenorphine was shown to produce morphine-like subjective, behavioral 
and physiological effects and morphine-like physical dependence. The 
abstinence syndrome observed after abrupt withdrawal of chronically 
administered buprenorphine (8 mg subcutaneous for 60 days) was delayed 
producing peak Himmelsbach abstinence scores after about two weeks. 
Peak withdrawal effects were clinically significant but of lesser 
magnitude than pure mu agonists. Withdrawal effects included loss of 
appetite, malaise, insomnia, sensitivity of the skin, lacrimation, 
rhinorrhea, perspiration, gooseflesh, nausea, leg aches and backaches. 
These effects were variably reported as mild to moderate and clients 
requested an opiate to alleviate the symptoms.
    In another study examining the physical dependence profile of 
buprenorphine, 19 heroin dependent male subjects were maintained on 8 
mg sublingual buprenorphine for 16 days followed by an additional 18 
days of daily or every other day dosing of 8 mg (Fudala et al., 1990). 
Abrupt discontinuation in buprenorphine dosing produced an abstinence 
syndrome starting within the first 72 hours, peaking within 3 to 5 days 
and diminishing after 8 to 10 days. Over 50 percent of the participants 
required therapeutic intervention for withdrawal symptoms.
    In a report on the use of Subutex[reg] in France (Ministry of 
Health of France, 1998), clinicians describe a buprenorphine abstinence 
syndrome similar to abrupt withdrawal from methadone, characterized by 
2 to 3 days of no symptoms followed by 10 days of unpleasant symptoms. 
Abrupt withdrawal of buprenorphine produced effects approaching that of 
methadone withdrawal but with periods that were very difficult to bear 
due to the continual switching between a normal state and a state of 
withdrawal.
    One of the clearest indications of buprenorphine physical 
dependence potential is data gathered on neonates of buprenorphine 
maintained mothers (Fisher et al., 2000). Buprenorphine neonatal 
abstinence syndrome (NAS) was also reported in postmarketing data from 
France. The withdrawal syndrome, including tremor and autonomic 
hyperreflexia, is generally mild to moderate in severity. Between 1996 
and the first six months of 1999, 66 reports of NAS were reported to 
the manufacturer.
    The extent of psychological dependence produced by buprenorphine is 
largely dependent on its ability to produce pleasurable effects and the 
desire or need to continue the use of this drug for those effects. High 
psychological dependence is associated with significant loss of drug 
use control, escalation of dose, drug seeking behaviors and maladaptive 
patterns of substance use despite serious negative consequences. In 
reviewing the psychological dependence profile of buprenorphine, the 
DEA considered a number of factors including: drug effects, evidence of 
diversion, trafficking and abuse of buprenorphine, patterns of drug use 
and physical or psychological problems associated with continued abuse 
of this drug.
    As reviewed earlier, buprenorphine produces significant morphine-
like effects over a wide range of doses and in numerous populations of 
drug abusers. However, buprenorphine's partial agonist activity often 
results in shallower dose-response curves with reduced maximal amounts 
of euphoria, drug liking and/or ``good drug'' effects than many of the 
pure mu agonists that have been compared to buprenorphine.
    Buprenorphine has been extensively diverted, trafficked and abused 
throughout many countries although those activities have often been 
fueled by the lack of high purity heroin and limited regulatory 
controls placed on buprenorphine (Lavelle et al., 1991; Rainey, 1986; 
Strang, 1995, 1991; Tracqui et al., 1998; Kintz, 2000; Basu, 1998; 
Robinson et al., 1993; Dore et al., 1997, Singh et al., 1992; Chowdhury 
et al., 1998). Surveys in several countries show that buprenorphine, 
along with heroin, temazepam, and amphetamines, ranks among the top 
drugs most frequently abused (Lavelle et al., 1991; Arditti et al., 
1992; Lapeyre-Mestre et al., 1997; Thirion et al., 1999; Shewan et al., 
1998; Taylor et al., 1996; Coggans et al., 1991; Barnard et al., 1998). 
Falsified prescriptions, theft, doctor shopping and street buys have 
all been identified as sources for buprenorphine.
    Buprenorphine use is associated with maladaptive patterns of 
substance use. In an analysis of 11,186 buprenorphine prescriptions 
(written in France during 4 months between September through December 
1999), 12 percent of the patients received prescriptions from more than 
two prescribers and 18 percent of the patients were judged as having 
deviant maintenance treatment with more than two prescribers or more 
than 20 mg per day of buprenorphine (Thirion et al., 2002). Data 
provided in a report generated by a multidisciplinary task force 
(working under an agreement with the Office of the Junior Minister for 
Health, the General Health Administration and Schering Plough 
Laboratories) on the use of Subutex[reg] in France noted that the sales 
of syringes in France remained stable despite the large numbers of 
individuals in treatment with Subutex[reg]. At the same time, there was 
a significant reduction in heroin trafficking and heroin-related 
deaths. As so many heroin addicts were in treatment and being 
prescribed medications that are not injectable formulations, the sales 
for injection equipment should have fallen off drastically. That did 
not occur. Survey data regarding buprenorphine use indicated that 
between 12 and 31 percent of buprenorphine users crush the 
buprenorphine tablets and inject

[[Page 62361]]

their own medication or diverted medication, often in combination with 
benzodiazepines (Ministry of Health of France, 1998). Benzodiazepines 
purportedly enhance and prolong the euphorigenic properties of 
buprenorphine. These injection practices are associated with the spread 
of HIV and other communicable diseases as well as serious overdose 
events. Over 100 deaths in France have been associated high dose 
buprenorphine injection in combination with benzodiazepines (Tracqui et 
al., 1998; Kintz, 2001). In another study of 1018 drug injectors in 
Glasgow during 1993 and 1994, 41 percent of the injectors reported 
using buprenorphine and, of those, 26 percent reported at least one 
overdose (Taylor et al., 1996).
    A number of case reports involving buprenorphine abuse demonstrate 
that buprenorphine is associated with a pathological pattern of use, 
tolerance development and an opiate abstinence syndrome (Quigley et 
al., 1984; Singh et al., 1992; Basu et al., 1990). Researchers who have 
compared the toxicologic and psychopathologic characteristics of 
buprenorphine dependence with those of heroin found no clinically 
significant differences (Torrens et al., 1993).
    The availability and use of high-dose sublingual tablets is a 
relatively new phenomenon. The ease with which addicts can be 
detoxified after extended use of buprenorphine at high maintenance 
doses has not been well established nor is there information regarding 
continued abstinence after detoxification from long-term, high-dose 
use/abuse of buprenorphine. The dependence capacity of buprenorphine 
may be heightened under these conditions.
    In summary, buprenorphine produces low to moderate physical 
dependence. The withdrawal syndrome is of less intensity and longer 
duration than most narcotics in Schedule I or II of the CSA. 
Therapeutic intervention may be necessary to help ameliorate some of 
the withdrawal affects. Buprenorphine abuse is associated with a loss 
of control, escalation of dose, drug seeking behaviors and maladaptive 
patterns of substance use. The data suggest that buprenorphine has a 
relatively high psychological dependence profile although it is 
generally less reinforcing than heroin and other pure mu agonists.

Answers to Specific Comments Regarding the Proposed Placement of 
Buprenorphine in Schedule III of the CSA

    Comment: The buprenorphine/naloxone product (Suboxone[reg]) should 
be placed in a lower schedule than the single entity product 
(Subutex[reg]) when/if approved for use in the United States. This 
differential scheduling would show the lower abuse potential of the 
combination product and would encourage physicians to preferentially 
prescribe the combination product.
    Answer: The addition of naloxone to the buprenorphine high dose 
sublingual tablets may be aversive in physically dependent opiate 
abusers but it will have little (may reduce agonist effects) or no 
effect in all other populations of abusers. It does not have 
significantly less abuse potential. For more information, see section 
on abuse potential.
    A physician with the appropriate training in narcotic addiction 
treatment (as mandated by the Drug Addiction Treatment Act of 2000) 
has, or will be provided, information about the merits of prescribing 
the combination product. Should the buprenorphine sublingual tablets be 
approved for use in the United States, the physician will, ultimately, 
write a prescription for Subutex[reg] or Suboxone[reg] based on an 
informed decision about what he/she feels is the best treatment for the 
patient.
    Comment: Because Buprenex[reg] has been in Schedule V and has not 
been associated with widespread diversion or abuse, there is no 
compelling reason to reschedule this medication.
    Answer: As a single entity product, Buprenex[reg] has no other 
active ingredient in its formulation that may mitigate its abuse 
potential. While no significant abuse of Buprenex[reg] has occurred in 
the United States (which both FDA and DEA believe is directly related 
to its limited use in the United States) many countries have 
experienced significant abuse of low dose buprenorphine in tablet and 
injectable formulations. Buprenex[reg] does not have less abuse 
potential than other buprenorphine products.
    Comment: Products containing less than 1 mg/ml of buprenorphine 
should be placed in Schedule V of the CSA.
    Answer: Because buprenorphine is significantly more potent than 
morphine with much greater bioavailability by the injection route of 
administration, intravenous injection of 0.3 mg of buprenorphine (1 
dosage unit of Buprenex[reg]) produces physiological and subjective 
effects equivalent to 10 mg or more of intravenous morphine (Zacny et 
al., 1997). Injection of 1 mg/ml buprenorphine would be approximately 
equivalent to the injection of 20-30 mg of morphine (calculated by 
extrapolation and considering the shallower dose-response curve). These 
doses produce significant opiate effects and, if available, are likely 
to be attractive to most opiate abusers. In addition, as an injectable 
product, Buprenex[reg] misuse/abuse is associated with possible 
behavioral risks including shared needles/syringes that contribute to 
the spread of HIV, hepatitis and other communicable diseases (also 
review previous comment and answer). There are no provisions in the CSA 
to schedule narcotic products based solely on the concentration of 
active ingredient.
    Comment: Buprenorphine diversion has been limited to use by out-of-
treatment, opioid-dependent, injection drug users.
    Answer: While buprenorphine has been primarily abused by injection, 
data indicates that it has been abused by other routes of 
administration and other populations of drug abusers. Data from France 
indicate that a significant percentage of treatment clients (prescribed 
high dose, single entity product) abuse their own or diverted 
medication (see discussions on abuse liability and dependence profile).
    Comment: Once buprenorphine has been approved for use in opioid 
substitution treatment, the DEA should study and evaluate abuse over a 
three-year period in order to more accurately determine whether 
placement in Schedule III is appropriate.
    Answer: Whenever a drug is placed under control in the CSA, the DEA 
is responsible for monitoring the use of that drug. In addition, the 
Drug Addiction Treatment Act (DATA) has mandated that DEA monitor the 
use of Schedule III-V narcotic treatment drugs utilized under DATA.
    Comment: The DEA has disregarded data on the development of the 
naloxone combination product that show significantly less potential for 
diversion and abuse.
    Answer: The DEA is aware that the combination product was 
specifically developed to deter injection abuse by physically dependent 
opioid injecting drug abusers. In addition, DEA wants to support and 
encourage manufacturers to develop products that will reduce the 
diversion and abuse of legitimate pharmaceuticals. This combination 
product will inhibit injection by non-buprenorphine dependent addicts 
and this is a positive outcome. However, after careful examination of 
all the relevant data regarding the abuse potential of this product in 
all populations at-risk for abuse (see section on abuse potential), the 
DEA has concluded that the combination product does not warrant lesser 
control than other buprenorphine products.

[[Page 62362]]

    Comment: The DEA has disregarded the additional controls that would 
be imposed on Subutex[reg] and Suboxone[reg] by the Drug Addiction 
Treatment Act of 2000 (DATA).
    Answer: As part of the review process, both the DEA and the DHHS 
carefully considered the use of these narcotic treatment drugs within 
the context of use under DATA. DATA was never intended to be a solitary 
regulatory piece of legislation and drugs used under this Act must 
first meet the findings of a Schedule III, IV or V substance as defined 
in the CSA (21 U.S.C. 812(b)). DATA does not have an impact on the 
criteria necessary for scheduling under the CSA. The scheduling 
criteria and procedures remain unchanged and continue to dictate the 
requirements for the scheduling of buprenorphine as well as any other 
controlled substance.
    Comment: The potential for buprenorphine to be abused, particularly 
when marketed in high-dose tablets, is consistent with the abuse 
potential of other Schedule II substances. The partial agonist 
activity, including safety in overdose, is not supported and, even if 
true, does not warrant a change from the conclusion that buprenorphine 
has a high potential for abuse.
    Answer: Under certain conditions and in various populations, 
buprenorphine has a high potential for abuse. Buprenorphine is 
recognized as morphine-like in many drug discrimination studies and 
produces effects similar to morphine over a wide range of doses. This 
data suggests that buprenorphine, if available, would be very 
attractive to most narcotic abusers (see section on abuse potential 
especially in regard to doses of 2 mg or more). However, the extent to 
which buprenorphine is able to produce euphoria, ``good drug'' effects, 
and respiratory depression is limited by its partial agonist 
properties. That is, almost uniformly, pure mu agonists are capable of 
producing greater levels of euphoria and other positive subjective 
effects than buprenorphine. This is an important issue for a drug-
tolerant/dependent narcotic abuser (those likely to be prescribed or 
have access to high-dose buprenorphine tablets). Buprenorphine may 
alleviate withdrawal, but may not produce the level of ``feel-good'' 
effects that the abuser is seeking. Although buprenorphine is abused by 
heroin addicts, it is rarely preferred over high quality heroin even 
when buprenorphine is co-administered with benzodiazepines. The low 
availability and high cost of high purity heroin compared to the high 
availability and low cost of buprenorphine have been factors in the 
high incidence of buprenorphine abuse in many countries. Currently, the 
availability and purity of heroin across the United States is very high 
while the price of heroin is relatively low in comparison to the 
projected cost of buprenorphine tablets.
    The DEA cited safety in overdose as an example of buprenorphine's 
partial agonist activity and as a mitigating factor differentiating the 
abuse potential of buprenorphine from mu agonists in Schedule II of the 
CSA. Factor (6) under 811(c) requires that the DEA consider what, if 
any, risk there is to the public health. The commenter argued that this 
margin of safety exists only when the drug is taken in a carefully 
controlled clinical setting without concomitant use of other drugs. In 
fact, narcotic addicts are likely to abuse benzodiazepines with 
buprenorphine and often by the injection route--all risk factors for 
buprenorphine-related deaths. The DEA agrees that the increased safety 
with respect to diminished respiratory depression may be negated under 
these circumstances. Data from France regarding buprenorphine-related 
deaths also supports this conclusion. However, for the initiate to 
opioid abuse or the non-dependent opioid abuser using buprenorphine, 
the concurrent injection use of buprenorphine with benzodiazepines is 
less likely to occur. In addition, accidental death or serious overdose 
by a child or other family member who ingests the medication of an 
individual prescribed buprenorphine is also less likely to occur. This 
is an advantage over drugs like morphine, oxycodone and methadone and a 
relevant factor that carries considerable significance when weighing 
public health risks and the need for regulatory scrutiny.
    In reviewing all the data relevant to the abuse potential, 
including the evaluation provided by the DHHS as well as all the 
comments, the DEA concludes that buprenorphine has an abuse potential 
less than narcotics in Schedule I or II of the CSA but greater than 
Schedule IV narcotics. It should be noted that a Schedule III substance 
can have a relatively high abuse potential. The law (21 U.S.C. 812 
(b)(3)) does not have an absolute descriptive term (i.e. high, low) 
relating to the abuse potential of Schedule III substances. However, 
the abuse potential must be less than Schedule I or II.
    Comment: The DEA failed to consider that the illusion of safety may 
result in greater potential for abuse.
    Answer: Prior to completing the final scheduling review document, 
the DEA received the FDA review document and a scheduling 
recommendation from the DHHS. The FDA specifically cited this concern 
in their document and the DEA considered this possibility. 
Buprenorphine has often been touted as a drug with minimal abuse 
potential and great safety in overdose. In many countries, these 
misconceptions have led to less regulatory oversight and freer 
prescribing practices by physicians resulting in easier access and 
greater availability of buprenorphine for abuse purposes. See sections 
on the abuse potential and dependence profile of buprenorphine. The 
narcotic abuser may view buprenorphine ``safety'' as a good reason to 
select buprenorphine over another narcotic or to use greater amounts of 
buprenorphine without regard to possible overdose.
    Comment: Scheduling under the CSA is a relative analysis and 
depends on aligning a drug with the closest set of comparators. 
Buprenorphine most closely resembles Schedule II narcotics.
    Answer: Scheduling is a relative analysis. The effects produced by 
buprenorphine were compared to many Schedule II substances and found, 
under certain conditions, to be similar. However, buprenorphine is a 
partial agonist and shares some very important properties with other 
partial agonists in Schedule IV (i.e. pentazocine and butorphanol). 
These partial agonist properties play an important role when comparing 
buprenorphine effects with pure mu agonist effects. Continued use of 
all narcotic agonists results in tolerance development, dependence and 
possible addiction. For the narcotic abuser, escalation of dose, to 
achieve enhanced effects or to compensate for drug tolerance, will, at 
some point, be compromised with a partial agonist: the dose-response 
curve of buprenorphine is more shallow and less linear than mu 
agonists. This means that buprenorphine may not produce the enhanced 
effects sought by the chronic drug abuser. In addition, the current 
data indicates that buprenorphine produces moderate physical dependence 
and relatively high psychological dependence, not the severe dependence 
of Schedule II narcotics. Both the DHHS and the DEA have determined 
that the available data on buprenorphine regarding the abuse potential 
and dependence profile are most closely aligned to, or defined by, a 
Schedule III narcotic. For review, please see previous sections on 
abuse potential and dependence profile found herein.
    Comment: Buprenorphine is a gateway drug compounding its public 
health risks.

[[Page 62363]]

    Answer: Generally, substances like alcohol, nicotine and marijuana 
are universally accepted as gateway drugs because data shows that they 
are often the first drugs used by adolescents and a correlation exists 
between early experimental use of these substances and an escalation to 
serious drug abuse problems. One of the at-risk populations for 
buprenorphine abuse is na[iuml]ve (inexperienced) opioid abusers (see 
section on abuse potential). Early experimentation with buprenorphine 
may lead to serious drug abuse problems.
    Comment: The DEA has not been consistent in its decision making 
process and has failed to meet the ``non-arbitrary agency 
requirements.'' The finding that buprenorphine has a potential for 
abuse less than Schedule I or II substances is arbitrary and capricious 
and not supported by underlying administrative record.
    Answer: The DEA has not been arbitrary or capricious in the 
decision making process regarding the abuse potential of buprenorphine. 
Buprenorphine has a very unique pharmacological profile and produces a 
range of opioid effects typical of both pure mu agonists and 
prototypical partial agonists depending on dose, pattern of use, and 
population taking this drug. Most single entity pure mu agonists are 
controlled in Schedule I or II of the CSA, while partial agonists, 
butorphanol and pentazocine, are controlled in Schedule IV. After 
reviewing all the relevant data, the DEA concluded that buprenorphine's 
abuse potential is most closely defined by Schedule III (see section on 
abuse potential and answers to previous comments).
    Comment: One of the strongest signs that a drug has a high 
potential for abuse is evidence that it is abused through multiple 
routes of administration, and that it is used with other drugs of 
abuse. Among other things, this shows that drug abusers not only like 
the drug, they are trying to enhance its effects. DEA's finding on the 
abuse potential of buprenorphine failed to consider and give adequate 
weight to the evidence on this point.
    Answer: The DEA did consider various pharmacological parameters 
relating to the use of buprenorphine by various routes of 
administration (see section on abuse potential). Drug abusers 
frequently abuse more than one drug. The reasons for this are varied. 
Abusers may be trying to enhance the effects of the drug they are using 
and/or trying to ameliorate some of the unwanted side effects. The DEA 
believes appropriate weight was placed on this issue.
    Comment: DEA's conclusion that buprenorphine most closely resembles 
a Schedule III drug, with respect to physical and psychological 
dependence, is contrary to evidence.
    Answer: This comment was followed by a number of citations that 
were taken from the buprenorphine scheduling review documents of both 
DEA and FDA (those reviews that were conducted prior to the proposal to 
place buprenorphine in Schedule III). These comments, for the most 
part, were taken out of context, interpreted differently or weighted 
differently than by DEA and/or FDA. For example, the statement that 
buprenorphine produces ``morphine-like physical dependence'' does not 
mean that morphine and buprenorphine have the same physical dependence 
capacity. It does mean that the physiological changes produced by 
buprenorphine and morphine are similar and they share similar 
withdrawal signs. The statement that ``under most conditions, 
buprenorphine's physiological and psychological effects are essentially 
the same as morphine or hydromorphone'' means that buprenorphine is 
capable of producing effects (i.e., miosis, respiratory depression, 
analgesia, drug euphoria, drug liking and sedation) on a par with 
morphine and hydromorphone ``under most conditions''. A more 
appropriate caveat would be ``under many conditions''. This was a 
statement taken out of context and does not mean that these drugs 
produce the same dependence profile. It is important to note that, in 
making scheduling decisions, all the available information regarding a 
substance must be synthesized and weighed. The section on dependence 
profile found herein does not contain all the data DEA relied upon but 
does provide a summary of some important data and the rationale used by 
DEA in concluding that buprenorphine produces moderate physical 
dependence and relatively high psychological dependence.
    Comment: In the absence of sufficient data on physical and 
psychological dependence, the DEA must give weight to its abuse 
liability assessment.
    Answer: While some data was lacking regarding the dependence 
profile of long-term use/abuse of high dose buprenorphine, sufficient 
data is available for making a determination regarding buprenorphine 
dependence (see previous section on dependence profile). In addition, 
DEA did not find that buprenorphine has an abuse potential consistent 
with Schedule II.
    Comment: Whether buprenorphine will be eligible for office-based 
use under recently enacted federal legislation is not a relevant factor 
in the scheduling analysis and DEA erred by considering it.
    Answer: In the March 21, 2002, Federal Register notice on the 
proposed rule for buprenorphine scheduling, the DEA made the following 
statement under a section on consequences of this proposed rule: ``The 
DEA recognizes the need to expand narcotic treatment and this factor 
was a consideration in proposing Schedule III placement for 
buprenorphine.''
    The proposed placement of buprenorphine in Schedule III was not 
made on the basis of making buprenorphine products available for 
office-based narcotic treatment. Taken out of context, we recognize 
that this statement could possibly lead to that interpretation. This 
statement was meant as a preamble to express DEA's concerns regarding 
the use of buprenorphine within the context of office-based narcotic 
treatment. The DEA does recognize the need to expand treatment. As part 
of our scheduling review, DEA did consider the impact of buprenorphine 
treatment products used within the context of office-based practice.
    The factors for determining the placement of a substance within one 
of the schedules of controlled substances are specifically laid out in 
Title 21 U.S.C. 812(b). The manner in which a substance will be used 
and its availability to the public are among the elements that must be 
considered in determining a substance's actual or relative potential 
for abuse (see section on abuse potential). The DEA did not consider 
the need to expand narcotic treatment as a specific factor in 
determining the placement of buprenorphine under the CSA. Certainly the 
anticipated use of buprenorphine for addiction treatment was a point of 
consideration in terms of its possible impact on the relative potential 
for abuse, however, it was not a determining factor.
    Comment: To the extent that DEA considered the placement of 
buprenorphine under Schedule III, in order to expand access to narcotic 
treatment (67 FR at 13115), DEA was required to do a complete analysis 
of the impact of its proposal under the Regulatory Flexibility Act (5 
U.S.C. 601 et seq.). Among other things, DEA was required to consider 
the impact of the decision on small businesses, including methadone 
treatment programs.
    Answer: As stated previously, the DEA did not propose placement of

[[Page 62364]]

buprenorphine in Schedule III in order to have it available for office 
based treatment; it was DEA's analysis of the factors laid out in 
Section 811(c) that resulted in the determination that buprenorphine 
should be placed in Schedule III.
    With respect to the issue of possible economic impact, DEA does not 
view the placement of buprenorphine into Schedule III as having a 
direct economic impact on the activities of traditional narcotic 
treatment programs. As a Schedule III controlled substance, 
buprenorphine will be equally available to traditional NTP programs as 
well as office-based treatment providers. The migration of stabilized 
patients from NTP's to office-based treatment programs will be driven 
more by the differences in the program requirements and 
characteristics. The office-based programs may be more attractive to 
the stabilized patients. As such, DEA stands by its certification that 
placement of buprenorphine in Schedule III will not have a significant 
economic impact on a substantial number of small business entities.
    Comment: In its concluding statement (of the proposed rule), DEA 
notes that buprenorphine's abuse potential and dependence profile 
suggest that there may be significant abuse and diversion of the 
tablets in the United States. DEA therefore intends to initiate action 
to increase regulatory control, should that occur. This approach, 
however, is fundamentally at odds with the approach required under the 
CSA. The CSA requires DEA to make a reasonable predictive judgment 
about a drug, and to act proactively to address it. As Congress 
recognized, the risks associated with drug abuse are too great from a 
law enforcement and public health perspective to take a reactive 
posture.
    Answer: Sublingual tablets of buprenorphine have not been available 
in the United States. Both the DEA and FDA relied heavily on foreign 
experience with these products and no country has marketed a high dose, 
naloxone-combination product. While drug abuse and addiction are 
universal problems, the availability of potent narcotic pharmaceuticals 
and high purity heroin in the United States will likely alter the types 
of abuse problems experienced with high dose buprenorphine tablets 
when/if they are approved for marketing. That is, one of the motivators 
involved in the abuse of buprenorphine in many countries has been the 
lack of affordable, high purity heroin and fewer, more restrictive 
controls placed on potent narcotic analgesics. At the same time, 
narcotic treatment under DATA will be a considerable departure from the 
more structured Narcotic Treatment Programs of the past decades. Should 
these products be approved, they will be prescribed by physicians, who 
may not have extensive experience in dealing with this patient 
population, and used by addicts, who are likely to abuse/divert their 
medications. This activity, under DATA, will occur in the absence of 
enforceable minimal standards of treatment. DEA believes that these 
conditions increase the likelihood of diversion and abuse of these 
products.
    In light of these uncertainties and in consideration of all the 
data relevant to buprenorphine's abuse potential and dependence 
capacity, the DEA has concluded that Schedule III placement and the 
constraints placed on physicians under the Drug Addiction Treatment Act 
of 2000 (Pub. L. 106-310) will be sufficient to curb significant abuse 
problems. However, if our assessment is not correct, the DEA will take 
appropriate actions.
    Comment: The DEA has not presented an adequate basis for the 
proposed rulemaking. Many of the studies cited by DEA and FDA are not 
described in sufficient detail. Moreover, some important information 
from these studies has not been considered by DEA.
    Answer: The proposed rule outlines the basic facts. It provides a 
brief description about the action being proposed, describes 
buprenorphine as a derivative of thebaine, a partial agonist and its 
efficacy as an analgesic (with far greater potency than morphine). The 
two NDAs for buprenorphine products pending at FDA are mentioned with 
respect to being high-dose sublingual tablets intended for narcotic 
treatment. The notice outlines an FDA review as part of an NDA process 
for the proposed treatment drugs. Greater human experience and new 
scientific data prompted a scheduling review by FDA that resulted in a 
DHHS rescheduling recommendation. The DEA considered this 
recommendation and carefully reviewed the FDA scheduling review 
document (in matters of science and medicine, DHHS findings are binding 
on DEA). The DEA then conducted a final review and, outlined in the 
proposed notice, the factors DEA considered in making the decision to 
propose Schedule III for buprenorphine and all products containing 
buprenorphine. This was the basis for this proposed rulemaking. Upon 
request, the DEA did provide the FDA and DEA review documents to 
interested parties.
    In this final rule, the DEA has included summaries of the data DEA 
relied upon in determining the abuse potential and dependence profile 
of buprenorphine. However, like most review documents, specific details 
about all the studies cannot be given. Citations, however, are 
provided.
    This commentator stated that DEA's statements regarding 
buprenorphine's potency with respect to morphine and the fact that 
buprenorphine is a derivative of thebaine have no bearing on 
buprenorphine's abuse potential. As a derivative of thebaine, 
buprenorphine was originally classified under the CSA as a narcotic. 
This statement was not made to imply anything with respect to abuse 
potential. Many substances (i.e. opiate antagonists) are derived from 
thebaine and have no abuse potential. Potency, however, is an element 
that directly affects the abuse potential. As mentioned in an earlier 
comment, 1 mg/ml of buprenorphine produces substantial euphoria. If 
buprenorphine is marketed in 2 and 8 mg tablets, those tablets can be 
dissolved in water and shared by several opiate abusers (depending on 
level of narcotic tolerance). The implications of this activity speak 
directly to the abuse potential and the possible public health risks 
associated with shared injection equipment.
    The DEA did review and consider the information in the literature 
cited, as well as countless other scientific papers, law enforcement 
and drug abuse data bases, and law enforcement documents that were not 
cited.
    Comment: The proposed rule has not adequately described the 
pharmacology of the drug substance buprenorphine or the drug products 
that would be affected by this rule.
    Answer: The section herein on abuse potential reviews the 
pharmacological profile of buprenorphine. Currently, only one 
buprenorphine product, Buprenex[reg], will be affected by this rule. 
This drug product is an injectable formulation containing 0.3 mg/ml of 
buprenorphine. It is approved for use for moderate to severe pain 
management.
    Two New Drug Applications (NDA) have been submitted to FDA for high 
dose sublingual tablets. These potential addiction treatment products 
include: (1) Subutex[reg], a mono or single entity buprenorphine 
product, and (2) Suboxone[reg], a combination product in a 4:1 ratio of 
buprenorphine to naloxone. The Subutex[reg] and Suboxone[reg] NDAs 
remain pending at the FDA. When/if these products are approved for 
marketing they will also be affected by this rule.

[[Page 62365]]

    Comment: Many facts cited by the DEA and FDA in their conclusions 
have been removed from their proper scientific context. This is 
particularly evident in the description of buprenorphine and in the 
basis for the DEA conclusion that buprenorphine may cause high 
psychological dependence.
    Answer: Concluding statements rarely provide detail and, by their 
nature, are brief statements regarding conclusions that are made 
regarding all the available data. The section on buprenorphine's 
dependence profile herein and previous comments/answers regarding this 
issue, provide a detailed discussion of the basis for DEA's conclusions 
regarding dependence potential.
    Comment: The DEA and FDA have not explained why data generated 
since the original scheduling action for buprenorphine in 1985 would 
alter the original conclusions that buprenorphine has a low potential 
for abuse and low potential for physical and psychological dependence.
    Answer: The DEA has reviewed all the documents pertaining to the 
original placement of buprenorphine in Schedule V of the CSA. In 1981, 
buprenorphine hydrochloride (Buprenex[reg]) was approved for use in the 
United States as an analgesic. In 1982, the Assistant Secretary of 
Health recommended that buprenorphine be placed in Schedule V of the 
CSA. This recommendation was based on findings that buprenorphine had 
an approved medical use in the United States and that its abuse 
potential and dependence capacity was low and consistent with Schedule 
V placement. The DEA published a proposal to place buprenorphine in 
Schedule V in 1982. This rulemaking was finalized on April 1, 1985 (50 
FR 8104) following a hearing requested by Reckitt & Colman (now Reckitt 
Benckiser), the patent holder and manufacturer for buprenorphine 
worldwide. The company's objection to the proposal was based on their 
contention that buprenorphine did not have sufficient potential for 
abuse to warrant Schedule V placement in the CSA and that buprenorphine 
should not be classified as a narcotic as defined by the CSA. Data was 
provided from several countries including West Germany, Australia and 
New Zealand (where buprenorphine had been available for a limited 
period of time) showing buprenorphine abuse, diversion and trafficking. 
In addition, FDA provided testimony at the administrative hearing on 
buprenorphine regarding the basis for their decision to recommend 
Schedule V.
    In reviewing this data, the science, at that time, relied heavily 
on preclinical studies that indicated that buprenorphine had minimal 
abuse potential and dependence producing capacity. While Jasinski's 
(1978) original clinical abuse liability study was available and 
considered, more weight was placed on the fact that buprenorphine's 
partial agonist activity mitigated the development of any serious abuse 
problems and the belief that this was an exceedingly safe drug in 
overdose. Clinical use in foreign countries, where it had already been 
approved for marketing, was limited but did indicate that buprenorphine 
had some abuse potential. However, as a low-dose, injectable 
formulation for the treatment of moderate to severe pain, widespread 
use and availability was not anticipated.
    Since that time, the use, abuse and available data have increased. 
Clinical experience with various dosage forms for both pain management 
and addiction treatment is now available. In addition, the anticipated 
use of high-dose buprenorphine tablets with the possibility that they 
could be prescribed by physicians and used in an office based setting 
for the treatment of opioid addiction prompted FDA to re-evaluate the 
status of buprenorphine under the CSA. In reviewing all the available 
data, both FDA and DEA have concluded that placement in Schedule III as 
a narcotic is the most appropriate schedule for buprenorphine and 
products containing buprenorphine.
    Comment: DEA and FDA rely heavily on data concerning abuse of 
buprenorphine in foreign countries that occurred prior to the 
international control of buprenorphine in 1989 under the 1971 
Psychotropic Convention.
    Answer: Both DEA and FDA reviewed all the available data that 
addressed the eight factors that are used as a basis for making a final 
scheduling decision. Published literature regarding the use, misuse, 
abuse, diversion and trafficking in buprenorphine was gathered and 
assessed. Published data about the abuse of any drug often provides a 
wealth of information including: who is abusing it, how it is being 
abused, source of the drug and possible street prices, extent or 
seriousness of the abuse, drug effects, concurrent use of other drugs, 
and reasons it is sought and abused. Much of this information is 
timeless and speaks to the ability of a drug to produce certain effects 
that some humans find pleasurable. Both DEA and FDA considered 
buprenorphine abuse data within the context of regulatory controls, 
heroin availability and purity, and availability and use of other 
pharmaceutical narcotics.
    Comment: The DEA and FDA have inadequately described the conditions 
of use of Subutex[reg] in France and the impact of such use on either 
the mortality associated with heroin addiction or the frequency of 
abuse of buprenorphine. It is asserted without supporting data that the 
conditions of use that will apply to Suboxone[reg] and Subutex[reg], 
should they be approved for use in the United States, will inevitably 
lead to significant abuse of buprenorphine. There is no discussion of 
how the proposed use of Subutex[reg] in the United States may differ 
from the use of this product in France. There is not an acknowledgment 
in the proposed rule that one of the products under development, which 
is not available in France, contains naloxone to deter intravenous 
abuse.
    Answer: Buprenorphine was first marketed in France in 1987 as a low 
dose sublingual tablet (Arditti et al., 1992). Between 1992 and 1993, 
buprenorphine was identified as the third most commonly appearing drug 
in falsified prescriptions in southwestern France (Baumevielle et al., 
1997). In December 1992, the French government instituted special 
dispensing and prescribing procedures similar to those governing 
narcotic drugs: buprenorphine was monitored by the French Medical 
Association; prescriptions were required to be written on a voucher 
taken from a counterfoil prescription book that was specifically 
designed for narcotic drugs; and prescriptions could be filled by any 
pharmacy, but had to be retained by the pharmacist for three years.
    In 1996, general practitioners were permitted to prescribe 
buprenorphine sublingual tablets (Subutex[reg], 2 and 8 mg) for 
treating opiate dependence for up to 28 days per prescription. This 
system of treatment is a considerable departure from previous policy. 
Prior to 1996, France provided very limited treatment with methadone in 
state-run clinics (on a per capita basis, France had the lowest 
narcotic treatment of any European country). The spread of HIV and 
other communicable diseases by intravenous drug users and the 
acceptance of various types of narcotic replacement treatment in other 
countries (methadone, morphine, heroin and low-dose buprenorphine), 
combined with data suggesting that high-dose buprenorphine was a safer 
treatment drug, set the stage for France's new policy. When 
Subutex[reg] was first launched, the street price of an 8 mg sublingual 
tablet was 100 francs (Auriacombe et al., 1997). More recently

[[Page 62366]]

(Dru, 1999), the street price for buprenorphine in Paris was 10 to 15 
francs and was reported as being easily accessible on the illicit 
market. This reduction in street pricing for buprenorphine is likely 
the result of widespread availability, by licit and illicit means. 
Because of continuing reports of abuse and diversion, in September 
1999, restrictions on dispensing of buprenorphine were tightened to a 
7-day supply per prescription.
    Information regarding the use of Subutex[reg] in France comes from 
a variety of sources. One of the first and most comprehensive reports 
was generated by a multidisciplinary task force (working under an 
agreement with the Office of the Junior Minister for Health, the 
General Health Administration and Schering Plough Laboratories) and 
reported on the early use of Subutex[reg] in France. Data presented in 
the report suggested that trafficking in heroin and heroin overdose 
deaths significantly declined in France since Subutex[reg] became 
available (an estimated 75 percent reduction). However, data also 
showed that Subutex[reg] use is associated with significant public 
health risks. The following points were made by the task force:
    [sbull] The use of benzodiazepines in combination with 
buprenorphine products is frequently encountered (both self-reports of 
addicts and studies have verified the frequency of this combination: 
about 20 to 44 percent of addicts treated with Subutex[reg] also 
administer benzodiazepines). From February 1996 to October 1997, health 
officials were aware of 17 deaths associated with this combination.
    [sbull] Sales of syringes remained stable despite the large numbers 
of individuals in treatment with Subutex[reg] (50,000 buprenorphine-
treated patients in 1997). Addicts reported that they continue to 
inject, often crushing, dissolving and injecting their buprenorphine 
tablets as well as other drugs of abuse.
    [sbull] Survey data indicated that general practitioners were 
unable to obtain psychological services for their patients, as few 
psychiatrists want to treat intravenous drug users (less than 1 percent 
of the psychiatrists were linked to addiction treatment or had 
experience in treating addiction).
    [sbull] Subutex[reg] was diverted and abused by a significant 
percentage of individuals receiving buprenorphine prescriptions: 12 to 
31 percent injected their own medication and 2 to 9 percent received 
multiple prescriptions from 2 or more physicians.
    [sbull] Young abusers, not yet addicted to narcotics, were using 
buprenorphine as a ``gateway'' drug (the degree to which this occurs 
was unknown).
    Recent data regarding Subutex[reg] use in France is provided by 
Thirion et al. (2002), who conducted an analysis of 11,186 
buprenorphine prescriptions (written between September through December 
1999) to determine how buprenorphine was being used by French 
practitioners. Eighty five percent of the buprenorphine prescriptions 
were written by general practitioners who often prescribed for only one 
or two patients. The mean dose was 11.5 mg/day. Twelve percent of the 
patients received prescriptions from more than two prescribers and 43 
percent of the maintained patients had an associated benzodiazepine 
prescription, often on the same prescription form. Sixty one percent of 
the patients had regular follow-up, 21 percent had occasional 
consultations and 18 percent had deviant maintenance treatment (more 
than two prescribers or more than 20 mg per day of buprenorphine). The 
authors concluded that the easy access to maintenance treatment in 
France is associated with a high risk of buprenorphine abuse.
    A number of studies have examined buprenorphine-related deaths in 
France. In a compilation of the case reports and analysis involving 
buprenorphine overdoses (29 non-fatal and 20 fatal occurring between 
February 1996 and October 1997 at the hospitals and forensic 
laboratories in Strasbourg, France), Tracqui and colleagues (1998) 
speculated that the high dosage of Subutex[reg] tablets is likely to 
play a role in the occurrence of accidents in spite of the theoretical 
``ceiling effect.'' However, almost all cases involved diverted 
medication and the use of other psychoactive drugs, especially 
benzodiazepines. Intravenous injection of the crushed tablet also 
appears to be a risk factor and was associated with 8 deaths and 10 
non-fatal overdoses.
    Kintz (2001) reported an additional 117 deaths involving 
buprenorphine. These fatalities were observed at the Institute of Legal 
Medicine of Strasbourg from March 1998--July 2000 (39 cases) and at 13 
other French forensic centers from mid 1996--March 2000 (78 cases). 
Eighty two percent of the cases involved males. Needle marks suggesting 
recent intravenous injection(s) were observed in about half of the 
subjects. All but one case involved concomitant intake of other 
psychotropic substances. Benzodiazepines were most commonly found in 
combination with buprenorphine (91 cases). The author concluded that 
intravenous injection, concomitant use of CNS depressants (especially 
benzodiazepines) and high-dose buprenorphine formulation were risk 
factors in buprenorphine-associated fatalities. He further concluded 
that the total number of buprenorphine-related deaths in France is 
probably underestimated due to: (1) The drug is difficult to analyze 
(low concentration and no readily available immunoassay in France); (2) 
only some forensic centers responded to the question of fatalities 
involving buprenorphine; and (3) in numerous cases, an obvious overdose 
(known drug addict, presence of syringe or packages of Subutex[reg]), 
no autopsy is requested by the police or a judge.
    If approved for use in the United States, the prescription of 
Subutex[reg] or Suboxone[reg] in an office based setting will be a 
significant departure from years of regulated narcotic treatment 
practice. While physicians who want to prescribe these drugs for 
narcotic treatment must be certified by CSAT and can only treat up to 
30 opiate-dependent patients at any given time, other regulatory 
requirements are less restrictive than those in France.
    The above data show a pattern of increased regulatory control 
measures as a consequence of increasing levels of diversion and abuse. 
Injection of the Subutex[reg] tablets is a common practice among 
treatment clients and prescription data indicates that they are also 
using benzodiazepines. Addiction is a medical disease associated with 
predictive behaviors that transcend national boundaries. Even in the 
best treatment programs, recurrent relapse occurs. As stated 
previously, providing prescriptions of narcotic substances to known 
drug abusers for the treatment of opiate dependence, in the absence of 
any enforceable treatment standards, is likely to be related with the 
diversion and abuse of these medications.
    Comment: The additional controls that would be provided by moving 
buprenorphine to Schedule III are not described and no rationale is 
provided for the assertion that the Drug Addiction Treatment Act will 
not provide adequate safeguards for the public health.
    Answer: The regulatory controls for those who handle Schedule III 
narcotics are described later in this final rule. There are some 
additional regulatory requirements beyond what is required of Schedule 
V narcotics: prescription refills are limited to 5 refills in 6 months, 
a permit is required to export this drug, and both manufacturers and 
distributors must file reports with the DEA. For individuals involved 
in illicit

[[Page 62367]]

activities, trafficking penalties and fines are significantly 
increased.
    The Drug Addiction Treatment Act (DATA) does not have an impact on 
DEA's scheduling responsibilities under the CSA. The scheduling 
criteria and procedures remain unchanged and continue to dictate the 
requirements for the scheduling of buprenorphine as well as any other 
controlled substance.
    Comment: The overwhelming scientific and medical evidence 
demonstrates that buprenorphine should not be rescheduled. If 
buprenorphine is rescheduled, it should not be placed any higher than 
Schedule IV.
    Answer: Both the DEA and the DHHS have determined that the 
preponderance of evidence indicates that buprenorphine has an abuse 
potential and dependence profile consistent with Schedule III of the 
CSA. The sections on abuse potential and dependence profile and answers 
to previous comments address this issue.

Conclusion

    Relying on the scientific and medical evaluation and scheduling 
recommendation of the DHHS in accordance with Section 201(b) of the Act 
(21 U.S.C. 811 (b)), and after a careful consideration of all comments 
and a final, independent review by the DEA, the Deputy Administrator 
finds that:
    1. Buprenorphine has a potential for abuse less than the drugs or 
other substances in Schedule I and II.
    2. Buprenorphine has a currently accepted medical use in treatment 
in the United States.
    3. Abuse of buprenorphine may lead to moderate or low physical 
dependence or high psychological dependence

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Regulatory Requirements

    Persons who manufacture, distribute, dispense, import, export, 
store or engage in research with buprenorphine must comply with the 
following regulatory requirements:
    1. Registration. Any person who manufactures, distributes, 
dispenses, imports or exports buprenorphine or engages in research or 
conducts instructional activities or chemical analysis with respect to 
this substance must be registered to conduct such activities in 
accordance with 21 CFR part 1301. Those individuals who are currently 
registered to handle buprenorphine in Schedule V may continue 
activities under that registration until approved or denied 
registration in Schedule III provided such registrant has filed an 
application for registration in Schedule III with DEA on or before 
November 6, 2002. Any persons not currently registered and proposing to 
engage in such activities may not conduct activities with the substance 
until properly registered in Schedule III.
    2. Security. Buprenorphine must be manufactured, distributed and 
stored in accordance with 21 CFR 1301.71, 1301.72(b), (c), and (d), 
1301.73, 1301.74, 1301.75(b) and (c) and 1301.76.
    3. Labeling and packaging. Products manufactured, distributed or 
dispensed before October 7, 2002 and labeled as Schedule V may be 
distributed and dispensed until April 7, 2002. Products manufactured, 
distributed or dispensed after October 7, 2002 shall comply with the 
requirement of 21 CFR 1302.03-1302.07.
    4. Inventory. Registrants possessing buprenorphine are required to 
take inventories pursuant to 21 CFR 1304.03, 1304.04 and 1304.11.
    5. Records and reports. All registrants must keep records and 
provide reports pursuant to 21 CFR 1304.03, 1304.04, 1304.21-1304.25 
and 1304.33.
    6. Prescriptions. All prescriptions for buprenorphine or 
prescriptions for products containing buprenorphine are to be issued 
pursuant to 21 CFR 1306.03-1306.07 and 1306.21-1306.26.
    7. Importation and Exportation. All importation and exportation of 
buprenorphine shall be in compliance with 21 CFR part 1312.
    8. Criminal Liability. Any activity with buprenorphine not 
authorized by, or in violation of, the CSA or the Controlled Substances 
Import and Export Act or the Narcotic Addict Treatment Act of 2000, 
shall continue to be unlawful on or after October 7, 2002, except as 
authorized in this rule.

Regulatory Certifications

Regulatory Flexibility Act

    The Deputy 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.

Executive Order 12866

    In accordance with the provisions of the CSA (21 U.S.C. 811(a)), 
this action

[[Page 62370]]

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 Deputy 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 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),and redelegated to the Deputy Administrator pursuant to 28 
CFR 0.104, the Deputy Administrator hereby amends 21 CFR part 1308 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 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          9803
 or 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         9804
 or 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) is revised 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: October 1, 2002.
John B. Brown, III,
Deputy Administrator.
[FR Doc. 02-25293 Filed 10-4-02; 8:45 am]
BILLING CODE 4410-09-P